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Systemic Intermittent Hypoxic Therapy (IHT) relies on the adaptive response to hypoxic stress. We investigated allogenic bone-graft resorption in the lumbar spine in 48 mice. The mice were exposed to IHT for 1 week before surgery or 1 week after surgery and compared with controls after 1 and 4 weeks. Complete graft resorption was observed in 33–36% of the animals in the control group, but none in the preoperative IHT group. Increased bone-graft volume was demonstrated by micro-computed tomography in the preoperative IHT group after 1 week (p = 0.03) while a non-significant difference was observed after 4 weeks (p = 0.12). There were no significant differences in the postoperative IHT group. Increased concentration of immune cells was localized in the graft area, and more positive tartrate-resistant acid phosphatase (TRAP) staining was found in controls compared with IHT allogenic bone grafts. Systemic IHT resulted in a significant increase of the major osteoclast inhibitor osteoprotegerin as well as osteogenic and angiogenic regulators Tgfbr3, Fst3l, Wisp1, and Vegfd. Inflammatory cytokines and receptor activator of nuclear factor kappa-B ligand (RANKL) stimulators IL-6, IL-17a, IL-17f, and IL-23r increased after 1 and 4 weeks, and serum RANKL expression remained constant while Ccl3 and Ccl5 decreased. We conclude that the adaptive response to IHT activates numerous pathways leading to inhibition of osteoclastic activity and inhibition of allogenic bone-graft resorption.

4-1BB is a T cell costimulatory receptor and a member of the tumor necrosis factor receptor superfamily. Here, we show that Galectin-3 (Gal-3) decreases the cellular response to its ligand (4-1BBL). Gal-3 binds to both soluble 4-1BB (s4-1BB) and membrane-bound 4-1BB (mem4-1BB), without blocking co-binding of 4-1BBL. In plasma, we detected complexes composed of 4-1BB and Gal-3 larger than 100 nm in size; these complexes were reduced in synovial fluid from rheumatoid arthritis. Both activated 4-1BB + T cells and 4-1BB-transfected HEK293 cells depleted these complexes from plasma, followed by increased expression of 4-1BB and Gal-3 on the cell surface. The increase was accompanied by a 4-fold decrease in TNFα production by the 4-1BB high Gal-3 + T cells, after exposure to 4-1BB/Gal-3 complexes. In RA patients, complexes containing 4-1BB/Gal-3 were dramatically reduced in both plasma and SF compared with healthy plasma. These results support that Gal-3 binds to 4-1BB without blocking the co-binding of 4-1BBL. Instead, Gal-3 leads to formation of large soluble 4-1BB/Gal-3 complexes that attach to mem4-1BB on the cell surfaces, resulting in suppression of 4-1BBL’s bioactivity.

Efanesoctocog alfa is a factor VIII fusion agent that permits weekly treatment to prevent bleeding. In this study, two thirds of treated patients had no bleeding episodes, and the annualized bleeding rate fell by 77%.

IntroductionHaemophilia A is a rare bleeding disorder caused by coagulation factor VIII (FVIII) deficiency. This is treated with factor VIII, conventionally using products with a half-life of 8–12 hours typically administered every 2–3 days. Recombinant FVIII Fc (rFVIIIFc) represents a new generation of products with an extended half-life allowing higher FVIII levels and longer dosing interval. The efficacy and safety of rFVIIIFc have been established in clinical studies and several years of postmarketing use. However, there remains a need to compare treatment outcome with conventional products in routine clinical use.Methods and analysisA-SURE is an ongoing, non-interventional European study with the primary objective to compare the clinical effectiveness of rFVIIIFc with conventional factor products used for haemophilia A prophylaxis. Data covering a 24-month prospective period and a 12-month retrospective period will be collected. Three primary endpoints: bleeding rate, injection frequency and factor consumption will be used to evaluate treatment outcomes. Enrolment of 175 patients on rFVIIIFc and 175 on conventional products is planned. All eligible patients from participating centres will be invited to participate. Visits and treatments follow routine clinical practice. Bias will be reduced by patient matching for age at baseline and the last weekly prophylaxis dose of a conventional product prior to baseline. Propensity scores will be calculated based on prognostic factors and potential confounders assessed at baseline and adjusted for in the estimation of the treatment effect.Ethics and disseminationStudy approval was obtained by local independent ethics committees and/or authorities, and informed consent from patients or their legal representative is a requirement for participation. Names of ethical committees and approval numbers are provided as supplementary information. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences.Trial registration number NCT02976753, Pre-results.

In the phase 3 B‐LONG study (NCT01027364), prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) every 7 to >14 days was associated with low annualized bleed rates (ABRs) in males aged ≥12 years with severe hemophilia B. The long‐term safety and efficacy of rFIXFc prophylaxis was confirmed in the B‐YOND study (NCT01425723), an extension of the B‐LONG clinical trial. The aim of this post‐hoc analysis was to evaluate the efficacy of a ≥14‐day rFIXFc dosing interval in patients treated prophylactically during B‐LONG or B‐YOND. The analysis included 22 patients aged ≥12 years who received prophylactic rFIXFc with a ≥14‐day dosing interval at any time during B‐LONG or B‐YOND up until the second interim analysis of B‐YOND (September 2015). The median (interquartile range [IQR]) rFIXFc exposure on the ≥14‐day dosing interval was 3.4 (1.8‐4) years. Patients treated with a ≥14‐day dosing interval were well controlled with a median (IQR) overall ABR of 1.6 (0.6‐2.7) and a median (IQR) spontaneous ABR of 0.7 (0.3‐1.1) in 18 evaluable patients. A rFIXFc dosing interval of ≥14 days was well tolerated, with no new safety concerns identified. Most patients on rFIXFc prophylaxis, with a dosing interval of ≥14 days, remained well controlled; ABRs were consistent with those reported in the overall study population. A ≥14‐day dosing interval can be utilized in some well controlled individuals and reduces the burden imposed by frequent prophylactic injections while maintaining adequate bleed suppression.

Purpose: The purpose of this study was to elucidate the potential of human breast cancer cells (BCC) to induce matrix degradation and neo-vascularization, essential for continued tumor growth, in osteolytic lesions. Methods: BCC were inoculated into the left cardiac ventricle of female athymic mice and osteolytic lesions were radiologically visualized within 4 weeks from inoculation. Results: Histomorphometric analysis of bone sections revealed a significant increase in the number and maturity of osteoclasts (OCl) lining the bone surfaces next to tumor tissue when compared to corresponding bone surfaces in healthy mice. In addition, a large number of newly formed blood vessels could be visualized by immunohistochemistry at the periphery of and within tumor tissue. When bone marrow (BM) cells were cultured in the presence of BCC the OCl formation was increased threefold. These OCl were also found to be more mature and to have greater resorptive activity. Moreover, BCC were found to stimulate proliferation, migration, and differentiation of BM-derived endothelial cells. Conclusions: Matrix destruction and neo-vascularization are accomplished by BCC arrested in the BM cavity by increasing recruitment and activity of OCl and by induction of angiogenesis within or in proximity to the tumor tissue.

The effect of 17-beta-estradiol (E2) on the induction of osteolytic lesions by estrogen receptor (ER)-negative breast cancer cells was investigated in 4-week-old female nude mice. Exposure to exogenous E2 was found to increase osteolytic areas on radiographs up to 5.3 times in mice inoculated intracardially with MDA-231 human breast cancer cells. The MDA-231 cells were ER-negative, both before inoculation, and after isolation from osteolytic lesions, and the corresponding cell cultures were insensitive to E2. The induction of skeletal lesions by E2 in this mouse model was mainly effectuated at the early development of bone metastases, since exposure to E2 for 8 days around MDA-231 inoculation increased osteolysis to the same level, as did E2 given throughout the entire 31-day experimental period, and because E2-exposure for just the final 14 days had no effect. Independently of exposure to E2, histology revealed cancer cells in hind limp long bones of approximately 80% of the mice, and tumors were absent in non-skeletal organs. In vitro studies showed that the number and activity of osteoclasts generated from mouse bone marrow cells were increased 5-6 times when co-cultured with MDA-231 cells. Addition of 0.1-10 nM E2 further dose-dependently increased the osteoclastogenesis and associated bone resorption in these co-cultures. In conclusion, E2 was found to increase the morbidity in mice inoculated with ER-negative MDA-231 cells, and to stimulate osteoclast formation and bone resorption in co-cultures of bone marrow cells and MDA-231, suggesting that the progression of osteolytic metastases by ER-negative breast cancer cells can be induced by E2 due to stimulation of osteoclastogenesis.

Two oysters, the native flat oyster, Ostrea edulis , and the non-indigenous Pacific oyster, Crassostrea gigas , have partially overlapping distributions in European waters. Relatively little is known about particle selection by O. edulis , and the goal of the present study was to establish baselines for particle selection by both oyster species under controlled conditions in the laboratory. The study was carried out with adult oysters of similar shell size collected in the Limfjord estuary, Denmark (56°47′N, 08°51′E), in November 2011. The feeding traits of both species [clearance rate (CR), retention efficiency (RE) and lower threshold for clearance (LTC)] were compared using five algal species with different cell sizes (5−32 µm ESD) ( Isochrysis galbana , Rhodomonas salina , Thalassiosira weissflogii , Prorocentrum micans and Akashiwo sanguinea ). Oysters were acclimated to an experimental temperature of 22 °C and a salinity of 25. The CR of O. edulis was one to three times lower than that of C. gigas for the three smaller algal species (5−15 µm) but not different for the two larger algae. Algae in the size range 7−32 µm were retained with 100% RE by both oysters, but the smallest alga was retained with reduced RE (~35%). There were no differences in LTC between the two oysters. A closer examination of the relationship between LTC and different measures of the algae present (cell size, cell volume, chl a , C and N) suggests that the LTC, and also the CR, may depend in part on the internal energy status of the oysters.

Copepoda is one of the most ecologically important animal groups on Earth, yet very few genetic resources are available for this Subclass. Here, we present the first whole genome sequence (WGS, acc. UYDY01) and the first mRNA transcriptome assembly (TSA, Acc. GHAJ01) for the tropical cyclopoid copepod species Apocyclops royi. Until now, only the 18S small subunit of ribosomal RNA gene and the COI gene has been available from A. royi, and WGS resources was only available from one other cyclopoid copepod species. Overall, the provided resources are the 8th copepod species to have WGS resources available and the 19th copepod species with TSA information available. We analyze the length and GC content of the provided WGS scaffolds as well as the coverage and gene content of both the WGS and the TSA assembly. Finally, we place the resources within the copepod order Cyclopoida as a member of the Apocyclops genus. We estimate the total genome size of A. royi to 450 Mb, with 181 Mb assembled nonrepetitive sequence, 76 Mb assembled repeats and 193 Mb unassembled sequence. The TSA assembly consists of 29,737 genes and an additional 45,756 isoforms. In the WGS and TSA assemblies, >80% and >95% of core genes can be found, though many in fragmented versions. The provided resources will allow researchers to conduct physiological experiments on A. royi, and also increase the possibilities for copepod gene set analysis, as it adds substantially to the copepod datasets available.

Subitaneous eggs from an euryhaline calanoid copepod Acartia tonsa were challenged by changes in salinity within the range from full strength salinity, down to zero and up to >70 psu. Egg volume changed immediately, increasing from 2.8 × 10 5  μm 3 at full strength salinity (35 psu) to 3.8 × 10 5  μm 3 at 0 psu and back to its initial volume when gradually being returned to full strength salinity. Egg osmolality followed the molality of the surrounding water when challenged within a salinity range from 2 to 50 psu. Egg respiration was not affected when eggs kept at 35 psu was exposed to low salinity (2 psu). These results suggest that eggs are unable to regulate their volume or osmolality when challenged with changes in salinity. Gradual changes in salinity from 35 to 2 psu and back did not harm the eggs (embryos), since the hatching success remained unaffected by such changes in salinity. In contrast, extreme hyper-saline conditions (76 psu) made the eggs implode and killed the embryo. We propose that the embryo is protected from salinity stress by its plasma membrane and that water exchange driven by osmosis is restricted to the perivitelline space of the egg, which acts as a perfect osmometer in the salinity range of 5–35 psu. We hypothesize further that the embryo is able to keep its volume and osmolality constant due to the impermeability of the inner plasma membrane of the egg or by a combination of osmoregulation and reduced permeability of the inner plasma membrane.