Angiogenesis inhibition is a promising approach for treating metastatic colorectal cancer (mCRC). Recent evidences support the seemingly counterintuitive ability of certain antiangiogenic drugs to ...promote normalization of residual tumor vessels with important clinical implications. Lenalidomide is an oral drug with immune-modulatory and anti-angiogenic activity against selected hematologic malignancies but as yet little is known regarding its effectiveness for solid tumors. The aim of this study was to determine whether lenalidomide can normalize colorectal cancer neo-vessels in vivo, thus reducing tumor hypoxia and improving the benefit of chemotherapy.
We set up a tumorgraft model with NOD/SCID mice implanted with a patient-derived colorectal cancer liver metastasis. The mice were treated with oral lenalidomide (50 mg/Kg/day for 28 days), intraperitoneal 5-fluorouracil (5FU) (20 mg/Kg twice weekly for 3 weeks), combination (combo) of lenalidomide and 5FU or irrelevant vehicle. We assessed tumor vessel density (CD146), pericyte coverage (NG2; alphaSMA), in vivo perfusion capability of residual vessels (lectin distribution essay), hypoxic areas (HP2-100 Hypoxyprobe) and antitumor activity in vivo and in vitro.
Treatment with lenalidomide reduced tumor vessel density (p = 0.0001) and enhanced mature pericyte coverage of residual vessels (p = 0.002). Perfusion capability of tumor vessels was enhanced in mice treated with lenalidomide compared to controls (p = 0.004). Accordingly, lenalidomide reduced hypoxic tumor areas (p = 0.002) and enhanced the antitumor activity of 5FU in vivo. The combo treatment delayed tumor growth (p = 0.01) and significantly reduced the Ki67 index (p = 0.0002). Lenalidomide alone did not demonstrate antitumor activity compared to untreated controls in vivo or against 4 different mCRC cell lines in vitro.
We provide the first evidence of tumor vessel normalization and hypoxia reduction induced by lenalidomide in mCRC in vivo. This effect, seemingly counterintuitive for an antiangiogenic compound, translates into indirect antitumor activity thus enhancing the therapeutic index of chemotherapy. Our findings suggest that further research should be carried out on synergism between lenalidomide and conventional therapies for treating solid tumors that might benefit from tumor vasculature normalization.
Summary
Background Vitiligo is a pigmentary disorder which may have disfiguring consequences. Its treatment remains a challenge.
Objectives We designed a parallel‐group randomized controlled trial ...to compare the effectiveness of 308‐nm excimer laser alone or in combination with topical hydrocortisone 17‐butyrate cream in patients with vitiligo unresponsive to previous treatment with topical steroids or narrow‐band ultraviolet (UV) B phototherapy.
Methods Consecutive patients aged 18–75 years with nonsegmental vitiligo localized on the face and/or neck lacking response to previous conventional treatment were eligible. In total, 84 patients (44 women and 40 men, mean age 44 years) were randomized to 308‐nm excimer laser phototherapy twice weekly alone or in combination with topical hydrocortisone 17‐butyrate cream twice daily for three periods of 3 weeks followed by a 1‐week steroid‐free interval. The primary outcome was a reduction of at least 75% of the overall lesional areas as judged by automatic image analysis on reflected UV photographs, conducted blind to treatment assignment, at 12 weeks compared with baseline. Secondary outcomes were clearance, and improvements on Physician’s Global Assessment (PGA) and Skindex‐29 scores.
Results A total of 76 (90%) patients completed the study. In an intention‐to‐treat analysis, seven 16·6%; 95% confidence interval (CI) 5·3–27·8% patients in the excimer monotherapy arm and 18 (42·8%; 95% CI 27·8–57·8%) in the combination arm showed ≥ 75% reduction of vitiligo lesions at 12 weeks (χ2 test 6·89, P = 0·0087). Clearance was observed in two (4·7%; 95% CI 1·6–11·2%) and nine (21·4%; 95% CI 9·0–33·8%) patients, respectively (Fisher’s exact test P = 0·04). A significant difference also emerged for PGA scores, while no difference was documented for Skindex‐29.
Conclusions Recalcitrant vitiligo of the face and neck may benefit from the combination of excimer laser phototherapy with topical hydrocortisone 17‐butyrate cream.
Summary
This study evaluates cytokines production in bone and bone marrow of patients with an osteoporotic fracture or with osteoarthritis by real time PCR, Western blot and immunohistochemistry. We ...demonstrate that the cytokine pattern is shifted towards osteoclast activation and osteoblast inhibition in patients with osteoporotic fractures.
Introduction
Fragility fractures are the resultant of low bone mass and poor bone architecture typical of osteoporosis. Cytokines involved in the control of bone cell maturation and function are produced by both bone itself and bone marrow cells, but the roles of these two sources in its control and the amounts they produce are not clear. This study compares their production in patients with an osteoporotic fracture and those with osteoarthritis.
Methods
We evaluated 52 femoral heads from women subjected to hip-joint replacement surgery for femoral neck fractures due to low-energy trauma (37), or for osteoarthritis (15). Total RNA was extracted from both bone and bone marrow, and quantitative PCR was used to identify the receptor activator of nuclear factor kB Ligand (RANKL), osteoprotegerin (OPG), macrophage colony stimulating factor (M-CSF), transforming growth factor β (TGFβ), Dickoppf-1 (DKK-1) and sclerostin (SOST) expression. Immunohistochemistry and Western blot were performed in order to quantify and localize in bone and bone marrow the cytokines.
Results
We found an increase of RANKL/OPG ratio, M-CSF, SOST and DKK-1 in fractured patients, whereas TGFβ was increased in osteoarthritic bone. Bone marrow produced greater amounts of RANKL, M-CSF and TGFβ compared to bone, whereas the production of DKK-1 and SOST was higher in bone.
Conclusions
We show that bone marrow cells produced the greater amount of pro-osteoclastogenic cytokines, whereas bone cells produced higher amount of osteoblast inhibitors in patients with fragility fracture, thus the cytokine pattern is shifted towards osteoclast activation and osteoblast inhibition in these patients.
A long‐term numerical experiment has been conducted using the Whole Atmosphere Community Climate Model (WACCM) to investigate the response of the middle atmosphere to time‐varying spectral solar ...irradiance over multiple 11‐year cycles, modeled on the basis of observed 10.7‐cm radio flux (F10.7). The model domain covers from the Earth's surface to the lower thermosphere with approximately two‐degree horizontal resolution and 66 vertical layers. Sea surface temperatures are prescribed by a climatological annual cycle, and boundary data for chemical compositions are held constant. The experiment does not include spontaneous nor imposed quasi‐biennial oscillation. Temperature and ozone differences near the stratopause between solar max and min, typically 0.8 K and 1.6% corresponding to approximately 100 units of F10.7 variation, have general agreement with the current scientific understanding. The model's dynamical responses as an indirect solar effect are substantially weak during winter against evidences from past empirical studies. The indirect solar signal tends to appear when the polar vortex becomes weak. The most striking signal is more frequent stratospheric sudden warmings during solar max in the Northern Hemisphere late winter through early spring, supporting observed tendencies. This modulation has an aspect of the annular mode and results in a major impact on the troposphere in early spring. Such a signal, however, does not appear in the Southern Hemisphere where the model has a westerly bias. There is no marked response in the equatorial lower stratosphere.
Summary
This study shows that teriparatide promotes the circulating osteoblast (OB) precursor degree of maturation in patients affected by postmenopausal osteoporosis.
Introduction
Anabolic treatment ...with teriparatide has proven effective for the therapy of postmenopausal osteoporosis and significantly reduces the risk of non-vertebral fragility fractures. The aim of this study was to investigate the effect of teriparatide on circulating OB precursors.
Methods
We evaluated by flow cytometry and real-time PCR the expression of OBs typical markers in peripheral blood mononuclear cells during treatment with teriparatide plus calcium and vitamin D, raloxifene plus calcium and vitamin D or calcium and vitamin D alone at various time points. Serum bone alkaline phosphatase and osteocalcin (OC) were measured as markers of bone turnover.
Results
Our results show that circulating OB precursors are more numerous and more immature in patients affected by fragility fractures than in osteoporotic patients without fractures. We also show that teriparatide treatment increases the expression of alkaline phosphatase and of OC in OB precursors; thus, it increases their degree of maturation.
Conclusions
We suggest that teriparatide acts as anabolic agents also by promoting the maturation of OB precursors.
Global meteorological analyses from an assimilation of operational and research observations spanning the ∼0–90 km altitude range confirm earlier tentative suggestions that high‐altitude winds ...throughout the upper mesosphere reversed a week before the major stratospheric sudden warming (SSW) of January 2009. Analyzed winds reveal descent of mean easterlies from the upper mesosphere to the lower stratosphere, followed by more easterly winds throughout the Arctic troposphere in the weeks after the SSW, indicating that these descending Northern Annular Mode (NAM) anomalies reached the surface. Eliassen‐Palm fluxes reveal that the mesospheric precursor to this event was driven by transient nonstationary wave‐2 planetary waves that propagated rapidly from the troposphere into the upper mesosphere, where they dissipated and produced easterly mean‐flow accelerations. This early SSW phase was characterized by both descending mesospheric easterlies and poleward expansion of subtropical stratospheric easterlies, which eventually merged in the extratropical upper stratosphere. These wind structures may in turn have focused transient wave‐2 planetary wave activity emerging from the troposphere in ways that intensified the SSW.
We compare two simulations of the middle atmosphere using the NCAR Whole Atmosphere Community Climate Model, which includes a comprehensive middle atmosphere chemistry model. Ozone is fully ...interactive in the first simulation. A zonal mean and monthly mean ozone climatology is constructed from the interactive simulation. That ozone climatology is used to determine the radiative heating rates in the second simulation. Comparison of the two simulations shows that using the zonal‐mean ozone climatology significantly affects the climate of the middle atmosphere. Differences between the two simulations are statistically significant throughout the tropics in the upper stratosphere and lower mesosphere.
Microalgae are emerging as a promising feedstock for bioplastics, with Chlorella vulgaris yielding significant amounts of starch. This polysaccharide is convertible into thermoplastic starch (TPS), a ...biodegradable plastic of industrial relevance. In this study, we developed a pilot-scale protocol for extracting and purifying starch from 430 g (dry weight – DW) of starch-enriched Chlorella vulgaris biomass. More than 200 gDW of starch were recovered, with an extraction yield and starch purity degree reaching 98 and 87 %, respectively. We have characterized this extracted starch and processed it into TPS using twin-screw extrusion and injection molding. Microalgal starch showed similar properties to those of native plant starch, but with smaller granules. We compared the mechanical properties of microalgal TPS with two controls, namely a commercial TPS and a TPS prepared from commercial potato starch granules. TPS prepared from microalgal starch showed a softer and more ductile behavior compared to the reference materials. This study demonstrates the feasibility of recovering high-purity microalgal starch at pilot scale with high yields, and highlights the potential of microalgal starch for the production of TPS using industrially relevant processes.
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