Extensive research has identified stereotypic behavioral and biological abnormalities in post-traumatic stress disorder (PTSD), such as heightened autonomic activity, an exaggerated startle response, ...reduced basal cortisol levels and cognitive impairments. We have reviewed primary research in this area, noting that factors involved in the susceptibility and expression of PTSD symptoms are more complex and heterogeneous than is commonly stated, with extensive findings which are inconsistent with the stereotypic behavioral and biological profile of the PTSD patient. A thorough assessment of the literature indicates that interactions among myriad susceptibility factors, including social support, early life stress, sex, age, peri- and post-traumatic dissociation, cognitive appraisal of trauma, neuroendocrine abnormalities and gene polymorphisms, in conjunction with the inconsistent expression of the disorder across studies, confounds attempts to characterize PTSD as a monolithic disorder. Overall, our assessment of the literature addresses the great challenge in developing a behavioral and biomarker-based diagnosis of PTSD.
Selenium-binding protein 1 (SBP1) is a highly conserved protein that covalently binds selenium. SBP1 may play important roles in several fundamental physiological functions, including protein ...degradation, intra-Golgi transport, cell differentiation, cellular motility, redox modulation, and the metabolism of sulfur-containing molecules. SBP1 expression is often reduced in many cancer types compared to the corresponding normal tissues and low levels of SBP1 are frequently associated with poor clinical outcome. In this review, the transcriptional regulation of
, the different physiological roles reported for SBP1, as well as the implications of SBP1 function in cancer and other diseases are presented.
Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA ...exonuclease Trex1 is induced by radiation doses above 12-18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-β by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-β production, resulting in recruitment and activation of Batf3-dependent dendritic cells. This effect is essential for priming of CD8
T cells that mediate systemic tumour rejection (abscopal effect) in the context of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumour immunity. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy.
To evaluate whether Attachment-Based Family Therapy (ABFT) is more effective than Enhanced Usual Care (EUC) for reducing suicidal ideation and depressive symptoms in adolescents.
This was a ...randomized controlled trial of suicidal adolescents between the ages of 12 and 17, identified in primary care and emergency departments. Of 341 adolescents screened, 66 (70% African American) entered the study for 3 months of treatment. Assessment occurred at baseline, 6 weeks, 12 weeks, and 24 weeks. ABFT consisted of individual and family meetings, and EUC consisted of a facilitated referral to other providers. All participants received weekly monitoring and access to a 24-hour crisis phone. Trajectory of change and clinical recovery were measured for suicidal ideation and depressive symptoms.
Using intent to treat, patients in ABFT demonstrated significantly greater rates of change on self-reported suicidal ideation at post-treatment evaluation, and benefits were maintained at follow-up, with a strong overall effect size (ES = 0.97). Between-group differences were similar on clinician ratings. Significantly more patients in ABFT met criteria for clinical recovery on suicidal ideation post-treatment (87%; 95% confidence interval CI = 74.6-99.6) than patients in EUC (51.7%; 95% CI = 32.4-54.32). Benefits were maintained at follow-up (ABFT, 70%; 95% CI = 52.6-87.4; EUC 34.6%; 95% CI = 15.6-54.2; odds ratio = 4.41). Patterns of depressive symptoms over time were similar, as were results for a subsample of adolescents with diagnosed depression. Retention in ABFT was higher than in EUC (mean = 9.7 versus 2.9).
ABFT is more efficacious than EUC in reducing suicidal ideation and depressive symptoms in adolescents. Additional research is warranted to confirm treatment efficacy and to test the proposed mechanism of change (the Family Safety Net Study).Clinical Trial Registry Information: Preventing Youth Suicide in Primary Care: A Family Model, URL: http://www.clinicaltrials.gov, unique identifier: NCT00604097.
Tianeptine is a clinically used antidepressant that has drawn much attention, because this compound challenges traditional monoaminergic hypotheses of depression. It is now acknowledged that the ...antidepressant actions of tianeptine, together with its remarkable clinical tolerance, can be attributed to its particular neurobiological properties. The involvement of glutamate in the mechanism of action of the antidepressant tianeptine is consistent with a well-developed preclinical literature demonstrating the key function of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression. This article reviews the latest evidence on tianeptine's mechanism of action with a focus on the glutamatergic system, which could provide a key pathway for its antidepressant action. Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders.
Radiotherapy (RT) used at immunogenic doses leads to accumulation of cytosolic double-stranded DNA (dsDNA) in cancer cells, which activates type I IFN (IFN-I) via the cGAS/STING pathway. Cancer ...cell-derived IFN-I is required to recruit BATF3-dependent dendritic cells (DC) to poorly immunogenic tumors and trigger antitumor T-cell responses in combination with immune checkpoint blockade. We have previously demonstrated that the exonuclease TREX1 regulates radiation immunogenicity by degrading cytosolic dsDNA. Tumor-derived DNA can also activate cGAS/STING-mediated production of IFN-I by DCs infiltrating immunogenic tumors. However, how DNA from cancer cells is transferred to the cytoplasm of DCs remains unclear. Here, we showed that tumor-derived exosomes (TEX) produced by irradiated mouse breast cancer cells (RT-TEX) transfer dsDNA to DCs and stimulate DC upregulation of costimulatory molecules and STING-dependent activation of IFN-I.
, RT-TEX elicited tumor-specific CD8
T-cell responses and protected mice from tumor development significantly better than TEX from untreated cancer cells in a prophylactic vaccination experiment. We demonstrated that the IFN-stimulatory dsDNA cargo of RT-TEX is regulated by TREX1 expression in the parent cells. Overall, these results identify RT-TEX as a mechanism whereby IFN-stimulatory dsDNA is transferred from irradiated cancer cells to DCs. We have previously shown that the expression of TREX1 is dependent on the RT dose size. Thus, these data have important implications for the use of RT with immunotherapy.
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Donor-to-recipient lung size matching at lung transplantation (LTx) can be estimated by the predicted total lung capacity (pTLC) ratio (donor pTLC/recipient pTLC). We aimed to determine whether the ...pTLC ratio is associated with the risk of primary graft dysfunction (PGD) after bilateral LTx (BLT).
We calculated the pTLC ratio for 812 adult BLTs from the Lung Transplant Outcomes Group between March 2002 to December 2010. Patients were stratified by pTLC ratio >1.0 ("oversized") and pTLC ratio ≤1.0 ("undersized"). PGD was defined as any ISHLT Grade 3 PGD (PGD3) within 72 hours of reperfusion. We analyzed the association between risk factors and PGD using multivariable conditional logistic regression. As transplant diagnoses can influence the size-matching decisions and also modulate the risk for PGD, we performed pre-specified analyses by assessing the impact of lung size mismatch within diagnostic categories.
In univariate analyses oversizing was associated with a 39% lower odds of PGD3 (OR 0.61, 95% CI, 0.45-0.85, p = 0.003). In a multivariate model accounting for center-effects and known PGD risks, oversizing remained independently associated with a decreased odds of PGD3 (OR 0.58, 95% CI 0.38 to 0.88, p = 0.01). The risk-adjusted point estimate was similar for the non-COPD diagnosis groups (OR 0.52, 95% CI 0.32 to 0.86, p = 0.01); however, there was no detected association within the COPD group (OR 0.72, 95% CI 0.29 to 1.78, p = 0.5).
Oversized allografts are associated with a decreased risk of PGD3 after BLT; this effect appears most apparent in non-COPD patients.
We present estimates of black hole accretion rates (BHARs) and nuclear, extended, and total star formation rates for a complete sample of Seyfert galaxies. Using data from the Spitzer Space ...Telescope, we measure the active galactic nucleus (AGN) luminosity using the OIV lambda25.89 mum emission line and the star-forming luminosity using the 11.3 mum aromatic feature and extended 24 mum continuum emission. We find that black hole growth is strongly correlated with nuclear (r < 1 kpc) star formation, but only weakly correlated with extended (r > 1 kpc) star formation in the host galaxy. In particular, the nuclear star formation rate (SFR) traced by the 11.3 mum aromatic feature follows a relationship with the BHAR of the form SFR is proportional to M sub(BH) super(0.8), with an observed scatter of 0.5 dex. This SFR-BHAR relationship persists when additional star formation in physically matched r = 1 kpc apertures is included, taking the form SFR is proportional to M sub(BH) super(0.6). However, the relationship becomes almost indiscernible when total SFRs are considered. This suggests a physical connection between the gas on sub-kiloparsec and sub-parsec scales in local Seyfert galaxies that is not related to external processes in the host galaxy. It also suggests that the observed scaling between star formation and black hole growth for samples of AGNs will depend on whether the star formation is dominated by a nuclear or an extended component. We estimate the integrated black hole and bulge growth that occurs in these galaxies and find that an AGN duty cycle of 5%-10% would maintain the ratio between black hole and bulge masses seen in the local universe.
We describe the sample design for the SDSS-IV MaNGA survey and present the final properties of the main samples along with important considerations for using these samples for science. Our target ...selection criteria were developed while simultaneously optimizing the size distribution of the MaNGA integral field units (IFUs), the IFU allocation strategy, and the target density to produce a survey defined in terms of maximizing signal-to-noise ratio, spatial resolution, and sample size. Our selection strategy makes use of redshift limits that only depend on i-band absolute magnitude (Mi), or, for a small subset of our sample, Mi and color (NUV − i). Such a strategy ensures that all galaxies span the same range in angular size irrespective of luminosity and are therefore covered evenly by the adopted range of IFU sizes. We define three samples: the Primary and Secondary samples are selected to have a flat number density with respect to Mi and are targeted to have spectroscopic coverage to 1.5 and 2.5 effective radii (Re), respectively. The Color-Enhanced supplement increases the number of galaxies in the low-density regions of color-magnitude space by extending the redshift limits of the Primary sample in the appropriate color bins. The samples cover the stellar mass range and are sampled at median physical resolutions of 1.37 and 2.5 kpc for the Primary and Secondary samples, respectively. We provide weights that will statistically correct for our luminosity and color-dependent selection function and IFU allocation strategy, thus correcting the observed sample to a volume-limited sample.
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