Unrestrained cleavage of Roquin-1 by MALT1 induces spontaneous T cell activation and the development of autoimmunity.

Constitutive activation of the MALT1 paracaspase in conventional T cells of Malt1TBM/TBM (TRAF6 Binding Mutant = TBM) mice causes fatal inflammation and autoimmunity, but the involved targets and underlying molecular mechanisms are unknown. We genetically rendered a single MALT1 substrate, the RNA-binding protein (RBP) Roquin-1, insensitive to MALT1 cleavage. These Rc3h1Mins/Mins mice showed normal immune homeostasis. Combining Rc3h1Mins/Mins alleles with those encoding for constitutively active MALT1 (TBM) prevented spontaneous T cell activation and restored viability of Malt1TBM/TBM mice. Mechanistically, we show how antigen/MHC recognition is translated by MALT1 into Roquin cleavage and derepression of Roquin targets. Increasing T cell receptor (TCR) signals inactivated Roquin more effectively, and only high TCR strength enabled derepression of high-affinity targets to promote Th17 differentiation. Induction of experimental autoimmune encephalomyelitis (EAE) revealed increased cleavage of Roquin-1 in disease-associated Th17 compared to Th1 cells in the CNS. T cells from Rc3h1Mins/Mins mice did not efficiently induce the high-affinity Roquin-1 target IκBNS in response to TCR stimulation, showed reduced Th17 differentiation, and Rc3h1Mins/Mins mice were protected from EAE. These data demonstrate how TCR signaling and MALT1 activation utilize graded cleavage of Roquin to differentially regulate target mRNAs that control T cell activation and differentiation as well as the development of autoimmunity.

The Importance of a Detailed Geriatric Functional Assessment of Older Patients with Cancer.

BACKGROUND: For older patients with cancer, maintaining or regaining their ability to care of themselves is of major interest. Which tools are appropriate to measure this? Different tools to assess functional status (FS) are established in geriatric and oncological care, but they have been compared poorly in the past. PATIENTS AND METHODS: Within a prospective cohort trial, we included 483 patients: 198 older patients with cancer, 156 younger patients with cancer, and 129 older patients with benign disease. FS was assessed as Eastern Cooperative Oncology Group performance status (ECOG-PS), activities of daily living (ADL), and instrumental activities of daily living (IADL). Results were compared for their differences in identifying patients as functionally compromised. SUMMARY: The relative frequency of cancer patients with limitations in ECOG-PS, ADL, and IADL, respectively, increased from 25.7, 13.5, and 17.9% in those <60 years of age to 50.0, 47.1, and 66.7% in those ≥80 years. Results in older patients with cancer were comparable to older patients with benign disease. In older patients with cancer, 20.7 and 21.6% with a good ECOG-PS had limitations in ADL and IADL, respectively; of those without limitations in ADL and IADL, 34.7 and 26.0%, respectively, had a poor ECOG-PS. Treatment approach (curative vs. palliative) was found to be significantly associated with functional limitations. Key Messages: Geriatric and oncological measure of FS report differences in functional impairment. Geriatric functional measures are more sensitive to age-related changes and should be included as patient-reported outcomes in clinical trials and care.

Not just shades of grey: life is full of colour for the ocellate river stingray (Potamotrygon motoro).

Previous studies have shown that marine stingrays have the anatomical and physiological basis for colour vision, with cone spectral sensitivity in the blue to green range of the visible spectrum. Behavioural studies on Glaucostegus typus also showed that blue and grey can be perceived and discriminated. The present study is the first to assess visual opsin genetics in the ocellate river stingray (Potamotrygon motoro) and test whether individuals perceive colour in two alternative forced choice experiments. Retinal transcriptome profiling using RNA-Seq and quantification demonstrated the presence of lws and rh2 cone opsin genes and a highly expressed single rod (rh1) opsin gene. Spectral tuning analysis predicted these vitamin A1-based visual photopigments to exhibit spectral absorbance maxima at 461 nm (rh2), 496 nm (rh1) and 555 nm (lws); suggesting the presence of dichromacy in this species. Indeed, P. motoro demonstrates the potential to be equally sensitive to wavelengths from 380 to 600 nm of the visible spectrum. Behavioural results showed that red and green plates, as well as blue and yellow plates, were readily discriminated based on colour; however, brightness differences also played a part in the discrimination of blue and yellow. Red hues of different brightness were distinguished significantly above chance level from one another. In conclusion, the genetic and behavioural results support prior data on marine stingrays. However, this study suggests that freshwater stingrays of the family Potamotrygonidae may have a visual colour system that has ecologically adapted to a riverine habitat.

A Bowl with Marbles: Revision of the Thecate Amoeba Genus Lecythium (Chlamydophryidae, Tectofilosida, Cercozoa, Rhizaria) Including a Description of Four New Species and an Identification Key.

Although testate amoebae have attracted interest of protistologists for more than 150 years, some groups especially those with a hyaline, organic test (= theca) are still poorly known. One of those is the genus Lecythium (Chlamydophryidae, Tectofilosida, Cercozoa, Rhizaria), first described by Hertwig and Lesser in 1874. Only old, sometimes obscure, species descriptions were available until only recently a new species of Lecythium was described and a small ribosomal subunit RNA gene (SSU) sequence was provided. To shed light on the phylogeny and taxonomy of Lecythium, we (a) cultured six isolates of five Lecythium species and provide morphological as well as ecological observations, (b) obtained six new SSU sequences and conducted phylogenetic analyses of the Tectofilosida, showing that Lecythium splits into terrestrial and freshwater clades, and (c) did an intensive literature research on testate amoebae with a theca and provide an illustrated identification key focusing on Lecythium. For the first time, the presence of cysts in the genus Lecythium is reported and we compared those to the cysts of the presumed closely related Chlamydophrys stercorea. Our results suggest that still many undescribed Lecythium species will be found in terrestrial and freshwater habitats.

Smoking behaviors among patients receiving computed tomography for lung cancer screening. Systematic review in support of the U.S. preventive services task force.

RATIONALE: Lung cancer screening using low-dose computed tomography (LDCT) is now widely recommended for adults who are current or former heavy smokers. It is important to evaluate the impact of screening on smoking abstinence rates. OBJECTIVE: Among current and former smokers eligible for lung cancer screening, we sought to determine the consequence of screening with LDCT, as well as subsequent results, on smoking cessation and relapse rates. EVIDENCE REVIEW: We searched the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter, 2012), MEDLINE (2000 to May 31, 2013), reference lists of papers, and Scopus for relevant English-language studies and systematic reviews. To evaluate the effect of LDCT screening on smoking abstinence, we included only randomized controlled trials (RCTs) involving asymptomatic adults. To evaluate the association of particular results and/or recommendations from a screening CT with smoking behaviors, we included results from RCTs as well as cohort studies. MEASUREMENTS AND MAIN RESULTS: A total of 8,215 abstracts were reviewed. Three publications from two European RCTs and five publications from three cohort studies conducted in the United States met inclusion criteria. The process of LDCT lung cancer screening did not influence smoking behaviors. LDCT recipients with results concerning for lung cancer had higher abstinence rates than those with scans without such findings. This association may have a dose-response relationship in terms of the number of abnormal CT scans as well as the seriousness of the finding. CONCLUSIONS: Limited evidence suggests LDCT lung cancer screening itself does not influence smoking behaviors, but positive results are associated with increased abstinence. As lung cancer screening is implemented in the general population, it is very important to evaluate its association with smoking behaviors to maximize its potential as a teachable moment to encourage long-term abstinence. Clinicians should consider tailoring LDCT result communication to emphasize the importance of smoking abstinence.

Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive services task force recommendation.

BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States. Because early-stage lung cancer is associated with lower mortality than late-stage disease, early detection and treatment may be beneficial. PURPOSE: To update the 2004 review of screening for lung cancer for the U.S. Preventive Services Task Force, focusing on screening with low-dose computed tomography (LDCT). DATA SOURCES: MEDLINE (2000 to 31 May 2013), the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2012), Scopus, and reference lists. STUDY SELECTION: English-language randomized, controlled trials or cohort studies that evaluated LDCT screening for lung cancer. DATA EXTRACTION: One reviewer extracted study data about participants, design, analysis, follow-up, and results, and a second reviewer checked extractions. Two reviewers rated study quality using established criteria. DATA SYNTHESIS: Four trials reported results of LDCT screening among patients with smoking exposure. One large good-quality trial reported that screening was associated with significant reductions in lung cancer (20%) and all-cause (6.7%) mortality. Three small European trials showed no benefit of screening. Harms included radiation exposure, overdiagnosis, and a high rate of false-positive findings that typically were resolved with further imaging. Smoking cessation was not affected. Incidental findings were common. LIMITATIONS: Three trials were underpowered and of insufficient duration to evaluate screening effectiveness. Overdiagnosis, an important harm of screening, is of uncertain magnitude. No studies reported results in women or minority populations. CONCLUSION: Strong evidence shows that LDCT screening can reduce lung cancer and all-cause mortality. The harms associated with screening must be balanced with the benefits. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

PECAM-1 is expressed on hematopoietic stem cells throughout ontogeny and identifies a population of erythroid progenitors.

Platelet endothelial cell adhesion molecule-1 (PECAM-1) (CD31) is an adhesion molecule expressed on endothelial cells and subsets of leukocytes. Analysis of phenotypically defined hematopoietic stem cells (HSCs) from the yolk sac, fetal liver, and adult bone marrow demonstrates CD31 expression on these cells throughout development. CD31+ c-kit+ cells, but not CD31- c-kit+ cells, isolated from day-9.5 yolk sac give rise to multilineage hematopoiesis in vivo. Further evaluation of the CD31+ lineage marker-negative fraction of adult bone marrow reveals functionally distinct cell subsets. Transplantation of CD31+ Lin- c-kit- cells fails to protect lethally irradiated recipients, while CD31+ Lin- c-kit+ Sca-1- cells (CD31+ Sca-1-) provide radioprotection in the absence of long-term donor-derived hematopoiesis. Although donor-derived leukocytes were not detected in CD31+ Sca-1- recipients, donor-derived erythroid cells were transiently produced during the initial phases of bone marrow recovery. These results demonstrate CD31 expression on hematopoietic stem cells throughout ontogeny and identify a population of CD31+ short-term erythroid progenitors cells that confer protection from lethal doses of radiation.

Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells.

During early embryogenesis, blood vessels and hematopoietic cells arise from a common precursor cell, the hemangioblast. Recent studies have identified endothelial progenitor cells in the peripheral blood, and there is accumulating evidence that a subset of these cells is derived from precursors in the bone marrow. Here we show that adult bone marrow-derived, phenotypically defined hematopoietic stem cells (c-kit+, Sca-1+, lineage-) give rise to functional endothelial cells. With the exception of the brain, donor-derived cells are rapidly integrated into blood vessels. Durably engrafted endothelial cells express CD31, produce von Willebrand factor, and take up low-density lipoprotein. Analysis of DNA content indicates that donor-derived endothelial cells are not the products of cell fusion. Self-renewal of stem cells with hematopoietic and endothelial cell potential was revealed by serial transplantation studies. The clonal origin of both hematopoietic and endothelial cell outcomes was established by the transfer of a single cell. These results suggest that adult bone marrow-derived hematopoietic stem cells may serve as a reservoir for endothelial cell progenitors.