The incidence of melanoma is increasing, particularly in young women, and the disease remains incurable for many because of its aggressive, metastatic nature and its high rate of resistance to ...conventional, targeted, and immunological agents. Cathepsins are proteases that are critical for melanoma progression and therapeutic resistance. Intracellular cathepsins cleave or degrade proteins that restrict cancer progression, whereas extracellular cathepsins directly cleave the extracellular matrix and activate proinvasive proteases in the tumor microenvironment. Cathepsin secretion is markedly increased in cancer cells. We investigated the signaling pathways leading to increased cathepsin secretion in melanoma cells. We found that the nonreceptor tyrosine kinases Abl and Arg (Abl/Arg) promoted the secretion of cathepsin B and cathepsin L by activating transcription factors (namely, Ets1, Sp1, and NF-κB/p65) that have key roles in the epithelial-mesenchymal transition (EMT), invasion, and therapeutic resistance. In some melanoma cell lines, Abl/Arg promoted the Ets1/p65-induced secretion of cathepsin B and cathepsin L in a kinase-independent manner, whereas in other melanoma lines, Abl/Arg promoted the kinase-dependent, Sp1/Ets1/p65-mediated induction of cathepsin L secretion and the Sp1/p65-mediated induction of cathepsin B secretion. As an indication of clinical relevance, the abundance of mRNAs encoding Abl/Arg, Sp1, Ets1, and cathepsins was positively correlated in primary melanomas, and Abl/Arg-driven invasion in culture and metastasis in vivo required cathepsin secretion. These data suggest that drugs targeting Abl kinases, many of which are FDA-approved, might inhibit cathepsin secretion in some melanomas and potentially other aggressive cancers harboring activated Abl kinases.
Metastasis suppressors comprise a growing class of genes whose downregulation triggers metastatic progression. In contrast to tumor suppressors, metastasis suppressors are rarely mutated or deleted, ...and little is known regarding the mechanisms by which their expression is downregulated. Here, we demonstrate that the metastasis suppressor, NM23-H1, is degraded by lysosomal cysteine cathepsins (L,B), which directly cleave NM23-H1. In addition, activation of c-Abl and Arg oncoproteins induces NM23-H1 degradation in invasive cancer cells by increasing cysteine cathepsin transcription and activation. Moreover, c-Abl activates cathepsins by promoting endosome maturation, which facilitates trafficking of NM23-H1 to the lysosome where it is degraded. Importantly, the invasion- and metastasis-promoting activity of c-Abl/Arg is dependent on their ability to induce NM23-H1 degradation, and the pathway is clinically relevant as c-Abl/Arg activity and NM23-H1 expression are inversely correlated in primary breast cancers and melanomas. Thus, we demonstrate a novel mechanism by which cathepsin expression is upregulated in cancer cells (via Abl kinases). We also identify a novel role for intracellular cathepsins in invasion and metastasis (degradation of a metastasis suppressor). Finally, we identify novel crosstalk between oncogenic and metastasis suppressor pathways, thereby providing mechanistic insight into the process of NM23-H1 loss, which may pave the way for new strategies to restore NM23-H1 expression and block metastatic progression.
Objective
Children and adolescents have greater resting cerebral blood flow (rCBF) during periods of rapid brain growth. Overweight and obesity have a global impact on brain cerebrovascular health in ...adults, but whether these effects are discernable in adolescents with overweight and obesity remains unknown. This study examined differences in rCBF between adolescents with a healthy weight (HW) and adolescents with overweight or obesity (OW).
Methods
The current study focused on analyzing data from 58 participants (mean age = 15.43 SD 1.37 years). Participants were classified into OW (n = 38) and HW groups (n = 20) according to the Centers for Disease Control and Prevention’s guidelines for children. Voxelwise t tests between the HW and OW groups were conducted to test for regional group differences in rCBF, controlling for age and sex. Mean rCBF was extracted from a gray matter mask to compare global rCBF between the HW and OW groups.
Results
The HW group had greater rCBF compared with the OW group in five clusters, with peaks in the cerebellum, precentral gyrus, and supplementary motor area. No clusters survived correction for the OW > HW contrast. Global rCBF did not significantly differ between the groups (p = 0.09).
Conclusions
These results suggest that overweight and obesity in adolescence are associated with discernable reductions in blood flow to specific brain regions rather than having a global impact on rCBF.
...we analysed available incubation period data of 512 confirmed cases from five EVD outbreaks from the last ten years and found that the mean and median incubation periods of the gamma distributions ...fitted to the cases was 10 days (SD 5·3 days). ...we performed a literature review of experimental infection in non-human primates, which found that 103 (98%) of 105 non-human primates injected with lethal doses of EBOV showed initial signs of illness 3 or more days after injection (appendix pp 5–6). ...epidemiological investigations of EVD outbreaks that encounter cases where the incubation period is suspected to be shorter than 4 days should clarify whether these cases and their suspected source patients share a common origin of infection (eg, common source patient) that had not been previously identified.
Several evaluations and meta-analytic reviews have suggested that domestic violence (DV) treatment programs have only a modest impact on reducing DV recidivism. In response, a growing number of ...scholars and practitioners have called for the integration of evidence-based practices into DV treatment programming. In recent years, one leading approach has been to explore the infusion of the ‘principles of effective intervention (PEI),’ the prevailing evidence- based practice in correctional programming, into DV treatment. Findings from initial empirical studies from scholars and practitioners working to infuse the PEI into DV treatment programs have shown promise. This article provides an overview of the PEI and research exploring the integration of the PEI into DV treatment; a discussion on how these research findings can inform DV treatment programs interested in adopting a PEI framework; and practitioners’ perspectives on implementing programmatic changes and collaborating on evaluation research while also continuing to provide DV treatment.
Genograms are a valuable and non-threatening evaluation tool for hospice patients and families. The genogram provides basic information about the family including the role of each member and the ...family dynamics. As the diagram is drawn, family life cycle issues and relationships between family members become evident. The genogram may go beyond the household to include supportive neighbors, friends, and community resources. Religious and spiritual support is also noted. The information is used to assess family needs and to provide interventions both before the death and during bereavement.
Background
Preterm children face higher risk of cognitive and academic deficits compared with their full‐term peers. The objective of this study was to describe early childhood cognitive ability and ...kindergarten academic achievement across gestational age at birth in a population‐based longitudinal cohort.
Methods
The study population included singletons born at 24–42 weeks gestation enrolled in the Early Childhood Longitudinal Study‐Birth Cohort (n = 6150 for 2‐year outcome, n = 4450 for kindergarten outcome). Home‐based assessments measured cognitive ability at 2 years and reading and mathematics achievement at kindergarten age. Linear regression models estimated the association between gestational age and cognitive and academic scores using four different ways of modelling gestational age: continuous variable in linear and quadratic terms; categories for individual weeks; and clinical categories for early preterm, moderate preterm, late preterm, early term, full term, late term, and post‐term.
Results
Children born at early preterm (24–27 weeks), moderate preterm (28–33 weeks), and late preterm (34–36 weeks) scored significantly worse than full‐term (39–40 weeks) peers on 2‐year and kindergarten assessments; however, no deficits were observed for early term (37–38 weeks). These categories were a clinically useful and parsimonious approach to stratifying risk of adverse cognitive and academic outcomes.
Conclusions
This study estimated the relative performance of children born at 24–42 weeks in a population‐based birth cohort using multiple approaches to modelling gestational age, providing a more rigorous understanding of the relationships between the full spectrum of gestational age and cognitive and academic outcomes in early childhood and at school age.
Metastatic and localized mismatch repair-deficient (dMMR) tumors are exquisitely sensitive to immune checkpoint blockade (ICB). The ability of ICB to prevent dMMR malignant or pre-malignant neoplasia ...development in patients with Lynch syndrome (LS) is unknown. Of 172 cancer-affected patients with LS who had received ≥1 ICB cycles, 21 (12%) developed subsequent malignancies after ICB exposure, 91% (29/32) of which were dMMR, with median time to development of 21 months (interquartile range, 6-38). Twenty-four of 61 (39%) ICB-treated patients who subsequently underwent surveillance colonoscopy had premalignant polyps. Within matched pre-ICB and post-ICB follow-up periods, the overall rate of tumor development was unchanged; however, on subgroup analysis, a decreased incidence of post-ICB visceral tumors was observed. These data suggest that ICB treatment of LS-associated tumors does not eliminate risk of new neoplasia development, and LS-specific surveillance strategies should continue. These data have implications for immunopreventative strategies and provide insight into the immunobiology of dMMR tumors.
ABSTRACT
Background
Progressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off‐label in the hope of slowing disease ...progression. Results from these experiences are seldom shared, which limits evidence‐based knowledge to guide future treatment decisions.
Objectives
To describe an open‐label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP‐Richardson's syndrome (PSP‐RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies.
Methods
For 6 months, 10 PSP‐RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP‐RS patients from the davunetide clinical trial and the 4‐Repeat Tauopathy Neuroimaging Initiative.
Results
Salsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation SD) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (–0.07 ± 0.03), young plasma (–0.06 ± 0.03), and historical controls (–0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint.
Conclusions
Neither salsalate nor young plasma had a detectable effect on disease progression in PSP‐RS. Focused open‐label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP‐directed therapies.
We investigated the use of genome sequencing for preconception carrier testing. Genome sequencing could identify one or more of thousands of X-linked or autosomal recessive conditions that could be ...disclosed during preconception or prenatal counseling. Therefore, a framework that helps both clinicians and patients understand the possible range of findings is needed to respect patient preferences by ensuring that information about only the desired types of genetic conditions are provided to a given patient.
We categorized gene-condition pairs into groups using a previously developed taxonomy of genetic conditions. Patients could elect to receive results from these categories. A Return of Results Committee (RORC) developed inclusion and exclusion criteria for each category.
To date, the RORC has categorized 728 gene-condition pairs: 177 are categorized as life span-limiting, 406 are categorized as serious, 93 are categorized as mild, 41 are categorized as unpredictable, and 11 are categorized as adult-onset. An additional 64 gene-condition pairs were excluded from reporting to patients or put on a watch list, generally because evidence that a gene and condition were associated was limited.
Categorization of gene-condition pairs using our taxonomy simplifies communication regarding patient preferences for carrier information from a genomic test.Genet Med advance online publication 12 January 2017.
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