Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation.

Oligodendrocytes (OLs) are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). Demyelination is a common feature of many neurological diseases such as multiple sclerosis (MS) and leukodystrophies. Although spontaneous remyelination can happen after myelin injury, nevertheless, it is often insufficient and may lead to aggravated neurodegeneration and neurological disabilities. Our previous study has discovered that MEK/ERK pathway negatively regulates OPC-to-OL differentiation and remyelination in mouse models. To facilitate possible clinical evaluation, here we investigate several MEK inhibitors which have been approved by FDA for cancer therapies in both mouse and human OPC-to-OL differentiation systems. Trametinib, the first FDA approved MEK inhibitor, displays the best effect in stimulating OL generation in vitro among the four MEK inhibitors examined. Trametinib also significantly enhances remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model. More exciting, trametinib facilitates the generation of MBP+ OLs from human embryonic stem cells (ESCs)-derived OPCs. Mechanism study indicates that trametinib promotes OL generation by reducing E2F1 nuclear translocation and subsequent transcriptional activity. In summary, our studies indicate a similar inhibitory role of MEK/ERK in human and mouse OL generation. Targeting the MEK/ERK pathway might help to develop new therapies or repurpose existing drugs for demyelinating diseases.

In situ reprogramming of cardiac fibroblasts into cardiomyocytes in mouse heart with chemicals.

Cardiomyocytes are terminal differentiated cells and have limited ability to proliferate or regenerate. Condition like myocardial infarction causes massive death of cardiomyocytes and is the leading cause of death. Previous studies have demonstrated that cardiac fibroblasts can be induced to transdifferentiate into cardiomyocytes in vitro and in vivo by forced expression of cardiac transcription factors and microRNAs. Our previous study have demonstrated that full chemical cocktails could also induce fibroblast to cardiomyocyte transdifferentiation both in vitro and in vivo. With the development of tissue clearing techniques, it is possible to visualize the reprogramming at the whole-organ level. In this study, we investigated the effect of the chemical cocktail CRFVPTM in inducing in situ fibroblast to cardiomyocyte transdifferentiation with two strains of genetic tracing mice, and the reprogramming was observed at whole-heart level with CUBIC tissue clearing technique and 3D imaging. In addition, single-cell RNA sequencing (scRNA-seq) confirmed the generation of cardiomyocytes from cardiac fibroblasts which carries the tracing marker. Our study confirms the use of small molecule cocktails in inducing in situ fibroblast to cardiomyocyte reprogramming at the whole-heart level and proof-of-conceptly providing a new source of naturally incorporated cardiomyocytes to help heart regeneration.

Causal associations between blood lipids and brain structures: a Mendelian randomization study.

The potential causal association between dyslipidemia and brain structures remains unclear. Therefore, this study aimed to investigate whether circulating lipids are causally associated with brain structure alterations using Mendelian randomization analysis. Genome-wide association study summary statistics of blood lipids and brain structures were obtained from publicly available databases. Inverse-variance weighted method was used as the primary method to assess causality. In addition, four additional Mendelian randomization methods (MR-Egger, weighted median, simple mode, and weighted mode) were applied to supplement inverse-variance weighted. Furthermore, Cochrane's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis were performed for sensitivity analyses. After Bonferroni corrections, two causal associations were finally identified: elevated non-high-density lipoprotein cholesterol level leads to higher average cortical thickness (ß = 0.0066 mm, 95% confidence interval: 0.0045-0.0087 mm, P = 0.001); and elevated high-density lipoprotein cholesterol level leads to higher inferior temporal surface area (ß = 18.6077 mm2, 95% confidence interval: 11.9835-25.2320 mm2, P = 0.005). Four additional Mendelian randomization methods indicated parallel results. Sensitivity tests demonstrated the stability. Overall, the present study showed causal relationships between several lipid profiles and specific brain structures, providing new insights into the link between dyslipidemia and neurological disorders.

Mendelian randomization study supports relative carbohydrate intake as an independent risk factor for amyotrophic lateral sclerosis.

OBJECTIVES: Observational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear. Here, we performed a Mendelian randomization (MR) analysis to evaluate the causal impact of relative intake of (i) carbohydrate, (ii) fat, and (iii) protein on ALS risk. METHODS: The genome-wide association summary statistics of three dietary macronutrient intake traits and ALS were obtained. Initially, forward and reverse univariable MR (UVMR) analysis were conducted using the inverse variance weighted (IVW) method as the primary approach, supplemented by MR-Egger, weighted median, and maximum likelihood. Subsequently, multivariable MR (MVMR) analysis was performed to assess the independent causal effects of each dietary. Additionally, diverse sensitivity tests were conducted to evaluate the reliability of the MR analyses. RESULTS: The forward UVMR analysis conducted by IVW indicated that relative carbohydrate intake significantly increased ALS risk. Furthermore, results from three other MR methods paralleled those from IVW. However, the other two dietary intake traits did not have a causative impact on ALS risk. The reverse UVMR analysis indicated that ALS did not causatively influence the three dietary intake traits. The MVMR analysis showed that after adjusting for the effects of the other two dietary intake traits, relative carbohydrate intake independently and significantly increased ALS risk. Sensitivity tests indicated no significant heterogeneity or horizontal pleiotropy. DISCUSSION: MR analysis supported relative carbohydrate independently increasing ALS risk. Nevertheless, further validation of this finding in future large cohorts is required.Abbreviations: ALS: amyotrophic lateral sclerosis; CI: confidence interval; GWAS: genome-wide association study; IV: instrumental variable; IVW: iverse variance weighted; MR: Mendelian randomization; MVMR: multivariable Mendelian randomization; OR: odds ratio; RCT: randomized controlled trial; SNPs: single-nucleotide polymorphisms; UVMR: univariable Mendelian randomization.

Turning plastics/microplastics into valuable resources? Current and potential research for future applications.

Plastics are a wide range of synthetic or semi-synthetic materials, mainly consisting of polymers. The use of plastics has increased to over 300 million metric tonnes in recent years, and by 2050, it is expected to grow to 800 million. Presently, a mere 10% of plastic waste is recycled, with approximately 75% ended up in landfills. Inappropriate disposal of plastic waste into the environment poses a threat to human lives and marine species. Therefore, this review article highlights potential routes for converting plastic/microplastic waste into valuable resources to promote a greener and more sustainable environment. The literature review revealed that plastics/microplastics (P/MP) could be recycled or upcycled into various products or materials via several innovative processes. For example, P/MP are recycled and utilized as anodes in lithium-ion (Li-ion) and sodium-ion (Na-ion) batteries. The anode in Na-ion batteries comprising PP carbon powder exhibits a high reversible capacity of ∼340 mAh/g at 0.01 A/g current state. In contrast, integrating Fe3O4 and PE into a Li-ion battery yielded an excellent capacity of 1123 mAh/g at 0.5 A/g current state. Additionally, recycled Nylon displayed high physical and mechanical properties necessary for excellent application as 3D printing material. Induction heating is considered a revolutionary pyrolysis technique with improved yield, efficiency, and lower energy utilization. Overall, P/MPs are highlighted as abundant resources for the sustainable production of valuable products and materials such as batteries, nanomaterials, graphene, and membranes for future applications.

Transcriptomic-based analysis to identify candidate genes for blue color rose breeding.

KEY MESSAGE: Analysis of the flower color formation mechanism of 'Rhapsody in Blue' by BF and WF transcriptomes reveals that RhF3'H and RhGT74F2 play a key role in flower color formation. Rosa hybrida has colorful flowers and a high ornamental value. Although rose flowers have a wide range of colors, no blue roses exist in nature, and the reason for this is unclear. In this study, the blue-purple petals (BF) of the rose variety 'Rhapsody in Blue' and the white petals (WF) of its natural mutant were subjected to transcriptome analysis to find genes related to the formation of the blue-purple color. The results showed that the anthocyanin content was significantly higher in BF than in WF. A total of 1077 differentially expressed genes (DEGs) were detected by RNA-Seq analysis, of which 555 were up-regulated and 522 were down-regulated in the WF vs. BF petals. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of the DEGs revealed that a single gene up-regulated in BF was related to multiple metabolic pathways including metabolic process, cellular process, protein-containing complex, etc. Additionally, the transcript levels of most of the structural genes related to anthocyanin synthesis were significantly higher in BF than in WF. Selected genes were analyzed by qRT-PCR and the results were highly consistent with the RNA-Seq results. The functions of RhF3'H and RhGT74F2 were verified by transient overexpression analyses, and the results confirmed that both affect the accumulation of anthocyanins in 'Rhapsody in Blue'. We have obtained comprehensive transcriptome data for the rose variety 'Rhapsody in Blue'. Our results provide new insights into the mechanisms underlying rose color formation and even blue rose formation.

Relationship between plasma circulating cell-free DNA concentration and treatment outcomes including prognosis in patients with advanced non-small cell lung cancer.

BACKGROUND: Some research found that elevated plasma cell-free DNA (cfDNA) concentrations and poor prognosis are associated in non-small cell lung cancer (NSCLC). However, more studies need to be carried out to verify this conclusion. Therefore, this study investigated the relationship between cfDNA concentration and treatment outcomes including prognosis in patients with advanced NSCLC. METHODS: We retrospectively collected medical records and cfDNA data from 160 patients with advanced NSCLC. Progression-free survival (PFS) were calculated using the Kaplan-Meier method and were compared between groups using the log rank test. Cox regression analysis was used for estimating the independent predictors of PFS. And we used logistic regression to evaluate the relationship between baseline biomarkers and efficacy. In our study, BT1 cfDNA, BT2 cfDNA, and BT3 cfDNA were defined as cfDNA concentration before the first treatment (baseline cfDNA concentration), cfDNA concentration before the second treatment, and cfDNA concentration before the third treatment, respectively. RESULTS: Patients with low cfDNA (BT1 cfDNA < 15 (ng/mL)) were reported a significantly prolonged median progression-free survival (mPFS) compared with patients with patients with high cfDNA (BT1 cfDNA ≥ 15(ng/mL)) (mPFS: 14.6 vs. 8.3 months, P = 0.002), as well as patients with neutrophil/lymphocyte ratio (NLR)<2.98 (mPFS: 13.1 vs. 7.9 months, P = 0.023). In addition, Cox proportional hazards regression analysis identified independent indicators associated with PFS including BT1 cfDNA ≥ 15 (ng/mL), NLR ≥ 2.98 and extrapulmonary metastasis. The best cut-off value for BT3 cfDNA for predicting disease progression is 41.46 (ng/mL) (Area Under the Curve (AUC): 0.652, 95%CI: 0.516-0.788), achieving 90.7% sensitivity and 37.5% specificity for the prediction of disease progression. BT3 cfDNA (OR = 6.08, 95% CI: 1.94-19.57, P = 0.002) was an independent factor for disease progression in patients with advanced NSCLC. CONCLUSIONS: BT1 cfDNA may be a biomarker to assess the prognosis of advanced NSCLC. Patients with advanced NSCLC with lower cfDNA and NLR before treatment had a better prognosis. Increased BT3 cfDNA concentration was an independent factor of disease progression in advanced NSCLC patients. These findings may assist in identifying high-risk patients and guiding treatment strategies.

Impact of blood pressure and antihypertensive drug classes on intracranial aneurysm: a Mendelian randomization study.

BACKGROUND: Blood pressure is a risk factor for intracranial aneurysms (IA). Nevertheless, whether various antihypertensive drug classes discriminate in reducing IA risk is unclear. METHODS: Genome-wide association study summary statistics for systolic blood pressure (SBP), diastolic blood pressure (DBP), IA (non-ruptured), and IA [subarachnoid hemorrhage (SAH)] were downloaded. To proxy the effects of antihypertensive drugs, genetic variants associated with SBP adjacent to the coding regions of different antihypertensive drugs were selected. The inverse-variance-weighted (IVW) method was employed as the primary method for causal estimation. In addition, three additional MR methods and sensitivity tests were utilized to assess the reliability. RESULTS: Elevated blood pressure significantly increases the risk of IA: (i) SBP-IA (non-ruptured): odds ratio (OR) = 1.046, 95 % confidence interval (CI): 1.032-1.061, P = 1.05E-10; (ii) SBP-IA (SAH): OR = 1.040, 95 % CI: 1.030-1.050, P = 2.56E-15; (iii) DBP-IA (non-ruptured): OR = 1.082, 95 % CI: 1.056-1.110, P = 3.15E-10; (iv) DBP-IA (SAH): OR = 1.066, 95 % CI: 1.047-1.085, P = 1.25E-12. In addition, among calcium channel blockers (CCBs), beta-blockers (BBs), and thiazide diuretics (TDs), only SBP mediated by TDs target genes significantly increased the risk of IA (non-rupture) (OR = 1.164, 95 % CI: 1.060-1.279, P = 0.001) and IA (SAH) (OR = 1.136, 95 % CI: 1.063-1.214, P = 1.58E-04), while SBP mediated by target genes of BBs or CCBs did not causally associate with IA. CONCLUSION: Elevated blood pressure significantly increases IA risk, while TDs may be a promising antihypertensive medication for reducing IA risk. Further research with larger cohorts is essential for validation.

KCNN4-mediated Ca2+/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma.

As a member of the potassium calcium-activated channel subfamily, increasing evidence suggests that KCNN4 was associated with malignancies. However, the roles and regulatory mechanisms of KCNN4 in PDAC have been little explored. In this work, we demonstrated that the level of KCNN4 in PDAC was abnormally elevated, and the overexpression of KCNN4 was induced by transcription factor AP-1. KCNN4 was closely correlated with unfavorable clinicopathologic characteristics and poor survival. Functionally, we found that overexpression of KCNN4 promoted PDAC cell proliferation, migration and invasion. Conversely, the knockdown of KCNN4 attenuated the growth and motility of PDAC cells. In addition to these, knockdown of KCNN4 promoted PDAC cell apoptosis and led to cell cycle arrest in the S phase. In mechanistic investigations, RNA-sequence revealed that the MET-mediated AKT axis was essential for KCNN4, encouraging PDAC cell proliferation and migration. Collectively, these findings reveal a function of KCNN4 in PDAC and suggest it's an attractive therapeutic target and tumor marker. Our studies underscore a better understanding of the biological mechanism of KCNN4 in PDAC and suggest novel strategies for cancer therapy.

Correlating black soldier fly larvae growths with soluble nutrients derived from thermally pre-treated waste activated sludge.

Black soldier fly larvae (BSFL) have been deployed to valorize various organic wastes. Nonetheless, its growth rate whilst being offered with waste activated sludge (WAS) is not promising, likely by virtue of the presence of extracellular polymeric substances' structure in WAS. In this work, the WAS were first thermally pre-treated under different treatment temperatures and durations before being administered as the feeding substrates for BSFL. The results showed the thermal pre-treatment could improve WAS palatability and subsequently, enhance the growth of BSFL especially after the pre-treatments at 75 °C and above. The highest larva weight gained was recorded at 2.16 mg/larva for the WAS sample being pre-treated at 90 °C and 16 h. Furthermore, the samples pre-treated above 75 °C also achieved higher degradation rates, indicating that the 75 °C was a threshold temperature to effectively hydrolyze the WAS. The changes of WAS characteristics, namely, (i) soluble chemical oxygen demand (SCOD), (ii) soluble carbohydrate, (iii) soluble protein, (iv) humic substances and (v) total soluble protein and humic substances, after the thermal pre-treatments were also studied in correlating with the BSFL growth. Accordingly, a model was successfully developed with the highest R2 value attained at 0.95, evidencing the SCOD was the most suitable WAS characteristic to accurately predict the BSFL growth behavior.

Does robotic-assisted computer navigation improve acetabular cup positioning in total hip arthroplasty for Crowe III/IV hip dysplasia? A propensity score case-match analysis.

AIMS: Total hip arthroplasty (THA) in patients with hip-dislocation dysplasia remains challenging. This study aims to evaluate whether these patients may benefit from robotic-assisted techniques. METHODS: We reviewed 135 THAs (108 conventional THAs and 27 robotic-assisted THAs) for Crowe type III or IV from January 2017 to August 2019 in our institution. Robotic-assisted THAs were matched with conventional THAs at a 1:1 ratio (27 hips each group) using propensity score matching. The accuracy of cup positioning and clinical outcomes were compared between groups. RESULTS: The inclination of the cup for conventional THAs and robotic THAs was 42.1 ± 5.7 and 41.3 ± 4.6 (p = 0.574), respectively. The anteversion of the cup for conventional THAs was significantly greater than that of robotic THAs (29.5 ± 8.1 and 18.0 ± 4.6; p < 0.001), respectively. The ratio of the acetabular cup in the Lewinnek safe zone was 37% (10/27) in conventional THAs and 96.3% (26/27) in robotic THAs (p < 0.001). Robotic THAs did not achieve better leg length discrepancy than that of conventional THAs (- 0.4 ± 10.9 mm vs. 0.4 ± 8.8 mm, p = 0.774). There was no difference in Harris Hip Score and WOMAC Osteoarthritis index between groups at the 2-year follow-up. No dislocation occurred in all cases at the final follow-up. CONCLUSION: Robotic-assisted THA for patients with high dislocation improves the accuracy of the implantation of the acetabular component with respect to safe zone.

Environment impact and bioenergy analysis on the microwave pyrolysis of WAS from food industry: Comparison of CO2 and N2 atmosphere.

The alarming output of waste activated sludge (WAS) from industries requires proper management routes to minimize its impact on the environment during disposal. Pyrolysis is a feasible way of processing and valorizing WAS into higher-value products of alternate use. Despite extensive research into the potential of WAS through pyrolysis, the technology's long-term viability and environmental impact have yet to be fully revealed. In addition, the environmental effects of utilizing different pyrolysis atmosphere (N2 or CO2) has not been studied before, although benefits of CO2 reactivity during pyrolysis have been discovered. This study evaluates the process's environmental impact, carbon footprint, and bioenergy yield when different pyrolysis atmospheres are used. The global warming potential (GWP) for a functional unit of 1 t of dried WAS is 203.81 kg CO2 eq. The heat required during pyrolysis contributes the most (63.7%) towards GWP due to high energy usage, followed by the drying process (23.6%). Transportation contributes the most towards toxicity impact (59.3%) through dust, NOx, NH3 and SO2 emissions. The initial moisture content of raw WAS (65%) greatly impacts overall energy consumption and environmental impact. Pyrolysis in an N2 atmosphere will result in a higher overall bioenergy yield (833 kWh/tonne) and a lower carbon footprint (-1.09 kg CO2/tonne). However, when CO2 was used, the specific energy value within the biochar is higher (22.26 MJ/kg) due to enhanced carbonization. The carbon content of gas derived increased due to higher CO yield. From an energy perspective, the current setup will achieve a net positive bioenergy yield of 561 kW (CO2) and 833 kW (N2), where end products like biochar, bio-oil and gas can be used for power production. Despite the energy-intensive process, microwave pyrolysis has excellent potential to achieve a negative carbon footprint. The biochar used for soil amendment served as a good carbon sink. The utilization of CO2 as carrier gases provides a pathway to utilize anthropogenic CO2, which helps reduce global warming. This work demonstrates microwave pyrolysis as a negative emission, bioenergy-producing approach for WAS disposal and valorization.

I/O Efficient Early Bursting Cohesive Subgraph Discovery in Massive Temporal Networks.

Temporal networks are an effective way to encode temporal information into graph data losslessly. Finding the bursting cohesive subgraph (BCS), which accumulates its cohesiveness at the fastest rate, is an important problem in temporal networks. The BCS has a large number of applications, such as representing emergency events in social media, traffic congestion in road networks and epidemic outbreak in communities. Nevertheless, existing methods demand the BCS lasting for a time interval, which neglects the timeliness of the BCS. In this paper, we design an early bursting cohesive subgraph (EBCS) model based on the k-core to enable identifying the burstiness as soon as possible. To find the EBCS, we first construct a time weight graph (TWG) to measure the bursting level by integrating the topological and temporal information. Then, we propose a global search algorithm, called GS-EBCS, which can find the exact EBCS by iteratively removing nodes from the TWG. Further, we propose a local search algorithm, named LS-EBCS, to find the EBCS by first expanding from a seed node until obtaining a candidate k-core and then refining the k-core to the result subgraph in an optimal time complexity. Subsequently, considering the situation that the massive temporal networks cannot be completely put into the memory, we first design an I/O method to build the TWG and then develop I/O efficient global search and local search algorithms, namely I/O-GS and I/O-LS respectively, to find the EBCS under the semi-external model. Extensive experiments, conducted on four real temporal networks, demonstrate the efficiency and effectiveness of our proposed algorithms. For example, on the DBLP dataset, I/O-LS and LS-EBCS have comparable running time, while the maximum memory usage of I/O-LS is only 6.5 MB, which is much smaller than that of LS-EBCS taking 308.7 MB. Supplementary Information: The online version contains supplementary material available at 10.1007/s11390-022-2367-3.

Gene Manipulation Protocols in Autophagy.

Macroautophagy (referred to as autophagy hereafter) is a highly conserved catabolic process in eukaryotic cells. Autophagy is essential for cellular homeostasis through elimination and recycling of large cytoplasmic components, such as abnormal protein aggregates and damaged organelles, via lysosomal degradation. Since being originally identified by genetic screening in yeast, autophagy-related (ATG) genes have played a central role in autophagy research in different organisms, including plants, worms, flies, and mammals. Mouse models for monitoring autophagic activity or clarifying its biological functions have also been established. These mice are powerful tools to investigate roles of autophagy in vivo. Owing to the rapid technological advances in molecular biology, it is ever more efficient and simpler to manipulate autophagy-associated genes. Herein, we will introduce some commonly used approaches of gene silencing in mammalian cells, including CRIPSR/Cas9-mediated gene knockout and siRNA- and shRNA-mediated gene knockdown. We also summarized the common mouse models used for assessing autophagy. We hope to bring the researchers some useful information as they study autophagy.

Correcting severe flexion contracture with fusiform capsulectomy of posterior capsule during total knee arthroplasty.

PURPOSE: This study aimed to evaluate the safety and efficacy of fusiform capsulectomy of posterior capsule in correcting severe flexion contracture during total knee arthroplasty (TKA). METHODS: A retrospective analysis was performed in the patients who had preoperative severe flexion contracture (> 30 degrees) prior to TKA and received fusiform capsulectomy of posterior capsule during TKA between December 2013 and November 2018. Range of motion (ROM), knee functional score, forgotten joint score (FJS), post-operative complications, and radiographic results were collected and evaluated. RESULT: Twenty patients (32 knees) were enrolled in this study. The mean duration of follow-up was 27.19 ± 15.92 months. The flexion contracture improved from pre-operative 37.69 ± 11.79° to post-operative 5.78 ± 4.44° (p < 0.001), and ROM increased from pre-operative 63.50 ± 21.74° to post-operative 97.88 ± 13.20° (p < 0.001). KSS clinical score increased from pre-operative 32.94 ± 11.03 to post-operative 82.34 ± 10.73 (p < 0.001), and KSS function score increased from pre-operative 28.97 ± 18.43 to post-operative 68.75 ± 15.96 (p < 0.001). The post-operative FJS was 76.08 ± 2.14. There was no implant loosening, infection, obvious haematoma formation, resultant instability, neurovascular complications, or revision for any reasons in the cohort until the last follow-up. CONCLUSIONS: The technique of fusiform capsulectomy of posterior capsule to correct the severe flexion contracture during primary TKA is safe and effective and could provide good short-term results.

The Knowledge and Attitude Towards Advance Care Planning Among Chinese Patients with Advanced Cancer.

To describe the knowledge and attitude of Chinese patients with advanced cancer towards advanced care planning (ACP), a convenience sample of 275 patients with advanced cancer was recruited from a tertiary cancer hospital in Beijing, China, between February and December 2017. The multi-item questionnaire focused on patients' demographics, disease characteristics and knowledge about and attitude towards ACP and was administered to eligible patients. Descriptive statistics were performed. Most patients had never heard about ACP (82.2%) and had never talked about ACP (83.0%), but only a few (18.3%) were not willing to talk about ACP. A total of 67.8% patients chose to refuse resuscitation attempts or life-sustaining medical interventions, and 70.8% of patients hoped to have surrogate decision makers when they became unconscious. By binary logistic regression analysis, patients who were of greater age, female and living in urban areas preferred to refuse resuscitation attempts or life-sustaining medical interventions (OR = 1.023, P = 0.042; OR = 2.011, P = 0.020; OR = 0.254, P < 0.01); patients who had very rich or rich family economic status preferred to involve surrogate decision makers compared with patients of very poor family economic status (OR = 0.250, P = 0.011). There is a large gap between the knowledge about ACP and the expectation of implementing ACP in Chinese patients with advanced cancer. To develop culturally appropriate and individualized programmes to promote knowledge and implementation in practice of ACP among Chinese patients with advanced cancer and their relatives is still a significant challenge.

Tanshinone â ¡A inhibits homocysteine-induced proliferation of vascular smooth muscle cells via miR-145/CD40 signaling.

Tanshinone IIA (Tan IIA), isolated from the traditional Chinese herb Danshen, exhibits broad cardiovascular protective effects. However, the effect of Tan IIA on Homocysteine (Hcy)-induced proliferation of vascular smooth muscle cells (VSMCs) remains unknown. We herein determined whether Tan IIA exerted anti-proliferative effect in Hcy-treating VSMCs, and further investigated the underlying mechanism (miR-145/CD40 signaling). The results showed that Tan IIA significantly inhibited VSMCs proliferation induced by Hcy in a dose-dependent manner, and reversed the VSMCs injury as indicated by decreased KLF4 and increased Calponin expression. In view of the key role of miR-145 in VSMCs, we further explored the role of miR-145 on the protective effect of Tan IIA against Hcy-induced VSMCs proliferation. The miR-145 expression was down-regulated and its targeted gene CD40 was up-regulated in Hcy-treating VSMCs, while the Tan IIA reversed the effect of Hcy, suggesting the miR-145/CD40 may be involve in the protective effect of Tan IIA. To determine the speculation, miR-145 inhibitor was used to inhibit miR-145 expression. The results indicated that miR-145 inhibitor can suppress the protective effects of Tan IIA against Hcy-induced VSMCs proliferation. Collectively, present study demonstrates that Tan IIA inhibits Hcy-induced proliferation of VSMCs via miR-145/CD40 signaling.

Rise in Low-Density Lipoprotein Cholesterol during Hospitalization is Related with Poor Outcome at Discharge in Patients with Acute Ischemic Stroke.

BACKGROUND: The statistical association between a short-term rise in low-density lipoprotein cholesterol (LDL-C) levels and the short-term outcome of acute ischemic stroke remains unknown. We aimed to evaluate the association in acute ischemic stroke patients during hospitalization. METHODS: Patients with acute ischemic stroke who received statin at discharge were enrolled in this multicenter registry study. LDL-C values were measured on the first day after admission and on the day before discharge to determine the rise in LDL-C levels. Poor outcome was defined as a modified Ranking Scale score ≥2 at discharge. The National Institutes of Health Stroke Scale increase from admission to discharge by 2 points was defined as clinical deterioration. Logistic regression analyses were used to analyze the relationship between LDL-C rise during hospitalization and poor outcome at discharge. Variables that were significantly different between the LDL-C rise and LDL-C fall groups were considered in adjustment for confounding variables in model 1. Age, sex, and those variables in model 1 were considered in adjustment for confounding variables in model 2. RESULTS: Among the 676 patients, 110 (16.3%) showed a rise in LDL-C levels during hospitalization. Multivariate analyses showed that LDL-C at admission <1.6 mmol/L was significantly correlated with LDL-C rise during hospitalization (p < 0.001). There were significantly more patients with a poor outcome in the "LDL-C rise" group than in the "LDL-fall" group (p = 0.002). Multiple models consistently showed that LDL-C rise increased the risk of a poor outcome at discharge in model 1 (OR [95% CI] 1.351 [1.059-1.723], p = 0.016) and model 2 (OR [95% CI] 1.370 [1.071-1.751], p = 0.012). LDL-C rise also increased the risk of clinical deterioration, although its p value only was 0.043 in model 1 and 0.048 in model 2. CONCLUSIONS: Rise in LDL-C during hospitalization from acute ischemic stroke is an independent predictor of poor outcome at discharge. In particular, patients with lower LDL-C values at admission are a higher at risk, and LDL-C in these patients should thus be monitored while in hospital.

Chemical cocktails enable hepatic reprogramming of human urine-derived cells with a single transcription factor.

Human liver or hepatocyte transplantation is limited by a severe shortage of donor organs. Direct reprogramming of other adult cells into hepatic cells may offer a solution to this problem. In a previous study, we have generated hepatocyte-like cells from mouse fibroblasts using only one transcription factor (TF) plus a chemical cocktail. Here, we show that human urine-derived epithelial-like cells (hUCs) can also be transdifferentiated into human hepatocyte-like cells (hiHeps) using one TF (Foxa3, Hnf1α, or Hnf4α) plus the same chemical cocktail CRVPTD (C, CHIR99021; R, RepSox; V, VPA; P, Parnate; T, TTNPB; and D, Dznep). These hiHeps express multiple hepatocyte-specific genes and display functions characteristic of mature hepatocytes. With the introduction of the large T antigen, these hiHeps can be expanded in vitro and can restore liver function in mice with concanavalin-A-induced acute liver failure. Our study provides a strategy to generate functional hepatocyte-like cells from hUCs by using a single TF plus a chemical cocktail.

Androgen receptor suppresses prostate cancer cell invasion via altering the miR-4496/ß-catenin signals.

Previous study found that AR in prostate may act as both a proliferator and a suppressor to promote or suppress the metastasis of prostate cancer (PCa). In current work, we demonstrated that AR could suppress PCa cell invasion through altering the miR-4496/ß-catenin signals. And mechanisms dissection found that AR could negatively regulate the expression of ß-catenin through enhancing the miR-4496 expression via directly binding to the AR-response-elements (AREs) of miR-4496 promoter, subsequently, the miRNA could directly target the 3' UTR of the ß-catenin-mRNA to reduce its expression. To conclude, our work suggests that AR might play an important role to suppress PCa cell invasion, targeting the newly identified AR/miR-4496/ß-catenin signaling with small molecules may help us to build up new therapeutic approaches to better suppress the metastasis of PCa.