MIR-21 regulating distribution of intestinal flora through TNF-α promotes progression of ulcerative colitis.

Background: To study the changes in intestinal flora in patients with ulcerative colitis (UC), and to explore its correlations with micro ribonucleic acid (miR)-21 and serum tumor necrosis factor-a (TNF-α). Methods: A total of 150 patients with UC were selected and divided into remission group and seizure group according to the severity of disease. At the same time, 150 healthy people receiving physical examination in the hospital during the same period were selected as control group. The levels of fecal miR-21 and TNF-α in all subjects were determined via reverse transcription-polymerase chain reaction (RT-PCR). The correlation between miR-21 and TNF-α and their associations with the changes in intestinal bacteria in UC were analyzed using Pearson correlation analysis. The risk factors affecting the occurrence of UC were explored via multivariate logistic regression analysis.

Pose estimation and motion analysis of ski jumpers based on ECA-HRNet.

Ski jumping is a high-speed sport, which makes it difficult to accurately analyze the technical motion in a subjective way. To solve this problem, we propose an image-based pose estimation method for analyzing the motion of ski jumpers. First, an image keypoint dataset of ski jumpers (KDSJ) was constructed. Next, in order to improve the precision of ski jumper pose estimation, an efficient channel attention (ECA) module was embedded in the residual structures of a high-resolution network (HRNet) to fuse more useful feature information. At the training stage, we used a transfer learning method which involved pre-training on the Common Objection in Context (COCO2017) to obtain feature knowledge from the COCO2017 for using in the task of ski jumper pose estimation. Finally, the detected keypoints of the ski jumpers were used to analyze the motion characteristics, using hip and knee angles over time (frames) as an example. Our experimental results showed that the proposed ECA-HRNet achieved the average precision of 73.4% on the COCO2017 test-dev set and the average precision of 86.4% on the KDSJ test set using the ground truth bounding boxes. These research results can provide guidance for auxiliary training and motion evaluation of ski jumpers.

Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2-5 Years with Cystic Fibrosis and at Least One F508del Allele.

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and effective in people with cystic fibrosis (CF) aged ⩾6 years with at least one F508del-CFTR allele but has not been studied in younger children. Objectives: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA in children with CF aged 2-5 years. Methods: In this phase 3, open-label, two-part study (parts A and B), children weighing <14 kg (on Day 1) received ELX 80 mg once daily (qd), TEZ 40 mg qd, and IVA 60 mg each morning and 59.5 mg each evening; children weighing ⩾14 kg received ELX 100 mg qd, TEZ 50 mg qd, and IVA 75 mg every 12 hours. Measurements and Main Results: The primary endpoints for part A (15-d treatment period) were pharmacokinetics and safety and tolerability. For part B (24-wk treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5, defined as the number of lung turnovers required to reduce the end tidal N2 concentration to 2.5% of its starting value) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in part A confirmed the appropriateness of the part B dosing regimen. In part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events, which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (-57.9 mmol/L; 95% confidence interval [CI], -61.3 to -54.6; n = 69) and LCI2.5 (-0.83 U; 95% CI, -1.01 to -0.66; n = 50) were observed from baseline through Week 24. Mean body mass index was within the normal range at baseline and remained stable at Week 24. Conclusions: In this open-label study in children 2-5 years of age, ELX/TEZ/IVA treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and LCI2.5. Clinical trial registered with www.clinicaltrials.gov (NCT04537793).

Pose ResNet: 3D Human Pose Estimation Based on Self-Supervision.

The accurate estimation of a 3D human pose is of great importance in many fields, such as human-computer interaction, motion recognition and automatic driving. In view of the difficulty of obtaining 3D ground truth labels for a dataset of 3D pose estimation techniques, we take 2D images as the research object in this paper, and propose a self-supervised 3D pose estimation model called Pose ResNet. ResNet50 is used as the basic network for extract features. First, a convolutional block attention module (CBAM) was introduced to refine selection of significant pixels. Then, a waterfall atrous spatial pooling (WASP) module is used to capture multi-scale contextual information from the extracted features to increase the receptive field. Finally, the features are input into a deconvolution network to acquire the volume heat map, which is later processed by a soft argmax function to obtain the coordinates of the joints. In addition to the two learning strategies of transfer learning and synthetic occlusion, a self-supervised training method is also used in this model, in which the 3D labels are constructed by the epipolar geometry transformation to supervise the training of the network. Without the need for 3D ground truths for the dataset, accurate estimation of the 3D human pose can be realized from a single 2D image. The results show that the mean per joint position error (MPJPE) is 74.6 mm without the need for 3D ground truth labels. Compared with other approaches, the proposed method achieves better results.

Diagnostic value of 18F-PSMA-1007 PET/CT combined with prostate specific antigen derived indicators in gray area prostate cancer. / 18F-PSMA-1007 PET/CTè”åˆå‰åˆ—è ºç‰¹å¼‚æ€§æŠ—åŽŸè¡ç”ŸæŒ‡æ ‡å¯¹ç°åŒºå‰åˆ—è ºç™Œçš„è¯Šæ–­ä»·å€¼.

OBJECTIVES: The incidence of prostate cancer is increasing every year, and precision diagnosis and treatment can help reduce unnecessary prostate punctures for prostate cancer patients in the gray area. This study aims to investigate the diagnostic value of 18F-prostate specific membrane antigen (PSMA) imaging combined with prostate specific antigen (PSA)-derived indicators for gray zone prostate cancer. METHODS: A total of 107 patients who underwent 18F-PSMA PET/CT imaging for suspicious prostate cancer with tPSA of 4 to 10 µg/L (PSA gray zone) in a hospital were retrospectively included, and were divided into a prostate cancer group and a non-prostate cancer group based on pathological findings. Patients underwent PSA testing, 18F-PSMA, and abdominal ultrasound, and age, tPSA, fPSA, f/tPSA, prostate volume, PSA density (PSAD), maximum standardized uptake value (SUVmax), and molecular imaging prostate specific membrane antigen (miPSMA) score were compared between the 2 groups. Multivariate logistic regression was used to analyze the influencing factors the diagnosis of gray zone prostate cancer. Receiver operating characteristic (ROC) curves were constructed to evaluate the efficacy of PSAD and SUVmax alone and in combination in diagnosing gray zone prostate cancer. RESULTS: The volume of the prostate cancer group [42.00(34.00, 58.00) cm3 vs 49.00(41.27, 60.41) cm3] was smaller than that of the non-prostate cancer group (Z=-2.376, P=0.017), and the PSAD [(0.18±0.06) µg/(L·cm3) vs 0.15±0.05 µg/(L·cm3)] and SUVmax [18.63(8.03, 28.57) vs 9.33(5.90, 13.52)] were higher than those in the non-prostate cancer group (both P<0.05). The percentage of miPSMA score ≥2 in the prostate cancer group was higher than that in the non-prostate cancer group (χ2=40.987, P<0.001). PSAD (OR=22.154, 95% CI 1.430 to 873.751, P=0.042) and SUVmax (OR=1.301, 95% CI 1.034 to 1.678, P=0.009) were independent influential factors for the diagnosis of prostate cancer in the gray zone. The optimal cut-off values of PSAD and SUVmax were 0.22 µg/(L·cm3) and 8.02, respectively, and the AUCs for the diagnosis of prostate cancer in the gray zone alone and in combination were 0.628 (95% CI 0.530 to 0.720, P<0.05) and 0.806 (95% CI 0.718 to 0.876, P<0.05), 0.847 (95% CI 0.765 to 0.910, P<0.05), with sensitivities of 41.03%, 76.92%, and 74.36% and specificities of 79.41%, 89.71%, and 92.65%, respectively. CONCLUSIONS: PSAD and SUVmax are increased in patients with gray zone prostate cancer, and the combination of PSAD and SUVmax is of high value in diagnosing gray zone prostate cancer.

Inflammation and tumor microenvironment. / 炎症与肿瘤微环境.

There is a connection between inflammation and cancer. Inflammation is one of the hallmarks of cancer, affecting tumor progression, transition to a malignant phenotype, and the efficacy of tumor chemotherapy. The tumor microenvironment impacts the biological characteristics of tumors through various specific factors and signaling mechanisms. The interaction between inflammation and the tumor microenvironment involves inflammation affecting the tumor microenvironment by inducing immune suppression, while acute inflammation promotes tumor suppression by producing anti-tumor immune responses. This review elaborates on how inflammation affects the tumor microenvironment and thus affects the progression and treatment of tumors, starting from the components of the tumor microenvironment, inflammasomes, cytokines, non-coding RNAs, and other aspects. Inflammatory factors play an important role in regulating inflammatory responses and immune reactions, and they also affect the development of tumors through various pathways in the tumor microenvironment. In addition, non-coding RNAs play an important role in the tumor microenvironment, regulating tumors and inflammation. They are involved in regulating the occurrence, development of tumors, the process of inflammation, as well as regulating inflammation-induced cancer or tumor-related inflammation, and the interaction between the tumor microenvironment, inflammatory factors, and immune cells. Therefore, gaining a deeper understanding of the interaction between inflammation and the tumor microenvironment and its connection to the occurrence and development of cancer can provide a theoretical basis for combating tumors and finding new therapeutic strategies.

An analysis of delay-constrained consensus-based optimal algorithms in virtual power plants.

In virtual power plants (VPPs), consensus-based distributed optimal dispatch algorithms aim to collectively minimize the operating cost. As ubiquitous latency on communication networks may lead to divergence, convergence to a nonoptimal solution, or a longer convergence time, mitigating the impacts of arbitrarily large but bounded time-varying delays is significant both in theory and in practice. To modify a typical consensus-based optimal dispatch algorithm under time-varying delays, this paper designs new update rules and introduces a reduction approach to evaluate the performance of the algorithm. The results reveal that the modified algorithm can always converge to the optimal solution with a tactical initial setup in a distributed manner if the undirected interaction topology is connected and the gain parameter is sufficiently small. The analytical expression of the gain is also given. Furthermore, we show that the convergence time is determined by the maximum time delays, the number of generators, and the convergence accuracy. Several numerical simulation studies validate our theory.

Reassessing the Pediatric Dosing Recommendations for Unfractionated Heparin Using Real-World Data: A Pharmacokinetic-Pharmacodynamic Modeling Approach.

Optimal pediatric dosing of unfractionated heparin (UFH) is challenging because of the paucity of clinical outcome and pharmacokinetic-pharmacodynamic (PK/PD) studies in pediatrics. This study aimed to: (i) develop a PK/PD model for UFH, quantified by anti-factor Xa assay, and the UFH effect, measured by activated partial thromboplastin time (aPTT); and (ii) use simulations to evaluate pediatric UFH infusions for achieving the anti-factor Xa (0.3-0.7 IU/mL) therapeutic target. Electronic health record data were retrospectively collected from 633 patients aged <19 years admitted to Texas Children's Hospital. The PK/PD model was developed using a 70% (training)/30% (testing) split-sample approach. A 1-compartment PK model with linear elimination adequately described the UFH PK. An allometrically scaled body weight on clearance (CL) and volume of distribution (Vd) with an age-dependent maturation function of extracellular water on Vd were the covariates identified. Comparable with literature, the typical values for CL and Vd were 3.28 L/(h·50 kg) and 8.83 L/50 kg, respectively. A linear model adequately described the UFH-aPTT relationship with an estimated slope of 150 seconds/(IU/mL). Simulations of the currently recommended starting infusions (28 IU/h/kg for pediatrics <1 year old or 20 IU/h/kg for pediatrics >1 year old) showed that the anti-factor Xa therapeutic target was achieved only in 15.3%, 14.6%, 36.9%, and 45.11% of subjects in the age groups of <1 year, 1-6 years, 6-12 years, and 12-19 years, respectively. In conclusion, the UFH anti-factor Xa target is not achieved initially, especially in young pediatrics, suggesting the need to optimize UFH dosing to achieve higher therapeutic success.

MicroRNA miR-145-5p regulates cell proliferation and cell migration in colon cancer by inhibiting chemokine (C-X-C motif) ligand 1 and integrin α2.

Colon cancer (CC), which has high morbidity and mortality, can be regulated by microRNAs. This study aimed to investigate the regulatory function of microRNA miR-145-5p in CC cells. Bioinformatics analysis was used to screen key genes in CC. The expression of miR-145-5p, chemokine (C-X-C motif) ligand 1 (CXCL1), and integrin α2 (ITGA2) in CC was confirmed by quantitative reverse transcription polymerase chain reaction and western blotting. After cell transfection, changes in proliferation and migration in CC cells were detected using the cell counting kit-8 (CCK-8), colony formation assay, and wound healing assay. A luciferase assay was conducted to confirm the interactome of miR-145-5p, CXCL1, and ITGA2 in CC cells. Bioinformatics analysis confirmed that CXCL1 and ITGA2 were key genes in CC. After performing several cell functional experiments, the results confirmed that upregulation of miR-145-5p attenuated proliferation and migration of CC cells. Luciferase assay and western blotting confirmed that CXCL1 and ITGA2 were targets of miR-145-5p, and their expression in CC could be suppressed by miR-145-5p. In conclusion, miR-145-5p is a tumor suppressor in CC and can inhibit the expression of CXCL1 and ITGA2.

Study on the variation of air pollutant concentration and its formation mechanism during the COVID-19 period in Wuhan.

To prevent the spread of COVID-19 (2019 novel coronavirus), from January 23 to April 8 in 2020, the highest Class 1 Response was ordered in Wuhan, requiring all residents to stay at home unless absolutely necessary. This action was implemented to cut down all unnecessary human activities, including industry, agriculture and transportation. Reducing these activities to a very low level during these hard times meant that some unprecedented naturally occurring measures of controlling emissions were executed. Ironically, however, after these measures were implemented, ozone levels increased by 43.9%. Also worthy of note, PM2.5 decreased 31.7%, which was found by comparing the observation data in Wuhan during the epidemic from 8th Feb. to 8th Apr. in 2020 with the same periods in 2019. Utilizing CMAQ (The Community Multiscale Air Quality modeling system), this article investigated the reason for these phenomena based on four sets of numerical simulations with different schemes of emission reduction. Comparing the four sets of simulations with observation, it was deduced that the emissions should decrease to approximately 20% from the typical industrial output, and 10% from agriculture and transportation sources, attributed to the COVID-19 lockdown in Wuhan. More importantly, through the CMAQ process analysis, this study quantitatively analyzed differences of the physical and chemical processes that were affected by the COVID-19 lockdown. It then examined the differences of the COVID-19 lockdown impact and determined the physical and chemical processes between when the pollution increased and decreased, determining the most affected period of the day. As a result, this paper found that (1) PM2.5 decreased mainly due to the reduction of emission and the contrary contribution of aerosol processes. The North-East wind was also in favor of the decreasing of PM2.5. (2) O3 increased mainly due to the slowing down of chemical consumption processes, which made the concentration change of O3 pollution higher at about 4 p.m.-7 p.m. of the day, while increasing the concentration of O3 at night during the COVID-19 lockdown in Wuhan. The higher O3 concentration in the North-East of the main urban area also contributed to the increasing of O3 with unfavorable wind direction.

Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques From Intrarectal Challenge With SHIV109CP3.

BACKGROUND: MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is a novel reverse transcriptase-translocation inhibitor. METHODS: We assessed MK-8591 as preexposure prophylaxis in the rhesus macaque model of intrarectal challenge with simian/human immunodeficiency virus (SHIV). In study 1, 8 rhesus macaques received 3.9 mg/kg of MK-8591 orally on day 0 and once weekly for the next 14 weeks. Eight controls were treated with vehicle. All rhesus macaques were challenged with SHIV109CP3 on day 6 and weekly for up to 12 challenges or until infection was confirmed. The dose of MK-8591 was reduced to 1.3 and 0.43 mg/kg/week in study 2 and further to 0.1 and 0.025 mg/kg/week in study 3. In studies 2 and 3, each dose was given up to 6 times once weekly, and animals were challenged 4 times once weekly with SHIV109CP3. RESULTS: Control macaques were infected after a median of 1 challenge (range, 1-4 challenges). All treated animals in studies 1 and 2 were protected, consistent with a 41.5-fold lower risk of infection (P < .0001, by the log-rank test). In study 3, at a 0.1-mg/kg dose, 2 rhesus macaques became infected, consistent with a 7.2-fold lower risk of infection (P = .0003, by the log-rank test). The 0.025-mg/kg dose offered no protection. CONCLUSIONS: These data support MK-8591's potential as a preexposure prophylaxis agent.

Novel insights into molecular mechanisms of Pseudourostyla cristata encystment using comparative transcriptomics.

The encystment of many ciliates is an advanced survival strategy against adversity and the most important reason for ciliates existence worldwide. However, the molecular mechanism for the encystment of free-living ciliates is poorly understood. Here, we performed comparative transcriptomic analysis of dormant cysts and trophonts from Pseudourostyla cristata using transcriptomics, qRT-PCR and bioinformatic techniques. We identified 2565 differentially expressed unigenes between the dormant cysts and the trophonts. The total number of differentially expressed genes in GO database was 1752. The differential unigenes noted to the GO terms were 1993. These differential categories were mainly related to polyamine transport, pectin decomposition, cytoplasmic translation, ribosome, respiratory chain, ribosome structure, ion channel activity, and RNA ligation. A total of 224 different pathways were mapped. Among them, 184 pathways were upregulated, while 162 were downregulated. Further investigation showed that the calcium and AMPK signaling pathway had important induction effects on the encystment. In addition, FOXO and ubiquitin-mediated proteolysis signaling pathway jointly regulated the encystment. Based on these findings, we propose a hypothetical signaling network that regulates Pseudourostyla cristata encystment. Overall, these results provide deeper insights into the molecular mechanisms of ciliates encystment and adaptation to adverse environments.

Global view on China's foggy-haze associated with air-pollutant conveyor belts.

Upper air and surface data from 1960 to 2016, NCEP reanalysis from 1990 to 2016, air composition data from 2015 to 2016, and data from the drift automatic weather station in the Arctic from August 2012 to February 2013 are used to analyze the heavy foggy haze in China from a global perspective. Our findings show that sensitive foggy haze in winter is located in the eastern region of China because of the comprehensive effect of multi-factor meteorological conditions and the response to climate change under global warming as follows. (1) For the past half-century, two winter monsoon airflows blow from the East Asian continent and adjacent sea to North China. The airflow in the intermediate zone (North China) between the two winter monsoon airflows generates a retained circulation owing to the Earth's rotation because wind velocities over land and sea are different and their wind intensities are weakened. The circulation retention index has been on the rise in recent years, causing a "static stability" that retains or stabilizes air masses over this area. (2) Under global warming, polar ice has shrunk to a historical lowest over the years. The melting polar ice results in explosive heating and humidification in the lower troposphere leading to increased aerosol concentrations, which is conducive to maintaining or strengthening the Arctic haze. (3) The two winter monsoon pathways run over the Eurasian continent and the surface of the adjacent Sea of Okhotsk, thus affecting North China. These results are consistent with the airflow of the pollutant conveyor belt channeling from the Arctic haze zone. As a result, the pollutant conveyor belt from the Arctic haze zone as well as the pollutant conveyor belts from West Asia and North Africa contribute substantially to the high frequency of winter foggy haze over eastern China.

Protection against HEMA-Induced Mitochondrial Injury In Vitro by Nrf2 Activation.

Dental resin monomers such as 2-hydroxyethyl methacrylate (HEMA) disturb vital cell functions and induce mitochondrial intrinsic apoptosis via generation of oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the gene expression of antioxidative enzymes and plays a crucial role in the maintenance of cellular redox equilibrium and mitochondrial homeostasis. The present study investigated the functional significance of Nrf2 in cellular response toward HEMA. It was found that HEMA stimulation promoted nuclear translocation of Nrf2 and increased Nrf2 and heme oxygenase-1 (HO-1) expression, which was further enhanced by Nrf2 activator tert-butylhydroquinone (tBHQ), but suppressed by Nrf2 inhibitor ML385. Pretreatment of primary human dental pulp cells (hDPCs) with tBHQ protected the cells from HEMA-induced oxidative injury (increased reactive oxygen species production and apoptosis) and mitochondrial impairment (morphological alterations, decreased ATP production, suppressed oxidative phosphorylation activity, depolarization of mitochondrial membrane potential, and disrupted electron transport chain). In contrast, pretreatment with ML385 increased cell sensitivity to these injurious processes. This protective effect on mitochondria could be related to peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α)/nuclear respiratory factor 1 (NRF1) pathway. These results contribute to the understanding of the function of Nrf2 and the development of novel therapies to counteract the adverse effects of dental resin monomers.

Influence of meteorological conditions on explosive increase in O3 concentration in troposphere.

Ozone (O3) pollution in the troposphere, especially at the surface layer, has become a focus of attention in recent years. High O3 concentration events tend to occur frequently in north China, Yangtze, the Pearl River Delta, and the Sichuan Basin, among others. Studies on the meteorological contribution to O3 in the troposphere have become a new direction for the scientific community. This research intends to explore how meteorological conditions contribute to O3 pollution in all seasons on the basis of further studies of the PLAM index. Our findings are as follows. (1) In pollution-sensitive areas, following a height uplift in the pollution mixing layer (H_PML), NO2 concentration decreases initially, followed by an explosive increase (EI) in O3 concentration after sunrise. (2) This process varies significantly by season and area. (3) According to an analysis of the meteorological conditions causing rises in O3 concentration within a few hours after sunrise, the initial decrease-subsequent increase in NO2 versus O3 concentration satisfies the law of exponent power rule, according to which seasonal and regional differences in coastal and inland areas depend on coefficients α and ß. The explosive increase in O3 concentration, decrease in NO2 concentration, and characteristics of their diurnal cycles are also discussed. (4) Under the meteorological condition of static stability, below the static and stable cover, the H_PML of the polluted mixed layer consistently indicates the reciprocating cycle of day uplift and night pressure. The effect of air pump suction on the pollutant is an important mechanism of large-scale pollution in the study area under the condition of static and stable cover. (5) The influencing mechanism of meteorological conditions in the diurnal H_PML cycle aids in improving the understanding of O3 concentration increases in the troposphere.

New contribution to the morphology and molecular mechanism of Euplotes encysticus encystment.

Ciliated protists are a large group of single-cell eukaryotes, leading to the resting cysts in unfavorable environmental condition. However, the underlying molecular mechanism of encystment in the free-living ciliates is poorly understood. Here we show that the resting cysts are better than the vegetative cells of Euplotes encysticus in adverse survivor with respect to energy metabolism. Therefore scale identification of encystment-related proteins in Euplotes encysticus was investigated by iTRAQ analysis. We analyzed a total of 130 proteins, in which 19 proteins involving 12 upregulated and 7 downregulated proteins were associated with encystment in the resting cysts in comparison with the vegetative cells. Moreover, direct fluorescent labeling analysis showed that the vegetative cells treated with shRNA-ß-tubulin recombinant E. coli accumulated a large number of granular materials, and dramatic cell morphology changes. Importantly, the cell membrane rupture phenomenon was observed after three weeks of shRNA-ß-tubulin interference as compared to the control group. These results revealed that different proteins might play an important role in the process of the vegetative cells into the resting cysts. These results will help to reveal the morphological changes and molecular mechanism of resting cyst formation of ciliates.

Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention.

Regimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (HIV) infection. Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. The administration of long-acting formulations in a clinical setting enables health care providers to directly track adherence. MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) drug candidate under investigation as part of a regimen for HIV treatment, with potential utility as a single agent for preexposure prophylaxis (PrEP). The active triphosphate of MK-8591 (MK-8591-TP) exhibits protracted intracellular persistence and, together with the potency of MK-8591, supports its consideration for extended-duration dosing. Toward this end, drug-eluting implant devices were designed to provide prolonged MK-8591 release in vitro and in vivo Implants, administered subcutaneously, were studied in rodents and nonhuman primates to establish MK-8591 pharmacokinetics and intracellular levels of MK-8591-TP. These data were evaluated against pharmacokinetic and pharmacodynamic models, as well as data generated in phase 1a (Ph1a) and Ph1b clinical studies with once-weekly oral administration of MK-8591. After a single administration in animals, MK-8591 implants achieved clinically relevant drug exposures and sustained drug release, with plasma levels maintained for greater than 6 months that correspond to efficacious MK-8591-TP levels, resulting in a 1.6-log reduction in viral load. Additional studies of MK-8591 implants for HIV treatment and prevention are warranted.

miR-944 inhibits cell migration and invasion by targeting MACC1 in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a common disease in Southern China with high prevalence. miR-944 has been reported to play a vital role in progression of a variety of cancers. The present study aimed to investigate the potential role of miR-944 in NPC cell migration and invasion through elucidating the interaction with its target genes, MACC1. Expression of miR-944 in NPC tissues and cell lines was examined with quantitative RT-PCR. Overexpressed miR-944 and suppressed miR-944 were established with miR-944 mimics and miR-944 inhibitor, respectively. The effect of miR-944 on cell migration and invasion was determined using Transwell cell migration and Matrigel invasion assay. Luciferase assay was used to determine the target of miR-944. Knocked down of MACC1 was done by MACC1 siRNA. Expression of MET related-markers was examined using Western blot analysis. The expression level of miR-944 was downregulated in NPC tissues and cell lines. Overexpression of miR-944 significantly inhibited the cell migration and invasion in NPC 6-10B cells. In contrast, suppression of miR-944 promoted cell migration and invasion in NPC C-6661 cells. MACC1 is a direct target of miR-944. MACC1 expression was repressed in miR-944 mimic transfected cells while it was enhanced in miR-944 inhibitor transfected cells. MACC1 knock down inhibited cell migration and invasion. Either miR-944 restoration or MACC1 knockdown caused enhanced E-cadherin, reduced N-cadherin, and vimentin expression. In conclusion, miR-944 could inhibit MET and metastasis of NPC by targeting MACC1. This study suggests that miR-944 has anti-tumor and anti- metastatic properties and could thus be a novel therapeutic agent for NPC treatment.

Missing-in-metastasis B (MIM-B) combined with caveolin-1 promotes metastasis of hepatocellular carcinoma.

BACKGROUND: Increasing amounts of evidence indicate that Missing in metastasis B (MIM-B) promotes cancer metastasis. Here, we sought to better understand the mechanism through which MIM-B promotes tumor metastasis in hepatocellular carcinoma (HCC). METHODS: We performed confocal microscopy analysis to determine the distributions of MIM-B and caveolin-1 and conducted co-immunoprecipitation assays to detect the interactions between MIM-B and caveolin-1 in vitro. We performed transwell assays to analyze the invasive ability of HCC cells. Changes in the expression levels of key genes and some molecular makers were detected by immunohistochemistry and western blotting in HCC tissue samples. RESULTS: We found that MIM-B co-localizes with caveolin-1 and demonstrated that MIM-B and caveolin-1 interact in vitro. Repressing MIM-B and caveolin-1 expression inhibited the epidermal growth factor receptor signaling pathway. We overexpressed MIM-B and caveolin-1 in Hep3B cells, which enhanced Hep3B cell invasiveness. Furthermore, MHCC97H cell invasiveness was significantly decreased in cells in which MIM-B and caveolin-1 expression was inhibited. Additionally, we found that MIM-B and caveolin-1 were expressed at higher levels in HCC tissues than in paired normal tissues. Moreover, HCC patients with MIM-B and caveolin-1 up-regulation experienced significantly worse outcomes than controls (P < 0.001), and HCC patients with high MIM-B and caveolin-1 expression levels often developed pulmonary metastasis (P < 0.001). CONCLUSIONS: MIM-B combined with caveolin-1 promotes metastasis of HCC, and elevated MIM-B and caveolin-1 expression levels are associated with a poor prognosis in HCC patients; therefore, MIM-B and caveolin-1 may represent novel targets for the diagnosis and treatment of HCC.