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Betel quid (BQ) use disorder (BUD) is prevalent in many Asian countries, impacting approximately 600 million people. We conducted a randomized clinical trial to analyze the impact of MAOA genetic variations on the severity of BQ craving. This was measured using DSM-5 criteria and the Yale-Brown Obsessive-Compulsive Scale modified for betel quid use (Y-BOCS-BQ). Participants were grouped according to the severity of BUD and MAOA gene single-nucleotide polymorphism (SNP) rs5953210 genotypes. The Y-BOCS-BQ scores were assessed at baseline (week 0) and during follow-up at weeks 2, 4, 6, and 8. The AA genotype group showed significantly greater reductions in Y-BOCS-BQ at weeks 2 ( p = 0.0194), 4 ( p = 0.0078), 6 ( p = 0.0277), and 8 ( p = 0.0376) compared to the GG genotype group. Additionally, within the antidepressant group, the AA genotype showed significant reductions in the Y-BOCS-BQ scores at weeks 2 ( p = 0.0313), 4 ( p = 0.0134), 6 ( p = 0.0061), and 8 ( p = 0.0241) compared to the GG genotype. The statistical analysis revealed a significant interaction between the treatment and placebo groups based on MAOA genotypes, with the AA genotype in the treatment group exhibiting a more pronounced decrease in Y-BOCS-BQ score ( p interaction <0.05) at week 6. Our study highlights the importance of considering genetic factors when developing personalized treatment plans for BUD.

Betel quid (BQ) is the fourth most popular psychoactive substance in the world, and BQ use disorder (BUD) is prevalent in Asian countries. Although the mechanisms underlying BUD remain unclear, studies have reported influences from monoamine oxidase inhibitor. We enrolled 50 patients with BUD and assessed their BQ consumption habits, emotional conditions, and the clinical severity of addiction-assessed using the Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] ( DSM-5 ) criteria, Substance Use Severity Rating Scale, and Yale-Brown Obsessive Compulsive Disorder Rating Scale for BQ. Patients were categorized into the severe group when showing six or more symptoms defined by DSM-5 . A genome-wide association study was conducted for single nucleotide polymorphisms in BRCA1 , COL9A1 , NOTCH1 , HSPA13 , FAT1 , and MAOA by using patients' blood samples. More severe BUD symptoms were associated with younger age of using BQ and poor oral hygiene and with severe craving for and more anxiety toward BQ use. The MAOA rs5953210 polymorphism was significantly associated with severe BUD (odds ratio, 6.43; 95% confidence interval, 5.12-7.74; p < 0.01) and might contribute to BQ-associated cancer risk. Further studies are required to investigate the addictive properties of BQ and the development of novel diagnostic tools and pharmacotherapeutic alternatives to BUD treatment.

Although phthalate esters contribute to airway remodeling by increasing bronchial cells' migration and proliferation, the relationship between human exposure to phthalates and asthma is not understood. We measured phthalate exposure in the human body and evaluated its effect on asthma. Asthma ( n = 123) and asthma-free ( n = 139) participants were, respectively, recruited from an asthma clinic and the community in Taiwan. The urine levels of six phthalate metabolites were determined by liquid chromatography tandem mass spectrometry. Compared with the controls, male asthma patients had higher means of mono-(2-ethylhexyl) phthalate (MEHP) (116.3 nmol/g), monobutyl phthalate (MBP) (850.3 nmol/g) and monoethyl phthalate (MEP) (965.8 nmol/g), and female patients had greater MBP (2902.4 nmol/g). Each 10-fold increase in the level of these phthalate metabolites was correspondingly associated with a 5.0-, 5.8-, 4.2- and 5.3-fold risk of contracting asthma. Male asthma patients were identified to have a higher proportion of MEHP exposure (32.5%) than the controls (25.3%). In asthma patients, an increase in urine MEHP levels and the total phthalate metabolite concentration were notably linked to increased risks of emergency room visits and being hospitalized. For the occurrence and acute clinical events of adult asthma, phthalate exposures and MEHP retention may contribute to higher risks of contracting this respiratory disorder.

Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline N -oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with N -acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial-mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-β1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis.

Human pluripotent stem cells (PSCs), including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), represent valuable cell sources to replace diseased or injured tissues in regenerative medicine. iPSCs exhibit the potential for indefinite self-renewal and differentiation into various cell types and can be reprogrammed from somatic tissue that can be easily obtained, paving the way for cell therapy, regenerative medicine, and personalized medicine. Cell therapies using various iPSC-derived cell types are now evolving rapidly for the treatment of clinical diseases, including Parkinson's disease, hematological diseases, cardiomyopathy, osteoarthritis, and retinal diseases. Since the first interventional clinical trial with autologous iPSC-derived retinal pigment epithelial cells (RPEs) for the treatment of age-related macular degeneration (AMD) was accomplished in Japan, several preclinical trials using iPSC suspensions or monolayers have been launched, or are ongoing or completed. The evolution and generation of human leukocyte antigen (HLA)-universal iPSCs may facilitate the clinical application of iPSC-based therapies. Thus, iPSCs hold great promise in the treatment of multiple retinal diseases. The efficacy and adverse effects of iPSC-based retinal therapies should be carefully assessed in ongoing and further clinical trials.

Background: Deregulation of conventional protein kinases is associated with the growth and development of cancer cells. Alpha-kinase 1 (ALPK1) belongs to a newly discovered family of serine/threonine protein kinases with no sequence homology to conventional protein kinases, and its function in cancer is poorly understood., Methods: In this systematic review, we searched for and analyzed studies linking ALPK1 to cancer development and progression., Results: Based on the current evidence obtained using human, animal, cellular, and tissue models, ALPK1 is located upstream and triggers cancer cell development and metastasis by regulating the inflammatory response through phosphorylation. Its mRNA and protein levels were found to correlate with advanced tumor size and lymph node metastasis, which occur from the cellular cytoplasm into the nucleus. ALPK1 is also strongly associated with gout, chronic kidney disease, and diabetes, which are considered as inflammatory diseases and associated with cancer., Conclusion: ALPK1 is an oncogene involved in carcinogenesis. Chronic inflammation is the common regulatory mechanism between cancer and these diseases. Future research should focus on identifying inhibitors of serine/threonine and ALPK1 at their phosphorylation sites, which would block various signal transductions and potentially offer kinase-targeted therapeutic agents for patients with cancer and inflammatory diseases.

Laxatives are commonly prescribed for constipation management; however, they are recognized as an independent factor associated with cardiovascular diseases. Arteriovenous fistula (AVF) is the closest to the ideal model of hemodialysis (HD) vascular access and part of the cardiovascular system. Our study aims to explore the association of contact laxative use with AVF maturation outcomes in patients undergoing HD. We conducted a multi-center cohort study of 480 contact laxative users and 472 non-users who had undergone initial AVF creation. All patients were followed until the outcomes of AVF maturation were confirmed. Multivariable logistic regression models were performed to evaluate the risk of AVF maturation failure imposed by laxatives. Here, we found that patients who used contact laxatives were significantly associated with an increased risk of AVF maturation failure compared to non-users (adjusted odds ratio, 1.64; p = 0.003). Notably, the risk of AVF maturation failure increased when increasing their average daily doses and cumulative treatment days. In conclusion, our study found a significant dose- and duration-dependent relationship between contact laxative use and an increased risk of AVF maturation failure. Thus, laxatives should be prescribed with caution in this population. Further studies are needed to validate these observations and investigate the potential mechanisms.

Breast cancer is the leading cause of global cancer incidence and breast cancer stem cells (BCSCs) have been identified as the target to overcome breast cancer in patients. In this study, we purified a BCSC inhibitor from Dendropanax morbiferus H.Lév. leaves through several open column and high-performance liquid chromatography via activity-based purification. The purified cancer stem cell (CSC) inhibitor was identified as dihydroconiferyl ferulate using nuclear magnetic resonance and mass spectrometry. Dihydroconiferyl ferulate inhibited the proliferation and mammosphere formation of breast cancer cells and reduced the population of CD44 high /CD24 low cells. Dihydroconiferyl ferulate also induced apoptosis, inhibited the growth of mammospheres and reduced the level of total and nuclear EGFR protein. It suppressed the EGFR levels, the interaction of Stat3 with EGFR, and c-Myc protein levels. Our findings show that dihydroconiferyl ferulate reduced the level of nuclear epidermal growth factor receptor (EGFR) and induced apoptosis of BCSCs through nEGFR/Stat3-dependent c-Myc deregulation. Dihydroconiferyl ferulate exhibits potential as an anti-CSC agent through nEGFR/Stat3/c-Myc signaling.

To discover the new medical entity from edible marine algae, our continuously natural product investigation focused on endophytes from marine macroalgae Grateloupia sp. Two new azaphilones, 8a- epi -hypocrellone A ( 1 ), 8a- epi -eupenicilazaphilone C ( 2 ), together with five known azaphilones, hypocrellone A ( 3 ), eupenicilazaphilone C ( 4 ), ((1 E ,3 E )-3,5-dimethylhepta-1,3-dien-1-yl)-2,4-dihydroxy-3-methylbenzaldehyde ( 5 ), sclerotiorin ( 6 ), and isochromophilone IV ( 7 ) were isolated from the alga-derived fungus Penicillium sclerotiorum . The structures of isolated azaphilones ( 1 - 7 ) were elucidated by spectrometric identification, especially HRESIMS, CD, and NMR data analyses. Concerning bioactivity, cytotoxic, anti-inflammatory, and anti-fibrosis activities of those isolates were evaluated. As a result, compound 1 showed selective toxicity toward neuroblastoma cell line SH-SY5Y among seven cancer and one fibroblast cell lines. 20 μM of compounds 1 , 3 , and 7 inhibited the TNF-α-induced NFκB phosphorylation but did not change the NFκB activity. Compounds 2 and 6 respectively promoted and inhibited SMAD-mediated transcriptional activities stimulated by TGF-β.

The Hedgehog (HH) signaling pathway plays an important role in embryonic development and adult organ homeostasis. Aberrant activity of the Hedgehog signaling pathway induces many developmental disorders and cancers. Recent studies have investigated the relationship of this pathway with various cancers. GPCR-like protein Smoothened (SMO) and the glioma-associated oncogene (GLI1) are the main effectors of Hedgehog signaling. Physalin A, a bioactive substance derived from Physalis alkekengi , inhibits proliferation and migration of breast cancer cells and mammospheres formation. Physalin A-induced apoptosis and growth inhibition of mammospheres, and reduced transcripts of cancer stem cell (CSC) marker genes. Physalin A reduced protein expressions of SMO and GLI1/2. Down-regulation of SMO and GLI1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation by reducing GLI1 gene expression. Down-regulation of GLI1 reduced CSC marker genes. Physalin A reduced protein level of YAP1. Down-regulation of YAP1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation through reduction of YAP1 gene expression. Down-regulation of YAP1 reduced CSC marker genes. We showed that treatment of MDA-MB-231 breast cancer cells with GLI1 siRNA induced inhibition of mammosphere formation and down-regulation of YAP1, a Hippo pathway effector. These results show that Hippo signaling is regulated by the Hedgehog signaling pathway. Physalin A also inhibits the canonical Hedgehog and Hippo signaling pathways, CSC-specific genes, and the formation of mammospheres. These findings suggest that physalin A is a potential therapeutic agent for targeting CSCs.

Dental implants are among the most common treatments for missing teeth. The thickness of the crestal cortical bone at the potential dental implant site is a critical factor affecting the success rate of dental implant surgery. However, previous studies have predominantly focused on female patients, who are at a high risk of osteoporosis, for the discussion of bone quality and quantity at the dental implant site. This study aimed to investigate the effect of male patients' age on the crestal cortical bone of the jaw at the dental implant site by using dental cone-beam computed tomography (CBCT). This study performed dental CBCT on 84 male patients of various ages to obtain tomograms of 288 dental implant sites at the jawbone (41 sites in the anterior maxilla, 95 in the posterior maxilla, 59 in the anterior mandible, and 93 in the posterior mandible) for measuring the cortical bone thickness. A one-way analysis of variance and Scheffe's test were performed on the measurement results to compare the cortical bone thickness at implant sites in the four jaw areas. The correlation between male patient age and cortical bone thickness at the dental implant site was determined. The four jaw areas in order of the cortical bone thickness were as follows: posterior mandible (1.07 ± 0.44 mm), anterior mandible (0.99 ± 0.30 mm), anterior maxilla (0.82 ± 0.32 mm), and posterior maxilla (0.71 ± 0.27 mm). Apart from dental implant sites in the anterior and posterior mandibles, no significant correlation was observed between male patients' age and the cortical bone thickness at the dental implant site.

We study the orientation and ordering of nanodomains of a thickness-modulated lamellar block copolymer (BCP) thin film at each thickness region inside a topological nano/micropattern of bare silicon wafers without chemical pretreatments. With precise control of the thickness gradient of a BCP thin film and the width of a bare silicon trench, we successfully demonstrate (i) perfectly oriented lamellar nanodomains, (ii) pseudocylindrical nanopatterns as periodically aligned defects from the lamellar BCP thin film, and (iii) half-cylindrical nanostructure arrays leveraged by a trench sidewall with the strong preferential wetting of the PMMA block of the BCP. Our strategy is simple, efficient, and has an advantage in fabricating diverse nanopatterns simultaneously compared to conventional BCP lithography utilizing chemical pretreatments, such as a polymer brush or a self-assembled monolayer (SAM). The proposed self-assembly nanopatterning process can be used in energy devices and biodevices requiring various nanopatterns on the same device and as next-generation nanofabrication processes with minimized fabrication steps for low-cost manufacturing techniques.

Cancer stem cells have certain characteristics, such as self-renewal, differentiation, and drug resistance, which are related to tumor progression, maintenance, recurrence, and metastasis. In our study, we targeted breast cancer stem cells (BCSCs) using a natural compound, coriolic acid, from Salicornia herbacea L. This compound was isolated by mammosphere formation inhibition bioassay-guided fractionation and identified by using NMR spectroscopy and electrospray ionization mass spectrometry. Coriolic acid inhibited the formation of mammospheres and induced BCSC apoptosis. It also decreased the subpopulation of CD44 high /CD24 low cells, a cancer stem cell (CSC) phenotype, and specific genes related to CSCs, such as Nanog, Oct4 , and CD44 . Coriolic acid decreased the transcriptional and translational levels of the c-Myc gene, which is a CSC survival factor. These results indicated that coriolic acid could be a novel compound to target BCSCs via regulation of c-Myc.

Satisfactory host bone quality and quantity promote greater primary stability and better osseointegration, leading to a high success rate in the use of dental implants. However, the increase in life expectancy as a result of medical advancements has led to an aging population, suggesting that osteoporosis may become a problem in clinical dental implant surgery. Notably, relative to the general population, bone insufficiency is more common in women with post-menopausal osteoporosis. The objective of this study was to compare the thickness of the crestal cortical bone at prospective dental implant sites between menopausal and non-menopausal women. Prospective dental implant sites in the jawbone were evaluated in two groups of women: a younger group (<50 years old), with 149 sites in 48 women, and an older group (>50 years old) with 191 sites, in 37 women. The thickness of the crestal cortical bone at the dental implant site was measured based on each patient's dental cone-beam computed tomography images. For both groups, one-way analysis of variance and Tukey's post-test were used to assess the correlation between cortical bone thickness and the presence of implants in the four jawbone regions. Student's t -test was further used to compare differences between the older and younger groups. From the retrospective study results, for both groups, thickness of the crestal cortical bone was the highest in the posterior mandible, followed by anterior mandible, anterior maxilla, and posterior maxilla. Compared with the younger group, the older group had a lower mean thickness of the crestal cortical bone. Among the four regions, however, only in the posterior maxilla was the crestal cortical bone significantly thinner in the older group than in the younger group.

Breast cancer is a major health problem that affects lives worldwide. Breast cancer stem cells (BCSCs) are small subpopulations of cells with capacities for drug resistance, self-renewal, recurrence, metastasis, and differentiation. Herein, powder extracts of beetroot were subjected to silica gel, gel filtration, thin layer chromatography (TLC), and preparatory high-pressure liquid chromatography (HPLC) for isolation of one compound, based on activity-guided purification using tumorsphere formation assays. The purified compound was identified as betavulgarin, using nuclear magnetic resonance spectroscopy and electrospray ionization (ESI) mass spectrometry. Betavulgarin suppressed the proliferation, migration, colony formation, and mammosphere formation of breast cancer cells and reduced the size of the CD44 + /CD24 - subpopulation and the expression of the self-renewal-related genes, C-Myc , Nanog , and Oct4 . This compound decreased the total level and phosphorylated nuclear level of signal transducer and activator of transcription 3 (Stat3) and reduced the mRNA and protein levels of sex determining region Y (SRY)-box 2 (SOX2), in mammospheres. These data suggest that betavulgarin inhibit the Stat3/Sox2 signaling pathway and induces BCSC death, indicating betavulgarin might be an anticancer agent against breast cancer cells and BCSCs.

In many solid tumors, tissue of the mesenchymal subtype is frequently associated with epithelial-mesenchymal transition (EMT), strong stromal infiltration, and poor prognosis. Emerging evidence from tumor ecosystem studies has revealed that the two main components of tumor stroma, namely, infiltrated immune cells and cancer-associated fibroblasts (CAFs), also express certain typical EMT genes and are not distinguishable from intrinsic tumor EMT, where bulk tissue is concerned. Transcriptomic analysis of xenograft tissues provides a unique advantage in dissecting genes of tumor (human) or stroma (murine) origins. By transcriptomic analysis of xenograft tissues, we found that oral squamous cell carcinoma (OSCC) tumor cells with a high EMT score, the computed mesenchymal likelihood based on the expression signature of canonical EMT markers, are associated with elevated stromal contents featured with fibronectin 1 (Fn1) and transforming growth factor-β (Tgfβ) axis gene expression. In conjugation with meta-analysis of these genes in clinical OSCC datasets, we further extracted a four-gene index, comprising FN1, TGFB2, TGFBR2, and TGFBI, as an indicator of CAF abundance. The CAF index is more powerful than the EMT score in predicting survival outcomes, not only for oral cancer but also for the cancer genome atlas (TCGA) pan-cancer cohort comprising 9356 patients from 32 cancer subtypes. Collectively, our results suggest that a further distinction and integration of the EMT score with the CAF index will enhance prognosis prediction, thus paving the way for curative medicine in clinical oncology., Competing Interests: The authors declare that they have no competing interests.

In the complex tumor microenvironment, cancer stem cells (CSCs), a rare population of cells, are responsible for malignant tumor initiation, metastasis, drug resistance and recurrence. Controlling breast CSCs (BCSCs) using natural compounds is a novel potential therapeutic strategy for clinical cancer treatment. In this study, a mammosphere assay-guided isolation protocol including silica gel, a C18 column, gel filtration, and high-pressure liquid chromatography was used to isolate an inhibitory compound from Cynanchum auriculatum extracts. The isolated inhibitory compound was identified as caudatin. Caudatin inhibited breast cancer cell proliferation, mammosphere formation and tumor growth. Caudatin decreased the CD44 + /CD24 - and aldehyde dehydrogenase + cell proportions and the levels of c-Myc, Oct4, Sox2, and CD44. Caudatin induced ubiquitin (Ub)-dependent glucocorticoid receptor (GR) degradation and blocked subsequent Yes-associated protein (YAP) nuclear accumulation and target gene transcription signals in BCSCs. These results show that the GR/YAP signaling pathway regulates BCSC formation and that caudatin may be a potential chemopreventive agent that targets breast cancer cells and CSCs.

Breast cancer stem cells (BCSCs) are responsible for tumor chemoresistance and recurrence. Targeting CSCs using natural compounds is a novel approach for cancer therapy. A CSC-inhibiting compound was purified from citrus extracts using silica gel, gel filtration and high-pressure liquid chromatography. The purified compound was identified as tangeretin by using nuclear magnetic resonance (NMR). Tangeretin inhibited cell proliferation, CSC formation and tumor growth, and modestly induced apoptosis in CSCs. The frequency of a subpopulation with a CSC phenotype (CD44 + /CD24 - ) was reduced by tangeretin. Tangeretin reduced the total level and phosphorylated nuclear level of signal transducer and activator of transcription 3 (Stat3). Our results in this study show that tangeretin inhibits the Stat3 signaling pathway and induces CSC death, indicating that tangeretin may be a potential natural compound that targets breast cancer cells and CSCs.

The discoidin domain receptor-1 (DDR1) is a non-integrin collagen receptor recently implicated in the collective cell migration of other cancer types. Previously, we identified an elevated expression of DDR1 in oral squamous cell carcinoma (OSCC) cells. Through the data mining of a microarray dataset composed of matched tumor-normal tissues from forty OSCC patients, we distilled overexpressed genes statistically associated with angiolymphatic invasion, including DDR1, COL4A5, COL4A6 and PDPN. Dual immunohistochemical staining further confirmed the spatial locations of DDR1 and PDPN in OSCC tissues indicative of collective cancer cell invasion. An elevated DDR1 expression at both the transcription and protein level was observed by treating keratinocytes with collagen of fibrillar or basement membrane types. In addition, inhibition of DDR1 kinase activity in OSCC TW2.6 cells disrupted cell cohesiveness in a 2D culture, reduced spheroid invasion in a collagen gel matrix, and suppressed angiolymphatic invasion in xenograft tissues. Taken together, these results suggest that collagen deposition in the affected tissues followed by DDR1 overexpression could be central to OSCC tumor growth and angiolymphatic invasion. Thus, DDR1 inhibitors are potential therapeutic compounds in restraining oral cancer, which has not been previously explored., Competing Interests: The authors declare no conflict of interest.

Nasopharyngeal carcinoma (NPC) is a unique malignancy derived from the epithelium of the nasopharynx. Despite great advances in the development of radiotherapy and chemotherapy, relapse and metastasis in NPC patients remain major causes of mortality. Evidence accumulated over recent years indicates that Epstein-Barr virus (EBV) lytic replication plays an important role in the pathogenesis of NPC and inhibition of EBV reactivation is now being considered as a goal for the therapy of EBV-associated cancers. With this in mind, a panel of dietary compounds was screened and emodin was found to have potential anti-EBV activity. Through Western blotting, immunofluorescence, and flow cytometric analysis, we show that emodin inhibits the expression of EBV lytic proteins and blocks virion production in EBV- positive epithelial cell lines. In investigating the underlying mechanism, reporter assays indicated that emodin represses Zta promoter (Zp) and Rta promoter (Rp) activities, triggered by various inducers. Mapping of the Zp construct reveals that the SP1 binding region is important for emodin-triggered repression and emodin is shown to be able to inhibit SP1 expression, suggesting that it likely inhibits EBV reactivation by suppression of SP1 expression. Moreover, we also show that emodin inhibits the tumorigenic properties induced by repeated EBV reactivation, including micronucleus formation, cell proliferation, migration, and matrigel invasiveness. Emodin administration also represses the tumor growth in mice which is induced by EBV activation. Taken together, our results provide a potential chemopreventive agent in restricting EBV reactivation and NPC recurrence.

Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from FLT3 -ITD-positive MV4-11 (MV4-11-P) cells and examine the development of resistance. The FLT3 -ITD mutation was retained in MV4-11-R; however, the protein was underglycosylated and less phosphorylated in these cells. Moreover, the phosphorylation of ERK1/2, Akt, MEK1/2 and p53 increased in MV4-11-R. The levels of Mcl-1 and p53 proteins were also elevated in MV4-11-R. A p53 D281G mutant emerged in MV4-11-R, in addition to the pre-existing R248W mutation. MV4-11-P and MV4-11-R showed similar sensitivity to cabozantinib, sorafenib, and MK2206, whereas MV4-11-R showed resistance to CI-1040 and idarubicin. MV4-11-R resistance may be associated with inhibition of Akt phosphorylation, but not ERK phosphorylation, after exposure to these drugs. The multi-kinase inhibitor cabozantinib inhibited FLT3-ITD signaling in MV4-11-R cells and MV4-11-R-derived tumors in mice. Cabozantinib effectively inhibited tumor growth and prolonged survival time in mice bearing MV4-11-R-derived tumors. Together, our findings suggest that Mcl-1 and Akt phosphorylation are potential therapeutic targets for p53 mutants and that cabozantinib is an effective treatment in cytarabine-resistant FLT3-ITD-positive AML., Competing Interests: The authors have no conflict of interests to declare.

Transmembrane pressure across the glomerular filter barrier may underlie renal failure. However, studies of renal failure have been difficult owing to a lack of in vitro models to capture the transmembrane pressure in a controlled approach. Here we report a microfluidic platform of podocyte culture to investigate transmembrane pressure induced glomerular leakage. Podocytes, the glomerular epithelial cells essential for filtration function, were cultivated on a porous membrane supplied with transmembrane pressure Δ P . An anodic aluminum oxide membrane with collagen coating was used as the porous membrane, and the filtration function was evaluated using dextrans of different sizes. The results show that dextran in 20 kDa and 70 kDa can penetrate the podocyte membrane, whereas dextran in 500 kDa was blocked until Δ P ≥ 60 mmHg, which resembles the filtration function when Δ P was in the range of a healthy kidney (Δ P < 60 mmHg) as well as the hypertension-induced glomerular leakage (Δ P ≥ 60 mmHg). Additionally, analysis showed that synaptopodin and actin were also downregulated when Δ P > 30 mmHg, indicating that the dysfunction of renal filtration is correlated with the reduction of synaptopodin expression and disorganized actin cytoskeleton. Taking together, our microfluidic platform enables the investigation of transmembrane pressure in glomerular filter membrane, with potential implications for drug development in the future.

Assemblies of four three-dimensional (3D) mixed-ligand coordination polymers (CPs) having formulas, {[Zn₂(bdc)₂(4-bpdh)]·C₂H₅OH·2H₂O} n ( 1 ), [Zn(bdc)(4-bpdh)] n ( 2 ), {[Zn₂(bdc)₂(4-bpdh)₂]·(4-bpdh)} n ( 3 ), and {[Zn(bdc)(4-bpdh)]·C₂H₅OH} n ( 4 ) (bdc 2- = dianion of 1,4-benzenedicarboxylic acid, 4-bpdh = 2,5-bis(4-pyridyl)-3,4-diaza-2,4-hexadiene) have been synthesized and structurally characterized by single-crystal X-ray diffraction method. Structural determination reveals that the coordination numbers (geometry) of Zn(II) ions in 1 , 2 , 3 , and 4 are five (distorted square-pyramidal (SP)), six (distorted octahedral (O h )), five (trigonal-bipyramidal (TBP)), and four (tetrahedral (T d )), respectively, and are bridged by 4-bpdh with bis -monodentate coordination mode and bdc 2- ligands with bis -bidentate in 1 , chelating/bidentate in 2 , bis -monodentate and bis -bidentate in 3 , and bis -monodentate in 4 , to generate two-fold interpenetrating 3D cube-like metal-organic framework (MOF) with pcu topology, non-interpenetrating 3D MOF, two-fold interpenetrating 3D rectangular-box-like MOF with pcu topology and five-fold interpenetrating diamondoid-like MOF with dia topology, respectively. These different intriguing architectures indicate that the coordination numbers and geometries of Zn(II) ions, coordination modes of bdc 2- ligand, and guest molecules play important roles in the construction of MOFs and the formation of the structural topologies and interpenetrations. Thermal stabilities, and photoluminescence study of 1 ⁻ 4 were also studied in detail. The complexes exhibit ligands based photoluminescence properties at room temperature., Competing Interests: The authors declare no conflict of interest.

In this paper, the washability of wearable textronic (textile-electronic) devices has been studied. Two different approaches aiming at designing, producing, and testing robust washable and reliable smart textile systems are presented. The common point of the two approaches is the use of flexible conductive PCB in order to interface the miniaturized rigid (traditional) electronic devices to conductive threads and tracks within the textile flexible fabric and to connect them to antenna, textile electrodes, sensors, actuators, etc. The first approach consists in the use of TPU films (thermoplastic polyurethane) that are deposited by the press under controlled temperature and pressure parameters in order to protect the conductive thread and electrical contacts. The washability of conductive threads and contact resistances between flexible PCB and conductive threads are tested. The second approach is focused on the protection of the whole system-composed of a rigid electronic device, flexible PCB, and textile substrate-by a barrier made of latex. Three types of prototypes were realized and washed. Their reliabilities are studied.

Casticin is one of the main components from Fructus Viticis, which is widely used as an anti-inflammatory agent. The mechanism of how casticin affects melanoma cell migration and invasion is still not well known. Here we studied the anti-metastasis effects of casticin on A375.S2 melanoma cells by using a non-lethal concentration. First; we used an adhesion assay to test the A375.S2 cells' adhesion ability after treatment with casticin. We next investigated the cell migration ability after casticin treatment by using a wound healing assay to prove that the migration of A375.S2 cells can be inhibited by casticin and double checked the results using the transwell-migration assay. The suppressive effects on matrix metalloproteinase-2; and -9 (MMP-2; and -9) activities were examined by gelatin zymography. Furthermore, western blotting was used to investigate the protein level changes in A375.S2 cells. We found that p-EGFR; Ras and p-ERK1/2 are decreased by casticin, indicating that casticin can down-regulate the migration and invasion ability of A375.S2 cells via the p-EGFR/Ras/p-ERK pathway. The NF-κB p65 and p-ERK levels in nuclear proteins are also decreased by treatment with casticin. An EMSA assay also discovered that the NF-κB p65 and DNA interaction is decreased. NF-κB p65 protein level was examined by immunofluorescence staining and also decreased. Our findings suggest that casticin has anti-metastatic potential by decreasing the invasiveness of A375.S2 cells. We also found that casticin suppressed A375.S2 cell proliferation and cell adhesion ability, but did not affect cell death, as examined using cytometry and a collagen adhesion assay. Based on these observations, casticin could be used as an inhibitor of migration and invasion of human melanoma cells in the future.