Strain-level structure of gut microbiome showed potential association with cognitive function in major depressive disorder: A pilot study.

BACKGROUND: Although the association between gut microbiota and the pathogenesis of major depressive disorder (MDD) has been well studied, it is unclear whether gut microbiota affects cognitive function in patients with MDD. In this study, we explored the association between gut microbiota and cognitive function in MDD and its possible mechanisms. METHODS: We enrolled 57 patients with MDD and 30 healthy controls (HCs) and used 16S rRNA gene sequencing analysis and shotgun metagenomic sequencing analysis to determine gut microbial composition. RESULTS: The richness and diversity of gut microbiota in patients with MDD were the same as those in HCs, but there were differences in the abundance of Bifidobacterium and Blautia. Compared with HCs, two strains (bin_32 and bin_55) were significantly increased, and one strain (bin_31) was significantly decreased in patients with MDD based on the strain-level meta-analysis. Time to complete the Stroop-C had significant negative correlations with bin_31 and bin_32. Bin_55 had significant negative correlations with time to complete the Stroop-C, time to complete the Stroop-CW, and repeated animal words in 60 s but significant positive correlations with correct answers in 120 s on the Stroop-CW. LIMITATIONS: This study only tested the cognitive function of MDD in a small sample, which may have caused some bias. CONCLUSIONS: Based on our strain-level analysis, we found that gut microbiota may be associated with the pathogenesis of MDD and may have potential effects on cognitive function.

Effectiveness of tisagenlecleucel versus real-world standard of care in relapsed/refractory follicular lymphoma.

Aim: To contextualize the effectiveness of tisagenlecleucel versus real-world standard of care (SoC) in relapsed/refractory follicular lymphoma. Materials & methods: A retrospective indirect matched comparison study using data from the phase II ELARA trial and the US Flatiron Health Research Database. Results: Complete response rate was 69.1 versus 17.7% and the overall response rate was 85.6 versus 58.1% in tisagenlecleucel versus SoC, post weighting by odds. For overall survival, an estimated reduction in the risk of death was observed in favor of tisagenlecleucel over SoC. The hazard ratio for progression-free survival was 0.45 (95% CI: 0.26, 0.88), and for time-to-next treatment was 0.34 (95% CI: 0.15, 0.78) with tisagenlecleucel versus SoC. Conclusion: A consistent trend toward improved efficacy end points was observed in favor of tisagenlecleucel versus SoC.

Factors associated with medication interruption among outpatients with severe mental illness exposed to COVID-19.

Many patients with severe mental illness (SMI) relapsed and deteriorated during the COVID-19 pandemic, as they experienced medication interruption. This study aimed to investigate factors affecting medication interruption in patients with SMI during the COVID-19 pandemic. A total of 2,077 patients with SMI participated in an online survey on medication interruption during the COVID-19 outbreak. The questionnaire comprised six parts: basic demographic information, COVID-19 exposure, state of disease, medication compliance before COVID-19, medication interruption during COVID-19, and the specific impact and needs. A total of 2,017 valid questionnaires were collected. Nearly 50% of patients with SMI have been affected to varying degrees of life expectancy and treatment. Among them, 74 patients stopped taking medicines for more than 14 days without a prescription. Logistic regression analysis showed that cohabitant exposure [OR = 26.629; 95% CI (3.293-215.323), p = 0.002], medication partial compliance and non-compliance pre-COVID-19 [OR = 11.109; 95% CI (6.093-20.251), p < 0.001; OR = 20.115; 95% CI (10.490-38.571), p < 0.001], and disease status [OR = 0.326; 95% CI (0.188-0.564), p < 0.001] were related to medication interruption. More than 50% of the patients wanted help in taking medications, follow-up, and receiving more financial support and protective materials. We found that the daily lives of patients with SMI were much more susceptible to impact during the pandemic. Patients with a history of partial or non-medication compliance before COVID-19 and an unstable disease state are more easily affected by pandemics and epidemics and need extra attention should similar large-scale outbreaks occur in the future.

PLCε promotes the Warburg effect and tumorigenesis through AKT/GSK3ß/Cdc25a in bladder cancer.

Phospholipase C epsilon (PLCε) is a oncogene in various malignancies and regulates diverse cellular functions. But understanding of the relation between PLCε and glycolytic pathways has not been clearly identified. In the present study, we explored the effect of PLCε on the Warburg effect and tumorigenesis in bladder cancer (BCa). In our study, we showed that PLCε expression was elevated in BCa samples compared with matched adjacent nonmalignant bladder tissues. PLCε depletion using Lentivirus-shPLCε (LV-shPLCε) dramatically decreased cell growth, glucose consumption and lactate production, arresting T24 and BIU cells in the S phase of the cell cycle. We also observed that PLCε was correlated with the activation of protein kinase B (AKT) and cell division cycle 25 homolog A (Cdc25a) overexpression. In addition, we demonstrated that AKT/glycogen synthase kinase 3 beta (GSK3ß)/Cdc25a signaling pathways are involved in the PLCε-mediated Warburg effect in BCa. Moreover, we showed that PLCε had an effect on tumorigenesis in in vivo experiments. In summary, our findings demonstrate that AKT/GSK3ß/Cdc25a is critical for the effect PLCε on Warburg effect and tumorigenesis.

Plasma levels of interleukin-8 and response to paroxetine in patients with major depressive disorder.

OBJECTIVES: Immune dysregulation plays a key role in major depressive disorder (MDD). However, little is known about the complicated involvement of various interleukins in MDD. This study was performed to investigate the correlation between plasma interleukin-8 (IL-8) levels and treatment outcome of paroxetine (a selective serotonin reuptake inhibitor) in patients with MDD. METHODS: A total of 115 hospitalized patients (36 males and 79 females), aged from 18 to 72 years, were enrolled. Plasma levels of IL-8 were measured before treatment initiation (baseline) and at 8 weeks after oral paroxetine treatment. Efficacy of paroxetine was evaluated by use of the Hamilton Depression Rating Scale (HAMD-17). Baseline IL-8 levels were compared between responders and non-responders to paroxetine treatment. RESULTS: Plasma IL-8 levels decreased significantly after an 8-week antidepressant treatment in responders, in association with a dramatic decrease in HAMD-17 scores. In non-responders, plasma IL-8 levels did not change significantly at 8 weeks after antidepressant treatment. Baseline plasma IL-8 levels were found to be significantly lower in responders than in non-responders, showing a correlation between IL-8 and antidepressant response to paroxetine. CONCLUSIONS: These results indicate that plasma IL-8 levels were related to treatment outcome of paroxetine, and therefore suggest that IL-8 could be a promising predicator of treatment response in individual patients with MDD.

Neferine alleviates chronic stress-induced depression by regulating monoamine neurotransmitter secretion and gut microbiota structure.

Neferine (Nef) might possess anti-depressive properties; however, its therapeutic effects are yet to be elucidated. Therefore, in this study, we aimed to explore the anti-depressant property of Nef using a mouse model of chronic stress-induced depression. Fifteen depression-prone mice were randomly selected and divided into three groups, namely, the model, Nef, and fluoxetine (Flu) groups. We observed that in tail suspension and forced swimming tests, the Nef and Flu treatments significantly decreased the immobility time of the depressed mice, and increased their sucrose preference indices. Moreover, both Nef and Flu treatments induced significant increases in the levels of anti-depressant neurotransmitters, including dopamine (DA), serotonin (5-HT), and norepinephrine (NE), and also reduced pathological damage to the hippocampus of the depressed mice. Incidentally, Illumina MiSeq sequencing analysis demonstrated that the relative abundance of Lactobacillus in the intestinal microbiota of depressed mice was restored after Nef/Flu treatment. Moreover, colonic Lactobacillus abundance was positively correlated with the levels of DA, 5-HT, and NE in the hippocampus of the mice. In conclusion, Nef improved monoamine neurotransmitter secretion and modulated the intestinal flora structure, particularly the abundance of Lactobacillus. Hence, it showed considerable anti-depressant potential, and might be a prospective anti-depressant therapeutic agent.

Gut microbiome: A potential indicator for predicting treatment outcomes in major depressive disorder.

The therapeutic outcomes in major depressive disorder (MDD), one of the most common and heterogeneous mental illnesses, are affected by factors that remain unclear and often yield unsatisfactory results. Herein, we characterized the composition and metabolic function of the gut microbiota of patients with MDD during antidepressant treatment, based on 16S rRNA sequencing and metabolomics. The microbial signatures at baseline differed significantly between responder and non-responder groups. The gut microbiota of the non-responder group was mainly characterized by increased relative abundances of the phylum Actinobacteria, families Christensenellaceae and Eggerthellaceae, and genera Adlercreutzia and Christensenellaceae R7 group compared to that of the responder group. Additionally, the gut microbiota composition of the responder and non-responder groups differed significantly before and after treatment, especially at the genus level. Moreover, 20 differential metabolites between the responder and non-responder groups were identified that were mainly involved in lipid metabolism (cholestane steroids and steroid esters). Eggerthellaceae and Adlercreutzia displayed strong co-occurrence relationships with certain metabolites, suggesting alternations in the gut microbiome, and associated metabolites may be potential mediators of successful antidepressant treatment. Overall, our study demonstrates that alterations in gut microbiota composition and metabolic function might be relevant to the response to antidepressants, thereby providing insight into mechanisms responsible for their efficacy.

Gut Microbiome: A Potential Indicator for Differential Diagnosis of Major Depressive Disorder and General Anxiety Disorder.

Background: Major depressive disorder (MDD) and general anxiety disorder (GAD) share many common features, leading to numerous challenges in their differential diagnosis. Given the importance of the microbiota-gut-brain axis, we investigated the differences in gut microbiota between representative cases of these two diseases and sought to develop a microbiome-based approach for their differential diagnosis. Methods: We enrolled 23 patients with MDD, 21 with GAD, and 10 healthy subjects (healthy crowd, HC) in the present study. We used 16S rRNA gene-sequencing analysis to determine the microbial compositions of the gut microbiome based on Illumina Miseq and according to the standard protocol. Results: GAD showed a significant difference in microbiota richness and diversity as compared with HC. Additionally, Otu24167, Otu19140, and Otu19751 were significantly decreased in MDD relative to HC, and Otu2581 and Otu10585 were significantly increased in GAD relative to MDD. At the genus level, the abundances of Sutterella and Fusicatenibacter were significantly lower in MDD relative to HC, and the abundances of Fusicatenibacter and Christensenellaceae_R7_group were significantly lower in GAD than in HC. The abundance of Sutterella was significantly higher whereas that of Faecalibacterium was significantly lower in GAD relative to MDD. Moreover, we observed that Christensenellaceae_R7_group negatively correlated with the factor score (Limited to Hopelessness) and total score of HAMD-24 (p < 0.05), whereas Fusicatenibacter negatively correlated with FT4 (p < 0.05). Furthermore, the GAD group showed significant differences at the genus level for Faecalibacterium, which negatively correlated with PTC (p < 0.05). Conclusions: This study elucidated a unique gut-microbiome signature associated with MDD and GAD that could facilitate differential diagnosis and targeted therapy.

Long noncoding RNA HOTAIR regulates the invasion and metastasis of prostate cancer by targeting hepaCAM.

BACKGROUND: The role of HOX transcript antisense RNA (HOTAIR) has been proven to be important in tumorigenesis. However, how this molecule promotes metastasis and invasion in PCa is still unclear. METHODS: The relationship between HOTAIR and hepatocellular adhesion molecule (hepaCAM) in PCa was identified by immunohistochemistry, immunofluorescence, plasmid transfection, quantitative real-time PCR and immunoblotting. The regulatory effects of HOTAIR on hepaCAM and MAPK signalling and their key roles in PCa metastasis were investigated in vitro. RESULTS: The expression of HOTAIR was inversely correlated with hepaCAM in the blood and tissue of PCa patients. Here, hepaCAM was identified as a novel target gene of HOTAIR and was critical for the invasiveness of PCa. HOTAIR recruited PRC2 to the hepaCAM promoter, resulting in high levels of H3K27me3 and the absence of hepaCAM with an abnormally activated MAPK pathway. Both HOTAIR depletion and EZH2 inhibition could induce hepaCAM re-expression with inhibitory MAPK signalling and decrease the invasive and metastatic capabilities of PCa cells. CONCLUSIONS: This study demonstrates that HOTAIR promotes invasion and metastasis of PCa by decreasing the inhibitory effect of hepaCAM on MAPK signalling. Therefore, the HOTAIR/hepaCAM/MAPK axis may provide a new avenue towards therapeutic strategies and prognostic indicators for advanced prostate cancer.

Estimation of Total Costs in Pediatric and Young Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia Receiving Tisagenlecleucel from a U.S. Hospital's Perspective.

BACKGROUND: Tisagenlecleucel was approved for the treatment of pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) based on the pivotal ELIANA trial. OBJECTIVE: To comprehensively evaluate the total costs associated with tisagenlecleucel treatment, including costs from pre- to postinfusion periods of tisagenlecleucel in addition to the cost of tisagenlecleucel. METHODS: An economic model was developed to estimate total costs associated with tisagenlecleucel treatment from the time of leukapheresis to 2 months postinfusion from a U.S. hospital's perspective. Costs were estimated based on resource use and safety management from the ELIANA trial and were considered during the pretreatment, tisagenlecleucel infusion, and follow-up periods of treatment. Cost components included leukapheresis, lymphodepleting chemotherapy, tisagenlecleucel infusion and hospital administration, inpatient and intensive care unit admissions, medical professional visits, laboratory tests and procedures, and management of major adverse events. Scenario analyses were conducted by varying key assumptions related to adverse events and hospitalization. RESULTS: The total cost associated with tisagenlecleucel treatment among pediatric and young adult patients with r/r ALL was estimated to be $612,779, of which $137,636 (22.5%) was in addition to the list price of tisagenlecleucel ($475,000) and the associated administration cost of $143.08. The top 3 drivers of the additional cost were adverse event management ($70,968; 51.6%), inpatient and intensive care unit admissions not attributed to adverse events ($57,952; 42.1%), and laboratory tests and procedures ($5,209; 3.8%). The costs incurred during the pretreatment, infusion, and follow-up periods were $29,002, $476,659, and $107,118, respectively. In the scenario analyses, the total costs ranged from $483,169 (tisagenlecleucel treatment in the outpatient setting without adverse events) to $672,373 (tisagenlecleucel treatment in the inpatient setting with grade 3/4 cytokine release syndrome and B-cell aplasia). CONCLUSIONS: In this economic model, tisagenlecleucel treatment among pediatric and young adult patients with r/r ALL was estimated to cost $612,779. The cost of care in addition to the price of tisagenlecleucel accounted for 22.5% of the total, with adverse event management and inpatient and intensive care unit admissions being main drivers. Further studies are warranted to assess the cost of tisagenlecleucel treatment in the context of current standards of care in real-world clinical practice. DISCLOSURES: This study was supported by Novartis. The study sponsor was involved in several aspects of the research, including the study design, the interpretation of data, the writing of the manuscript, and the decision to submit the manuscript for publication. Hao is an employee of Novartis and has stock/stock options. Yang, Chai, Qi, and Wu are employees of Analysis Group, which received consulting fees from Novartis for work on this study. Part of the material in this manuscript was presented at the American Society of Hematology Annual Meeting held December 7-10, 2019, in Orlando, FL.

The social psychological impact of the COVID-19 pandemic on medical staff in China: A cross-sectional study.

BACKGROUND: The COVID-19 outbreak required the significantly increased working time and intensity for health professionals in China, which may cause stress signs. METHODS: From March 2-13 of 2020, 4,618 health professionals in China were included in an anonymous, self-rated online survey regarding their concerns on exposure to the COVID-19 outbreak. The questionnaires consisted of five parts: basic demographic information and epidemiological exposure; occupational and psychological impact; concerns during the episode; coping strategies; and the Huaxi Emotional-Distress Index (HEI). RESULTS: About 24.2% of respondents experienced high levels of anxiety or/and depressive symptoms since the COVID-19 outbreak. Respondents who worried about their physical health and those who had COVID-19 infected friends or close relatives were more likely to have high HEI levels, than those without these characteristics. Further, family relationship was found to have an independent protective effect against high HEI levels. Their main concerns were that their families would not be cared for and that they would not be able to work properly. Compared to respondents with clear emotional problems, those with somewhat hidden emotional issues adopted more positive coping measures. CONCLUSIONS: About a quarter of medical staff experienced psychological problems during the pandemic of COVID-19. The psychological impact of stressful events was related to worrying about their physical health, having close COVID-19 infected acquaintances and family relationship issues. Therefore, the psychological supprot for medical staff fighting in the COVID-19 pandemic may be needed.

Estimation of total costs in patients with relapsed or refractory diffuse large B-cell lymphoma receiving tisagenlecleucel from a US hospital's perspective.

Aims: This study estimated the total costs associated with tisagenlecleucel treatment in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) based on the JULIET trial from a United States hospital's perspective.Methods: An economic model was developed to assess the total costs associated with tisagenlecleucel treatment (from leukapheresis to two months post-infusion) in adults (aged ≥18 years) with r/r DLBCL using a fee-for-service approach. Costs were considered during the pre-treatment, tisagenlecleucel infusion, and follow-up periods, and were estimated based on the health resource utilization and safety data from the JULIET trial. Cost components included leukapheresis, lymphodepleting chemotherapy, tisagenlecleucel infusion/administration, inpatient and intensive care unit (ICU) admission, medical professional visits, lab tests/procedures, and management of adverse events (AEs). The base-case model estimated the total costs using observed hospitalization, ICU, and AE data from JULIET, while scenario analyses varied key assumptions related to AEs and hospitalization.Results: The estimated overall cost associated with tisagenlecleucel treatment from leukapheresis to two months post-infusion was $437,927/patient, of which $64,784 (14.8%) was additional to tisagenlecleucel's list price ($373,000) and the associated administration cost ($143). The top three key drivers of the additional cost were AE management ($30,594; 47.2%), inpatient/ICU not attributed to AEs ($24,285; 37.5%), and lab tests/procedures ($5,443; 8.4%). In the scenario analyses, total costs ranged from $382,702 (no AEs, no hospitalization) to $469,006 (cytokine release syndrome and B-cell aplasia, hospitalization).Limitations: This analysis was limited to two months of follow-up after tisagenlecleucel infusion, which cannot capture long-term safety outcomes associated with the treatment and may underestimate AE costs.Conclusions: The total cost of tisagenlecleucel administration from leukapheresis to two months was estimated at $437,927. In addition to tisagenlecleucel's price, the main drivers were AE management costs and inpatient/ICU costs. Future studies based on real-world, long-term use of tisagenlecleucel are warranted.

CAR-T therapy and historical trends in effectiveness and cost-effectiveness of oncology treatments.

Aim: This study examines how chimeric antigen receptor T-cell (CAR-T) therapy's incremental effectiveness and cost-effectiveness profile fits into the recent history of anticancer treatments. Materials & methods: We conducted graphical and multivariable analyses using data from the Cost-Effectiveness Analysis Registry of the Tufts Medical Center and the Institute for Clinical and Economic Review's analysis of CAR-T therapies. We collected additional information including the US FDA approval years for pharmacologic innovations. Results: CAR-T provided 5.03 (95% CI: 3.88-6.18) more incremental quality-adjusted life-years than the average pharmaceutical intervention and 4.61 (95% CI: 1.67-7.56) more than the average nonpharmaceutical intervention, while retaining similar cost-effectiveness. There was evidence of worsening cost-effectiveness by approval year for pharmaceutical interventions. Limitations: Analysis is limited to anticancer treatments studied in cost-utility analyses, estimated to cover approximately 60% of FDA-approved antineoplastic agents. Conclusion: CAR-T therapy breaks a pattern of stagnant efficacy growth in pharmaceutical innovation and demonstrates significantly greater incremental effectiveness and similar cost-effectiveness to prior innovations.

PLCε promotes urinary bladder cancer cells proliferation through STAT3/LDHA pathway­mediated glycolysis.

Phospholipase Cε (PLCε) and anaerobic glycolysis were determined to be involved in the development of human urinary bladder cancer (UBC), but the mechanisms remain unclear. In the present study, 64 bladder cancer specimens and 42 adjacent tissue specimens were obtained from 64 patients, and immunochemistry indicated that PLCε and lactate dehydrogenase (LDHA) are overexpressed in UBC. PLCε and LDHA were demonstrated to be positively correlated at transcription levels, indicating that one of these two genes may be regulated by another. To elucidate the mechanisms, PLCε was knocked down in T24 cells by short hairpin RNA, and then signal transducer and activator of transcription 3 (STAT3) phosphorylation and LDHA were determined to be downregulated, which indicated that PLCε may serve roles upstream of LDHA through STAT3 to regulate glycolysis in UBC. Furthermore, chromatin immunoprecipitation and luciferase reporter assays were performed to confirm that STAT3 could bind to the promoter of the LDHA gene to enhance its expression. A xenograft tumor mouse model also demonstrated similar results as the in vitro experiments, further confirming the role of PLCε in regulating bladder cell growth in vivo. Collectively, the present study demonstrated that PLCε may regulate glycolysis through the STAT3/LDHA pathway to take part in the development of human UBC.

HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro.

Castration-resistant prostate cancer (CRPC) continues to be a major challenge in the treatment of prostate cancer (PCa). The expression of hepatocyte cell adhesion molecule (HepaCAM), a novel tumor suppressor, is frequently downregulated or lost in PCa. Overactivated Notch signaling is involved in the development and progression of PCa, including CRPC. In this study, we found that the activities of Notch signaling were elevated, while HepaCAM expression was decreased in CRPC tissues compared with matched primary prostate cancer (PPC) tissues. In addition, HepaCAM negativity was found to be associated with a worse progression­free survival (PFS). Furthermore, the overexpression of HepaCAM induced by transfection with a HepaCAM overexpression vector (Ad­HepaCAM) exerted antitumor effects by decreasing the proliferation, and suppressing the invasion and migration of bicalutamide­resistant (Bica­R) cells and enzalutamide­resistant (Enza­R) cells. Importantly, we found that the antitumor effects of HepaCAM on the resistant cells were associated with the downregulation of Notch signaling. Moreover, we revealed that PF­3084014 (a γ­secretase inhibitor) re­sensitized Enza­R cells to enzalutamide, and sequential dual­resistant (E+D­R) cells to docetaxel. Additionally, the findings of this study demonstrated that the use of PF­3084014 alone exerted potent antitumor effect on the resistant cells in vitro. On the whole, this study indicates that HepaCAM potentially represents a therapeutic target and PF­3084014 may prove to a promising agent for use in the treatment of refractory PCa.

Adherence to iron chelation therapy in patients who switched from deferasirox dispersible tablets to deferasirox film-coated tablets.

OBJECTIVE: To compare real-world adherence to and persistence with deferasirox film-coated tablets (DFX-FCT) and deferasirox dispersible tablets (DFX-DT) among patients who switched from DFX-DT to DFX-FCT, overall and by disease type (sickle cell disease [SCD], thalassemia, and myelodysplastic syndrome [MDS]). METHODS: Patients were ≥2 years old and had ≥2 DFX-FCT claims over the study period and ≥2 DFX-DT claims before the index date (first DFX-FCT claim). The DFX-DT period was defined from the first DFX-DT claim to the index date; the DFX-FCT period was defined from the index date to the end of the study period. Adherence was measured as medication possession ratio (MPR) and proportion of days covered (PDC). Persistence was defined as continuous medication use without a gap ≥30 or 60 days between refills. Comparisons were conducted using paired-sample Wilcoxon sign-rank and McNemar's tests. RESULTS: In total, 606 patients were selected (SCD: 348; thalassemia: 107; MDS: 106; other: 45). Adherence and persistence in the DFX-FCT vs DFX-DT period was significantly higher across all measures: mean MPR was 0.80 vs 0.76 (p < .001); 60.9% vs 54.3% of patients had MPR ≥ 0.8 (p = .009); mean 3-month PDC was 0.83 vs 0.71 (p < .001); 64.2% vs 45.4% of patients had 3-month PDC ≥ 0.8 (p < .001); 87.2% vs 63.4% of patients had 3-month persistence with no gap ≥30 days and 96.1% vs 79.9% with no gap ≥60 days (p < .001). Adherence and persistence improved after switching across all diseases, particularly MDS. CONCLUSIONS: Adherence and persistence improved significantly after switching from DFX-DT to DFX-FCT for all diseases, but especially MDS.

Numerical modelling of temporal and spatial patterns of petroleum hydrocarbons concentration in the Bohai Sea.

The discharge of petroleum hydrocarbons (PHs; ~10,000tons annually) into the Bohai Sea, a shallow inland sea in China, presents a serious threat to the marine environment. To evaluate the effects of PHs pollution and estimate the corresponding environmental capacity, we have developed a genetic algorithm-based coupled hydrodynamic/transport for simulating PHs concentration evolution and distribution from July 2006 to October 2007, with the predicted values being in good agreement with monitoring results. Importantly, the mean PHs concentrations and seasonal concentration variations were primarily determined by external loading, i.e., currents were shown to drive PHs transport, reconfigure local PHs patterns, and increase PHs concentration in water masses, even at large distances from discharge sources. The developed model could realistically simulate PHs distribution and evolution, thus being a useful tool for estimating the seasonal environmental capacity of PHs.

Knockdown of Phospholipase Cε (PLCε) Inhibits Cell Proliferation via Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN)/AKT Signaling Pathway in Human Prostate Cancer.

BACKGROUND Phospholipase Cε (PLCε), a member of the plc family, has been extensively studied to reveal its role in the regulation of different cell functions, but understanding of the underlying mechanisms remains limited. In the present study, we explored the effects of PLCε on PTEN (phosphatase and tensin homolog deleted on chromosome 10) in cell proliferation in prostate cancer cells. MATERIAL AND METHODS We assessed PLCε and PTEN expression in human benign prostate tissues compared to prostate cancer tissues by immunohistochemistry. Lentivirus-shPLCε (LV-shPLCε) was designed to silence PLCε expression in DU145 and PC3 cell lines, and the effectiveness was tested by qRT-PCR and Western blotting. MTT assay and colony formation assay were conducted to observe cell proliferation. Western blotting and immunofluorescence assays were used to detect changed PTEN expression in DU145. RESULTS We observed that PLCε expression was reduced in human benign prostate tissues compared to prostate cancer tissues, while PTEN expression showed the opposite trend. Silencing of the PLCε gene significantly inhibited cell proliferation in DU145 and PC3 cell lines. DU145 is a PTEN-expressing cell, while PC3 is PTEN-deficient. After infection by LV-shPLCε, we noticed that PTEN expression was up-regulated in DU145 cells but not in PC3 cells. Furthermore, we found that PLCε gene knockdown decreased P-AKT protein levels, but AKT protein levels were not affected. Immunofluorescence assays showed that PTEN expression had an intracellular distribution change in the DU145 cell line, and Western blot analysis showed that PTEN was obviously up-regulated in cell nucleus and cytoplasm. CONCLUSIONS PLCε is an oncogene, and knockdown of expression of PLCe inhibits PCa cells proliferation via the PTEN/AKT signaling pathway.

Economic burden following allogeneic hematopoietic stem cell transplant in patients with diffuse large B-cell lymphoma.

This study describes short-term and long-term healthcare resource utilization (HRU) and costs following an allogeneic hematopoietic stem cell transplant (HSCT) in adult patients with diffuse large B-cell lymphoma (DLBCL) in a real-world setting. Among 101 patients with DLBCL receiving an allogeneic HSCT, HRU and direct healthcare costs for up to three years after the allogeneic HSCT are described. HRU and costs were substantial, with the most intensive HRU and highest healthcare costs observed during the first year after HSCT (38 inpatient days; 68 days with office visits and average healthcare costs of $455,741). Although HRU and costs decreased over time, they remained high even in the third year after HSCT (four inpatient days; 27 days with office visits and average healthcare costs of $72,957). Overall, this study showed that the economic burden following an allogeneic HSCT in DLBCL patients is significant.

Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway.

Natural killer cells are the key components in tumor immunity and defects in function are necessary for tumor immune escape. Emerging studies on tumor cell-derived exosomes have shown the biological significance in tumor microenvironment, but the underlying role of exosomes in regulating natural killer cells functions in clear cell renal cell carcinoma patients remains unknown. Firstly, we precisely characterized the phenotype and function of natural killer cells in clear cell renal cell carcinoma patients vs healthy controls. With an inhibitory phenotype, tumor-infiltrating natural killer cells exhibited poor cytotoxic capacity and deficient potential to produce cytokines compared with natural killer cells from tumor margin tissue and non-tumor tissue. Next, we revealed that primary tumor cells trigged natural killer cell dysfunction in an exosome-dependent manner. Interestingly, exosomes from primary tumor cells were preferentially enriched with TGF-ß1 which acted as important mediator of natural killer cell functional deficiency. In vitro culture of exosomes induced natural killer cell dysfunction mediated by activation of the TGF-ß/SMAD signaling pathway, and abrogated by knockdown TGF-ß. Our data indicate that exosomes from clear cell renal cell carcinoma induce natural killer cells dysfunction by regulating the TGF-ß/SMAD pathway to evade innate immune surveillance.