Tag: pubmed

J Immunother Cancer. 2021 May;9(5):e002372. doi: 10.1136/jitc-2021-002372.

ABSTRACT

BACKGROUND: Emerging evidence has highlighted the importance of extracellular vesicle (EV)-based biomarkers of resistance to immunotherapy with checkpoint inhibitors in metastatic melanoma. Considering the tumor-promoting implications of urokinase-type plasminogen activator receptor (uPAR) signaling, this study aimed to assess uPAR expression in the plasma-derived EVs of patients with metastatic melanoma to determine its potential correlation with clinical outcomes.

METHODS: Blood samples from 71 patients with metastatic melanoma were collected before initiating immunotherapy. Tumor-derived and immune cell-derived EVs were isolated and analyzed to assess the relative percentage of uPAR⁺ EVs. The associations between uPAR and clinical outcomes, sex, BRAF status, baseline lactate dehydrogenase levels and number of metastatic sites were assessed.

RESULTS: Responders had a significantly lower percentage of tumor-derived, dendritic cell (DC)-derived and CD8⁺ T cell-derived uPAR +EVs at baseline than non-responders. The Kaplan-Meier survival curves for the uPAR⁺EV quartiles indicated that higher levels of melanoma-derived uPAR⁺ EVs were strongly correlated with poorer progression-free survival (p<0.0001) and overall survival (p<0.0001). We also found a statistically significant correlation between lower levels of uPAR⁺ EVs from both CD8⁺ T cells and DCs and better survival.

CONCLUSIONS: Our results indicate that higher levels of tumor-derived, DC-derived and CD8⁺ T cell-derived uPAR⁺ EVs in non-responders may represent a new biomarker of innate resistance to immunotherapy with checkpoint inhibitors. Moreover, uPAR⁺ EVs represent a new potential target for future therapeutic approaches.

PMID:33972390 | DOI:10.1136/jitc-2021-002372

Transl Psychiatry. 2021 May 10;11(1):264. doi: 10.1038/s41398-021-01376-w.

ABSTRACT

Molecular imaging studies have shown low cerebral concentration of serotonin transporter in patients suffering from depression, compared to healthy control subjects. Whether or not this difference also is present before disease onset and after remission (i.e. a trait), or only at the time of the depressive episode (i.e. a state) remains to be explored. We examined 17 patients with major depressive disorder with positron emission tomography using [¹¹C]MADAM, a radioligand that binds to the serotonin transporter, before and after treatment with internet-based cognitive behavioral therapy. In all, 17 matched healthy control subjects were examined once. Cerebellum was used as reference to calculate the binding potential. Differences before and after treatment, as well as between patients and controls, were assessed in a composite cerebral region and in the median raphe nuclei. All image analyses and confirmatory statistical tests were preregistered. Depression severity decreased following treatment (p < 0.001). [¹¹C]MADAM binding in patients increased in the composite region after treatment (p = 0.01), while no change was observed in the median raphe (p = 0.51). No significant difference between patients at baseline and healthy controls were observed in the composite region (p = 0.97) or the median raphe (p = 0.95). Our main finding was that patients suffering from a depressive episode show an overall increase in cerebral serotonin transporter availability as symptoms are alleviated. Our results suggest that previously reported cross-sectional molecular imaging findings of the serotonin transporter in depression most likely reflect the depressive state, rather than a permanent trait. The finding adds new information on the pathophysiology of major depressive disorder.

PMID:33972499 | DOI:10.1038/s41398-021-01376-w

eNeuro. 2021 May 10:ENEURO.0458-20.2021. doi: 10.1523/ENEURO.0458-20.2021. Online ahead of print.

ABSTRACT

Synucleinopathies including Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal intracellular inclusions of α-synuclein (α-synuclein). Parkinson’s disease dementia (PDD) and DLB are collectively the second most common cause of neurodegenerative dementia. In addition to associated inclusions, Lewy body diseases have dopaminergic neurodegeneration, motor defects and cognitive changes. The microtubule-associated protein tau has been implicated in LBDs, but the exact role of the protein and how it influences formation of α-synuclein inclusions is unknown. Reducing endogenous tau levels is protective in multiple models of Alzheimer’s disease (AD), tauopathies, and in some transgenic synucleinopathy mouse models. Recombinant α-synuclein and tau proteins interact in vitro Here, we show tau and α-synuclein colocalize at excitatory presynaptic terminals. However, tau heterozygous and tau knockout mice do not show a reduction in fibril-induced α-synuclein inclusions formation in primary cortical neurons, or after intrastriatal injections of fibrils at 1.5 month or 6 months later. At 6 months following intrastriatal injections, wild type, tau heterozygous and tau knockout mice showed a 50% reduction in dopamine neurons in the SNc compared to mice injected with α-synuclein monomer, but there were no statistically significant differences across genotypes. These data suggest the role of tau in the pathogenesis of LBDs is distinct from AD, and Lewy pathology formation may be independent of endogenous tau.Significance StatementVariations in the MAPT H1 haplotype are associated with PD, but it is possible that other genes within the H1 haplotype play a role in PD etiology. In vitro studies show α-synuclein and tau interact, leading to synergistic fibrillization. α-Synuclein and tau can co-exist in Lewy bodies. Tau reduction is protective in models of AD and tauopathies and has been suggested as a therapeutic strategy for PD. Here, we show reduction of endogenous tau does not influence formation of templated α-synuclein inclusion formation or loss of dopamine neurons, suggesting that therapeutics directed to tau for PD may be more complicated than tau reduction.

PMID:33972291 | DOI:10.1523/ENEURO.0458-20.2021

BMJ Open. 2021 May 10;11(5):e044284. doi: 10.1136/bmjopen-2020-044284.

ABSTRACT

OBJECTIVE: The main objective of this study was to assess the prevalence of a minimum acceptable diet (MAD) and associated factors.

DESIGN: Community-based cross-sectional study SETTING: Debre Berhan Town, Ethiopia.

PARTICIPANTS: An aggregate of 531 infants and young children mother/caregiver pairs participated in this study. A one-stage cluster sampling method was used to select study participants and clusters were selected using a lottery method. Descriptive statistics were calculated for all study variables. Statistical analysis was performed on data to determine which variables are associated with MAD and the results of the adjusted OR with 95% CI. P value of <0.05 considered statistically significant.

PRIMARY OUTCOME: Prevalence of MAD and associated factors RESULTS: The overall prevalence of MAD was 31.6% (95% CI: 27.7 to 35.2). Having mother attending secondary (adjusted OR, AOR=4.9, 95% CI: 1.3 to 18.9) and college education (AOR=6.4, 95% CI: 1.5 to 26.6), paternal primary education (AOR=1.3, 95% CI: 1.5 to 2.4), grouped in the aged group of 12-17 months (AOR=1.8, 95% CI: (1.0 to 3.4) and 18-23 months (AOR=2.2, 95% CI: 1.2 to 3.9), having four antenatal care (ANC) visits (AOR=2.0, 95% CI: 1.0 to 3.9), utilising growth monitoring (AOR=1.8, 95% CI: 1.1 to 2.9), no history of illness 2 weeks before the survey (AOR=2.9, 95% CI: 1.5 to 6.0) and living in the household with home garden (AOR=2.5, 95% CI: 1.5 to 4.3) were positively associated with increase the odds of MAD.

CONCLUSION: Generally, the result of this study showed that the prevalence of minimum acceptable was very low. Parent educational status, ANC visits, infant and young child feeding advice, child growth monitoring practice, age of a child, a child has no history of illness 2 weeks before the survey, and home gardening practice were the predictors of MAD. Therefore, comprehensive intervention strategies suitable to the local context are required to improve the provision of MAD.

PMID:33972337 | DOI:10.1136/bmjopen-2020-044284

Cancer Epidemiol Biomarkers Prev. 2021 May 10:cebp.1848.2021. doi: 10.1158/1055-9965.EPI-20-1848. Online ahead of print.

ABSTRACT

BACKGROUND: A positive association between circulating C-reactive protein (CRP) and colorectal cancer (CRC) survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically-predicted CRP concentrations and CRC-specific survival.

METHODS: We used individual-level data for 16,918 eligible CRC cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Due to the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically-predicted CRP concentrations and CRC-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components.

RESULTS: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to CRC. Genetically-predicted CRP concentration was not associated with CRC-specific survival (HD= -1.15, 95% CI: -2.76 to 0.47 per 100,000 person-years, P =0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location.

CONCLUSIONS: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on CRC-specific survival.

IMPACT: Future research evaluating genetically-determined levels of other circulating inflammatory biomarkers (i.e. interleukin-6) with CRC survival outcomes is needed.

PMID:33972368 | DOI:10.1158/1055-9965.EPI-20-1848

Antimicrob Agents Chemother. 2021 May 10:AAC.00546-21. doi: 10.1128/AAC.00546-21. Online ahead of print.

ABSTRACT

Chromoblastomycosis (CBM) is a chronic subcutaneous infection caused by genera of melanized fungi: Fonsecaea, Cladophialophora, Phialophora, Exophiala and Rhinocladiella Melanin is a virulence factor known to influence antifungal susceptibility. A specific inhibitor of melanin biosynthesis is tricyclazole. The aim of this study was to evaluate the effect of melanin inhibition on antifungal susceptibility of chromoblastomycosis agents and describe the susceptibility profile of some unusual CBM agents. Seventy-six clinical isolates, representing 13 species of the five main CBM agents genera, were studied. The antifungal susceptibility was performed according to the M38-A2 protocol of CLSI. In the melanin inhibition test, 16 mg/L of tricyclazole was added to the medium used in the inoculum preparation and the susceptibility assay. CBM agents were less susceptible to amphotericin B in comparison with azoles and terbinafine. The unusual species showed similar susceptibilities profiles to those of other species of the same genera. With tricyclazole exposition, MICs of terbinafine, posaconazole and itraconazole for Fonsecaea spp. significantly decreased (p<0,05). For Phialophora spp., this reduction was significative for posaconazole and itraconazole. For the other genera, there was a reduction in MICs of terbinafine and itraconazole, however, the statistical tests were not significant. Melanin inhibition can increase the antifungal susceptibility of most CBM agents to itraconazole and terbinafine, the main used drugs in the disease treatment. This increased susceptibility may open up new possibilities for therapy in refractory cases of CBM and/or caused by resistant fungal strains. Further studies are needed to confirm the same results in vivo.

PMID:33972246 | DOI:10.1128/AAC.00546-21

BMJ. 2021 May 10;373:n972. doi: 10.1136/bmj.n972.

ABSTRACT

OBJECTIVE: To evaluate the accuracy of the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) to screen for major depression among people with physical health problems.

DESIGN: Systematic review and individual participant data meta-analysis.

DATA SOURCES: Medline, Medline In-Process and Other Non-Indexed Citations, PsycInfo, and Web of Science (from inception to 25 October 2018).

REVIEW METHODS: Eligible datasets included HADS-D scores and major depression status based on a validated diagnostic interview. Primary study data and study level data extracted from primary reports were combined. For HADS-D cut-off thresholds of 5-15, a bivariate random effects meta-analysis was used to estimate pooled sensitivity and specificity, separately, in studies that used semi-structured diagnostic interviews (eg, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders), fully structured interviews (eg, Composite International Diagnostic Interview), and the Mini International Neuropsychiatric Interview. One stage meta-regression was used to examine whether accuracy was associated with reference standard categories and the characteristics of participants. Sensitivity analyses were done to assess whether including published results from studies that did not provide raw data influenced the results.

RESULTS: Individual participant data were obtained from 101 of 168 eligible studies (60%; 25 574 participants (72% of eligible participants), 2549 with major depression). Combined sensitivity and specificity was maximised at a cut-off value of seven or higher for semi-structured interviews, fully structured interviews, and the Mini International Neuropsychiatric Interview. Among studies with a semi-structured interview (57 studies, 10 664 participants, 1048 with major depression), sensitivity and specificity were 0.82 (95% confidence interval 0.76 to 0.87) and 0.78 (0.74 to 0.81) for a cut-off value of seven or higher, 0.74 (0.68 to 0.79) and 0.84 (0.81 to 0.87) for a cut-off value of eight or higher, and 0.44 (0.38 to 0.51) and 0.95 (0.93 to 0.96) for a cut-off value of 11 or higher. Accuracy was similar across reference standards and subgroups and when published results from studies that did not contribute data were included.

CONCLUSIONS: When screening for major depression, a HADS-D cut-off value of seven or higher maximised combined sensitivity and specificity. A cut-off value of eight or higher generated similar combined sensitivity and specificity but was less sensitive and more specific. To identify medically ill patients with depression with the HADS-D, lower cut-off values could be used to avoid false negatives and higher cut-off values to reduce false positives and identify people with higher symptom levels.

TRIAL REGISTRATION: PROSPERO CRD42015016761.

PMID:33972268 | DOI:10.1136/bmj.n972

J Acad Nutr Diet. 2021 May 7:S2212-2672(21)00237-9. doi: 10.1016/j.jand.2021.04.009. Online ahead of print.

ABSTRACT

BACKGROUND: Food insecurity, a state of not being able to consistently access nutritious food due to financial constraints, has been associated with poor dietary intake among college students. The extent to which campus food resources contribute to this association is unknown.

OBJECTIVES: This study examined the association between food insecurity and dietary intake in a sample of undergraduate students with unlimited meal plans and dining hall access at a large, public Midwestern university.

DESIGN: The study design is cross-sectional. The data used are baseline data from a broader sugar-sweetened beverage intervention study that were collected using a Qualtrics survey prior to the intervention.

PARTICIPANTS/SETTING: The sample consisted of 1033 undergraduate students recruited from 3 dining halls. The data were collected in November 2018.

MAIN OUTCOME MEASURES: Food security was assessed using the 6-item Short Form Food Security Survey Module. Dietary intake was assessed using the National Cancer Institute 26-item Dietary Screener Questionnaire and the Beverage Intake Questionnaire-15.

STATISTICAL ANALYSES PERFORMED: Generalized linear regression models were used to examine differences in dietary intake by students’ food security status, adjusting for students’ sociodemographic characteristics.

RESULTS: In the sample, 14% of students were food-insecure. After adjusting for sociodemographic variables, food-insecure students reported 9% lower intake of fruits (P = 0.02), 9% lower intake of vegetables (P < 0.001), 10% higher intake of dairy (P = 0.002), 6% higher intake of total added sugars (P = 0.01), 10% higher intake of added sugars from sugar-sweetened beverages (P = 0.01), 4% higher intake of calcium (P = 0.01), and 4% lower intake of fiber (P = 0.01) compared with food-secure students. With respect to beverage intake, food-insecure students had 56% higher intake of total sugar-sweetened beverages (P = 0.002), which was driven by 185% higher intake of energy and sports drinks (P = 0.001), and 121% higher intake of sweetened teas (P = 0.001).

CONCLUSIONS: Despite having identical food resources within campus dining halls, there were significant differences in the diets of college students by food security status.

PMID:33972204 | DOI:10.1016/j.jand.2021.04.009

Yi Chuan. 2021 May 20;43(5):487-500. doi: 10.16288/j.yczz.20-409.

ABSTRACT

Low pH with aluminum (Al) toxicity are the main limiting factors affecting crop production in acidic soil. Selection of legume crops with acid tolerance and nitrogen-fixation ability should be one of the effective measures to improve soil quality and promote agricultural production. The role of the rhizosphere microorganisms in this process has raised concerns among the research community. In this study, BX10 (Al-tolerant soybean) and BD2 (Al-sensitive soybean) were selected as plant materials. Acidic soil was used as growth medium. The soil layers from the outside to the inside of the root are bulk soil (BS), rhizosphere soil at two sides (SRH), rhizosphere soil after brushing (BRH) and rhizosphere soil after washing (WRH), respectively. High-throughput sequencing of 16S rDNA amplicons of the V4 region using the Illumina MiSeq platform was performed to compare the differences of structure, function and molecular genetic diversity of rhizosphere bacterial community of different genotypes of soybean. The results showed that there was no significant difference in alpha diversity and beta diversity in rhizosphere bacterial community among the treatments. PCA and PCoA analysis showed that BRH and WRH had similar species composition, while BS and SRH also had similar species composition, which indicated that plant mainly affected the rhizosphere bacterial community on sampling compartments BRH and WRH. The composition and abundance of rhizosphere bacterial community among the treatments were then compared at different taxonomic levels. The ternary diagram of phylum level showed that Cyanobacteria were enriched in WRH. Statistical analysis showed that the roots of Al-tolerant soybean BX10 had an enrichment effect on plant growth promoting rhizobacteria (PGPR), which included Cyanobacteria, Bacteroides, Proteobacteria and some genera and species related to the function of nitrogen fixation and aluminum tolerance. The rhizosphere bacterial community from different sampling compartments of the same genotype soybean also were selectively enriched in different PGPR. In addition, the functional prediction analysis showed that there was no significant difference in the classification and abundance of COG (clusters of orthologous groups of proteins) function among different treatments. Several COGs might be directly related to nitrogen fixation, including COG0347, COG1348, COG1433, COG2710, COG3870, COG4656, COG5420, COG5456 and COG5554. Al-sensitive soybean BD2 was more likely to be enriched in these COGs than BX10 in BRH and WRH, and the possible reason remains to be further investigated in the future.

PMID:33972218 | DOI:10.16288/j.yczz.20-409

Antimicrob Agents Chemother. 2021 May 10:AAC.02565-20. doi: 10.1128/AAC.02565-20. Online ahead of print.

ABSTRACT

Pharmacokinetics and antifungal activity of the echinocandins anidulafungin (AFG), micafungin (MFG) and caspofungin (CAS) were assessed in ascites fluid and plasma of critically ill adults treated for suspected or proven invasive candidiasis. Ascites fluid was obtained from ascites drains or during paracentesis. The antifungal activity of the echinocandins in ascites fluid was assessed by incubation of Candida (C.) albicans and C. glabrata at concentrations of 0.03 to 16.00 μg/ml. In addition, ascites fluid samples obtained from our study patients were inoculated with the same isolates and evaluated for fungal growth. These patient samples had to be spiked with echinocandins to restore the original concentrations, because echinocandins had been lost during sterile filtration. In ascites fluid specimens of 29 patients, echinocandin concentrations were below the simultaneous plasma levels. Serial sampling in 20 patients revealed a slower rise and decline of echinocandin concentrations in ascites fluid than in plasma. Proliferation of C. albicans in ascites fluid was slower than in culture medium and growth of C. glabrata was lacking, even in the absence of antifungals. In CAS-spiked ascites fluid samples, fungal CFU counts moderately declined, whereas spiking with AFG or MFG, had no relevant effect. In ascites fluid of our study patients, echinocandin concentrations achieved by therapeutic doses did not result in a consistent eradication of C. albicans or C. glabrata Thus, therapeutic doses of AFG, MFG, or CAS may result in ascites fluid concentrations preventing relevant proliferation of C. albicans and C. glabrata, but do not warrant reliable eradication.

PMID:33972242 | DOI:10.1128/AAC.02565-20