Assessing the Need for Adjuvant Chemotherapy After Stereotactic Body Radiation Therapy in Early-stage Non-small Cell Lung Carcinoma.

Surgery remains the standard treatment for medically operable patients with early-stage non-small cell lung carcinoma (NSCLC). Following surgical resection, adjuvant chemotherapy is recommended for large tumors >4 cm. For unfit patients, stereotactic body radiation therapy (SBRT) has emerged as an excellent alternative to surgery. This study aims to assess patterns of recurrence and discuss the role of chemotherapy after SBRT for NSCLC. We reviewed patients treated with SBRT for primary early-stage NSCLC between 2009 and 2015. Total target doses were between 50 and 60 Gy administered in three to eight fractions. All patients had a staging fluorodeoxyglucose (FDG) positron emission tomography (PET) integrated with computed tomography (CT) scan, and histologic confirmation was obtained whenever possible. Mediastinal staging was performed if lymph node involvement was suspected on CT or PET/CT. Survival outcomes were estimated using the Kaplan-Meier method. Among the 559 early-stage NSCLC patients treated with SBRT, 121 patients were stage T2N0. The one-year and three-year overall survival rates were 88% and 70%, respectively, for patients with T2 disease, compared to 95% and 81%, respectively, for the T1 patients (p<0.05). The one-year and three-year local control rates were equal in both groups (98% and 91%, respectively). In T2 patients, 25 (21%) presented a relapse, among which 21 (84%) were nodal or distant. The median survival of T2N0 patients following a relapse was 11 months. Lung SBRT provides high local control rates, even for larger tumors. When patients relapse, the majority of them do so at regional or distant sites. These results raise the question as to whether adjuvant treatment should be considered following SBRT for larger tumors

Sources of riverine mercury across the Mackenzie River Basin; inferences from a combined Hg\\C isotopes and optical properties approach

The Arctic environment harbors a complex mosaic of mercury (Hg) and carbon (C) reservoirs, some of which are rapidly destabilizing in response to climate warming. The sources of riverine Hg across the Mackenzie River basin (MRB) are uncertain, which leads to a poor understanding of potential future release. Measurements of dissolved and particulate mercury (DHg, PHg) and carbon (DOC, POC) concentration were performed, along with analyses of Hg stable isotope ratios (incl. Delta 199Hg, delta 202Hg), radiocarbon content (Delta 14C) and optical properties of DOC of river water. Isotopic ratios of Hg revealed a closer association to terrestrial Hg reservoirs for the particulate fraction, while the dissolved fraction was more closely associated with atmospheric deposition sources of shorter turnover time. There was a positive correlation between the Delta 14C-OC and riverine Hg concentration for both particulate and dissolved fractions, indicating that waters transporting older-OC (14C-depleted) also contained higher levels of Hg. In the dissolved fraction, older DOC was also associated with higher molecular weight, aromaticity and humic content, which are likely associated with higher Hg-binding potential. Riverine PHg concentration increased with turbidity and SO4 concentration. There were large contrasts in Hg concentration and OC age and quality among the mountain and lowland sectors of the MRB, which likely reflect the spatial distribution of various terrestrial Hg and OC reservoirs, including weathering of sulfate minerals, erosion and extraction of coal deposits, thawing permafrost, forest fires, peatlands, and forests. Results revealed major differences in the sources of particulate and dissolved riverine Hg, but nonetheless a common positive association with olde

A separable domain of the p150 subunit of human Chromatin Assembly Factor-1 promotes protein and chromosome associations with nucleoli

Chromatin Assembly Factor-1 (CAF-1) is a three-subunit protein complex conserved throughout eukaryotes that deposits histones during DNA synthesis. Here, we present a novel role for the human p150 subunit in regulating nucleolar macromolecular interactions. Acute depletion of p150 causes redistribution of multiple nucleolar proteins and reduces nucleolar association with several repetitive element-containing loci. Notably, a point mutation in a SUMO-interacting motif (SIM) within p150 abolishes nucleolar associations, whereas PCNA or HP1 interaction sites within p150 are not required for these interactions. Additionally, acute depletion of SUMO-2 or the SUMO E2 ligase Ubc9 reduces alpha-satellite DNA association with nucleoli. The nucleolar functions of p150 are separable from its interactions with the other subunits of the CAF-1 complex, because an N-terminal fragment of p150 (p150N) that cannot interact with other CAF-1 subunits is sufficient for maintaining nucleolar chromosome and protein associations. Therefore, these data define novel functions for a separable domain of the p150 protein, regulating protein and DNA interactions at the nucleolus

Improving lives by accelerating progress towards the UN Sustainable Development Goals for adolescents living with HIV: a prospective cohort study

BACKGROUND: Low-income and middle-income countries (LMICs) face major challenges in achieving the UN's Sustainable Development Goals (SDGs) for vulnerable adolescents. We aimed to test the UN Development Programme's proposed approach of development accelerators-provisions that lead to progress across multiple SDGs-and synergies between accelerators on achieving SDG-aligned targets in a highly vulnerable group of adolescents in South Africa. METHODS: We did standardised interviews and extracted longitudinal data from clinical records at baseline (2014-15) and 18-month follow-up (2016-17) for adolescents aged 10-19 years living with HIV in the Eastern Cape province of South Africa. We used standardised tools to measure 11 SDG-aligned targets-antiretroviral therapy adherence, good mental health, no substance use, HIV care retention, school enrolment, school progression, no sexual abuse, no high-risk sex, no violence perpetration, no community violence, and no emotional or physical abuse. We also assessed receipt at both baseline and follow-up of six hypothesised development accelerators-government cash transfers to households, safe schools (ie, without teacher or student violence), free schools, parenting support, free school meals, and support groups. Associations of all provisions with SDG-aligned targets were assessed jointly in a multivariate path model, controlling for baseline outcomes and sociodemographic and HIV-related covariates, and adjusted for multiple outcome testing. Cumulative effects were tested by marginal effects modelling. FINDINGS: 1063 (90%) of 1176 eligible adolescents were interviewed. Three provisions were shown to be development accelerators. Parenting support was associated with good mental health (odds ratio 2·13, 95% CI 1·43-3·15, p<0·0001), no high-risk sex (2·44, 1·45-5·03, p=0·005), no violence perpetration (2·59, 1·63-4·59, p<0·0001), no community violence (2·43, 1·65-3·86, p<0·0001), and no emotional or physical abuse (2·38, 1·65-3·76; p<0·0001). Cash transfers were associated with HIV care retention (1·87, 1·15-3·02, p=0·010), school progression (2·05, 1·33-3·24, p=0·003), and no emotional or physical abuse (1·76, 1·12-3·02, p=0·025). Safe schools were associated with good mental health (1·74, 1·30-2·34, p<0·0001), school progression (1·57, 1·17-2·13, p=0·004), no violence perpetration (2·02, 1·45-2·91, p<0·0001), no community violence (1·81, 1·30-2·55, p<0·0001), and no emotional or physical abuse (2·20, 1·58-3·17, p<0·0001). For five of 11 SDG-aligned targets, a combination of two or more accelerators showed cumulative positive associations, suggesting accelerator synergies of combination provisions. For example, the fitted probability of adolescents reporting no emotional or physical abuse (SDG 16.2) with no safe schools, cash transfers, or parenting support was 0·25 (0·16-0·34). With cash transfer alone it was 0·37 (0·33-0·42), with safe school alone 0·42 (0·30-0·55), and with parenting support alone 0·44 (0·30-0·59). With all three development accelerators combined, the probability of adolescents reporting no emotional or physical abuse was 0·76 (0·67-0·84). After correcting for multiple tests, four of the SDG-aligned targets (antiretroviral therapy adherence, no substance use, school enrolment, and no sexual abuse) were not associated with any hypothesised accelerators. INTERPRETATION: The findings suggest the UN's accelerator approach for this high-risk adolescent population has policy and potential financing usefulness. Services that simultaneously promote several SDG targets, or combine to support particular targets, might be important to meet not only health-related targets, but also to ensure that adolescents in LMICs thrive within a new development framework. FUNDING: Nuffield Foundation, UK Research and Innovation Global Challenges Research Fund, UKAID, Janssen Pharmaceutica, International AIDS Society, John Fell Fund, European Research Council, Economic and Social Research Council, Philip Leverhulme Trust, and UNICEF

MYOD1 involvement in myopathy

[Excerpt] Introduction Myogenic Differentiation 1 (MYOD1) encodes a transcription factor that plays an important role in myogenic determination into mature skeletal muscle [1]. The first loss-of-function mutation of MYOD1 in humans was described in three siblings with perinatal lethal fetal akinesia [2].[...]We thank the individual and family. Funding was provided by The Fonds de recherche du Québec - Santé (FRQS) and Canadian Institutes of Health Research (CIHR) to P.M.C., Fundação para a Ciência e Tecnologia (FCT) with the fellowship SFRH/BD/84650/2010 to F.L. and Groupe Pasteur Mutualité Foundation (GPM Foundation) to M.M.info:eu-repo/semantics/publishedVersio

Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

Pain after disease/damage of the nervous system is predominantly treated with opioids, but without exploration of the long-term consequences. We demonstrate that a short course of morphine after nerve injury doubles the duration of neuropathic pain. Using genetic and pharmacological interventions, and innovative Designer Receptor Exclusively Activated by Designer Drugs disruption of microglia reactivity, we demonstrate that opioid-prolonged neuropathic pain arises from spinal microglia and NOD-like receptor protein 3 inflammasome formation/activation. Inhibiting these processes permanently resets amplified pain to basal levels, an effect not previously reported. These data support the “two-hit hypothesis” of amplification of microglial activation—nerve injury being the first “hit,” morphine the second. The implications of such potent microglial “priming” has fundamental clinical implications for pain and may extend to many chronic neurological disorders

Monoubiquitination of syntaxin 3 leads to retrieval from the basolateral plasma membrane and facilitates cargo recruitment to exosomes

Syntaxin 3 (Stx3), a SNARE protein located and functioning at the apical plasma membrane of epithelial cells, is required for epithelial polarity. A fraction of Stx3 is localized to late endosomes/lysosomes, although how it traffics there and its function in these organelles is unknown. Here we report that Stx3 undergoes monoubiquitination in a conserved polybasic domain. Stx3 present at the basolateral—but not the apical—plasma membrane is rapidly endocytosed, targeted to endosomes, internalized into intraluminal vesicles (ILVs), and excreted in exosomes. A nonubiquitinatable mutant of Stx3 (Stx3-5R) fails to enter this pathway and leads to the inability of the apical exosomal cargo protein GPRC5B to enter the ILV/exosomal pathway. This suggests that ubiquitination of Stx3 leads to removal from the basolateral membrane to achieve apical polarity, that Stx3 plays a role in the recruitment of cargo to exosomes, and that the Stx3-5R mutant acts as a dominant-negative inhibitor. Human cytomegalovirus (HCMV) acquires its membrane in an intracellular compartment and we show that Stx3-5R strongly reduces the number of excreted infectious viral particles. Altogether these results suggest that Stx3 functions in the transport of specific proteins to apical exosomes and that HCMV exploits this pathway for virion excretion

Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with “corner fractures”

Heterozygous pathogenic variants in the FN1 gene, encoding fibronectin (FN), have recently been shown to be associated with a skeletal disorder in some individuals affected by spondylometaphyseal dysplasia with “corner fractures” (SMD-CF). The most striking feature characterizing SMD-CF is irregularly shaped metaphyses giving the appearance of “corner fractures”. An array of secondary features, including developmental coxa vara, ovoid vertebral bodies and severe scoliosis, may also be present. FN is an important extra cellular matrix component for bone and cartilage development. Here we report five patients affected by this subtype of SMD-CF caused by five novel FN1 missense mutations: p.Cys123Tyr, p.Cys169Tyr, p.Cys213Tyr, p.Cys231Trp and p.Cys258Tyr. All individuals shared a substitution of a cysteine residue, disrupting disulfide bonds in the FN type-I assembly domains located in the N-terminal assembly region. The abnormal metaphyseal ossification and “corner fracture” appearances were the most remarkable clinical feature in these patients. In addition, generalized skeletal fragility with low-trauma bilateral femoral fractures was identified in one patient. Interestingly, the distal femoral changes in this patient healed with skeletal maturation. Our report expands the phenotypic and genetic spectrum of the FN1-related SMD-CF and emphasizes the importance of FN in bone formation and possibly also in the maintenance of bone strength.Peer reviewe