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Written exposure therapy (WET) is a brief, 5-session treatment for posttraumatic stress disorder (PTSD) that aims to improve access to care. WET has been demonstrated to be an efficacious PTSD treatment with lower rates of dropout and noninferior PTSD symptom outcome compared to cognitive processing therapy (CPT), a 12-session, gold-standard treatment. To identify predictors of treatment outcome in both WET and CPT, the current study examined the content of participants’ written narratives. Participants were 123 adults with PTSD who were randomly assigned to receive WET (n = 61) or CPT (n = 62). The CHANGE coding system was used to code all available narratives in both treatment conditions for variables hypothesized to be relevant to therapeutic change. Linear regression analyses revealed that in WET, higher average levels of accommodated (healthy, balanced) beliefs and an increase in accommodated beliefs from the first to the final impact statement predicted better PTSD symptom outcome at 12 weeks post-randomization. In CPT, higher average levels of overgeneralized and accommodated beliefs and lower levels of avoidance expressed in the narratives predicted better PTSD outcome. There were no significant predictors of outcome in analyses of change from the first to final impact statement in CPT. These findings add to research identifying predictors of change in WET and CPT by highlighting the importance of low avoidance in CPT and of trauma-related cognitions in both CPT and WET, even though WET is a brief written intervention that does not explicitly target cognitive change.

Identifying predictors of cognitive decline in old age helps us understand its mechanisms and identify those at greater risk. Here, we examined how cognitive change from ages 11 to 70 is associated with cognitive change at older ages (70 to 82 years) in the Lothian Birth Cohort 1936 longitudinal study ( N = 1,091 at recruitment). Using latent-growth-curve models, we estimated rates of change from ages 70 to 82 in general cognitive ability ( g) and in three cognitive domains: visuospatial, memory, and processing speed. We found that g accounted for 71.3% of interindividual change variance. Greater cognitive gain from ages 11 to 70 predicted slower decline in g over 12 subsequent years (β = 0.163, p = .001), independently of cognitive level in childhood and at age 70, and domain-specific change beyond g. These results contribute to the goal of identifying people at higher risk of age-related cognitive decline.

Neighborhood features have been postulated to be key predictors of frailty. However, evidence is mainly limited to cross-sectional studies without indication of long-term impact. We explored how neighborhood social deprivation (NSD) across the life course is associated with frailty and frailty progression among older Scottish adults. Participants (n = 323) were persons selected from the Lothian Birth Cohort 1936 with historical measures of NSD in childhood (1936–1955), young adulthood (1956–1975), and mid- to late adulthood (1976–2014). Frailty was measured 5 times between the ages of 70 and 82 years using the Frailty Index. Confounder-adjusted life-course models were assessed using a structured modeling approach; associations were estimated for frailty at baseline using linear regression and for frailty progression using linear mixed-effects models. Accumulation was the most appropriate life-course model for males; greater accumulated NSD was associated with higher frailty at baseline (b = 0.017, 95% confidence interval: 0.005, 0.029). Among females, the mid- to late adulthood sensitive period was the best-fitting life-course model, and higher NSD in this period was associated with widening frailty trajectories (b = 0.005, 95% confidence interval: 0.0004, 0.009). To our knowledge, this is the first investigation of the life-course impact of NSD on frailty in a cohort of older adults. Policies designed to address deprivation and inequalities across the full life course may support healthy aging.

OBJECTIVE: Colorectal cancer poses a significant threat to both psychological and physical health. This study examined relationships between anxiety and depressive symptoms with pain, fatigue, and inflammation among colorectal patients. METHODS: Colorectal cancer patients (n = 88, stages 0-IV) completed a laboratory-based study visit before undergoing adjuvant cancer treatment. Patients completed questionnaires assessing depressive, anxiety, pain, and fatigue symptoms. A blood sample was also collected to measure c-reactive protein (CRP). Analyses controlled for age, sex, cancer stage, body mass index (BMI), and menopause status. RESULTS: Multiple linear regression analyses showed colorectal patients with higher depressive and anxiety symptoms had greater pain, fatigue, and CRP (ps < 0.03). Approximately one-third of patients with clinically significant depressive (CESD >16) and anxiety symptoms (BAI >16) also had clinically-elevated levels of CRP (>3 mg/L) (ps = 0.02). CONCLUSION: These results extend findings from other cancer subgroups showing heightened symptom burden among patients with depression and anxiety. They also highlight the detrimental role that elevated anxiety and depressive symptoms may play in the physical and biological side effects associated with colorectal cancer.

Climate change has become the greatest threat to the world's ecosystems. Locating and managing areas that contribute to the survival of key species under climate change is critical for the persistence of ecosystems in the future. Here, we identify 'Climate Priority' sites as coral reefs exposed to relatively low levels of climate stress that will be more likely to persist in the future. We present the first analysis of uncertainty in climate change scenarios and models, along with multiple objectives, in a marine spatial planning exercise and offer a comprehensive approach to incorporating uncertainty and trade-offs in any ecosystem. We first described each site using environmental characteristics that are associated with a higher chance of persistence (larval connectivity, hurricane influence, and acute and chronic temperature conditions in the past and the future). Future temperature increases were assessed using downscaled data under four different climate scenarios (SSP1 2.6, SSP2 4.5, SSP3 7.0 and SSP5 8.5) and 57 model runs. We then prioritized sites for intervention (conservation, improved management or restoration) using robust decision-making approaches that select sites that will have a benign climate under most climate scenarios and models. The modelling work is novel because it solves two important issues. (1) It considers trade-offs between multiple planning objectives explicitly through Pareto analyses and (2) It makes use of all the uncertainty around future climate change. Priority intervention sites identified by the model were verified and refined through local stakeholder engagement including assessments of local threats, ecological conditions and government priorities. The workflow is presented for the Insular Caribbean and Florida, and at the national level for Cuba, Jamaica, Dominican Republic and Haiti. Our approach allows managers to consider uncertainty and multiple objectives for climate-smart spatial management in coral reefs or any ecosystem across the globe.

Inflammation and ageing-related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood-based patterns relate to patterns within the brain, and how each associates with central cellular profiles. In this study, we profiled DNA methylation in both the blood and in five post-mortem brain regions (BA17, BA20/21, BA24, BA46 and hippocampus) in 14 individuals from the Lothian Birth Cohort 1936. Microglial burdens were additionally quantified in the same brain regions. DNA methylation signatures of five epigenetic ageing biomarkers (‘epigenetic clocks’), and two inflammatory biomarkers (DNA methylation proxies for C-reactive protein and interleukin-6) were compared across tissues and regions. Divergent correlations between the inflammation and ageing signatures in the blood and brain were identified, depending on region assessed. Four out of the five assessed epigenetic age acceleration measures were found to be highest in the hippocampus (β range=0.83-1.14, p≤0.02). The inflammation-related DNA methylation signatures showed no clear variation across brain regions. Reactive microglial burdens were found to be highest in the hippocampus (β=1.32, p=5×10-4); however, the only association identified between the blood- and brain-based methylation signatures and microglia was a significant positive association with acceleration of one epigenetic clock (termed DNAm PhenoAge) averaged over all five brain regions (β=0.40, p=0.002). This work highlights a potential vulnerability of the hippocampus to epigenetic ageing and provides preliminary evidence of a relationship between DNA methylation signatures in the brain and differences in microglial burdens.

In the current study, we examined the degree to which sudden gains (large, rapid, and stable symptom reduction in a one-session interval) predicted treatment outcome in adults randomized to two different trauma-focused treatments. Adults diagnosed with PTSD were randomized to either written exposure therapy (WET; n = 63), a brief, exposure-based treatment for posttraumatic stress disorder (PTSD), or the more time-intensive Cognitive Processing Therapy (CPT; n = 63). Findings showed that 20.6% of participants who received WET and 17.5% of participants who received CPT experienced sudden gains. Sudden gains occurred earlier in WET (M session = 2.69, SD = 0.75) than in CPT (M session = 5.64, SD = 3.01). However, there were no treatment condition differences in the magnitude of the sudden gains. Treatment outcomes were significantly better for those who experienced sudden gains compared with those who did not, regardless of treatment assignment. Exploratory analyses of participants’ trauma narratives revealed that expressing more negative emotion predicted the occurrence of sudden gains in both treatment conditions. Negative beliefs about the self and others did not predict sudden gains. The findings are discussed in terms of how they may help identify individual early response patterns that predict outcomes in trauma-focused treatments.

A panel of biomarkers may improve predictive performance over individual markers. Although many biomarker panels have been described for ovarian cancer, few studies used prediagnostic samples to assess the potential of the panels for early detection. We conducted a multisite systematic evaluation of biomarker panels using prediagnostic serum samples from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening trial.Using a nested case–control design, levels of 28 biomarkers were measured laboratory-blinded in 118 serum samples obtained before cancer diagnosis and 951 serum samples from matched controls. Five predictive models, each containing 6 to 8 biomarkers, were evaluated according to a predetermined analysis plan. Three sequential analyses were conducted: blinded validation of previously established models (step 1); simultaneous split-sample discovery and validation of models (step 2); and exploratory discovery of new models (step 3). Sensitivity, specificity, sensitivity at 98% specificity, and AUC were computed for the models and CA125 alone among 67 cases diagnosed within one year of blood draw and 476 matched controls. In step 1, one model showed comparable performance to CA125, with sensitivity, specificity, and AUC at 69.2%, 96.6%, and 0.892, respectively. Remaining models had poorer performance than CA125 alone. In step 2, we observed a similar pattern. In step 3, a model derived from all 28 markers failed to show improvement over CA125.Thus, biomarker panels discovered in diagnostic samples may not validate in prediagnostic samples; utilizing prediagnostic samples for discovery may be helpful in developing validated early detection panels. Cancer Prev Res; 4(3); 375–83. ©2011 AACR.

Perspectives on This Article from A Framework for Evaluating Biomarkers for Early Detection: Validation of Biomarker Panels for Ovarian Cancer

Supplementary Materials from A Framework for Evaluating Biomarkers for Early Detection: Validation of Biomarker Panels for Ovarian Cancer

The activation and differentiation of cancer-associated fibroblasts (CAF) are involved in tumor progression. Here, we show that the tumor-promoting lipid mediator prostaglandin E2 (PGE2) plays a paradoxical role in CAF activation and tumor progression. Restricting PGE2 signaling via knockout of microsomal prostaglandin E synthase-1 (mPGES-1) in PyMT mice or of the prostanoid E receptor 3 (EP3) in CAFs stunted mammary carcinoma growth associated with strong CAF proliferation. CAF proliferation upon EP3 inhibition required p38 MAPK signaling. Mechanistically, TGFβ–activated kinase-like protein (TAK1L), which was identified as a negative regulator of p38 MAPK activation, was decreased following ablation of mPGES-1 or EP3. In contrast with its effects on primary tumor growth, disruption of PGE2 signaling in CAFs induced epithelial-to-mesenchymal transition in cancer organoids and promoted metastasis in mice. Moreover, TAK1L expression in CAFs was associated with decreased CAF activation, reduced metastasis, and prolonged survival in human breast cancer. These data characterize a new pathway of regulating inflammatory CAF activation, which affects breast cancer progression.Significance:The inflammatory lipid prostaglandin E2 suppresses cancer-associated fibroblast expansion and activation to limit primary mammary tumor growth while promoting metastasis.

Supplementary Data Tables S1-S8 - Table S1. Details of all antibodies (A) and primer sequences (B) used in this study, Table S2. Differentially expressed genes of tumor organoids cultured in vitro, Table S3. Differentially expressed genes of FACS-purified tumor cells after organoid transplantation, Table S4. Differentially expressed genes of FACS-purified CAFs after organoid transplantation, Table S5. Differentially expressed genes of mouse fibroblasts cultured in vitro, Table S6. Summary of GSEA results, Table S7. iCAF and myCAF signatures, Table S8. Differentially expressed mouse genes identified in human CRC organoids upon xenotransplantation.

In this file we provide additional methods for the described procedures including organoid transduction/transgenesis, biological image processing and image quantification. We provide in-depth information on the RNA sequencing protocol used and describe details of subsequent bioinformatic workflows including 'NicheNet' analysis. Also we provide details on the in silico analysis of CRC patient data and Kaplan-Meier analysis.

Supplementary Figure from Disruption of Prostaglandin E2 Signaling in Cancer-Associated Fibroblasts Limits Mammary Carcinoma Growth but Promotes Metastasis

Supplementary Table from Disruption of Prostaglandin E2 Signaling in Cancer-Associated Fibroblasts Limits Mammary Carcinoma Growth but Promotes Metastasis

Figure S1. Generation of engineered tumor organoids, Figure S2. Characterization of Sfrp1-expressing organoids in vitro and upon transplantation, Figure S3. Characterization of APTK organoids upon transplantation, Figure S4. Characterization of Dkk1-expressing organoids in vitro and upon transplantation, Figure S5. Immunohistology of tumors after transplantation of organoids in NSG and Bl/6 mice, Figure S6. Study of tumor growth upon xenotransplantation of human CRC organoids, Figure S7. Analysis of stromal gene expression in tumors after xenotransplantation, Figure S8. Co-culture model to study the influence of fibroblast differentiation on tumor organoids, Figure S9. 'NicheNet' analysis for identification of candidate mediators of the stromal crosstalk, Figure S10. Phenotypic analysis of mice after fibroblast-specific deletion of β-catenin, Figure S11. Histologic characterization of tumor cell invasion after stromal Wnt inhibition.

Revised Supplementary Materials and Methods and Supplementary Figure Legends

Supplementary Figures S1-S9. Figure S1. Functional evaluation of the GpNLuc LumiFluor. Figure S2. In vitro characterization of FACS sorted mouse Em-Myc lymphoma and human non-small cell lung cancer (NSCLC) cells. Figure S3. Temporal development of A549 NSCLC xenograft tumors expressing GpNLuc or GpNLuc and the tumor suppressor LKB1. Figure S4. Detection of spontaneous lymph node metastasis from primary lung tumors. Figure S5. In vitro and in vivo characterization of independently derived E?-Myc lymphoma cells stably expressing GpNLuc. Figure S6. Bioluminescence imaging of E?-Myc lymphoma-GpNLuc allografts. Figure S7. A, in vivo dose-response kinetics of GpNLuc signal strength. Figure S8. Quantification of in vivo bioluminescence imaging and confirmation ex vivo. Figure S9. Flow cytometric analysis of inducibly expressed fluorescent proteins in stable lymphoma cell lines.

Living Image DLIT 3D reconstruction of Emu-Myc Lymphoma-GpNLuc orthotopic allograft transplant.

Living Image DLIT 3D reconstruction of A549-GpNLuc orthotopic xenograft transplant.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

BACKGROUND: Neuropsychiatric symptoms could form part of an early cerebral small vessel disease prodrome that is detectable before stroke or dementia onset. We aimed to identify whether apathy, depression, anxiety, and subjective memory complaints associate with longitudinal white matter hyperintensity (WMH) progression. METHODS: Community-dwelling older adults from the observational Lothian Birth Cohort 1936 attended three visits at mean ages 73, 76, and 79 years, repeating MRI, Mini-Mental State Examination, neuropsychiatric (Dimensional Apathy Scale, Hospital Anxiety and Depression Scale), and subjective memory symptoms. We ran regression and mixed-effects models for symptoms and normalised WMH volumes (cube root of WMH:ICV × 10). RESULTS: At age 73, 76, and 79, m = 672, n = 476, and n = 382 participants attended MRI respectively. Worse apathy at age 79 was associated with WMH volume increase (β = 0.27, p = 0.04) in the preceding 6 years. A 1SD increase in apathy score at age 79 associated with a 0.17 increase in WMH (β = 0.17 normalised WMH percent ICV, p = 0.009). In apathy subscales, executive (β = 0.13, p = 0.05) and emotional (β = 0.13, p = 0.04) scores associated with increasing WMH more than initiation scores (β = 0.11, p = 0.08). Increasing WMH also associated with age (β = 0.40, p = 0.002) but not higher depression (β = -0.01, p = 0.78), anxiety (β = 0.05, p = 0.13) scores, or subjective memory complaints (β = 1.12, p = 0.75). CONCLUSIONS: Apathy independently associates with preceding longitudinal WMH progression, while depression, anxiety, and subjective memory complaints do not. Patients with apathy should be considered for enrolment to small vessel disease trials.

Background To measure the association between individual life-course socioeconomic position (SEP) and hearing aid use, we examined childhood and adulthood socioeconomic variables collected at the Atherosclerosis Risk in Communities (ARIC) study baseline visit (1987–1989)/Life Course Socioeconomic Status study (2001–2002) and hearing aid use data collected at visit 6 (2016–2017). Methods ARIC is a prospective cohort study of older adults (45–64 years) recruited from 4 U.S. communities. This analysis included a subset of 2 470 participants with hearing loss at visit 6 (≥25 decibels hearing level [dB HL] better-ear) with complete hearing aid use data. Childhood SEP variables included parental education, parental occupation, and parental home ownership. Young and older adulthood SEP variables included income, education, occupation, and home ownership. Each life epoch was assigned a score ranging from 0 to 5 and then summed to calculate the individual cumulative SEP score. Multivariable-adjusted logistic regression was used to estimate the association between individual cumulative SEP and hearing aid use. Missing SEP scores were imputed for participants with incomplete socioeconomic data. Results Of the 2 470 participants in the analytic cohort (median [interquartile interval] age 79.9 [76.7–84.0], 1 330 [53.8%] women, 450 [18.2%] Black), 685 (27.7%) participants reported hearing aid use. Higher cumulative SEP was positively associated with hearing aid use (odds ratio [OR] = 1.09, 95% confidence interval [CI]: 1.04–1.14), and slightly stronger for childhood (OR = 1.09, 95% CI: 1.00–1.20) than older adulthood SEP score (OR = 1.06, 95% CI: 0.95–1.18). Conclusions In this community-based cohort of older adults with hearing loss, higher individual life-course SEP was positively associated with hearing aid use.

Vertebrate brains have a dual structure, composed of (i) axons that can be well-captured with graph-theoretical methods and (ii) axons that form a dense matrix in which neurons with precise connections operate. A core part of this matrix is formed by axons (fibers) that store and release 5-hydroxytryptamine (5-HT, serotonin), an ancient neurotransmitter that supports neuroplasticity and has profound implications for mental health. The self-organization of the serotonergic matrix is not well understood, despite recent advances in experimental and theoretical approaches. In particular, individual serotonergic axons produce highly stochastic trajectories, fundamental to the construction of regional fiber densities, but further advances in predictive computer simulations require more accurate experimental information. This study examined single serotonergic axons in culture systems (co-cultures and monolayers), by using a set of complementary high-resolution methods: confocal microscopy, holotomography (refractive index-based live imaging), and super-resolution (STED) microscopy. It shows that serotonergic axon walks in neural tissue may strongly reflect the stochastic geometry of this tissue and it also provides new insights into the morphology and branching properties of serotonergic axons. The proposed experimental platform can support next-generation analyses of the serotonergic matrix, including seamless integration with supercomputing approaches.

Diverse compounds target the Plasmodium falciparum Na+ pump PfATP4, with cipargamin and (+)-SJ733 the most clinically-advanced. In a recent clinical trial for cipargamin, recrudescent parasites emerged, with most having a G358S mutation in PfATP4. Here, we show that PfATP4G358S parasites can withstand micromolar concentrations of cipargamin and (+)-SJ733, while remaining susceptible to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation in Toxoplasma gondii ATP4, decrease the sensitivity of ATP4 to inhibition by cipargamin and (+)-SJ733, thereby protecting parasites from disruption of Na+ regulation. The G358S mutation reduces the affinity of PfATP4 for Na+ and is associated with an increase in the parasite’s resting cytosolic [Na+]. However, no defect in parasite growth or transmissibility is observed. Our findings suggest that PfATP4 inhibitors in clinical development should be tested against PfATP4G358S parasites, and that their combination with unrelated antimalarials may mitigate against resistance development.

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer in adults. When ccRCC is localized to the kidney, surgical resection or ablation of the tumor is often curative. However, in the metastatic setting, ccRCC remains a highly lethal disease. Here we use fresh patient samples that include treatment-naive primary tumor tissue, matched adjacent normal kidney tissue, as well as tumor samples collected from patients with bone metastases. Single-cell transcriptomic analysis of tumor cells from the primary tumors reveals a distinct transcriptional signature that is predictive of metastatic potential and patient survival. Analysis of supporting stromal cells within the tumor environment demonstrates vascular remodeling within the endothelial cells. An in silico cell-to-cell interaction analysis highlights the CXCL9/CXCL10-CXCR3 axis and the CD70-CD27 axis as potential therapeutic targets. Our findings provide biological insights into the interplay between tumor cells and the ccRCC microenvironment.

INTRODUCTION It remains unclear why age increases risk of Alzheimer’s disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing. METHODS We examined post-mortem brain from people in mid-life (n=15), healthy ageing with either maintained cognition (n=8) or lifetime cognitive decline (n=7), and Alzheimer’s disease (n=13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell-derived neurons were challenged with Alzheimer’s brain homogenate. RESULTS Synaptic pathology increased, and expression of genes involved in synaptic signalling decreased between mid-life, healthy ageing and Alzheimer’s. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signalling genes compared to people with cognitive decline. DISCUSSION Efficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing.

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and incidence rates are continuing to rise globally. HNSCC patient prognosis is closely related to the occurrence of tumor metastases, and collagen within the tumor microenvironment (TME) plays a key role in this process. Lysyl hydroxylase 2 (LH2), encoded by the Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 2 (PLOD2) gene, catalyzes hydroxylation of telopeptidyl lysine (Lys) residues of fibrillar collagens which then undergo subsequent modifications to form stable intermolecular cross-links that change the biomechanical properties (i.e. quality) of the TME. While LH2-catalyzed collagen modification has been implicated in driving tumor progression and metastasis in diverse cancers, little is known about its role in HNSCC progression. Thus, using gain- and loss-of-function studies, we examined the effects of LH2 expression levels on collagen cross-linking and cell behavior in vitro and in vivo using a tractable bioluminescent imaging-based orthotopic xenograft model. We found that LH2 overexpression dramatically increases HNSCC cell migratory and invasive abilities in vitro and that LH2-driven changes in collagen cross-linking robustly induces metastasis in vivo. Specifically, the amount of LH2-mediated collagen cross-links increased significantly with PLOD2 overexpression, without affecting the total quantity of collagen cross-links. Conversely, LH2 knockdown significantly blunted HNSCC cells invasive capacity in vitro and metastatic potential in vivo. Thus, regardless of the total “quantity” of collagen crosslinks, it is the “quality” of these cross-links that is the key driver of HNSCC tumor metastatic dissemination. These data implicate LH2 as a key regulator of HNSCC tumor invasion and metastasis by modulating collagen cross-link quality and suggest that therapeutic strategies targeting LH2-mediated collagen cross-linking in the TME may be effective in controlling tumor progression and improving disease outcomes.

BackgroundPrevious results have been mixed regarding the role of the apolipoprotein E e4 (APOE e4) allele in later-life depression: some studies note that carriers experience greater symptoms and increased risk while others find no such association. However, there are few prospective, population-based studies of the APOE e4-depression association and fewer that examine depressive symptom trajectory and depression risk longitudinally. We examined the association between APOE e4 allele status and longitudinal change in depressive symptoms and depression risk in later-life, over a 12-year follow-up period.MethodsWe used data from 690 participants of the Lothian Birth Cohort 1936 who took part in the Scottish Mental Survey 1947 (aged 11) and were followed-up in later-life over five waves from 2004 to 2019 (aged 70–82). We used APOE e4 allele status to predict longitudinal change in depressive symptom scores and risk of depression (defined by a symptom score threshold or use of depression-related medication). Models were adjusted for sex, childhood cognitive ability, childhood social class, education, adult social class, smoking status and functional limitations at baseline.ResultsDepressive symptom scores increased with age. Once adjusted for covariates, APOE e4 allele status did not significantly predict symptom score trajectories or depression risk. Greater functional limitations at baseline significantly predicted poorer symptom score trajectories and increased depression risk (defined by medications). APOE e4 allele status did not significantly moderate the contribution of sex, education or functional limitations.ConclusionsThere was no evidence that APOE e4 carriers experience an increased risk for later-life depression.

Trigeminal neuralgia, historically dubbed the “suicide disease,” is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)–approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

Vertebrate brains have a dual structure, composed of (

Radiobiology research in rectal cancer has been limited to cell lines, patient-derived organoids (PDOs), or xenografts. Here, we describe a protocol which recapitulates more efficiently the complex contributions of the tumor microenvironment. This approach establishes a preclinical mouse model of rectal cancer by intrarectal transplantation of genetically modified organoids into immunocompetent mice followed by precise image-guided radiotherapy (IGRT) of organoid-induced tumors. This model represents a useful platform to study the cellular and molecular determinants of therapy resistance in rectal cancer. For complete details on the use and execution of this protocol, please refer to Nicolas et al. (2022).

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer in adults. When ccRCC is localized to the kidney, surgical resection or ablation of the tumor is often curative. However, in the metastatic setting, ccRCC remains a highly lethal disease. Here we take advantage of fresh patient samples that include treatment-naive primary tumor tissue, matched adjacent normal kidney tissue, as well as tumor samples collected from patients with bone metastases. Single-cell transcriptomic analysis of tumor cells from the primary tumors revealed a distinct transcriptional signature that was predictive of metastatic potential and patient survival. Analysis of supporting stromal cells within the tumor environment demonstrated vascular remodeling within the endothelial cells and a proliferative signature within the fibroblasts that was associated with poor survival. An in silico cell-to-cell interaction analysis highlighted the CXCL9/CXCL10-CXCR3 axis and the CD70-CD27 axis as potential therapeutic targets. Our findings provide biological insights into the interplay between tumor cells and the ccRCC microenvironment.

Diverse compounds target the Plasmodium falciparum Na

Social monogamy is a reproductive strategy characterized by pair living and defense of a common territory. Pair bonding, sometimes displayed by monogamous species, is an affective construct that includes preference for a specific partner, distress upon separation, and the ability of the partner to buffer against stress. Many seahorse species show a monogamous social structure in the wild, but their pair bond has not been well studied. We examined the gene expression of lined seahorses (Hippocampus erectus) during and after the process of pairing in the laboratory as well as color change (luminance), a potential form of social communication and behavioral synchrony between pair mates. When a seahorse of either sex was interacting with its pair mate, their changes in luminance ("brightness") were correlated and larger than when interacting with an opposite-sex stranger. At the conclusion of testing, subjects were euthanized, RNA was extracted from whole brains and analyzed via RNA sequencing. Changes in gene expression in paired males versus those that were unpaired included processes governing metabolic activity, hormones and cilia. Perhaps most interesting is the overlap in gene expression change induced by pairing in both male seahorses and male prairie voles, including components of hormone systems regulating reproduction. Because of our limited sample size, we consider our results and interpretations to be preliminary, and prompts for further exploration. Future studies will expand upon these findings and investigate the neuroendocrine and genetic basis of these behaviors.

The discovery of new antimalarial medicines with novel mechanisms of action is key to combating the problem of increasing resistance to our frontline treatments. The Open Source Malaria (OSM) consortium has been developing compounds ("Series 4") that have potent activity against Plasmodium falciparum in vitro and in vivo and that have been suggested to act through the inhibition of PfATP4, an essential membrane ion pump that regulates the parasite’s intracellular Na+ concentration. The structure of PfATP4 is yet to be determined. In the absence of structural information about this target, a public competition was created to develop a model that would allow the prediction of anti-PfATP4 activity among Series 4 compounds, thereby reducing project costs associated with the unnecessary synthesis of inactive compounds.In the first round, in 2016, six participants used the open data collated by OSM to develop moderately predictive models using diverse methods. Notably, all submitted models were available to all other participants in real time. Since then further bioactivity data have been acquired and machine learning methods have rapidly developed, so a second round of the competition was undertaken, in 2019, again with freely-donated models that other participants could see. The best-performing models from this second round were used to predict novel inhibitory molecules, of which several were synthesised and evaluated against the parasite. One such compound, containing a motif that the human chemists familiar with this series would have dismissed as ill-advised, was active. The project demonstrated the abilities of new machine learning methods in the prediction of active compounds where there is no biological target structure, frequently the central problem in phenotypic drug discovery. Since all data and participant interactions remain in the public domain, this research project “lives” and may be improved by others.

In this study, we examined processes of change in trauma-focused cognitive behavioral therapy (TF-CBT) delivered to a community sample of 81 youths. Emotional processing theory (EPT) is used as an organizational framework. EPT highlights activating and changing pathological trauma-related responses and increasing adaptive responses across cognitive, emotional, behavioral, and physiological domains. We coded sessions during the trauma-narration and -processing phase of TF-CBT to examine the extent to which pathological and adaptive trauma-related responses were activated across domains. Higher scores indicate that more domains (range = 0–4) were activated at a threshold of moderate to high intensity. Curvilinear change (inverted U, increase then decrease) in multimodal negative response scores across sessions predicted improvement in internalizing symptoms and symptoms of posttraumatic stress disorder after treatment. Linear increases in multimodal positive responses predicted improvement in externalizing symptoms. Findings suggest value in activating and changing both pathological and adaptive trauma responses across multiple domains and examining nonlinear patterns of change.

Climate-driven changes to environmental conditions are driving severe declines of coral reef ecosystems. Current climate vulnerability estimates commonly focus on ocean warming and typically overlook ecological responses or use broad proxies to represent responses, leading to management decisions based on incomplete views of coral reef futures. We explore four underdeveloped aspects of climate vulnerability assessments and make the following recommendations: (1) use climate projections based on changes in global warming as future scenarios in place of the more common emissions scenarios; (2) include available high-resolution projections for climate variables in addition to thermal stress; (3) combine projected climate stressors accounting for uncertainty in future outcomes; and (4) quantitatively assess historical and project future ecological sensitivity and adaptive capacity of corals to multiple stressors. We demonstrate how this framework can be used to reduce uncertainty in projected climate vulnerability and facilitate targeted investment in managing reefs most likely to endure climatic disturbances.

Supplemental Digital Content is available in the text., Background: The Lothian Birth Cohort 1936 (LBC1936) is a highly phenotyped longitudinal study of cognitive and brain ageing. Given its substantial clinical importance, we derived an indicator of mild cognitive impairment (MCI) and amnestic and nonamnestic subtypes at 3 time points. Methods: MCI status was derived at 3 waves of the LBC1936 at ages 76 (n=567), 79 (n=441), and 82 years (n=341). A general MCI category was derived as well as amnestic MCI (aMCI) and nonamnestic MCI (naMCI). A comparison was made between MCI derivations using normative data from the LBC1936 cohort versus the general UK population. Results: MCI rates showed a proportional increase at each wave between 76 and 82 years from 15% to 18%. Rates of MCI subtypes also showed a proportional increase over time: aMCI 4% to 6%; naMCI 12% to 16%. Higher rates of MCI were found when using the LBC1936 normative data to derive MCI classification rather than UK-wide norms. Conclusions: We found that MCI and aMCI rates in the LBC1936 were consistent with previous research. However, naMCI rates were higher than expected. Future LBC1936 research should assess the predictive factors associated with MCI prevalence to validate previous findings and identify novel risk factors.

Objective Breast cancer survivors who experience psychological and physical symptoms after treatment have an increased risk for comorbid disease development, reduced quality of life, and premature mortality. Identifying factors that reduce or exacerbate their symptoms may enhance their long-term health and physical functioning. This study examined how survivors' marital status and marital satisfaction-key health determinants-impacted their psychological and physical health trajectories to understand when, and for whom, marriage offers health benefits. Methods Breast cancer survivors (n=209, stages 0-IIIC) completed a baseline visit before treatment and two follow-up visits 6 and 18 months after treatment ended. Women completed questionnaires assessing their marital status and satisfaction when applicable, as well as their psychological (depressive symptoms, stress) and physical (fatigue, pain) health at each visit. Results Married women-both those in satisfying and dissatisfying marriages-experienced improvements in their depressive symptoms, stress, and fatigue from pretreatment to 6- and 18-months posttreatment. Unmarried (i.e., single, divorced/separated, or widowed) women's depressive symptoms, stress, fatigue, and pain did not change over time, instead remaining elevated 6 and 18 months after treatment ended. Women in satisfying marriages also had fewer psychological and physical symptoms after treatment than those who were unmarried or in dissatisfying marriages. Conclusions Although marriage was associated with improved psychological and physical health, the gains were most notable when survivors' marriages were satisfying. Thus, the quality of survivors' marriages, rather than the marriage itself, provided the most benefits to their psychological and physical health. This article is protected by copyright. All rights reserved.

Tumor progression is recognized as a result of an evolving cross-talk between tumor cells and their surrounding nontransformed stroma. Although Wnt signaling has been intensively studied in colorectal cancer, it remains unclear whether activity in the tumor-associated stroma contributes to malignancy. To specifically interfere with stromal signals, we generated Wnt-independent tumor organoids that secrete the Wnt antagonist Sfrp1. Subcutaneous transplantation into immunocompetent as well as immunodeficient mice resulted in a strong reduction of tumor growth. Histologic and transcriptomic analyses revealed that Sfrp1 induced an epithelial–mesenchymal transition (EMT) phenotype in tumor cells without affecting tumor-intrinsic Wnt signaling, suggesting involvement of nonimmune stromal cells. Blockage of canonical signaling using Sfrp1, Dkk1, or fibroblast-specific genetic ablation of β-catenin strongly decreased the number of cancer-associated myofibroblasts (myCAF). Wnt activity in CAFs was linked with distinct subtypes, where low and high levels induced an inflammatory-like CAF (iCAF) subtype or contractile myCAFs, respectively. Coculture of tumor organoids with iCAFs resulted in significant upregulation of EMT markers, while myCAFs reverted this phenotype. In summary, we show that tumor growth and malignancy are differentially regulated via distinct fibroblast subtypes under the influence of juxtacrine Wnt signals. Significance: This study provides evidence for Wnt-induced functional diversity of colorectal cancer–associated fibroblasts, representing a non-cell autonomous mechanism for colon cancer progression.

The electromagnetically actuated MEMS $\mu $ Hammer was used to evaluate the effects of mechanical impact on the membrane permeability, apoptotic induction, and proliferation of human neural progenitor cells. The $\mu $ Hammer enabled application of two strain magnitudes ( $\varepsilon = 42{\%}$ and 69%) for two strain durations ( $10~\mu \text{s}$ and $100~\mu \text{s}$ ) to individual cells at unprecedented high strain rates ( $\dot {\varepsilon }\mathrm { } \boldsymbol {\sim } {200\times }10^{3}\,\,\text{s}^{-1}$ ) and high throughput (up to 36,000 cells/min). This enables large numbers of cells to be analyzed and the effects of strain magnitude and duration to be decoupled. The magnitude of applied strain significantly affected cell membrane permeability shortly after compression, whereas the duration of strain significantly increased early apoptosis in cells 24 hours after compression. Strain magnitude also significantly affected cell quantity over a 70-hour period, despite no significant difference in the cell doubling times. Understanding the relationship between mechanical strain and cellular response will ultimately lead to improved diagnostics and treatment of high strain rate mechanical injury conditions such as Traumatic Brain Injury. [2020-0171]

Objective This study aimed to identify differential patient change processes and mechanisms associated with long-term outcome in exposure-based cognitive therapy (EBCT) and cognitive-behavioral therapy (CBT) for depression. Method We drew on a randomized controlled trial in which 149 patients were randomly assigned to either EBCT or CBT, with the treatments showing comparable efficacy at 12-month follow-up (grosse Holtforth et al., 2019). Based on Doss's (2004) 4-step model of psychotherapy change and using sequential multilevel structural equation models, we tested putative theory-based change processes and mechanisms for both treatments. Specifically, we examined emotional processing and cognitive restructuring during treatment as hypothesized change processes of EBCT and CBT, respectively. Furthermore, as potential change mechanisms during follow-up, we examined theory-relevant mechanisms for each treatment, preselected via multilevel models. Results Although the full serial mediational pathways were not supported, EBCT fostered greater during-treatment increases in emotional processing and higher self-efficacy during follow-up than CBT, both of which associated with better long-term depression outcome. Unexpectedly, cognitive restructuring change did not differ between EBCT and CBT. Across both CBT and EBCT, greater during-treatment increases in cognitive restructuring related to lower cognitive-behavioral avoidance and greater self-efficacy across follow-up, which associated with lower long-term depression. Conclusions Results suggest that therapists might improve long-term depression outcome by fostering both emotional processing (via emotion-focused techniques as included in EBCT) and cognitive restructuring (by using general CBT techniques included in both treatments), which operate either directly or through varied treatment-common mechanisms (e.g., greater self-efficacy and reduced cognitive-behavioral avoidance). (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Cancer vaccine development has proven challenging with the exception of some virally induced cancers for which prophylactic vaccines exist. Currently, there is only one FDA approved vaccine for the treatment of prostate cancer and as such prostate cancer continues to present a significant unmet medical need. In this study, we examine the effectiveness of a therapeutic cancer vaccine that combines the ISCOMATRIX™ adjuvant (ISCOMATRIX) with the Toll-like receptor 3 agonist, polyinosinic–polycytidylic acid (Poly I:C), and Flt3L, FMS-like tyrosine kinase 3 ligand. We employed the TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) model of prostate cancer and the self-protein mPAP (prostatic acid phosphatase) as the tumor antigen. ISCOMATRIX™–mPAP–Poly I:C–Flt3L was delivered in a therapeutic prime-boost regime that was consistently able to achieve complete tumor regression in 60% of animals treated and these tumor-free animals were protected upon rechallenge. Investigations into the underlying immunological mechanisms contributing to the effectiveness of this vaccine identified that both innate and adaptive responses are elicited and required. NK cells, CD4+ T cells and interferon-γ were all found to be critical for tumor control while tumor infiltrating CD8+ T cells became disabled by an immunosuppressive microenvironment. There is potential for broader application of this cancer vaccine, as we have been able to demonstrate effectiveness in two additional cancer models; melanoma (B16-OVA) and a model of B cell lymphoma (Eµ-myc-GFP-OVA). Electronic supplementary material The online version of this article (10.1007/s00262-020-02597-6) contains supplementary material, which is available to authorized users.

BackgroundHearing loss affects over 1.3 billion individuals worldwide, with the greatest burden among adults. Little is known regarding the association between adult-onset hearing loss and employment.MethodsSeven databases (PubMed, Embase, Cochrane Library, ABI/Inform Collection, Business Source Ultimate, Web of Science and Scopus) were searched through to October 2018. The key word terms used related to hearing loss and employment, excluding paediatric or congenital hearing loss and deaf or culturally deaf populations.ResultsThe initial search resulted in 13 144 articles. A total of 7494 articles underwent title and abstract screening, and 243 underwent full-text review. Twenty-five articles met the inclusion criteria. Studies were set in 10 predominantly high-income countries. Seven of the 25 studies analysed regionally or nationally representative datasets and controlled for key variables. Six of these seven studies reported associations between hearing loss and employment.ConclusionThe highest quality studies currently available indicate that adult-onset hearing loss is associated with unemployment. However, considerable heterogeneity exists, and more rigorous studies that include low- and middle-income countries are needed.

Ferrihydrite (Fh) is a major Fe(III)-(oxyhydr)oxide nanomineral distinguished by its poor crystallinity and thermodynamic metastability. While it is well known that in suboxic conditions aqueous Fe(II) rapidly catalyzes Fh transformation to more stable crystalline Fe(III) phases such as lepidocrocite (Lp) and goethite (Gt), because of the low solubility of Fe(III) the mass transfer pathways enabling these rapid transformations have remained unclear for decades. Here, using a selective extractant, we isolated and quantified a critical labile Fe(III) species, one that is more reactive than Fe(III) in Fh, formed by the oxidation of aqueous Fe(II) on the Fh surface. Experiments that compared time-dependent concentrations of solid-associated Fe(II) and this labile Fe(III) against the kinetics of phase transformation showed that its accumulation is directly related to Lp/Gt formation in a manner consistent with the classical nucleation theory. 57Fe isotope tracer experiments confirm the oxidized Fe(II) origin of labile Fe(III). The transformation pathway as well as the accelerating effect of Fe(II) can now all be explained on a unified basis of the kinetics of Fe(III) olation and oxolation reactions necessary to nucleate and sustain growth of Lp/Gt products, rates of which are greatly accelerated by labile Fe(III).

Significance Cocaine is a monoamine transport inhibitor. Current models attributing pharmacologic actions of cocaine to inhibiting the activity of the amine transporters alone failed to translate to the clinic. Cocaine inhibition of the dopamine, serotonin, and norepinephrine transporters is relatively weak, suggesting that blockade of the amine transporters alone cannot account for the actions of cocaine, especially at low doses. There is evidence for significantly more potent actions of cocaine, suggesting the existence of a high-affinity receptor(s) for the drug. Identifying and characterizing such receptors will deepen our understanding of cocaine pharmacologic actions and pave the way for therapeutic development. Here we identify a high-affinity cocaine binding site associated with BASP1 that is involved in mediating the drug’s psychotropic actions.