Nevin Manimala

Sci Rep. 2021 May 10;11(1):9876. doi: 10.1038/s41598-021-88609-6.

ABSTRACT

PT150, a novel competitive glucocorticoid receptor (GR) antagonist, has proven safe in animal models, healthy volunteers, and people with depression. Our study is the first to investigate PT150’s safety with alcohol use. The primary objective of this study was to evaluate pharmacodynamic interactions between ethanol and PT150 in healthy subjects. This single-site, Phase I pilot trial consisted of community-recruited, healthy, alcohol-experienced participants aged 21-64 years. Of 32 participants screened, 11 were enrolled and randomized, one of which withdrew before intervention. PT150 (900 mg/day) was administered orally to all participants for five days. All participants received two beverage challenges on Day 1 (before PT150 administration) and Day 5 (after PT150 administration). On challenge days, they received both alcohol (16% ethanol) and placebo (1% ethanol) beverages in random order. Primary outcomes included breath alcohol level, blood pressure, heart rate, adverse events, and electrocardiogram changes. There were no statistically significant differences in vital signs or estimated blood alcohol concentrations between PT150 non-exposed and exposed groups during the ethanol challenge. There were no clinically significant abnormal electrocardiograms or serious adverse events. These data show that administration of PT150 with concurrent alcohol use is safe and well-tolerated. This study supports a future pharmacokinetic interaction study between PT150 and alcohol.Trial Registration ClinicalTrials.gov Identifier: NCT03548714.

PMID:33972573 | DOI:10.1038/s41598-021-88609-6

Sci Rep. 2021 May 10;11(1):9837. doi: 10.1038/s41598-021-87900-w.

ABSTRACT

Now a day’s variety of nanomaterials is available, among these Aluminum Alloys AA7072 and AA705 are significant due to their thermal, physical and mechanical characteristics. These extensively used in manufacturing of spacecraft, aircraft parts and building testing. Keeping in view the significance of nanoliquids, the analysis of methanol suspended by AA7072 and AA7075 alloys under the multiple physical flow conditions is reported. The model is successfully treated by coupling of RK and shooting algorithm and examined the results for the flow regimes by altering the ingrained physical parameters. Then physical interpretation of the results discussed comprehensively. To validate the analysis, a comparison between the presented and existing is reported under certain assumptions on the flow parameters. It is found that the results are reliable inline with existing once.

PMID:33972554 | DOI:10.1038/s41598-021-87900-w

Nat Commun. 2021 May 10;12(1):2580. doi: 10.1038/s41467-021-22648-5.

ABSTRACT

Combining genetic and cell-type-specific proteomic datasets can generate biological insights and therapeutic hypotheses, but a technical and statistical framework for such analyses is lacking. Here, we present an open-source computational tool called Genoppi (lagelab.org/genoppi) that enables robust, standardized, and intuitive integration of quantitative proteomic results with genetic data. We use Genoppi to analyze 16 cell-type-specific protein interaction datasets of four proteins (BCL2, TDP-43, MDM2, PTEN) involved in cancer and neurological disease. Through systematic quality control of the data and integration with published protein interactions, we show a general pattern of both cell-type-independent and cell-type-specific interactions across three cancer cell types and one human iPSC-derived neuronal cell type. Furthermore, through the integration of proteomic and genetic datasets in Genoppi, our results suggest that the neuron-specific interactions of these proteins are mediating their genetic involvement in neurodegenerative diseases. Importantly, our analyses suggest that human iPSC-derived neurons are a relevant model system for studying the involvement of BCL2 and TDP-43 in amyotrophic lateral sclerosis.

PMID:33972534 | DOI:10.1038/s41467-021-22648-5

Blood Cancer J. 2021 May 10;11(5):86. doi: 10.1038/s41408-021-00477-5.

ABSTRACT

Richter syndrome (RS) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. RS is known to be associated with a number of genetic alterations such as TP53 and NOTCH1 mutations. However, it is unclear what immune microenvironment changes are associated with RS. In this study, we analyzed expression of immune checkpoint molecules and infiltration of immune cells in nodal samples, and peripheral blood T-cell diversity in 33 CLL and 37 RS patients. Compared to CLL, RS nodal tissue had higher PD-L1 expression in histiocytes and dendritic cells (median 16.6% vs. 2.8%, P < 0.01) and PD1 expression in neoplastic B cells (median 26.0% vs. 6.2%, P < 0.01), and higher infiltration of FOXP3-positive T cells (median 1.7% vs. 0.4%, P < 0.01) and CD163-positive macrophages (median 23.4% vs. 9.1%, P < 0.01). In addition, peripheral blood T-cell receptor clonality was significantly lower in RS vs. CLL patients (median [25th-75th], 0.107 [0.070-0.209] vs. 0.233 [0.111-0.406], P = 0.046), suggesting that T cells in RS patients were significantly more diverse than in CLL patients. Collectively these data suggest that CLL and RS have distinct immune signatures. Better understanding of the immune microenvironment is essential to improve immunotherapy efficacy in CLL and RS.

PMID:33972504 | DOI:10.1038/s41408-021-00477-5

BDJ Open. 2021 May 10;7(1):17. doi: 10.1038/s41405-021-00072-7.

ABSTRACT

STATEMENT OF PROBLEM: Accuracy of internal fit and microleakage for CAD-CAM systems used in metal coping fabrication and veneered with layering or pressing porcelain in ceramometallic restoration is unclear.

MATERIAL AND METHODS: A master metal die was milled to resemble the right mandibular first molar preparation for coverage with ceramometallic restoration. Master die was duplicated to twenty-four resin specimen dies.They were divided into two groups according to metal coping construction technique using either conventional (C) or CAD (D) wax. Each group was subdivided into two subgroups (n = 6) according to the technique of porcelain veneering (layered or pressed) to fabricate ceramometallic restorations, where subgroup (CL, DL) were conventionally layered by porcelain and (CP, DP) were press veneered. A standardized thickness of metal and porcelain was performed in all specimens as per manufacturer’s instructions for techniques ceramometallic restoration construction. Evaluation of internal fit was done with silicone replica technique using stereomicroscope at ×24 magnification where the thickness of silicon layer was measured at 20 reference points on each specimen. Then specimens were subjected to thermocycling. Sectioned specimens were assessed for microleakage using a stereomicroscope at ×12 magnification along die-cement interface with a five scale score.

RESULTS: Mean internal gap values of veneering showed a statistically nonsignificant difference between specimens made with layering(L) and pressing(P). Different techniques of wax construction showed a non-significant difference in internal gap values between specimens made with conventional(C) and CAD(D) waxing. However, a significant difference was found in the internal gap at different sites. The highest internal gap was found at the occlusal surface, while the lowest gap was found at the finish line. The highest mean microleakage score was found with CAD wax and press veneering, while the lowest mean microleakage score was found with conventional wax and press veneering.

CONCLUSION: Both construction techniques of ceramometallic restoration were considered reliable in restoration production within a clinically acceptable range regarding internal fit and microleakage. There is a strong positive correlation between internal fit and microleakage of ceramometallic restoration constructed.

PMID:33972501 | DOI:10.1038/s41405-021-00072-7

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

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

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

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

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