Combined Inhibition of mTOR and CDK4/6 Is Required for Optimal Blockade of E2F Function and Long-term Growth Inhibition in Estrogen Receptor-positive Breast Cancer.

The cyclin dependent kinase (CDK)-retinoblastoma (RB)-E2F pathway plays a critical role in the control of cell cycle in estrogen receptor-positive (ER+) breast cancer. Small-molecule inhibitors of CDK4/6 have shown promise in this tumor type in combination with hormonal therapies, reflecting the particular dependence of this subtype of cancer on cyclin D1 and E2F transcription factors. mTOR inhibitors have also shown potential in clinical trials in this disease setting. Recent data have suggested cooperation between the PI3K/mTOR pathway and CDK4/6 inhibition in preventing early adaptation and eliciting growth arrest, but the mechanisms of the interplay between these pathways have not been fully elucidated. Here we show that profound and durable inhibition of ER+ breast cancer growth is likely to require multiple hits on E2F-mediated transcription. We demonstrate that inhibition of mTORC1/2 does not affect ER function directly, but does cause a decrease in cyclin D1 protein, RB phosphorylation, and E2F-mediated transcription. Combination of an mTORC1/2 inhibitor with a CDK4/6 inhibitor results in more profound effects on E2F-dependent transcription, which translates into more durable growth arrest and a delay in the onset of resistance. Combined inhibition of mTORC1/2, CDK4/6, and ER delivers even more profound and durable regressions in breast cancer cell lines and xenografts. Furthermore, we show that CDK4/6 inhibitor-resistant cell lines reactivate the CDK-RB-E2F pathway, but remain sensitive to mTORC1/2 inhibition, suggesting that mTORC1/2 inhibitors may represent an option for patients that have relapsed on CDK4/6 therapy. Mol Cancer Ther; 17(5); 908-20. ©2018 AACR.CRUK Cambridge Institute, Cambridge, UK (Jason Carroll, Igor Chernukhin, Rasmus Siersbæk3) Novo Nordisk Fonden (NNF 14136) (Rasmus Siersbæk

4D printing and annealing of PETG composites reinforced with short carbon fibers

In this study, for the first time, post-heat treatment was applied to improve the stress recovery of short carbon fiber reinforced PETG (SCFRPETG). PETG and SCFRPETG composite were printed under optimal conditions, and constrained and free shape memory cycles were applied under compression and three-point bending loadings to assess shape and stress recovery. The results of the free shape memory test for both vertical and horizontal patterns showed that PETG composite also has a higher shape memory effect (SME) compared to PETG. The SME was significantly improved by performing heat treatment. The stress recovery values for pure PETG, reinforced PETG before and after annealing are 2.48 MPa, 3.04 MPa and 3.18 MPa, respectively. It showed that the addition of 1.5% carbon fiber increases the stress recovery by 22%. The increasing trend reaches 28% by performing post-heat treatment. Additionally, altering the printing pattern affects the programming and stress recovery values. For the SCFRPETG composite samples before and after annealing, changing the printing pattern from horizontal to vertical, resulted in a 16% and 7% increase in recovery stress, respectively. SEM results confirm that the annealing process removes the layered structure, micro-holes caused by shrinkage and 4D printing mechanism. Using the controlled heat treatment method can be a practical solution to solve the problem of adhesion and reduce the anisotropy of FDM 3D printed layers

Religious Participation and DSM IV Major Depressive Disorder Among Black Caribbeans in the United States

This study examines the relationship between religious involvement and 12-month and lifetime DSM-IV major depressive disorder (MDD) within a nationally rep- resentative sample of Black Caribbean adults. MDD was assessed using the DSM-IV World Mental Health Com- posite International Diagnostic Interview (WMH-CIDI). Religious involvement included measures of religious coping, organizational and nonorganizational involvement, and subjective religiosity. Study findings indicate that religious involvement is associated with 12-month and lifetime prevalence of MDD. Multivariate relationships between religious involvement and MDD indicate lower prevalence of 12-month and lifetime MDD among persons who use religious coping and characterize themselves as being religious (for lifetime prevalence only); persons who frequently listen to religious radio programs report higher lifetime MDD. Lower rates of 12-month and lifetime MDD are noted for persons who attend religious services at least once a week (as compared to both higher and lower levels of attendance), indicating a curvilinear relationship. The findings are discussed in relation to previous research on religion and mental health concerns, conceptual models of the role of religion in mental health (e.g., prevention, resource mobilization) that specify multiple and often divergent pathways and mechanisms of religious effects on health outcomes, and the role of religion among Caribbean Blacks.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107411/1/Religious Participation and DSM IV Major Depressive Disorder Among Black Caribbeans in the United States.pdfDescription of Religious Participation and DSM IV Major Depressive Disorder Among Black Caribbeans in the United States.pdf : Main articl

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

BioRXiv version. Please see https://rubenarslan.github.io/generation_scotland_pedigree_gcta/ to access this website in a browsable form

Brugia malayi Antigen (BmA) inhibits HIV-1 trans-infection but neither BmA nor ES-62 alter HIV-1 infectivity of DC induced CD4+ Th-cells

One of the hallmarks of HIV-1 disease is the association of heightened CD4+ T-cell activation with HIV-1 replication. Parasitic helminths including filarial nematodes have evolved numerous and complex mechanisms to skew, dampen and evade human immune responses suggesting that HIV-1 infection may be modulated in co-infected individuals. Here we studied the effects of two filarial nematode products, adult worm antigen from Brugia malayi (BmA) and excretory-secretory product 62 (ES-62) from Acanthocheilonema viteae on HIV-1 infection in vitro. Neither BmA nor ES-62 influenced HIV-1 replication in CD4+ enriched T-cells, with either a CCR5- or CXCR4-using virus. BmA, but not ES-62, had the capacity to bind the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) thereby inhibiting HIV-1 trans-infection of CD4+ enriched T-cells. As for their effect on DCs, neither BmA nor ES-62 could enhance or inhibit DC maturation as determined by CD83, CD86 and HLA-DR expression, or the production of IL-6, IL-10, IL-12 and TNF-α. As expected, due to the unaltered DC phenotype, no differences were found in CD4+ T helper (Th) cell phenotypes induced by DCs treated with either BmA or ES-62. Moreover, the HIV-1 susceptibility of the Th-cell populations induced by BmA or ES-62 exposed DCs was unaffected for both CCR5- and CXCR4-using HIV-1 viruses. In conclusion, although BmA has the potential capacity to interfere with HIV-1 transmission or initial viral dissemination through preventing the virus from interacting with DCs, no differences in the Th-cell polarizing capacity of DCs exposed to BmA or ES-62 were observed. Neither antigenic source demonstrated beneficial or detrimental effects on the HIV-1 susceptibility of CD4+ Th-cells induced by exposed DCs

Prevalence and etiology of community-acquired pneumonia in immunocompromised patients

Background. The correct management of immunocompromised patients with pneumonia is debated. We evaluated the prevalence, risk factors, and characteristics of immunocompromised patients coming from the community with pneumonia. Methods. We conducted a secondary analysis of an international, multicenter study enrolling adult patients coming from the community with pneumonia and hospitalized in 222 hospitals in 54 countries worldwide. Risk factors for immunocompromise included AIDS, aplastic anemia, asplenia, hematological cancer, chemotherapy, neutropenia, biological drug use, lung transplantation, chronic steroid use, and solid tumor. Results. At least 1 risk factor for immunocompromise was recorded in 18% of the 3702 patients enrolled. The prevalences of risk factors significantly differed across continents and countries, with chronic steroid use (45%), hematological cancer (25%), and chemotherapy (22%) the most common. Among immunocompromised patients, community-acquired pneumonia (CAP) pathogens were the most frequently identified, and prevalences did not differ from those in immunocompetent patients. Risk factors for immunocompromise were independently associated with neither Pseudomonas aeruginosa nor non\u2013community-acquired bacteria. Specific risk factors were independently associated with fungal infections (odds ratio for AIDS and hematological cancer, 15.10 and 4.65, respectively; both P = .001), mycobacterial infections (AIDS; P = .006), and viral infections other than influenza (hematological cancer, 5.49; P < .001). Conclusions. Our findings could be considered by clinicians in prescribing empiric antibiotic therapy for CAP in immunocompromised patients. Patients with AIDS and hematological cancer admitted with CAP may have higher prevalences of fungi, mycobacteria, and noninfluenza viruses

Gaia Focused Product Release: A catalogue of sources around quasars to search for strongly lensed quasars

Context. Strongly lensed quasars are fundamental sources for cosmology. The Gaia space mission covers the entire sky with the unprecedented resolution of $0.18$" in the optical, making it an ideal instrument to search for gravitational lenses down to the limiting magnitude of 21. Nevertheless, the previous Gaia Data Releases are known to be incomplete for small angular separations such as those expected for most lenses. Aims. We present the Data Processing and Analysis Consortium GravLens pipeline, which was built to analyse all Gaia detections around quasars and to cluster them into sources, thus producing a catalogue of secondary sources around each quasar. We analysed the resulting catalogue to produce scores that indicate source configurations that are compatible with strongly lensed quasars. Methods. GravLens uses the DBSCAN unsupervised clustering algorithm to detect sources around quasars. The resulting catalogue of multiplets is then analysed with several methods to identify potential gravitational lenses. We developed and applied an outlier scoring method, a comparison between the average BP and RP spectra of the components, and we also used an extremely randomised tree algorithm. These methods produce scores to identify the most probable configurations and to establish a list of lens candidates. Results. We analysed the environment of 3 760 032 quasars. A total of 4 760 920 sources, including the quasars, were found within 6" of the quasar positions. This list is given in the Gaia archive. In 87\% of cases, the quasar remains a single source, and in 501 385 cases neighbouring sources were detected. We propose a list of 381 lensed candidates, of which we identified 49 as the most promising. Beyond these candidates, the associate tables in this Focused Product Release allow the entire community to explore the unique Gaia data for strong lensing studies further.Comment: 35 pages, 60 figures, accepted for publication by Astronomy and Astrophysic

Gaia Focused Product Release: Radial velocity time series of long-period variables

The third Gaia Data Release (DR3) provided photometric time series of more than 2 million long-period variable (LPV) candidates. Anticipating the publication of full radial-velocity (RV) in DR4, this Focused Product Release (FPR) provides RV time series for a selection of LPVs with high-quality observations. We describe the production and content of the Gaia catalog of LPV RV time series, and the methods used to compute variability parameters published in the Gaia FPR. Starting from the DR3 LPVs catalog, we applied filters to construct a sample of sources with high-quality RV measurements. We modeled their RV and photometric time series to derive their periods and amplitudes, and further refined the sample by requiring compatibility between the RV period and at least one of the $G$, $G_{\rm BP}$, or $G_{\rm RP}$ photometric periods. The catalog includes RV time series and variability parameters for 9\,614 sources in the magnitude range $6\lesssim G/{\rm mag}\lesssim 14$, including a flagged top-quality subsample of 6\,093 stars whose RV periods are fully compatible with the values derived from the $G$, $G_{\rm BP}$, and $G_{\rm RP}$ photometric time series. The RV time series contain a mean of 24 measurements per source taken unevenly over a duration of about three years. We identify the great most sources (88%) as genuine LPVs, with about half of them showing a pulsation period and the other half displaying a long secondary period. The remaining 12% consists of candidate ellipsoidal binaries. Quality checks against RVs available in the literature show excellent agreement. We provide illustrative examples and cautionary remarks. The publication of RV time series for almost 10\,000 LPVs constitutes, by far, the largest such database available to date in the literature. The availability of simultaneous photometric measurements gives a unique added value to the Gaia catalog (abridged)Comment: 36 pages, 38 figure