Bone Morphogenetic Protein 4 Gene Therapy in Mice Inhibits Myeloma Tumor Growth, But Has a Negative Impact on Bone.

Multiple myeloma is characterized by accumulation of malignant plasma cells in the bone marrow. Most patients suffer from an osteolytic bone disease, caused by increased bone degradation and reduced bone formation. Bone morphogenetic protein 4 (BMP4) is important for both pre- and postnatal bone formation and induces growth arrest and apoptosis of myeloma cells. BMP4-treatment of myeloma patients could have the potential to reduce tumor growth and restore bone formation. We therefore explored BMP4 gene therapy in a human-mouse model of multiple myeloma where humanized bone scaffolds were implanted subcutaneously in RAG2-/- γC-/-mice. Mice were treated with adeno-associated virus serotype 8 BMP4 vectors (AAV8-BMP4) to express BMP4 in the liver. When mature BMP4 was detectable in the circulation, myeloma cells were injected into the scaffolds and tumor growth was examined by weekly imaging. Strikingly, the tumor burden was reduced in AAV8-BMP4 mice compared with the AAV8-CTRL mice, suggesting that increased circulating BMP4 reduced tumor growth. BMP4-treatment also prevented bone loss in the scaffolds, most likely due to reduced tumor load. To delineate the effects of BMP4 overexpression on bone per se, without direct influence from cancer cells, we examined the unaffected, non-myeloma femurs by μCT. Surprisingly, the AAV8-BMP4 mice had significantly reduced trabecular bone volume, trabecular numbers, as well as significantly increased trabecular separation compared with the AAV8-CTRL mice. There was no difference in cortical bone parameters between the two groups. Taken together, BMP4 gene therapy inhibited myeloma tumor growth, but also reduced the amount of trabecular bone in mice. Our data suggest that care should be taken when considering using BMP4 as a therapeutic agent. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research

High prevalence of respiratory symptoms among workers in the development section of a manually operated coal mine in a developing country: A cross sectional study

BACKGROUND: Few studies of miners have been carried out in African countries; most are from South Africa, where the working conditions are assumed to be better than in the rest of Africa. Several studies have focused on respiratory disorders among miners, but development workers responsible for creating underground road ways have not been studied explicitly. This is the first study assessing the associations between exposure to dust and quartz and respiratory symptoms among coal mine workers in a manually operated coal mine in Tanzania, focusing on development workers, as they have the highest exposure to coal dust. METHODS: A cross-sectional study was carried out among 250 production workers from a coal mine. Interviews were performed using modified standardized questionnaires to elicit information on occupational history, demographics, smoking habits and acute and chronic respiratory symptoms. The relationships between current dust exposure as well as cumulative respirable dust and quartz and symptoms were studied by group comparisons as well as logistic regression. RESULTS: Workers from the development group had the highest dust exposure, with arithmetic mean of 10.3 mg/m(3 )for current respirable dust and 1.268 mg/m(3 )for quartz. Analogous exposure results for mine workers were 0.66 mg/m(3 )and 0.03 mg/m(3), respectively; and for other development workers were 0.88 mg/m(3 )and 0.10 mg/m(3), respectively. The workers from the development section had significantly higher prevalence of the acute symptoms of dry cough (45.7%), breathlessness (34.8%) and blocked nose (23.9%). In addition, development workers had significantly more chronic symptoms of breathlessness (17.0%) than the mine workers (6.4%) and the other production workers (2.4%). The highest decile of cumulative exposure to respirable dust was significantly associated with cough (OR = 2.91, 95% CI 1.06, 7.97) as were cumulative exposure to quartz and cough (OR = 2.87, CI 1.05, 7.88), compared with the reference consisting of the group of workers with the lowest quartile of the respective cumulative exposure. CONCLUSION: The development workers in a coal mine had more acute and chronic respiratory symptoms than the mine and the other production workers. In addition, there was an association between high cumulative coal dust and respiratory symptoms

Speciation in little: the role of range and body size in the diversification of Malagasy mantellid frogs

<p>Abstract</p> <p>Background</p> <p>The rate and mode of lineage diversification might be shaped by clade-specific traits. In Madagascar, many groups of organisms are characterized by tiny distribution ranges and small body sizes, and this high degree of microendemism and miniaturization parallels a high species diversity in some of these groups. We here investigate the geographic patterns characterizing the radiation of the frog family Mantellidae that is virtually endemic to Madagascar. We integrate a newly reconstructed near-complete species-level timetree of the Mantellidae with georeferenced distribution records and maximum male body size data to infer the influence of these life-history traits on each other and on mantellid diversification.</p> <p>Results</p> <p>We reconstructed a molecular phylogeny based on nuclear and mitochondrial DNA for 257 species and candidate species of the mantellid frog radiation. Based on this phylogeny we identified 53 well-supported pairs of sister species that we used for phylogenetic comparative analyses, along with whole tree-based phylogenetic comparative methods. Sister species within the Mantellidae diverged at 0.2-14.4 million years ago and more recently diverged sister species had geographical range centroids more proximate to each other, independently of their current sympatric or allopatric occurrence. The largest number of sister species pairs had non-overlapping ranges, but several examples of young microendemic sister species occurring in full sympatry suggest the possibility of non-allopatric speciation. Range sizes of species included in the sister species comparisons increased with evolutionary age, as did range size differences between sister species, which rejects peripatric speciation. For the majority of mantellid sister species and the whole mantellid radiation, range and body sizes were associated with each other and small body sizes were linked to higher mitochondrial nucleotide substitution rates and higher clade diversity. In contrast, small range sizes were unexpectedly associated with a slow-down of mitochondrial substitution rates.</p> <p>Conclusions</p> <p>Based on these results we define a testable hypothesis under which small body sizes result in limited dispersal capabilities and low physiological tolerances, causing smaller and more strongly fragmented ranges. This can be thought to facilitate reproductive isolation and thus favor speciation. Contrary to the expectation of the faster speciation of such microendemic phenotype species, we only found small body sizes of mantellid frogs to be linked to higher diversification and substitution rates, but not small range sizes. A joint analysis of various species-rich regional anuran radiations might provide enough species with all combinations of range and body sizes for a more conclusive test of this hypothesis.</p

Regulation of RKIP Function by Helicobacter pylori in Gastric Cancer

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that infects more than half of the world’s population and is a major cause of gastric adenocarcinoma. The mechanisms that link H. pylori infection to gastric carcinogenesis are not well understood. In the present study, we report that the Raf-kinase inhibitor protein (RKIP) has a role in the induction of apoptosis by H. pylori in gastric epithelial cells. Western blot and luciferase transcription reporter assays demonstrate that the pathogenicity island of H. pylori rapidly phosphorylates RKIP, which then localizes to the nucleus where it activates its own transcription and induces apoptosis. Forced overexpression of RKIP enhances apoptosis in H. pylori-infected cells, whereas RKIP RNA inhibition suppresses the induction of apoptosis by H. pylori infection. While inducing the phosphorylation of RKIP, H. pylori simultaneously targets non-phosphorylated RKIP for proteasome-mediated degradation. The increase in RKIP transcription and phosphorylation is abrogated by mutating RKIP serine 153 to valine, demonstrating that regulation of RKIP activity by H. pylori is dependent upon RKIP’s S153 residue. In addition, H. pylori infection increases the expression of Snail, a transcriptional repressor of RKIP. Our results suggest that H. pylori utilizes a tumor suppressor protein, RKIP, to promote apoptosis in gastric cancer cells

Neuroendocrine–immune disequilibrium and endometriosis: an interdisciplinary approach

Endometriosis, a chronic disease characterized by endometrial tissue located outside the uterine cavity, affects one fourth of young women and is associated with chronic pelvic pain and infertility. However, an in-depth understanding of the pathophysiology and effective treatment strategies of endometriosis is still largely elusive. Inadequate immune and neuroendocrine responses are significantly involved in the pathophysiology of endometriosis, and key findings are summarized in the present review. We discuss here the role of different immune mechanisms particularly adhesion molecules, protein–glycan interactions, and pro-angiogenic mediators in the development and progression of the disease. Finally, we introduce the concept of endometrial dissemination as result of a neuroendocrine-immune disequilibrium in response to high levels of perceived stress caused by cardinal clinical symptoms of endometriosis

Advances in understanding and treating ADHD

Attention deficit hyperactivity disorder (ADHD) is a neurocognitive behavioral developmental disorder most commonly seen in childhood and adolescence, which often extends to the adult years. Relative to a decade ago, there has been extensive research into understanding the factors underlying ADHD, leading to far more treatment options available for both adolescents and adults with this disorder. Novel stimulant formulations have made it possible to tailor treatment to the duration of efficacy required by patients, and to help mitigate the potential for abuse, misuse and diversion. Several new non-stimulant options have also emerged in the past few years. Among these, cognitive behavioral interventions have proven popular in the treatment of adult ADHD, especially within the adult population who cannot or will not use medications, along with the many medication-treated patients who continue to show residual disability

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Moose and snowshoe hare competition and a mechanistic explanation from foraging theory

Moose ( Alces alces ) and snowshoe hare ( Lepus americanus ) appear to compete with each other. This was determined using the “natural experiments” of populations found in sympatry and allopatry on islands at Isle Royale National Park, Michigan, and manipulated exclosures. The population densities from these areas are fit to a series of competition models based upon different competitive mechanisms (Schoener 1974a), using non-linear regression techniques. A model of competition for food where the food can be separated into exclusively used and shared categories is found to predict observed densities of moose and hare best. Finally, the competition model's parameters (fraction of food shared and competition coefficients) are shown to agree with values predicted independently from a foraging model.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47750/1/442_2004_Article_BF00396753.pd

Investigation of Genetic Variation Underlying Central Obesity amongst South Asians

The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966,G0700931), the Wellcome Trust (084723/Z/08/Z), and the NIHR (RP-PG-0407-10371). The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The Sikh Diabetes Study is supported by National Institute of Health grants KO1TW006087, funded by the Fogarty International Center, R01DK082766, funded by National Institute of Diabetes and Digestive and Kidney Diseases, and a seed grant from University of Oklahoma Health Sciences Center, Oklahoma City, USA. The Mauritius Family Study is supported by the Mauritius Ministry of Health and Quality of Life, Australian Government National Health and Medical Research Council NHMRC project grant numbers 1020285 and 1037916, the Victorian Government’s OIS Program, and partly funded by US National Institutes of Health Grant DK-25446. We thank the participants and research staff who made the study possible.South Asians are 1/4 of the world’s population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10−6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans.Yeshttp://www.plosone.org/static/editorial#pee