SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model

SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT) subunit A fused to human vascular endothelial growth factor (VEGF). It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1) and inhibits the growth of primary tumors in subcutaneous models of breast and prostate cancer and inhibits metastatic dissemination in orthotopic models of pancreatic cancer. We examined the efficacy of SLT-VEGF in limiting tumor growth and metastasis in an orthotopic melanoma model, using NCR athymic nude mice inoculated with highly metastatic Line IV Cl 1 cultured human melanoma cells. Twice weekly injections of SLT-VEGF were started when tumors became palpable at one week after intradermal injection of 1 × 106 cells/mouse. Despite selective depletion of VEGFR-2 overexpressing endothelial cells from the tumor vasculature, SLT-VEGF treatment did not affect tumor growth. However, after primary tumors were removed, continued SLT-VEGF treatment led to fewer tumor recurrences (p = 0.007), reduced the incidence of lung metastasis (p = 0.038), and improved survival (p = 0.002). These results suggest that SLT-VEGF is effective at the very early stages of tumor development, when selective killing of VEGFR-2 overexpressing endothelial cells can still prevent further progression. We hypothesize that SLT-VEGF could be a promising adjuvant therapy to inhibit or prevent outgrowth of metastatic foci after excision of aggressive primary melanoma lesions

Parameter uncertainty and sensitivity in a liquid-effluent dose model

Radioactive materials which are released into streams on the Savannah River Site (SRS) eventually flow into the Savannah River. Tritium, 90 Sr, 137 Cs, and 239 Pu account for the majority of the radiation dose received by users of the Savannah River. This paper focuses on the dose uncertainties originating from variability in parameters describing the transport and uptake of these nuclides. Parameter sensitivity has also been determined for each liquid pathway exposure model. The models used here to estimate radiation dose to an exposed individual provide a range of possible dose estimates that span approximately one order of magnitude. A pathway analysis reveals that aquatic food and water consumption account for more than 95% of the total dose to an individual.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42692/1/10661_2004_Article_BF00547126.pd

Polygenic basis and biomedical consequences of telomere length variation

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community

Aging-related defects in macrophage function are driven by MYC and USF1 transcriptional programs

Macrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age-related changes remain poorly understood, particularly in human macrophages. We report a substantial reduction in phagocytosis, migration, and chemotaxis in human monocyte-derived macrophages (MDMs) from older (>50 years old) compared with younger (18–30 years old) donors, alongside downregulation of transcription factors MYC and USF1. In MDMs from young donors, knockdown of MYC or USF1 decreases phagocytosis and chemotaxis and alters the expression of associated genes, alongside adhesion and extracellular matrix remodeling. A concordant dysregulation of MYC and USF1 target genes is also seen in MDMs from older donors. Furthermore, older age and loss of either MYC or USF1 in MDMs leads to an increased cell size, altered morphology, and reduced actin content. Together, these results define MYC and USF1 as key drivers of MDM age-related functional decline and identify downstream targets to improve macrophage function in aging

An Amish founder variant consolidates disruption of CEP55 as a cause of hydranencephaly and renal dysplasia

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.The centrosomal protein 55 kDa (CEP55 (OMIM 610000)) plays a fundamental role in cell cycle regulation and cytokinesis. However, the precise role of CEP55 in human embryonic growth and development is yet to be fully defined. Here we identified a novel homozygous founder frameshift variant in CEP55, present at low frequency in the Amish community, in two siblings presenting with a lethal foetal disorder. The features of the condition are reminiscent of a Meckel-like syndrome comprising of Potter sequence, hydranencephaly, and cystic dysplastic kidneys. These findings, considered alongside two recent studies of single families reporting loss of function candidate variants in CEP55, confirm disruption of CEP55 function as a cause of this clinical spectrum and enable us to delineate the cardinal clinical features of this disorder, providing important new insights into early human development.Medical Research CouncilNewlife Foundation for disabled childre

Polygenic basis and biomedical consequences of telomere length variation.

Funder: Health Data Research UK EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart (11607).Funder: Health Data Research UKTelomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community

Mental health in South African adolescents living with HIV: correlates of internalising and externalising symptoms

Although declining in all other age groups, AIDS-related deaths among adolescents are increasing. In the context of HIV, mental health problems are associated with negative health outcomes, including non-adherence to life-saving ART. For effective programming it is essential to identify factors associated with psychological outcomes in this population. Adopting a socioecological perspective, we aimed to identify correlates of internalising and externalising symptoms in a large, representative sample of South African adolescents living with HIV. HIV-positive adolescents (n = 1060), who received care in public health facilities in South Africa’s Eastern Cape, completed measures of internalising and externalising symptoms. Hypothesised correlates included HIV and health-related factors (physical health, mode of infection, medication side effects, disclosure, stigma), health-service related factors (negative interactions with clinic staff, clinic support group), interpersonal factors (abuse, bullying victimisation, social support), parenting-related factors (orphanhood, positive parenting, parental monitoring, parent communication), as well as individual and demographic-related factors (self-efficacy, age, gender, urban/rural location, poverty). Correlates operating across a variety of contexts were identified. Bullying victimisation, self-efficacy, and positive parenting may be particularly salient intervention targets as they were associated with better outcomes on most or all mental health measures, can be addressed without directly targeting adolescents living with HIV (reducing the chances of accidental exposure and stigma), and are associated with better adolescent mental health in South Africa more generally.IS

Automatic structure classification of small proteins using random forest

<p>Abstract</p> <p><b>Background</b></p> <p>Random forest, an ensemble based supervised machine learning algorithm, is used to predict the SCOP structural classification for a target structure, based on the similarity of its structural descriptors to those of a template structure with an equal number of secondary structure elements (SSEs). An initial assessment of random forest is carried out for domains consisting of three SSEs. The usability of random forest in classifying larger domains is demonstrated by applying it to domains consisting of four, five and six SSEs.</p> <p><b>Result</b>s</p> <p>Random forest, trained on SCOP version 1.69, achieves a predictive accuracy of up to 94% on an independent and non-overlapping test set derived from SCOP version 1.73. For classification to the SCOP <it>Class, Fold, Super-family </it>or <it>Family </it>levels, the predictive quality of the model in terms of Matthew's correlation coefficient (MCC) ranged from 0.61 to 0.83. As the number of constituent SSEs increases the MCC for classification to different structural levels decreases.</p> <p>Conclusions</p> <p>The utility of random forest in classifying domains from the place-holder classes of SCOP to the true <it>Class, Fold, Super-family </it>or <it>Family </it>levels is demonstrated. Issues such as introduction of a new structural level in SCOP and the merger of singleton levels can also be addressed using random forest. A real-world scenario is mimicked by predicting the classification for those protein structures from the PDB, which are yet to be assigned to the SCOP classification hierarchy.</p

Radioecological studies related to the BANEBERRY event

On December 18, 1970, at 7:30 a.m., PST, a venting occurred at the Nevada Test Site in conjunction with the Baneberry test. The Lawrence Radiation Laboratory (LRL) Bio-Medical Research Division and the University of Utah responded to this event by activating their jointly operated air-sampling network and by gathering forage, milk, and animal samples. These data are used to calculate the dose to humans from inhalation, submersion, and food-chain contamination; food-chain contamination calculations are limited to the cow-milk pathway, but included bovine inhalation. The question of food-chain contamination is explored under both the actual situation that dairy cows were fed stored feed and under the hypothetical situation that dairy cows were fed fresh feed. Our results show that {sup 131}I was the significant radionuclide emitted by the event and that the strongest dose was received by the thyroid glands of both foraging animals and humans. The integrated concentrations of {sup 131}I were higher in the northern part of Utah; the maximum value of 1100 pCi h m{sup {minus}3} was recorded at Draper (near Salt Lake City). For conservative results, we calculated the dose to a child rather than an adult. For the actual conditions following the venting, we estimate on the basis of measurements of baled hay and or milk that the dose to an infant's thyroid via the cow-milk pathway was between 0.0065 and 0.012 rad at Draper. If cows had been continuously on fresh pasture, we estimate that the dose to the infant thyroid for the same integrated air concentration would have been 1.3 rad for dry deposition and up to 100 rad for wet deposition. 24 refs., 3 figs., 13 tabs

Relationship Contexts as Sources of Socialization: An Exploration of Intimate Partner Violence Experiences of Economically Disadvantaged African American Adolescents

Intimate partner violence (IPV) among African Americans is a serious public health concern. Research suggest that African Americans adolescents, particularly those from economically disadvantaged communities, are at heightened risk for experiencing and perpetrating dating violence compared to youth from other racial and ethnic groups. In the present study, we examined different relationship contexts that are sources of IPV socialization. Semi-structured interviews were conducted with 22 economically disadvantaged African American adolescents. Content analysis yielded five relationship contexts through which the participants witnessed, experienced, and perpetrated IPV: (a) adolescents’ own dating relationships (64%), (b) siblings and extended family members (e.g., cousins, aunts, uncles) (59%), (c) parent-partners (27%), (d) friends (23%), and (e) neighbors (18%). Adolescents also frequently described IPV in their own dating relationships and in parent-partner relationships as mutual. Moreover, they appeared to minimize the experience of IPV in their own relationships. Efforts to reduce rates of IPV among economically disadvantaged African American adolescents should consider these relational contexts through which adolescents are socialized with regards to IPV and adolescents’ beliefs about mutual violence in relationships. Results highlight the importance of culturally relevant prevention and intervention programs that consider these relationship contexts