Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy.

Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of combined mTOR inhibitor sirolimus (1 mg-5 mg PO daily) and HDAC inhibitor vorinostat (100 mg-400 mg PO daily) in patients with advanced cancer. Seventy patients were enrolled and 46 (66%) were evaluable for DLT assessment since they completed cycle 1 without dose modification unless they had DLT. DLTs comprised grade 4 thrombocytopenia (n = 6) and grade 3 mucositis (n = 1). Sirolimus 4 mg and vorinostat 300 mg was declared RP2D because MTD with sirolimus 5 mg caused significant thrombocytopenia. The grade 3 and 4 drug-related toxic effects (including DLTs) were thrombocytopenia (31%), neutropenia (8%), anemia (7%), fatigue (3%), mucositis (1%), diarrhea (1%), and hyperglycemia (1%). Of the 70 patients, 35 (50%) required dose interruption or modification and 61 were evaluable for response. Partial responses were observed in refractory Hodgkin lymphoma (-78%) and perivascular epithelioid tumor (-54%), and stable disease in hepatocellular carcinoma and fibromyxoid sarcoma. In conclusion, the combination of sirolimus and vorinostat was feasible, with thrombocytopenia as the main DLT. Preliminary anticancer activity was observed in patients with refractory Hodgkin lymphoma, perivascular epithelioid tumor, and hepatocellular carcinoma

Physical, cognitive, social and mental health in near-centenarians and centenarians living in New York City: findings from the Fordham Centenarian Study

Background: Despite their strong increase, the population of the very old, including near-centenarians and centenarians, represent an unstudied and underserved population. Available studies mostly concentrate on predictors of exceptional longevity, but rarely extend their focus to other areas of functioning. Also, little is known about what contributes to experiencing a quality life in very old age. The present population-based study aims at providing a comprehensive picture of key domain of functioning, including physical, cognitive, social and mental function in very old individuals and to determine predictors of mental health indicators. Methods: A total of 119 individuals aged 95 to 107 living in private dwellings and residential care facilities were recruited based on the New York City Voters Registry. Participants answered questions regarding their health and activities of daily living. Their cognitive functioning was determined using the Mini-Mental State Examination and the Global Deterioration Scale. Social resources were measured with number of children and the Lubben Scale. Mental health was assessed with the Geriatric Depression Scale and the Satisfaction with Life Scale. Results: An unexpectedly large proportion of the sample lived in the community. On average, cognitive functioning was high. Although five diseases were reported on average, participants reported good health. Functional status was reduced. Most participants had at least one person for communication/social support. On average, depression was below cut-off, and most participants reported high life satisfaction. Regression analyses indicated that individual differences in depression were associated with subjective health, IADL and relatives support. For life satisfaction, subjective health, ADL and number of children were most important. Demographic characteristics, number of illnesses or cognitive status were not significant. Conclusions: Despite reduced levels of physical functioning and social resources, very old participants were in good mental health suggesting high resilience and ability to adapt to age-associated challenges. That a large proportion of them lived in the community further highlights their desire for leading an autonomous life, which may have been facilitated by New York service culture. More research is necessary to provide guidance for the development of well-suited services for this very old population

Sexual reproduction is the null hypothesis for life cycles of rust fungi

Sexual reproduction, mutation, and reassortment of nuclei increase genotypic diversity in rust fungi. Sexual reproduction is inherent to rust fungi, coupled with their coevolved plant hosts in native pathosystems. Rust fungi are hypothesised to exchange nuclei by somatic hybridisation with an outcome of increased genotypic diversity, independent of sexual reproduction. We provide criteria to demonstrate whether somatic exchange has occurred, including knowledge of parental haplotypes and rejection of fertilisation in normal rust life cycles

<i>Campylobacter jejuni</i> Type VI Secretion System: Roles in Adaptation to Deoxycholic Acid, Host Cell Adherence, Invasion, and <i>In Vivo</i> Colonization

The recently identified type VI secretion system (T6SS) of proteobacteria has been shown to promote pathogenicity, competitive advantage over competing microorganisms, and adaptation to environmental perturbation. By detailed phenotypic characterization of loss-of-function mutants, in silico, in vitro and in vivo analyses, we provide evidence that the enteric pathogen, Campylobacter jejuni, possesses a functional T6SS and that the secretion system exerts pleiotropic effects on two crucial processes – survival in a bile salt, deoxycholic acid (DCA), and host cell adherence and invasion. The expression of T6SS during initial exposure to the upper range of physiological levels of DCA (0.075%–0.2%) was detrimental to C. jejuni proliferation, whereas down-regulation or inactivation of T6SS enabled C. jejuni to resist this effect. The C. jejuni multidrug efflux transporter gene, cmeA, was significantly up-regulated during the initial exposure to DCA in the wild type C. jejuni relative to the T6SS-deficient strains, suggesting that inhibition of proliferation is the consequence of T6SS-mediated DCA influx. A sequential modulation of the efflux transporter activity and the T6SS represents, in part, an adaptive mechanism for C. jejuni to overcome this inhibitory effect, thereby ensuring its survival. C. jejuni T6SS plays important roles in host cell adhesion and invasion as T6SS inactivation resulted in a reduction of adherence to and invasion of in vitro cell lines, while over-expression of a hemolysin co-regulated protein, which encodes a secreted T6SS component, greatly enhanced these processes. When inoculated into B6.129P2-IL-10tm1Cgn mice, the T6SS-deficient C. jejuni strains did not effectively establish persistent colonization, indicating that T6SS contributes to colonization in vivo. Taken together, our data demonstrate the importance of bacterial T6SS in host cell adhesion, invasion, colonization and, for the first time to our knowledge, adaptation to DCA, providing new insights into the role of T6SS in C. jejuni pathogenesis.</p

Campylobacter jejuni Type VI Secretion System: Roles in Adaptation to Deoxycholic Acid, Host Cell Adherence, Invasion, and In Vivo Colonization

The recently identified type VI secretion system (T6SS) of proteobacteria has been shown to promote pathogenicity, competitive advantage over competing microorganisms, and adaptation to environmental perturbation. By detailed phenotypic characterization of loss-of-function mutants, in silico, in vitro and in vivo analyses, we provide evidence that the enteric pathogen, Campylobacter jejuni, possesses a functional T6SS and that the secretion system exerts pleiotropic effects on two crucial processes – survival in a bile salt, deoxycholic acid (DCA), and host cell adherence and invasion. The expression of T6SS during initial exposure to the upper range of physiological levels of DCA (0.075%–0.2%) was detrimental to C. jejuni proliferation, whereas down-regulation or inactivation of T6SS enabled C. jejuni to resist this effect. The C. jejuni multidrug efflux transporter gene, cmeA, was significantly up-regulated during the initial exposure to DCA in the wild type C. jejuni relative to the T6SS-deficient strains, suggesting that inhibition of proliferation is the consequence of T6SS-mediated DCA influx. A sequential modulation of the efflux transporter activity and the T6SS represents, in part, an adaptive mechanism for C. jejuni to overcome this inhibitory effect, thereby ensuring its survival. C. jejuni T6SS plays important roles in host cell adhesion and invasion as T6SS inactivation resulted in a reduction of adherence to and invasion of in vitro cell lines, while over-expression of a hemolysin co-regulated protein, which encodes a secreted T6SS component, greatly enhanced these processes. When inoculated into B6.129P2-IL-10[superscript tm1Cgn] mice, the T6SS-deficient C. jejuni strains did not effectively establish persistent colonization, indicating that T6SS contributes to colonization in vivo. Taken together, our data demonstrate the importance of bacterial T6SS in host cell adhesion, invasion, colonization and, for the first time to our knowledge, adaptation to DCA, providing new insights into the role of T6SS in C. jejuni pathogenesis

Mapping language function with task-based vs. resting-state functional MRI

BACKGROUND: Use of functional MRI (fMRI) in pre-surgical planning is a non-invasive method for pre-operative functional mapping for patients with brain tumors, especially tumors located near eloquent cortex. Currently, this practice predominantly involves task-based fMRI (T-fMRI). Resting state fMRI (RS-fMRI) offers an alternative with several methodological advantages. Here, we compare group-level analyses of RS-fMRI vs. T-fMRI as methods for language localization. PURPOSE: To contrast RS-fMRI vs. T-fMRI as techniques for localization of language function. METHODS: We analyzed data obtained in 35 patients who had both T-fMRI and RS-fMRI scans during the course of pre-surgical evaluation. The RS-fMRI data were analyzed using a previously trained resting-state network classifier. The T-fMRI data were analyzed using conventional techniques. Group-level results obtained by both methods were evaluated in terms of two outcome measures: (1) inter-subject variability of response magnitude and (2) sensitivity/specificity analysis of response topography, taking as ground truth previously reported maps of the language system based on intraoperative cortical mapping as well as meta-analytic maps of language task fMRI responses. RESULTS: Both fMRI methods localized major components of the language system (areas of Broca and Wernicke) although not with equal inter-subject consistency. Word-stem completion T-fMRI strongly activated Broca\u27s area but also several task-general areas not specific to language. RS-fMRI provided a more specific representation of the language system. CONCLUSION: We demonstrate several advantages of classifier-based mapping of language representation in the brain. Language T-fMRI activated task-general (i.e., not language-specific) functional systems in addition to areas of Broca and Wernicke. In contrast, classifier-based analysis of RS-fMRI data generated maps confined to language-specific regions of the brain

Spatial overlaps between the global protected areas network and terrestrial hotspots of evolutionary diversity

AIM : A common approach for prioritizing conservation is to identify concentrations (hotspots) of biodiversity. Such hotspots have traditionally been designated on the basis of species‐level metrics (e.g., species richness, endemism and extinction vulnerability). These approaches do not consider phylogenetics explicitly, although phylogenetic relationships reflect the ecological, evolutionary and biogeographical processes by which biodiversity is generated, distributed and maintained. The aim of this study was to identify hotspots of phylogenetic diversity and compare these with hotspots based on species‐level metrics and with the existing protected areas network. LOCATION : Global. TIME PERIOD : Contemporary. MAJOR TAXA STUDIED : Terrestrial vertebrates (mammals, birds and amphibians) and angiosperms. METHODS : We used comprehensive phylogenies and distribution maps of terrestrial birds, mammals, amphibians and angiosperms to identify areas with high concentrations of phylogenetic diversity, phylogenetic endemism, and evolutionary distinctiveness and global endangerment. We compared the locations of these areas with those included within the current network of protected areas and concentrations of species‐level indices: species richness, species endemism and species threat. RESULTS : We found spatial incongruence among the three evolutionary diversity metrics in each taxonomic group. Spatial patterns of diversity and endemism also differed among taxonomic groups, with some differences between vertebrates and angiosperms. Complementarity analyses of phylogenetic diversity identified the minimal area that encapsulates the full branch lengths for each taxonomic group. The current network of protected areas and species‐level hotspots largely does not overlap with areas of high phylodiversity. MAIN CONCLUSION : Overall, < 10% of hotspot areas were designated as protected areas. Patterns of diversity, endemism and vulnerability differ among taxonomic groups.http://wileyonlinelibrary.com/journal/geb2020-06-01hj2019Plant Production and Soil ScienceZoology and Entomolog