Development and validation of a new multiplex panel using SNaPshot-based DIP-TriSNP markers for forensic DNA mixtures.

Short tandem repeat analysis is challenging when dealing with unbalanced mixtures in forensic cases due to the presence of stutter peaks and large amplicons. In this research, we propose a novel genetic marker called DIP-TriSNP, which combines deletion/insertion polymorphism (DIP) with tri-allelic single nucleotide polymorphism in less than 230 bp length of human genome. Based on multiplex PCR and SNaPShot, a panel, including 14 autosomal DIP-TriSNPs and one Y chromosomal DIP-SNP, had been developed and applied to genotyping 102 unrelated Han Chinese individuals in Sichuan of China and simulated a mixture study. The panel sensitivity can reach as low as 0.1 ng DNA template, and the minor contributor of DNA can be detected with the highest ratio of 19:1, as indicated by the obtained results. In the Sichuan Han population, the cumulative probability of informative genotypes reached 0.997092, with a combined power of discrimination of 0.999999998801. The panel was estimated to detect more than two alleles in at least one locus in 99.69% of mixtures of the Sichuan Han population. In conclusion, DIP-TriSNPs have shown promising as an innovative DNA marker for identifying the minor contributor in unbalanced DNA mixtures, offering advantages such as short amplifications, increased polymorphism, and heightened sensitivity.

Current Status and Future Direction of Albumin-Bilirubin in Hepatocellular Carcinoma: A Bibliometric Analysis.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common malignant tumor, so we need a convenient and objective way to diagnose and treat HCC. We discuss the current situation, progress, hotspots, and existing problems of Albumin-Bilirubin (ALBI) in HCC, which can provide new ideas for the prevention, diagnosis, and treatment of HCC. METHODS: We adopt Excel 2019 software and visual analysis tools based on Web of Science database search. This manuscript uses VOSviewer, Co-Occurrence13.3 (COOC13.3) software to conduct overall trend analysis, synonym merging, frequency of countries, journals, institutions, funds, dissimilarity matrices, co-occurrence matrices, bimodal matrices, coupling matrices, cluster analysis of topic evolution time zone graphs. RESULTS: A total of 610 papers were included, and the number of papers output showed an overall upward trend. ALBI has been valued by the industry in HCC and plays an important role in diagnosing and treating HCC, even better than the classic Child-Pugh (C-P) grade. At the same time, hot spots in the treatment of HCC and other applications of ALBI were discovered. CONCLUSION: ALBI score is a convenient and objective liver function evaluation index, which plays an important role in the prediction of patient survival rate and prognosis. Promoting the ALBI score in HCC can help doctors judge the patient's condition and improve the diagnosis and precise treatment effect.

A Bibliometric and Visual Analysis of the Current Status and Trends of Forensic Mixed Stain Research.

OBJECTIVES: To explore the context and hotspot changes of forensic mixed stain research through bibliometric approach. METHODS: The literature of forensic mixed stain included in the core collection of Web of Science database from 2011 to 2022 were collected as the study object, and the annual publication number, countrie (region), institution, journal, keywords, etc. were bibliometrically and visually analyzed using the R-based Bibliometrix 1.1.6 package and VOSviewer 1.6.18 software. RESULTS: A total of 732 articles on forensic mixed stain were included from 2011 to 2022, with the annual number of articles published and the annual citation frequency showing a steady increase year by year. Among the 59 countries (regions) with the most published articles, the United States ranked first with 246 articles, followed by China with 153 articles. The literature came from 104 journals, and the total number of articles published in the top 10 journals was 633. FORENSIC SCI INT GENET ranked first with 307 articles. Visual analysis using VOSviewer software showed that keywords could be divided into four research clusters, namely the genetic marker development group (blue), the mixed stain typing analysis theory group (red), the sequencing analysis group (yellow), and the case sample research group (green). It can be divided into four development stages in terms of different time periods: early development (2011-2013), middle development (2014-2016), rapid development (2017-2020) and latest development (2021-2022). CONCLUSIONS: The number of publications by domestic and foreign scholars in the study of mixed stain in forensic science is showing a relatively stable trend. Machine learning, next generation sequencing and other research have been the hottest topics that have attracted the most attention in recent years, which is expected to further develop the theory of mixed stain typing and sequencing analysis in forensic mixed stain research.

The Integration of Nanomedicine with Traditional Chinese Medicine: Drug Delivery of Natural Products and Other Opportunities.

The integration of progressive technologies such as nanomedicine with the use of natural products from traditional medicine (TM) provides a unique opportunity for the longed-for harmonization between traditional and modern medicine. Although several actions have been initiated decades ago, a disparity of reasons including some misunderstandings between each other limits the possibilities of a truly complementation. Herein, we analyze some common challenges between nanomedicine and traditional Chinese medicine (TCM). These challenges, if solved in a consensual way, can give a boost to such harmonization. Nanomedicine is a recently born technology, while TCM has been used by the Chinese people for thousands of years. However, for these disciplines, the regulation and standardization of many of the protocols, especially related to the toxicity and safety, regulatory aspects, and manufacturing procedures, are under discussion. Besides, both TCM and nanomedicine still need to achieve a wider social acceptance. Herein, we first briefly discuss the strengths and weaknesses of TCM. This analysis serves to focus afterward on the aspects where TCM and nanomedicine can mutually help to bridge the existing gaps between TCM and Western modern medicine. As discussed, many of these challenges can be applied to TM in general. Finally, recent successful cases in scientific literature that merge TCM and nanomedicine are reviewed as examples of the benefits of this harmonization.

Effects of exergaming on cognitive functions and loneliness of older adults with cognitive frailty.

OBJECTIVES: Cognitive frailty combines physical frailty and cognitive impairment in the absence of dementia. The prompt detection of cognitive frailty and early implementation of preventive interventions may reduce the incidence of dementia. However, intervention studies of exergaming in older adults with cognitive frailty are scant. Therefore, we aim to investigate the effectiveness of exergaming on cognitive functions and loneliness among older adults with cognitive frailty. DESIGN: Quasi-experimental design. METHODS: Participants were recruited from four community settings. The experimental group participated in two 40-min group exergaming sessions weekly for eight weeks; the control group received usual care. The outcome measures were the Montreal Cognitive Assessment (MoCA) and the Chinese Version of the Loneliness Scale. Analyses of covariance were conducted to analyze whether exergaming influenced participants' cognitive functions and loneliness. In addition, the effect size of the posttest of the experimental group relative to its baseline value was calculated to determine the effectiveness of the intervention. RESULT: 69 older adults with cognitive frailty were included, and 35 and 34 were assigned to the experimental and control groups, respectively. The exergaming effectively improved the cognitive function of older adults with cognitive frailty. CONCLUSIONS: Exergaming interventions can effectively improve the cognitive functions of older adults with cognitive frailty but do not positively affect loneliness. We provide evidence to healthcare workers to apply exergaming interventions for older adults with cognitive frailty to improve cognitive function.

A comparison of treatment between mini T-plate and headless cannulated compression screw in calcaneal osteotomy.

PURPOSE: In clinical studies, we discovered that when using headless cannulated compression screw fixation, many patients complain of heel pain and frequently need to have the screws removed, whereas this occurrence is uncommon with plate fixation. This study aims to compare the clinical outcome of a mini T-plate and headless cannulated compression screws in calcaneal osteotomy. METHODS: We reviewed the medical records of patients who had calcaneal osteotomy performed by one senior chief surgeon in our hospital between January 2014 and May 2021. Thirty-nine patients met the selection criteria: 22 were fixed using a mini T-plate through a modified small "L" incision on the lateral aspect of the calcaneus and 17 were fixed using double screws through an oblique incision on the lateral aspect of the calcaneus. Then, we compared the patient demographics, surgical statistics, and postoperative complications in calcaneal osteotomy between a mini T-plate and double 6.5-mm headless cannulated compressed screws. RESULTS: Each patient attained radiographic union. The average age was 49.23±13.80 (range: 24-76) years and the average follow-up duration was 47.07±8.64 (range: 36-66) weeks. The average operation duration and times of intraoperative fluoroscopy were significantly lower in the mini T-plate group (P<0.05). There was a savings of $838.88 per patient when using double screws for fixation. The incidence of hardware-related pain and implant removal was lower in the mini T-plate group (P<0.05). There is no significant difference between the two groups in terms of delayed incision healing and clinical neurological complications (P>0.05). CONCLUSIONS: In calcaneal osteotomy, the operation duration, times of intraoperative fluoroscopy, hardware-related pain, and implant removal rate were lower with mini T-plate fixation than with double screws fixation. Therefore, we consider that the mini T-plate would be a good alternative to double screws in calcaneal osteotomy.

Herbal Medicine Nanocrystals: A Potential Novel Therapeutic Strategy.

Herbal medicines have gained recognition among physicians and patients due to their lower adverse effects compared to modern medicines. They are extensively used to treat various diseases, including cancer, cardiovascular issues, chronic inflammation, microbial contamination, diabetes, obesity, and hepatic disorders, among others. Unfortunately, the clinical application of herbal medicines is limited by their low solubility and inadequate bioavailability. Utilizing herbal medicines in the form of nanocrystals (herbal medicine nanocrystals) has shown potential in enhancing solubility and bioavailability by reducing the particle size, increasing the specific surface area, and modifying the absorption mechanisms. Multiple studies have demonstrated that these nanocrystals significantly improve drug efficacy by reducing toxicity and increasing bioavailability. This review comprehensively examines therapeutic approaches based on herbal medicine nanocrystals. It covers the preparation principles, key factors influencing nucleation and polymorphism control, applications, and limitations. The review underscores the importance of optimizing delivery systems for successful herbal medicine nanocrystal therapeutics. Furthermore, it discusses the main challenges and opportunities in developing herbal medicine nanocrystals for the purpose of treating conditions such as cancer, inflammatory diseases, cardiovascular disorders, mental and nervous diseases, and antimicrobial infections. In conclusion, we have deliberated regarding the hurdles and forthcoming outlook in the realm of nanotoxicity, in vivo kinetics, herbal ingredients as stabilizers of nanocrystals, and the potential for surmounting drug resistance through the utilization of nanocrystalline formulations in herbal medicine. We anticipate that this review will offer innovative insights into the development of herbal medicine nanocrystals as a promising and novel therapeutic strategy.

The Effective Treatment of Purpurin on Inflammation and Adjuvant-Induced Arthritis.

Rubia cordifolia L. (Rubiaceae), one of the traditional anti-rheumatic herbal medicines in China, has been used to treat rheumatoid arthritis (RA) since ancient times. Purpurin, an active compound of Rubia cordifolia L., has been identified in previous studies and exerts antibacterial, antigenotoxic, anticancer, and antioxidant effects. However, the efficacy and the underlying mechanism of purpurin to alleviate RA are unclear. In this study, the effect of purpurin on inflammation was investigated using macrophage RAW264.7 inflammatory cells, induced by lipopolysaccharide (LPS), and adjuvant-induced arthritis (AIA) rat was established to explore the effect of purpurin on joint damage and immune disorders; the network pharmacology and molecular docking were integrated to dig out the prospective target. Purpurin showed significantly anti-inflammatory effect by reducing the content of IL-6, TNF-α, and IL-1ß and increasing IL-10. Besides, purpurin obviously improved joint injury and hypotoxicity in the liver and spleen and regulated the level of FOXP3 and CD4+/CD8+. Furthermore, purpurin reduced the MMP3 content of AIA rats. Network pharmacology and molecular docking also suggested that MMP3 may be the key target of purpurin against RA. The results of this study strongly indicated that purpurin has a potential effect on anti-RA.

The small molecule chemical compound cinobufotalin attenuates resistance to DDP by inducing ENKUR expression to suppress MYH9-mediated c-Myc deubiquitination in lung adenocarcinoma.

The small molecule chemical compound cinobufotalin (CB) is reported to be a potential antitumour drug that increases cisplatin (DDP) sensitivity in nasopharyngeal carcinoma. In this study, we first found that CB decreased DDP resistance, migration and invasion in lung adenocarcinoma (LUAD). Mechanistic studies showed that CB induced ENKUR expression by suppressing PI3K/AKT signalling to downregulate c-Jun, a negative transcription factor of ENKUR. Furthermore, ENKUR was shown to function as a tumour suppressor by binding to ß-catenin to decrease c-Jun expression, thus suppressing MYH9 transcription. Interestingly, MYH9 is a binding protein of ENKUR. The Enkurin domain of ENKUR binds to MYH9, and the Myosin_tail of MYH9 binds to ENKUR. Downregulation of MYH9 reduced the recruitment of the deubiquitinase USP7, leading to increased c-Myc ubiquitination and degradation, decreased c-Myc nuclear translocation, and inactivation of epithelial-mesenchymal transition (EMT) signalling, thus attenuating DDP resistance. Our data demonstrated that CB is a promising antitumour drug and may be a candidate chemotherapeutic drug for LUAD patients.

Analysis of Genetic Polymorphism and Population Genetic Structure of 57 Autosomal InDel Loci in Beichuan Qiang Population.

OBJECTIVES: To investigate the genetic information of 57 autosomal InDel loci (A-InDels) included in AGCU InDel 60 fluorescence detection kit in the Beichuan Qiang population of Sichuan Province and evaluate its application value in forensic medicine. METHODS: A total of 200 unrelated healthy individuals from Beichuan Qiang population of Sichuan Province were typing detected by AGCU InDel 60 fluorescence detection kit. Allele frequencies and population genetic parameters of the 57 A-InDels were statistically analyzed and compared with the available data of 26 populations. RESULTS: After Bonferroni correction, there was no linkage disequilibrium between the 57 A-InDels, and all loci were in Hardy-Weinberg equilibrium. Except for rs66595817 and rs72085595, the minor allele frequencies of 55 A-InDels were above 0.3. PIC ranged from 0.298 3 to 0.375 0, CDP was 1-2.974 8×10-24, CPEduo was 0.999 062 660, and CPEtrio was 0.999 999 999. The calculation of the genetic distance showed that Beichuan Qiang population had the closest genetic distances with Beijing Han and South China Han populations, but far away from African populations. CONCLUSIONS: The 57 A-InDels in AGCU InDel 60 fluorescence detection kit have a good genetic polymorphism in Beichuan Qiang population of Sichuan Province, which can be used as effective supplemental for individual identification and paternity identification in forensic medicine.

MiR-1307-5p targeting TRAF3 upregulates the MAPK/NF-κB pathway and promotes lung adenocarcinoma proliferation.

BACKGROUND: Non-small cell lung cancer (NSCLC) includes lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). MicroRNA (miRNA) plays an important role in the regulation of post-transcriptional gene expression in animals and plants, especially in lung adenocarcinoma. METHODS: MiR-1307-5p is an miRNA with significant differences screened by the second generation of high-throughput sequencing in the early stage of our research group. In the current study, a series of in vitro and in vivo experiments were carried out. MiR-1307-5p mimic, miR-1307-5p inhibitor, and NC were transfected into A549 and H1299 lung adenocarcinoma cells. The correlation between miR-1307-5p and clinicopathological features in pathological samples was analyzed using a lung adenocarcinoma tissue microarray, and miR-1307-5p expression was detected by qPCR. CCK-8, EdU, colony formation, scratch test, and Transwell assays were used to observe cell proliferation and migration. Double luciferase assay, western blot, qPCR, and immunohistochemistry were employed in confirming the target relationship between miR-1307-5p and TRAF3. Western blotting was used to analyze the relationship between miR-1307-5p and the NF-κB/MAPK pathway. Finally, the effect of miR-1307-5p on tumor growth was studied using a subcutaneous tumorigenesis model in nude mice. RESULTS: Increased miR-1307-5p expression was significantly related to decreased overall survival rate of lung adenocarcinoma patients, revealing miR-1307-5p as a potential oncogene in lung adenocarcinoma. MiR-1307-5p mimic significantly promoted while miR-1307-5p inhibitor reduced the growth and proliferation of A549 and H1299 cells. MiR-1307-5p overexpression significantly enhanced the migration ability while miR-1307-5p inhibition reduced the migration ability of A549 and H1299 cells. Target binding of miR-1307-5p to TRAF3 was confirmed by double luciferase assay, western blot, qPCR, and immunohistochemistry. miR-1307-5p caused degradation of TRAF3 mRNA and protein. MiR-1307-5p targeted TRAF3 and activated the NF-κB/MAPK pathway. TRAF3 colocalized with p65 and the localization of TRAF3 and p65 changed in each treatment group. Tumor volume of the lv-miR-1307-5p group was significantly larger than that of the lv-NC group, and that of the lv-miR-1307-5p-inhibitor group was significantly smaller than that of the lv-NC group. CONCLUSION: In conclusion, miR-1307-5p targets TRAF3 and activates the NF-κB/MAPK pathway to promote proliferation in lung adenocarcinoma.

Neuroprotective Effects of Deuterium-Depleted Water (DDW) Against H2O2-Induced Oxidative Stress in Differentiated PC12 Cells Through the PI3K/Akt Signaling Pathway.

Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Induction of endogenous antioxidants to act against oxidative stress-mediated neuronal damage seems to be a reasonable strategy for delaying the progression of such diseases. In this study, we investigated the neuroprotective effect of deuterium-depleted water (DDW) against H2O2-induced oxidative stress in differentiated PC12 cells and the possible signaling pathways involved. The differentiated PC12 cell line was pretreated with DDW containing different concentrations (50-100 ppm) of deuterium and then treated with H2O2 to induce oxidative stress and neurotoxicity. We assessed cell survival, reactive oxygen species (ROS) generation, TUNEL assay, catalase (CAT), copper and zinc-containing superoxide dismutase (CuZn-SOD) and superoxide dismutase (SOD) activity and performed Western blot analysis to investigate the neuroprotective effect of DDW. The results indicated that DDW could attenuate H2O2-induced apoptosis, reduce ROS formation, and increase CAT, CuZn-SOD and SOD activity in H2O2-treated PC12 cells. Western blot analysis revealed that DDW treatment significantly increased the expression of p-Akt, Bcl-2 and GSK-3ß. However, the protective effect of DDW on cell survival and the DDW-mediated increases in p-Akt, Bcl-2 and GSK-3ß were abolished by pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002. In summary, DDW may protect differentiated PC12 cells against H2O2-induced oxidative stress through the PI3K/Akt signaling pathway.

Construction and evaluation of multidomain attention training to improve alertness attention, sustained attention, and visual-spatial attention in older adults with mild cognitive impairment: A randomized controlled trial.

OBJECTIVES: We aimed to analyze the effects of multidomain attention training on alertness, sustained attention, and visual-spatial attention in older adults with mild cognitive impairment (MCI). DESIGN: The design used in this study was a two-arm, parallel group, double-blind randomized controlled trial. SETTING AND PARTICIPANTS: The participants of the study were seventy-eight older adults with MCI (mean age: 79.5 ± 7.9 years) from retirement centers and community housing for the elderly. INTERVENTION: The participants were randomly assigned to an experimental group (multidomain attention training, n = 39) or an active control group (n = 39). Both groups underwent training sessions for 45 minutes three times per week for 6 weeks (18 sessions in total). MEASURES: The main efficacy indicator was alertness (Trail Making Test Part B), sustained attention (Digit Vigilance Test), and visual-spatial attention (Trail Making Test Part A). The secondary outcome indicators were other cognitive functions (Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA] subscales). Measurements were obtained at pretest, posttest, and 3 and 6 months after training. RESULTS: The results were analyzed by a generalized estimating equation (GEE), which indicated that attention outcomes (alertness, sustained attention, and visual-spatial attention) of the experimental group did not improve after training. However, the experimental group displayed a significant improvement in the attention, memory, and orientation of MMSE and MoCA subscales over a period of 6 months and also showed superior results compared with the control group. CONCLUSIONS: Multidomain attention training demonstrated improved alertness and visual-spatial attention for posttest after 6 months. We also outline potential future advances in attention training for improving attention in older adults with MCI.

The Construction and Evaluation of Executive Attention Training to Improve Selective Attention, Focused Attention, and Divided Attention for Older Adults With Mild Cognitive Impairment: A Randomized Controlled Trial.

OBJECTIVES: To examine the immediate and long-term effects of executive attention training on selective attention, focused attention, and divided attention in older adults with mild cognitive impairment. METHODS: A double-blind, multisite randomized controlled trial at five sites. Seventy participants (mean age: 78.19 ± 7.22 years) were assigned to an experimental group (executive attention training, n = 35) or an active control group (n = 35). The training duration was the same for both groups (45 minutes per session, 3 times per week, 18 sessions in total). Primary outcome measure was selective attention (Digit Span Task). Secondary outcome measures included focused attention (Stroop Color Word Test) and divided attention (Trail-Making Test Part B). Data were collected at pretest, post-test, 3-month follow-up, and 6-month follow-up. RESULTS: In GEE analysis, findings indicated a significant improvement in selective attention at post-test, whereas divided attention showed significant reducing omission error at 3-month follow-up. There was no significant effect of group in focused attention associated with the executive attention training compared with active control group. CONCLUSION: The executive attention training significantly improved selective attention and divided attention performance. Future studies should identify transfer effects of attention training, and that can employ early screening to provide integrated attention training, and decrease its relevant risks on competency in performing daily activities, such as falling and driving.

Development and effectiveness of virtual interactive working memory training for older people with mild cognitive impairment: a single-blind randomised controlled trial.

BACKGROUND: memory training is a potential intervention for retaining memory and reducing dementia risk in older adults with mild cognitive impairment (MCI). OBJECTIVE: this study examined the effect of virtual interactive working memory training (VIMT) in older adults with MCI. DESIGN: single-blind, two-arm parallel-group, randomised controlled design. SETTING: retirement homes, institutions, and communities. SUBJECTS: a total of 66 older adults with MCI were recruited (mean age: 78.5 ± 7.6 years). METHODS: participants were randomly assigned to the experimental group (VIMT, n = 33) or active control group (n = 33). The VIMT program used the CogniPlus (includes four training modules). Both groups attended 45 min sessions 3 times per week, a total of 36 sessions. The primary outcome was working memory; secondary outcomes were immediate memory, delayed memory, subjective memory complaints and global cognitive function. All variables were measured at pre-test, post-test, and 3-month follow-up. RESULTS: between group, the effect of working memory adjusted mean difference by 1.75 (95% CI: 0.56 to 2.94; P < 0.01) at post-test. The results were analysed by a generalised estimating equation, which indicated that VIMT group significantly improved working memory at post-test (P = 0.01) relative to the active control group. CONCLUSIONS: the applied VIMT program can enable older adults with MCI to maintain their working memory and reduce the rate of cognitive deterioration. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov (no.: NCT02462135).

[Project to Increase the Percentage of Nursing Staffs Passing Clinical Ladder-3 Certification in the Intensive Care Unit].

BACKGROUND & PROBLEMS: Clinical ladder (CL)-3 nurses should have both an ability to integrate the clinical information of critically ill patients and to carry out the administrative work of the intensive care unit. However, in our unit, only 15.3% of nurses hold CL-3 certification, which is much lower than the hospital average of 23.1%. Thus, we initiated a project to raise this percentage in our unit. An analysis in January 2016 showed that the main obstacles to obtaining CL-3 certification in our unit were inability to write case reports, inadequate in-service education, and a lack of certified educators. PURPOSE: The purpose of this project was to increase the number of CL-3-certified nurses in our intensive care unit. RESOLUTION: The resolution included holding courses on case report writing, briefings, and oral presentation techniques; assigning a preceptor to make nursing staff assignments; encouraging nurses to participate in the clinical nursing preceptor education training camp; and conducting practice tests using a multiple assessment tool. RESULTS: After implementation of this project, the percentage of unit nurses who had passed CL-3 increased to 39.0%. CONCLUSIONS: This project not only allowed our fellow nurses to share in the joy of clinical ladder advancement but also improved the atmosphere in the unit by encouraging self-development. This project helped stimulate professional growth among our staff and improved the quality of clinical care.

Nucleotide Prodrug Containing a Nonproteinogenic Amino Acid To Improve Oral Delivery of a Hepatitis C Virus Treatment.

Delivery of pharmacologically active nucleoside triphosphate analogs to sites of viral infection is challenging. In prior work we identified a 2'-C-methyl-1'-cyano-7-deaza-adenosine C-nucleotide analog with desirable selectivity and potency for the treatment of hepatitis C virus (HCV) infection. However, the prodrug selected for clinical development, GS-6620, required a high dose for meaningful efficacy and had unacceptable variability due to poor oral absorption as a result of suboptimal solubility, intestinal metabolism, and efflux transport. While obtaining clinical proof of concept for the nucleotide analog, a more effective prodrug strategy would be necessary for clinical utility. Here, we report an alternative prodrug of the same nucleoside analog identified to address liabilities of GS-6620. A phosphoramidate prodrug containing the nonproteinogenic amino acid methylalanine, an isopropyl ester and phenol in the (S) conformation at phosphorous, GS2, was found to have improved solubility, intestinal stability, and hepatic activation. GS2 is a more selective substrate for hepatically expressed carboxyl esterase 1 (CES1) and is resistant to hydrolysis by more widely expressed hydrolases, including cathepsin A (CatA) and CES2. Unlike GS-6620, GS2 was not cleaved by intestinally expressed CES2 and, as a result, was stable in intestinal extracts. Levels of liver triphosphate following oral administration of GS2 in animals were higher than those of GS-6620, even when administered under optimal conditions for GS-6620 absorption. Combined, these properties suggest that GS2 will have better oral absorption in the clinic when administered in a solid dosage form and the potential to extend the clinical proof of concept obtained with GS-6620.

FoxM1 promotes epithelial-mesenchymal transition, invasion, and migration of tongue squamous cell carcinoma cells through a c-Met/AKT-dependent positive feedback loop.

Forkhead box protein M1 (FoxM1) has been associated with cancer progression and metastasis. However, the function of FoxM1 in tongue squamous cell carcinoma (TSCC) remains largely unknown. The purpose of this study was to determine the role of FoxM1 in regulation of epithelial-mesenchymal transition (EMT) and migration of TSCC cells. We found that FoxM1 induced EMT and increased invasion/migration capacity in SCC9 and SCC25 cells. FoxM1 stimulation increased c-Met, pAKT, and vimentin levels but decreased E-cadherin level. Chromatin immunoprecipitation assay established that FoxM1 is bound to the promoter of c-Met to activate its transcription. In turn, c-Met promoted the expression of FoxM1 and pAKT. Blocking AKT signaling attenuated the invasion and migration of SCC9 and SCC25 cells stimulated by FoxM1 or c-Met. These results indicate that a positive feedback loop controls the EMT and migration of TSCC cells induced by FoxM1 and c-Met through AKT. Furthermore, the expression levels of FoxM1, pAKT, and c-Met were found to significantly increase in TSCC tissues compared with normal tissues, and these three biomarkers were concomitantly expressed in TSCC tissues. Clinical association analyses indicated that the expression of FoxM1, c-Met, and pAKT was associated with clinicopathological characteristics of patients with TSCC including tumor stage, tumor size, and lymph node metastasis. Taken together, our findings suggest that FoxM1 promotes the EMT, invasion and migration of TSCC cells, and cross-talks with c-Met/AKT signaling to form a positive feedback loop to promote TSCC development.

Microwave-Assisted Rapid Synthesis of Self-Assembled T-Nb2 O5 Nanowires for High-Energy Hybrid Supercapacitors.

Recently ion-intercalation hybrid supercapacitors, with high energy density at high power density, have been widely investigated to meet ever-increasing practical demands. Here, a unique hybrid supercapacitor has been designed and fabricated using self-assembled orthorhombic-phase niobium oxide@carbon (T-Nb2 O5 @C) nanowires as an anode and commercially available activated carbon as a cathode. The 3D-interconnected T-Nb2 O5 @C nanowires have been synthesized through a highly efficient microwave-solvothermal method, combined with subsequent thermal treatment. The experimental parameters (e.g., time and temperature) can be easily programmed, and the synthesis time can be significantly shortened, thus enabling the buildup of abundant recipes for the engineering of scaled-up production. The Li-ion intercalation pseudocapacitance electrode, made from the as-formed self-assembled T-Nb2 O5 @C nanowires, shows excellent charge storage and transfer capability. When assembled into a hybrid supercapacitor with a cathode of activated carbon, a high energy density of 60.6 Wh kg-1 and a high power density of 8.5 kW kg-1 with outstanding stability are achieved. In virtue of easy optimization and programmability of the synthetic strategy, and the remarkable electrochemical performance, the self-assembled T-Nb2 O5 @C nanowires offer a promising anode for asymmetric hybrid supercapacitors.

Evidence for the Participation of Acid-Sensing Ion Channels (ASICs) in the Antinociceptive Effect of Curcumin in a Formalin-Induced Orofacial Inflammatory Model.

Curcumin, a major bioactive component of turmeric, has diverse therapeutic effects such as anti-inflammatory, antioxidant, anticancer, and antinociceptive activities. The acid-sensing ion channels (ASICs), which can be activated by acute drops in the extracellular pH, play an important role in nociception. However, very little is known about the interaction between ASICs and curcumin in nociception of inflammation. In our study, we investigated whether the antinociceptive effects of curcumin are mediated via ASICs using an orofacial nociceptive model and in vitro western blotting, immunofluorescence, whole-cell patch-clamp recordings in the trigeminal system. Intraperitoneally administered curcumin at a dose of 50 mg/kg can reduce hyperalgesia in both the phases of a formalin-induced orofacial nociceptive model. Curcumin reduced the amplitude of ASICs currents in a dose-dependent manner in trigeminal ganglion (TG) neurons, and curcumin also reduced the protein quantity but did not change the distribution of ASICs in TG. Thus, our results indicate that curcumin can reduce formalin-induced ASICs activation and thus inhibit ASICs-mediated inflammatory pain hypersensitivity.