Identification of the principal neuropeptide MIP and its action pathway in larval settlement of the echiuran worm Urechis unicinctus.

BACKGROUND: Larval settlement and metamorphosis represent critical events in the life history of marine benthic animals. Myoinhibitory peptide (MIP) plays a pivotal role in larval settlement of marine invertebrates. However, the molecular mechanisms of MIP involved in this process are not well understood. RESULTS: In this study, we evaluated the effects of thirteen MIP mature peptides on triggering the larval settlement of Urechis unicinctus (Xenopneusta, Urechidae), and determined that MIP2 was the principal neuropeptide. Transcriptomic analysis was employed to identify differentially expressed genes (DEGs) between the MIP2-treated larvae and normal early-segmentation larvae. Both cAMP and calcium signaling pathways were enriched in the DEGs of the MIP2-treated larvae, and two neuropeptide receptor genes (Spr, Fmrfar) were up-regulated in the MIP2-treated larvae. The activation of the SPR-cAMP pathway by MIP2 was experimentally validated in HEK293T cells. Furthermore, fourteen cilia-related genes, including Tctex1d2, Cfap45, Ift43, Ift74, Ift22, Cav1 and Mns1, etc. exhibited down-regulated expression in the MIP2-treated larvae. Whole-mount in situ hybridization identified two selected ciliary genes, Tctex1d2 and Cfap45, were specially expressed in circumoral ciliary cells of the early-segmentation larvae. Knocking down Tctex1d2 mRNA levels by in vivo RNA interference significantly increased the larval settlement rate. CONCLUSION: Our findings suggest that MIP2 inhibits the function of the cilia-related genes, such as Tctex1d2, through the SPR-cAMP-PKA pathway, thereby inducing larval settlement in U. unicinctus. The study contributes important data to the understanding of neuropeptide regulation in larval settlement.

Non-Myeloablative Chemotherapy as Consolidation Strategy After High-Dose Methotrexate-Based Chemoimmunotherapy in Patients With Primary CNS Lymphoma: A Retrospective Single Center Study in China.

Primary central nervous system lymphoma (PCNSL) remains a disease with poor outcome and high recurrence rate. We retrospectively analyzed the clinical data of 243 immunocompetent patients with PCNSL in Beijing Tiantan Hospital. The median age of PCNSL patients was 57 years (range 10-95 years). For induction therapy, 94.7% of patients received high-dose methotrexate (HD-MTX) containing regimens, and 59.3% received rituximab, which increased over time. The overall response rate was 72.8%, with 58.8% achieving complete response. With a median follow-up of 27.0 months (95% confidence interval 23.6-30.4), the median progression-free survival (PFS) time was 14.0 months (95% CI 9.45-18.55), and the 2-year PFS rate was 33.2%. The median overall survival (OS) was not reached (NR), with an estimated overall survival rate at 4 years of 61.6%. Among 95 patients who completed sequential consolidation chemotherapy with either pemetrexed or etoposide plus cytarabine, the median PFS was 28 months (95% CI 17.11-38.89), and the estimated overall survival at 4 years was 78.7%. In conclusion, HD-MTX based induction chemotherapy with non-myeloablative sequential consolidation chemotherapy is an alternative feasible treatment option.

[Applying evidence-based practice: delirium].

Delirium often occurs in older hospitalized inpatients. However, it is frequently not diagnosed or prevented at an early stage. Delirium leads to poor prognoses and prolongs hospitalized days. This article integrates current evidence-based literature to summarize prevention, early assessment and management strategies for delirium. The authors further present a delirium management algorithm. The authors hope this study will provide a reference for healthcare professionals responsible for delirium patient care.

Treatment of secondary central nervous system involvement in systemic aggressive B cell lymphoma using R-MIADD chemotherapy: a single-center study.

BACKGROUND: Secondary central nervous system lymphoma (SCNSL) is defined as lymphoma involvement within the central nervous system (CNS) that originated elsewhere, or a CNS relapse of systemic lymphoma. Prognosis of SCNSL is poor and the most appropriate treatment is still undetermined. METHODS: We conducted a retrospective study to assess the feasibility of an R-MIADD (rituximab, high-dose methotrexate, ifosfamide, cytarabine, liposomal formulation of doxorubicin, and dexamethasone) regimen for SCNSL patients. RESULTS: Nineteen patients with newly diagnosed CNS lesions were selected, with a median age of 58 (range 20 to 72) years. Out of 19 patients, 11 (57.9%) achieved complete remission (CR) and 2 (10.5%) achieved partial remission (PR); the overall response rate was 68.4%. The median progression-free survival after CNS involvement was 28.0 months (95% confidence interval 11.0-44.9), and the median overall survival after CNS involvement was 34.5 months. Treatment-related death occurred in one patient (5.3%). CONCLUSIONS: These single-centered data underscore the feasibility of an R-MIADD regimen as the induction therapy of SCNSL, further investigation is warranted.

[Establishment of Secondary HLH Mouse Model and Effect of Ruxolitinib on Disease Manifestations of Model Mide].

OBJECTIVE: To establish a secondary hemophagocytic lymphohistiocytosis(HLH) mouse model, and to investigate the effect of ruxolitinib on the disease manifestation of model mice. METHODS: Wild type C57BL/6 mice were randomly divided into 4 groups: two groups of mice were intraperitoneally injected with CpG oligodeoxynucleotide 1826 (CpG-ODN1826) every other day to induce HLH, and other two groups were control groups. One group of the CpG-ODN1826 groups and one of the control groups were given ruxolitinib, and other two groups were given the same amount of PBS. Blood samples, serum ferritin and hepatic/spleen weights of experimental mice were detected and serum cytokine levels were measured by ELISA. RESULTS: Compared with the control groups, the levels of white blood cells, hemoglobin and platelets in the CpG-ODN1826 groups were significantly lower (P＜0.05); and liver/body weight, spleen/body weight, serum ferritin, sCD25, IL-10, IL-1ß, IFN-Ƴ, IL-12p70, GM-CSF, TNF-α and IL-18 levels significantly increased (P＜0.05). There was no significant difference in the levels of IL-2, IL-4, IL-5, IL-6, IL-22, IL-13, IL-27 and IL-23 between the two groups (P＞0.05). The spleen in CpG group had disordered internal structure, expanding red pulp and hyperplastic nucleated cells. The liver had severe perivascular inflammations. The spleen/weight of the ruxolitinib-treated mice in the CpG-ODN1826 group was significantly smaller than that of the unapplied ruxolitinib (P＜0.05). CONCLUSION: The CpG-ODN1826 can induce secondary HLH symptoms in wild type C57BL/6 mice. Ruxolitinib can alleviate the symptoms of splenomegaly in HLH model mice.

Expression of hypoxia-inducible factor 1α, glucose transporter 1, and hexokinase 2 in primary central nervous system lymphoma and the correlation with the biological behaviors.

BACKGROUND: It has been indicated that abnormal glucose metabolism mediated by hypoxia-inducible factor 1α (HIF-1α) played an essential role in the development of solid tumor. However, there were rare studies about the role of them in primary central nervous system lymphoma (PCNSL). OBJECTIVE: To investigate the protein levels of HIF-1α, glucose transporter 1 (GLUT1), and hexokinase 2 (HK2) in PCNSL and whether their levels are associated with prognostic factors. METHODS: Expression of HIF-1α, GLUT1, and HK2 in 39 tumor tissues was evaluated by immunohistochemical stainning. The correlation of the expression of HIF-1α with the protein level of GLUT1 and HK2 was investigated. In addition, the association between these protein expression levels and clinical parameters and prognosis was analyzed. RESULTS: In the tumor specimens of PCNSL, positive stainings of HIF-1α, GLUT1, and HK2 were in 23 patients (58.97%), 25 patients (64.1%), and 26 patients (66.67%), respectively, which were associated with the expression level of lactic dehydrogenase (LDH), but not with age, gender, number of lesion, ECOG score, or deep structure. The expression of HIF-1α was positively correlated with the expression of GLUT1 (p < .01, r = .749) and HK2 (p < .01, r = .787). Univariate analysis showed that upregulated GLUT1 was unfavorable predictors of progression-free survival (PFS) in PCNSL. The results of Cox proportional hazards model showed GLUT1 was significantly associated with shorter PFS (hazard ration: 5.65; 95% confidence interval: 1.23-25.84; p = .026). CONCLUSIONS: This study indicated that there was a hypoxic microenvironment and HIF-1α was involved in the regulation of glycolysis pathway in PCNSL. GLUT1 might be a potential marker for shorter PFS in PCNSL.

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults and adolescents-a life-threatening disease: analysis of 133 cases from a single center.

OBJECTIVES: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis is the most common type of infection-associated HLH. Previous studies were focused on pediatric EBV-HLH patients, therefore there lack of adult data. METHOD: We performed a retrospective analysis of 133 EBV-HLH patients (≥14 years old) in Beijing Friendship Hospital from March 2009 to April 2016 to evaluate the clinical manifestation and the effects and prognosis of existing regimens of EBV-HLH in adult and adolescents. RESULTS: Of these patients, 91 male and 42 female cases had a median age of 26 (14-77) years. EBV-DNA load on admission was at a median of 6.6E + 05 IU/ml. The one-year mortality of these patients was 78%. 112 patients received the HLH-94/04 regimen as the initial treatment, 52 patients (46.43%) had response. Of the 6 patients who received the L-DEP regimen as the initial treatment, 5 patients (83.33%) had response. The rest 15 patients received initial treatment without etoposide, 5 cases achieved PR. 69 refractory or relapsed patients received DEP or L-DEP regimen, 55 (79.71%) cases had response. In addition, who received the L-DEP regimen, with the overall response rate significantly higher than the DEP regimen (88.37% VS 65.38%, P = 0.031). 36 out of 133 EBV-HLH patients eventually received allo-HSCT, with the overall survival rate of 52.78%. In summary, EBV-HLH is a highly lethal disease. CONCLUSION: DEP/L-DEP was a good salvage treatment. L-DEP might be a more effective first-line initial regimen than HLH-94/04 regimen for EBV-HLH. Finally, allo-HSCT is an effective radical treatment for EBV-HLH.

Primary hemophagocytic lymphohistiocytosis in adults: the utility of family surveys in a single-center study from China.

BACKGROUND: This study investigated the clinical characteristics of primary hemophagocytic lymphohistiocytosis (HLH) in adults, including immunological markers, pedigree findings, and conditions of allogeneic hematopoietic stem cell transplantation (Allo-HSCT). METHODS: The study included clinical data of 18 adult patients with primary HLH treated in our center from June 2010 to January 2017. RESULTS: Of these 18 cases, pathogenic variants were found in the following genes: PRF1 (n = 11), UNC13D (n = 5), SH2D1A (n = 2), RAB27a (n = 1), and LYST (n = 2). One patient had pathogenic variants in both PRF1 and UNC13D genes, one patient had pathogenic variants in both LYST and UNC13D genes and another patient had pathogenic variants in both PRF1 and SH2D1A genes. Additionally, 3 of the 18 cases involved homozygous pathogenic variants, while 2 cases involved hemizygous pathogenic variants. The remaining 13 cases involved compound heterozygous pathogenic variants. The natural killer (NK) cell activity test was conducted in all 18 cases where 14(77.8%)patients showed reduction in NK cell activity. Furthermore, this article presents 3 representative results of the pedigree findings from 12 patients who underwent family surveys. The 8 patients who underwent Allo-HSCT had a median survival of 27.2 months, as compared with the median survival of 7 months for the10 patients who did not undergo Allo-HSCT, a significant difference between the two groups of patients (p = 0.006). CONCLUSION: PRF1 was one of the most commonly mutated gene in adult patients with primary HLH. Family surveys and immunological markers were important for the HLH diagnosis and the selection of an appropriate donor. Allo-HSCT was an effective therapy for adult primary HLH.

Multivariate analysis of prognosis for patients with natural killer/T cell lymphoma-associated hemophagocytic lymphohistiocytosis.

OBJECTIVE: A major cause of hemophagocytic lymphohistiocytosis (HLH) is malignant neoplasms of the blood system, among which NK/T cell lymphoma is one of the most common risk factors. Patients with NK/T cell lymphoma hemophagocytic lymphohistiocytosis (NK/T-LAHS) have a worse prognosis and higher mortality. We aimed to explore the factors that affect the prognosis of NK/T-LAHS. METHODS: Clinical data of 42 patients with NK/T-LAHS diagnosed by Beijing Friendship Hospital from June 2008 to June 2016 were analyzed retrospectively. The survival time was counted until 1 August 2016. RESULTS: For the 42 NK/T-LAHS patients, 1-month survival rate was 48.9%, 2-month survival rate was 36.7%, 3-month survival rate was 28.8%, 6-month survival rate was 23.0%, and 12-month survival rate was 15.4%. NK/T-LAHS patients who underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT) (p = 0.000), exhibited peripheral blood Epstein-Barr virus (EBV)-positivity (p = 0.004), and achieved overall response (OR) remission after initial induction therapy (p = 0.007) had statistical significance. CONCLUSION: NK/T-LAHS is a disease of poor prognosis and high mortality. NK/T-LAHS patients who achieved OR remission after the initial induction therapy had a better prognosis than non-remission patients and Allo-HSCT was an effective way to prolong the survival of NK/T-LAHS patients. However, EBV positivity in peripheral blood was a poor prognostic factor in NK/T-LAHS patients.

Elevation of CD16+CD56+ NK-cells and down-regulation of serum interleukin-21 (IL-21) and IL-1α after splenectomy in relapsed hemophagocytic lymphohistiocytosis of unknown cause.

OBJECTIVES: Encouraging progress has been made in application of splenectomy in the treatment of relapsed hemophagocytic lymphohistiocytosis (HLH) of unknown cause. The aim was to determine the roles of lymphocyte subpopulations and inflammatory cytokines in splenectomy. METHODS: We retrospectively analyzed changes in lymphocyte subpopulations and levels of inflammatory cytokines at different time-points before and after splenectomy in the patients with relapsed HLH of unknown cause, as well as the correlations between these changes and the disease prognosis. RESULTS: During the period from June 2006 to June 2016, we enrolled 107 patients with relapsed HLH of unknown cause, of whom 29 were treated with splenectomy. Among the 29 patients, 7 cases were non-Hodgkin lymphomas based on spleen pathology, 1 case withdrew and the remaining 21 non-lymphoma cases were available for analysis. Results showed a significant increase in both percentage of CD16+CD56+ NK cells (P = 0.003) and NK cell activity (P = 0.028) at 24 wk after splenectomy compared to their baseline pre-surgery levels. We also examined seven patients for the changes in cytokine levels before and after splenectomy and found that IL-21 and IL-1α decreased at 4 wk after splenectomy (P < 0.05). Seven non-lymphoma patients determined as no response to treatment (NR) prior to splenectomy had significantly longer survival (P = 0.001) compared to the 24 patients with relapsed HLH of unknown cause who were also determined as NR but not treated by splenectomy. DISCUSSION: Splenectomy can improve clinical symptoms and survival of patients with relapsed HLH of unknown cause. The mechanism is likely related to the changes in percent NK cells and cytokines (IL-21 and IL-1α) after surgery.

PEG-aspargase and DEP regimen combination therapy for refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.

BACKGROUND: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is the most frequent subtype of secondary HLH triggered by infections. Previous studies have shown that ~30 % or more of patients with EBV-HLH do not respond to standard therapy. This study investigated the efficacy and safety profile of a modified DEP regimen in combination with PEG-aspargase (L-DEP) as a salvage therapy for refractory EBV-HLH. METHODS: In this study from October 2014 to October 2015, 28 patients with refractory EBV-HLH received a L-DEP regimen at the Beijing Friendship Hospital, Capital Medical University. Treatment efficacy and adverse events were evaluated at 2 and 4 weeks after L-DEP treatment. RESULTS: Median EBV-DNA concentrations before and 2 weeks after receiving the L-DEP regimen were 9.6 × 10(5) (1.5 × 10(4) - 1 × 10(9)) copies/mL and 2.2 × 10(5) (3.8 × 10(2) - 1.2 × 10(7)) copies/mL, respectively; the post-treatment values were significantly lower than that of the pretreatment (P = 0.048). Nine of the 28 study patients achieved complete response (CR) and 15 partial response (PR), resulting in an overall response rate of 85.7 % (CR+PR). Four patients who did not achieve response died within 4 weeks of receiving L-DEP. Thirteen of the 24 patients who achieved partial or complete response received subsequent allogenic hematopoietic stem cell transplantation (allo-HSCT). Ten of these 13 patients survived until 1 March 2016. The major adverse effects of the L-DEP regimen were high serum amylase concentrations, abnormal liver function, and coagulation disorders. CONCLUSIONS: This study suggests that L-DEP is a safe and effective salvage therapy prior to allo-HSCT for refractory EBV-HLH and increases the possibility of such patients receiving allo-HSCT. A prospective multicenter large-scale clinical trial that aims to validate the L-DEP regimen for refractory EBV-HLH is currently underway (ClinicalTrails.gov Identifier: NCT02631109).

Comparison of bypass surgery and drug-eluting stenting in diabetic patients with left main and/or multivessel disease: A systematic review and meta-analysis of randomized and nonrandomized studies.

BACKGROUND: With advances in theinterventional field, the choice between coronary artery bypass grafting (CABG) and percutaneous coronary intervention with drug-eluting stents (PCI-DES) for the diabetic subset with left main (LM) and/or multivessel disease (MVD) remains consistently controversial. METHODS AND RESULTS: We conducted a systematic review of randomized controlled trials (RCTs) and observational controlled trials (OCTs) comparing the two strategies for the diabetic subset with LM and/or MVD. PubMed, EMBASE, CENTRAL databases, Google Scholar and SinoMed were systematically searched for eligible studies without language and publication restrictions. We identified 19 trials (4 randomized and 15 nonrandomized), enrolling 5,805 patients in OCTs and 3,060 patients in RCTs, respectively. PCI-DES was associated with higher mortality compared with CABG (11.7% DES vs. 9.1% CABG, RR 1.23, 95% CI 1.00-1.53, p = 0.06). Patients after PCI-DES had higher prevalence of myocardial infarction (MI) when compared with CABG (8.5% DES vs. 4.6% CABG, RR 1.68, 95% CI 1.20-2.37, p = 0.003). PCI-DES patients were at substantially lower risk of stroke (2.0% DES vs. 3.9% CABG, RR 0.51, 95% CI 0.39-0.67, p < 0.00001), but at several-fold higher risk of repeat revascularization (19.0% DES vs. 6.3% CABG, RR 2.95, 95% CI 2.46-3.55, p < 0.00001). The OCT patients risked a lower mortality as compared to the RCT patients (9.6% OCTs vs. 11.9% RCTs, RR 0.81, 95% CI 0.71-0.92, p = 0.001). CONCLUSIONS: CABG for patients with diabetes mellitus and LM and/or MVD had advantages over PCI-DES in all-cause death, nonfatal MI, and repeat revascularization, but the substantial disadvantage in nonfatal stroke. The high-selected patients (RCTs) risked a higher mortality than the real-world patients (OCTs).