The vast opportunities for biomaterials design and functionality enabled by mimicking nature continue to stretch the limits of imagination. As both biological understanding and engineering ...capabilities develop, more sophisticated biomedical materials can be synthesized that have multifaceted chemical, biological and physical characteristics designed to achieve specific therapeutic goals. Mimicry is being used in the design of polymers for biomedical applications that are required locally in tissues, systemically throughout the body, and at the interface with tissues.
The Posttraumatic Stress Disorder Checklist (PCL-5; Weathers et al., 2013) was recently revised to reflect the changed diagnostic criteria for posttraumatic stress disorder (PTSD) in the fifth ...edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013). We investigated the psychometric properties of PCL-5 scores in a large cohort (N = 912) of military service members seeking PTSD treatment while stationed in garrison. We examined the internal consistency, convergent and discriminant validity, and DSM-5 factor structure of PCL-5 scores, their sensitivity to clinical change relative to PTSD Symptom Scale-Interview (PSS-I; Foa, Riggs, Dancu, & Rothbaum, 1993) scores, and their diagnostic utility for predicting a PTSD diagnosis based on various measures and scoring rules. PCL-5 scores exhibited high internal consistency. There was strong agreement between the order of hypothesized and observed correlations among PCL-5 and criterion measure scores. The best-fitting structural model was a 7-factor hybrid model (Armour et al., 2015), which demonstrated closer fit than all other models evaluated, including the DSM-5 model. The PCL-5's sensitivity to clinical change, pre- to posttreatment, was comparable with that of the PSS-I. Optimally efficient cut scores for predicting PTSD diagnosis were consistent with prior research with service members (Hoge, Riviere, Wilk, Herrell, & Weathers, 2014). The results indicate that the PCL-5 is a psychometrically sound measure of DSM-5 PTSD symptoms that is useful for identifying provisional PTSD diagnostic status, quantifying PTSD symptom severity, and detecting clinical change over time in PTSD symptoms among service members seeking treatment.
Centrosomes are important cell organizers. They consist of a pair of centrioles surrounded by pericentriolar material (PCM) that expands dramatically during mitosis—a process termed centrosome ...maturation. How centrosomes mature remains mysterious. Here, we identify a domain in Drosophila Cnn that appears to be phosphorylated by Polo/Plk1 specifically at centrosomes during mitosis. The phosphorylation promotes the assembly of a Cnn scaffold around the centrioles that is in constant flux, with Cnn molecules recruited continuously around the centrioles as the scaffold spreads slowly outward. Mutations that block Cnn phosphorylation strongly inhibit scaffold assembly and centrosome maturation, whereas phosphomimicking mutations allow Cnn to multimerize in vitro and to spontaneously form cytoplasmic scaffolds in vivo that organize microtubules independently of centrosomes. We conclude that Polo/Plk1 initiates the phosphorylation-dependent assembly of a Cnn scaffold around centrioles that is essential for efficient centrosome maturation in flies.
Display omitted
•Plk1/Polo phosphorylates Cnn in vitro•Phosphorylation appears to occur specifically at centrosomes during mitosis•Phosphorylation allows Cnn to assemble into a dynamic scaffold around centrioles•Cnn scaffold assembly is required for proper centrosome maturation
Centrosomes, important cellular organizers, form when centrioles recruit pericentriolar material (PCM) around themselves. Conduit et al. shed light on PCM spreading/centrosome maturation during mitosis, showing that Polo kinase initiates phosphorylation-dependent assembly of PCM protein Cnn as a scaffold around centrioles. This scaffold then spreads outward to support an expanded PCM.
Pericarditis refers to the inflammation of the pericardial layers, resulting from a variety of stimuli triggering a stereotyped immune response, and characterized by chest pain associated often with ...peculiar electrocardiographic changes and, at times, accompanied by pericardial effusion. Acute pericarditis is generally self-limited and not life-threatening; yet, it may cause significant short-term disability, be complicated by either a large pericardial effusion or tamponade, and carry a significant risk of recurrence. The mainstay of treatment of pericarditis is represented by anti-inflammatory drugs. Anti-inflammatory treatments vary, however, in both effectiveness and side-effect profile. The objective of this review is to summarize the up-to-date management of acute and recurrent pericarditis.
VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.
Eighty ...bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A,
= 50) or pembrolizumab monotherapy (cohort B,
= 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.
Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% 95% confidence interval (CI), 16.3-41.5, median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant
, unmethylated
, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.
Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.
Infectious disease and group size: more than just a numbers game Nunn, Charles L.; Jordán, Ferenc; McCabe, Collin M. ...
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
05/2015, Letnik:
370, Številka:
1669
Journal Article
Recenzirano
Odprti dostop
Increased risk of infectious disease is assumed to be a major cost of group living, yet empirical evidence for this effect is mixed. We studied whether larger social groups are more subdivided ...structurally. If so, the social subdivisions that form in larger groups may act as barriers to the spread of infection, weakening the association between group size and infectious disease. To investigate this ‘social bottleneck’ hypothesis, we examined the association between group size and four network structure metrics in 43 vertebrate and invertebrate species. We focused on metrics involving modularity, clustering, distance and centralization. In a meta-analysis of intraspecific variation in social networks, modularity showed positive associations with network size, with a weaker but still positive effect in cross-species analyses. Network distance also showed a positive association with group size when using intraspecific variation. We then used a theoretical model to explore the effects of subgrouping relative to other effects that influence disease spread in socially structured populations. Outbreaks reached higher prevalence when groups were larger, but subgrouping reduced prevalence. Subgrouping also acted as a ‘brake’ on disease spread between groups. We suggest research directions to understand the conditions under which larger groups become more subdivided, and to devise new metrics that account for subgrouping when investigating the links between sociality and infectious disease risk.
Patients with or receiving potentially cardiotoxic treatment for cancer are susceptible to developing decrements in left ventricular mass, diastolic function, or systolic function. They may also ...experience valvular heart disease, pericardial disease, or intracardiac masses. Cardiovascular magnetic resonance may be used to assess cardiac anatomy, structure, and function and to characterize myocardial tissue. This combination of features facilitates the diagnosis and management of disease processes in patients with or those who have survived cancer. This report outlines and describes prior research involving cardiovascular magnetic resonance for assessing cardiovascular disease in patients with or previously having received treatment for cancer.
Display omitted
Treatment strategies involving immune-checkpoint blockade (ICB) have significantly improved survival for a subset of patients across a broad spectrum of advanced solid cancers. Despite this, ...considerable room for improving response rates remains. The tumor microenvironment (TME) is a hurdle to immune function, as the altered metabolism-related acidic microenvironment of solid tumors decreases immune activity. Here, we determined that expression of the hypoxia-induced, cell-surface pH regulatory enzyme carbonic anhydrase IX (CAIX) is associated with worse overall survival in a cohort of 449 patients with melanoma. We found that targeting CAIX with the small-molecule SLC-0111 reduced glycolytic metabolism of tumor cells and extracellular acidification, resulting in increased immune cell killing. SLC-0111 treatment in combination with immune-checkpoint inhibitors led to the sensitization of tumors to ICB, which led to an enhanced Th1 response, decreased tumor growth, and reduced metastasis. We identified that increased expression of
is associated with a reduced Th1 response in metastatic melanoma and basal-like breast cancer TCGA cohorts. These data suggest that targeting CAIX in the TME in combination with ICB is a potential therapeutic strategy for enhancing response and survival in patients with hypoxic solid malignancies.
PDF
