Critical Role of AKT in Myeloma-induced Osteoclast Formation and Osteolysis

Abnormal osteoclast formation and osteolysis are the hallmarks of multiple myeloma (MM) bone disease, yet the underlying molecular mechanisms are incompletely understood. Here, we show that the AKT pathway was up-regulated in primary bone marrow monocytes (BMM) from patients with MM, which resulted in sustained high expression of the receptor activator of NF-κB (RANK) in osteoclast precursors. The up-regulation of RANK expression and osteoclast formation in the MM BMM cultures was blocked by AKT inhibition. Conditioned media from MM cell cultures activated AKT and increased RANK expression and osteoclast formation in BMM cultures. Inhibiting AKT in cultured MM cells decreased their growth and ability to promote osteoclast formation. Of clinical significance, systemic administration of the AKT inhibitor LY294002 blocked the formation of tumor tissues in the bone marrow cavity and essentially abolished the MM-induced osteoclast formation and osteolysis in SCID mice. The level of activating transcription factor 4 (ATF4) protein was up-regulated in the BMM cultures from multiple myeloma patients. Adenoviral overexpression of ATF4 activated RANK expression in osteoclast precursors. These results demonstrate a new role of AKT in the MM promotion of osteoclast formation and bone osteolysis through, at least in part, the ATF4-dependent up-regulation of RANK expression in osteoclast precursors

In vitro and ex vivo evaluation of bi-layered effervescent microenvironmental pH modifying buccal films with saquinavir

Buccal delivery of saquinavir has the advantage to bypass the hepatic first-pass metabolism associated with oral administration. Local microenvironmental pH (pHM) modification at the buccal mucosa might increase absorption of saquinavir by balancing the solubility and partition of saquinavir into the buccal mucosa. The present study aimed to evaluate a novel saquinavir pHM modifying buccal film using effervescence, as well as to elucidate the relationship between pHM and permeation of saquinavir released from the buccal films. Hydroxypropyl methylcellulose-based films were prepared: 1) a bilayered effervescent film composed of an alkaline layer and a layer containing saquinavir and malic acid, 2) a monolayered film composed of saquinavir and malic acid (pHM modifying film), and 3) a monolayered film composed of saquinvir (control). The release of saquinavir from these films and permeation of saquinavir across porcine mucosae were evaluated. The monolayered pHM modifying film led to a decrease in pHM from pH 6.8 to 3.0 after 5.5 min, while the effervescent film had an initial decrease in pHM (from pH 6.8 to 4.0) caused by the co-release of malic acid and a subsequent pHM increase (from pH 4.0 to 5.9) caused by the release of carbonate from the alkaline layer within 15 min. Saquinavir released faster from the pHM modifying film than from the effervescent film. However, a higher permeation of saquinavir and mucosal accumulation was observed for the effervescent film. This could be attributed to the higher concentration of ionized specie and a faster tissue partitioning of unionized saquinavir, respectively. These results suggest that effervescent pHM modifying film is a potential formulation strategy for buccal delivery of saquinavir

Skeletal muscle structural lipids improve during weight-maintenance after a very low calorie dietary intervention

<p>Abstract</p> <p>Background</p> <p>The objective was to investigate in a group of obese subjects the course in skeletal muscle phospholipid (SMPL) fatty acids (FA) during a 24-weeks weight maintenance program, which was preceded by a successful very low calorie dietary intervention (VLCD). Special focus was addressed to SMPL omega-3 FA, which is a lipid entity that influences insulin action.</p> <p>Methods</p> <p>Nine obese subjects (BMI = 35.7 ± 1.0 kg/m²), who had completed an 8 weeks VLCD (weight-loss = -9.7 ± 1.6 kg, P < 0.001), had obtained skeletal muscle biopsies (vastus lateralis) before and after a dietician-guided 24-weeks weight-maintenance program (-1.2 ± 1.5 kg, P = ns). SMPL FA composition was determined by gas liquid chromatography. During the preceding VLCD, insulin sensitivity (HOMA-IR) and glycemic control (HbA1c) improved but no change in SMPL omega-3 FA was observed. During the weight-maintenance program five subjects received the pancreas lipase inhibitor Orlistat 120 mg t.i.d. versus placebo.</p> <p>Results</p> <p>HOMA-IR and HbA1c stabilized and SMPL total omega-3 FA, docosahexaenoic acid and ratio of n-3/n-6 polyunsaturated FA increased by 24% (P < 0.01), 35% (P < 0.02) and 26% (P < 0.01), respectively, whereas saturated and monounsaturated FA did not change. Plasma total-cholesterol and LDL-cholesterol, which decreased during the VLCD, reverted to pre-VLCD levels (P < 0.01). Orlistat therapy was associated with weight-loss (P < 0.05), trends for better glycemic control (P = 0.15) and greater increase in SMPL docosahexaenoic acid (P = 0.12) but similar reversal of plasma cholesterols compared to placebo.</p> <p>Conclusion</p> <p>The data are consistent with the notion that greater SMPL omega-3 FA obtained during a weight-maintenance program may play a role for preserving insulin sensitivity and glycemic control being generated during a preceding VLCD.</p

Design of Mobile Communication Indoor Distribution System

With the development of economy, the improvement of people's living standard has been increasing and theconstruction of buildings is becoming more demanding. These buildings are large in scale and of good quality andhave a strong shielding effect on mobile phone signals. In the middle of the large-scale buildings, undergroundshopping malls, underground parking and other environments, the mobile communication signal is weak hence thephone cannot be used normally and forming a mobile communication blind area and shadow area. In the middlefl oor, due to the surrounding diff erent base station signal overlap, the ping-pong eff ect, frequent switching of mobilephones and even dropped calls are seriously aff ecting the normal use of mobile phones. In the building's higher fl oors,due to the height of the base station antenna, it has abnormal coverage and there is also mobile communication blindspot. In addition, in some buildings, although the phone can answer normal call but the user density, base stationchannel congestion and mobile phone line is diffi cult. In particular, the network coverage, capacity and quality ofmobile communication are the key factors for operators to gain competitive advantage. Network coverage, networkcapacity and network quality fundamentally refl ects the mobile network service level and is the theme of all mobilenetwork optimization work. The indoor coverage system is produced under this background. According to the relevantstatistics in some areas of indoor traffi c in the total traffi c accounted for a higher proportion. Therefore, strengtheningthe indoor coverage is of great signifi cance to improve the quality of mobile communication

Evaluation of the impact of the COVID-19 pandemic on health service utilization in China: A study using auto-regressive integrated moving average model

BackgroundThe outbreak of COVID-19 in early 2020 presented a major challenge to the healthcare system in China. This study aimed to quantitatively evaluate the impact of COVID-19 on health services utilization in China in 2020.MethodsHealth service-related data for this study were extracted from the China Health Statistical Yearbook. The Auto-Regressive Integrated Moving Average model (ARIMA) was used to forecast the data for the year 2020 based on trends observed between 2010 and 2019. The differences between the actual 2020 values reported in the statistical yearbook and the forecast values from the ARIMA model were used to assess the impact of COVID-19 on health services utilization.ResultsIn 2020, the number of admissions and outpatient visits in China declined by 17.74 and 14.37%, respectively, compared to the ARIMA model’s forecast values. Notably, public hospitals experienced the largest decrease in outpatient visits and admissions, of 18.55 and 19.64%, respectively. Among all departments, the pediatrics department had the greatest decrease in outpatient visits (35.15%). Regarding geographical distribution, Beijing and Heilongjiang were the regions most affected by the decline in outpatient visits (29.96%) and admissions (43.20%) respectively.ConclusionThe study’s findings suggest that during the first year of the COVID-19 pandemic, one in seven outpatient services and one in six admissions were affected in China. Therefore, there is an urgent need to establish a green channel for seeking medical treatment without spatial and institutional barriers during epidemic prevention and control periods