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Background: While financial toxicity (FT) is prevalent in patients with cancer, young and middle-aged patients with stroke are also affected by FT, which can exacerbate their physical and psychological challenges. Understanding the patient's experience and response measures can further understand the impact of FT on patients with stroke, to help alleviate FT. However, little is known concerning the experience of patients with stroke with FT or their coping strategies. Therefore, this study aimed to describe the experiences of FT in young and middle-aged patients with stroke and their coping strategies. Methods: A phenomenological method was utilized. Semi-structured interviews were conducted with 21 young and middle-aged stroke patients (aged 18–59) between October 2022 and March 2023. The participants were recruited from a tertiary hospital in Shanghai, China. The research team used NVivo 12.0 software. Giorgi's phenomenological analysis method was used to analyse the interview data. Results: The interview results were divided into two categories in terms of patients' experiences of FT and their coping strategies. Nine subthemes were constructed. The experience category included four subthemes: (1) taking on multifaceted economic pressure, (2) dual choice of treatment, (3) decline in material living standards, and (4) suffering from negative emotions such as anxiety and depression. The coping strategy category included five subthemes: (1) reducing expenses, (2) improving living habits, (3) proactive participation in medical decision-making, (4) making a job position choice, and (5) seeking social support. Conclusions: FT in young and middle-aged patients with stroke, which affected their physical and mental health, led them to implement strategies for dealing with FT. The Chinese government needs to broaden the reach of health insurance coverage and advance the fairness of healthcare policies. Healthcare professionals must pay active attention to FT in such patients in terms of strengthening their health education and considering their needs and preferences. Patients need to improve their sense of self-efficacy, actively reintegrate into society, and adhere to rehabilitation and treatment. Individuals at a high risk of stroke are recommended to purchase health insurance. Multifaceted efforts are needed to reduce the impact of FT in young and middle-aged patients with stroke. [ABSTRACT FROM AUTHOR]

Aging involves cognitive decline and prominent alterations in brain activity. Electroacupuncture (EA), a traditional Chinese medicine approach, is demonstrated to be effective in improving cognitive function of older adults. However, the specific neural mechanism underlying this modulation effect remains unclear. In this study, we used functional magnetic resonance imaging (fMRI) to investigate whether EA could improve cognitive performance of community-dwelling older adults and whether these potential improvements are associated with the EA-induced brain functional connectivity alterations. Thirty healthy older adults were recruited and randomly assigned to the EA group and the control group. Behaviorally, we observed an EA-induced improvement in cognitive performance of older adults in the Montreal Cognitive Assessment. On a neural perspective, the EA intervention significantly increased the functional connectivity within the default mode network. Moreover, we found a positive association between the improvement in delayed memory performance and the alterations in the ventral medial prefrontal cortex-hippocampal formation connectivity in the EA group. This study extends previous findings by showing that healthy older adults exhibit neural plasticity manifested as increased functional connectivity after EA sessions, which could induce therapeutic effects in the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Karst ecosystems are becoming increasingly problematic, and high calcium is one of the main characteristics of soils in rocky desertification areas. Chlorophyll fluorescence is one of the most important indicators of the extent to which plants are affected by their environment. There are few reports on the effects of changes in exogenous calcium levels on the chlorophyll fluorescence properties of Fraxinus malacophylla seedlings. In the present study, we investigated the growth, chlorophyll fluorescence properties and antioxidant system of Fraxinus malacophylla seedlings in response to exogenous calcium (as the concentrations of 0, 25, 50, 75 mmol L−1). The results showed that Ca2+ concentration (25–50 mmol L−1) treatment mainly promoted the growth, biomass accumulation, root activity, and chlorophyll synthesis and effect on chlorophyll fluorescence in Fraxinus malacophylla ; the developed root system became a strong linking hub for calcium adaptation. In addition, the activities of the antioxidant enzymes peroxidase (POD) and catalase (CAT) are upregulated and play an important role in preventing excessive oxidative damage. OJIP test parameters changed significantly with the addition of exogenous calcium, and parameters related to each photosystem II (PSII) reaction centre, such as ABS/RC and DIo/RC, increased significantly in the OJIP test, with enhanced function of the PSII electron donor lateral oxygen evolution complex. In conclusion, the addition of exogenous calcium (25–50 mmol L−1) had an important protective effect on the photosynthetic mechanism of Fraxinus malacophylla , promoting photosynthesis, better growth and better adaptability. • A multifaceted approach reveals the adaptation mechanisms of Fraxinus malacophylla in karst areas with high calcium. • The addition of exogenous calcium facilitates the growth of Fraxinus malacophylla. • The addition of exogenous calcium contributes to the development of photosynthetic mechanisms in Fraxinus malacophylla. • The well-developed root system of the Fraxinus malacophylla acts as a powerful linking hub for calcium adaptation. [ABSTRACT FROM AUTHOR]

Ferritin is a ubiquitous iron storage protein that plays an important role in host defence against pathogen infections. In the present study, native ferritin was isolated from the hemolymph of Bombyx mori using native-polyacrylamide gel electrophoresis (native-PAGE) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The results revealed that ferritin consisted of two subunits, designated as BmFerHCH and BmFerLCH. Previously integrated previous transcriptome and iTRAQ data showed that the two subunits were down-regulated in resistant silkworm strain BC9 and there was no obvious change in the expression levels of the subunits in susceptible silkworm strain P50 after BmNPV infection. Virus overlay assays revealed that B. mori ferritin as the form of heteropolymer had an interaction with B. mori nucleopolyhedrovirus (BmNPV), but it can't interact with BmNPV after depolymerisation. What's more, reverse transcription quantitative PCR (RT-qPCR) analysis suggested that BmFerHCH and BmFerLCH could be induced by bacteria, virus and iron. This is the first study to extract B. mori ferritin successfully and confirms their roles in the process of BmNPV infection. All these results will lay a foundation for further research the function of B. mori ferritin. [ABSTRACT FROM AUTHOR]

Aging associates with sleep dysfunction as well as brain alterations. However, the association between age-related brain alterations and their subjective sleep changes is less understood. To address this issue, we recorded T1 weighted structural and resting-state functional magnetic resonance imaging from both young ( n  = 62) and older adults ( n  = 108). In addition, all participants completed a battery of psychometric tests, including the Pittsburg Sleep Quality Index. We found that the age-related atrophy of cerebral gray matter, hippocampal and thalamic volume were associated with subjective sleep decline, and the atrophy of cerebral gray matter mediated the age effect on sleep. In addition, older adults exhibited decreased functional connectivity within the medial temporal lobe subsystem than their young counterparts. Moreover, there is a significant positive association between sleep and functional connectivity in young but not in older adults. In light of our findings, we suggest a neuropathological model in which age-related brain alterations may partially explain the well-documented declines in sleep with aging. [ABSTRACT FROM AUTHOR]

Micro-milling is widely used in aerospace and precision optical part manufacturing. Residual stress is an important index of surface integrity, which signally affects the performance of the micro-parts. This paper presents an analytical model to predict micro-milling residual stresses considering tool edge radius, material strengthening effects, and initial stress. A micro-milling cutting force prediction model is proposed, in which tool edge radius and material strengthening effects are taken into account. The imaginary heat source is utilized to estimate the temperature distribution in the workpiece. This model considers the prediction results of cutting force and temperature as thermomechanical loads experienced by the workpiece. Also, the effect of initial stress is taken into account during the estimation of residual stresses. After loading, unloading, and stresses release, the results of residual stresses in micro-milling are finally obtained. Both the micro-milling cutting force and residual stresses prediction results are validated by NAK80 steel on a three-axis ultra-precision machine. The predicted results capture the experiment results well in terms of distribution and value. Finally, the model is analyzed and discussed. The influences of tool edge radius, rake angle, feed per tooth, and spindle speed on residual stresses are preliminarily explored. [ABSTRACT FROM AUTHOR]

Background: Deregulation of microRNAs (miRNAs) has been associated with a variety of cancers, including non-small cell lung cancer (NSCLC). Here, we investigated anomalous miR-613 expression and its possible functional consequences in primary NSCLC samples and NSCLC-derived cell lines. Methods: The expression of miR-613 was measured by quantitative RT-PCR in 56 primary NSCLC tissues and adjacent non-tumor tissues. The effect of miR-613 up- or down-regulation in NSCLC-derived cells was evaluated in vitro by cell viability and colony formation assays and in vivo by growth assays in xenografted nude mice. Results: Using quantitative RT-PCR, we found that miR-613 was down-regulated in 76.8 % (43/56) of the primary NSCLC tissues tested when compared to the adjacent non-tumor tissues. We also found that the miR-613 mimic used reduced in vitro cell viability and colony formation by inducing cell cycle arrest in NSCLC-derived cells, and inhibited in vivo tumor cell growth in xenografted nude mice. Inversely, we found that the miR-613 inhibitor used increased the viability and colony forming capacity of NSCLC-derived cells and tumor cell growth in xenografted nude mice. In addition, we identified CDK4 as a potential target of miR-613 using in silico Miranda predictions. Subsequent dual-luciferase reporter assays revealed that CDK4 acts as a direct target of miR-613. Concordantly, we found that both miR-613 mimics and inhibitors could decrease and increase CDK4 protein levels in NSCLC-derived cells, respectively. Conclusions: From our results we conclude that miR-613 may act as a tumor suppressor in NSCLC and may serve as a tool for miRNA-based NSCLC therapy. [ABSTRACT FROM AUTHOR]

Three wood-inhabiting fungal species, Xylodon laceratus, X. montanus, and X. tropicus spp. nov., were collected from southern China, here proposed as new taxa based on a combination of morphological features and molecular evidence. Xylodon laceratus is characterized by the resupinate basidiomata with grandinioid hymenophore having cracked hymenial surface, and ellipsoid basidiospores; X. montanus is characterized by the annual basidiomata having the hard, brittle hymenophore with cream hymenial surface, and ellipsoid to broadly ellipsoid basidiospores (3.9–5.3 × 3.2–4.3 µm); and X. tropicus is characterized by its grandinioid hymenophore with buff to a pale brown hymenial surface and subglobose basidiospores measuring 2–4.8 × 1.6–4 µm. Sequences of ITS and nLSU rRNA markers of the studied samples were generated, and phylogenetic analyses were performed with maximum likelihood, maximum parsimony, and Bayesian inference methods. The ITS+nLSU analysis of the order Hymenochaetales indicated that the three new species clustered into the family Schizoporaceae, located in genus Xylodon; based on further analysis of ITS dataset, X. laceratus was a sister to X. heterocystidiatus; X. montanus closely grouped with X. subclavatus and X. xinpingensis with high support; while X.tropicus was retrieved as a sister to X. hastifer. [ABSTRACT FROM AUTHOR]

We explored the contribution of nitrosamine metabolism to lung cancer in a pilot investigation of genetic variation in CYP2B6, a high-affinity enzymatic activator of tobacco-specific nitrosamines with a negligible role in nicotine metabolism. Previously we found that variation in CYP2A6 and CHRNA5-CHRNA3-CHRNB4 combined to increase lung cancer risk in a case-control study in European American ever-smokers (n = 860). However, these genes are involved in the pharmacology of both nicotine, through which they alter smoking behaviours, and carcinogenic nitrosamines. Herein, we separated participants by CYP2B6 genotype into a high- vs. low-risk group (*1/*1 + *1/*6 vs. *6/*6). Odds ratios estimated through logistic regression modeling were 1.25 (95% CI 0.68-2.30), 1.27 (95% CI 0.89-1.79) and 1.56 (95% CI 1.04-2.31) for CYP2B6, CYP2A6 and CHRNA5-CHRNA3-CHRNB4, respectively, with negligible differences when all genes were evaluated concurrently. Modeling the combined impact of high-risk genotypes yielded odds ratios that rose from 2.05 (95% CI 0.39-10.9) to 2.43 (95% CI 0.47-12.7) to 3.94 (95% CI 0.72-21.5) for those with 1, 2 and 3 vs. 0 high-risk genotypes, respectively. Findings from this pilot point to genetic variation in CYP2B6 as a lung cancer risk factor supporting a role for nitrosamine metabolic activation in the molecular mechanism of lung carcinogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Studies concentrating on hydrogen bonding between the base of exobidentate bis(imidazole) derivatives, and 2-aminoheterocyclic compounds, and (±)-1,10-binaphthalene-2,2′-diol have led to an increased understanding of the role the aromatic N-containing compounds have in binding with (±)-1,10-binaphthalene-2,2′-diol. Here anhydrous multicomponent adducts of N-containing aromatic bases such as 1,4-bis(N-imidazolyl)butane (L1), 1,3-bis(N-benzimidazolyl)propane (L2), 1,4-bis(N-benzimidazolyl)butane (L3), 1,5-bis(N-benzimidazolyl)-3-oxapentane (L4), 2-amino-4-phenylthiazole (L5), and 2-amino-5,7-dimethyl-1,8-naphthyridine (L6) have been prepared with (±)-1,10-binaphthalene-2,2′-diol (binol). The six crystalline forms reported are cocrystals of which the crystals and complexes were characterized by X-ray diffraction analysis, IR, mp, and elemental analysis. The inter-ring angles (naphthol/naphthol) in the same binol of the six cocrystals ranged from 70.71° to 104.2° as the organic bases varied. In the six cocrystals, the binols exist either as both of the enantiomers of rac-binol or as only of its single enantiomer. All supramolecular architectures of cocrystals 1–6 are stabilized by O–H⋯N hydrogen bonds. In addition other non-conventional interactions (CH–π, CH3–π, NH–π, S–π, and π–π interactions) play an important role in the solid-state packing of co-crystallization as well. These weak interactions combined, all of the six complexes displayed 3D network structure. [Copyright &y& Elsevier]

Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal–Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively. [ABSTRACT FROM PUBLISHER]

Two new corticioid fungal species, Phanerochaete pruinosa and P. rhizomorpha spp. nov. are proposed based on a combination of morphological features and molecular evidence. Phanerochaete pruinosa is characterized by the resupinate basidiomata with the pruinose hymenial surface, a monomitic hyphal system with simple-septate generative hyphae and subcylindrical basidiospores measuring as 3.5–6.7 × 1.5–2.7 µm. Phanerochaete rhizomorpha is characterized by having a smooth hymenophore covered by orange hymenial surface, the presence of rhizomorphs, subulate cystidia, and narrower ellipsoid to ellipsoid basidiospores. Sequences of ITS+nLSU nrRNA gene regions of the studied specimens were generated and phylogenetic analyses were performed with maximum likelihood, maximum parsimony, and Bayesian inference methods. These phylogenetic analyses showed that two new species clustered into genus Phanerochaete, in which P. pruinosa was sister to P. yunnanensis with high supports (100% BS, 100% BT, 1.00 BPP); morphologically differing by a pale orange to greyish orange and densely cracked hymenial surface. Another species P. rhizomorpha was closely grouped with P. citrinosanguinea with lower supports; morphologically having yellow to reddish yellow hymenial surface, and smaller cystidia measuring as 31–48 × 2.3–4.8 µm. [ABSTRACT FROM AUTHOR]

The competitive displacement of interfacial proteins, including soy protein isolate (SPI), casein, and modified SPIs (heat, sodium sulfite and succinic anhydride treatment), by Tween 20 was investigated. The structural characteristics of the soy proteins, such as the surface hydrophobicity, exposed free sulfhydryl content and ξ-potential, were analyzed to explore their effects on the protein displacement by Tween 20. The sequence of Tween 20 addition significantly affected the displacement of SPI and casein from the interfaces. The highest degrees of displacement of SPI and casein were 91.04% and 90.67%, respectively, when Tween 20 was added before homogenization. However, the corresponding values became 41.29% and 87.70% when Tween 20 was added after homogenization. The lower level of the latter value was mainly attributed to the fact that SPI formed viscoelastic interfacial films, as confirmed by interfacial rheological property measurements. Although both the ξ-potentials of the SPI emulsions and the mechanical strength of the interfacial protein films decreased due to Tween 20 addition, the physical stability of the emulsions was significantly enhanced. In regard to the modified SPIs, although a high surface hydrophobicity and a low content of exposed free sulfhydryl were associated with low degrees of protein displacement in some cases, the protein charge was the dominant factor affecting the displacement by Tween 20. The emulsion stability of both SPI and the modified SPIs was improved by Tween 20, likely because Tween 20 effectively reduced the hydrophobic interactions between the oil droplets by partially displacing proteins or binding to residual interfacial proteins. Image 1 • Soy proteins form more viscoelastic interfacial films than casein and Tween 20. • The sequence of Tween 20 addition affects the displacement of soy proteins. • The succinylated soy proteins are more easily displaced by Tween 20. • Tween 20 addition improves the stability of the soy protein-stabilized emulsions. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified. Methods: In silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM's effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment. Results: We defined "a pro-tumor cirrhotic-ECM" which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors' institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1. Conclusions: Cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC. [ABSTRACT FROM AUTHOR]

With advanced age, older adults show functional deterioration in sleep. Transcranial direct current stimulation (tDCS), a noninvasive brain stimulation, modulates individuals' behavioral performance in various cognitive domains. However, the modulation effect and neural mechanisms of tDCS on sleep, especially for the elderly population are not clear. Here, we aimed to investigate whether high-definition transcranial direct current stimulation (HD-tDCS) could modulate community-dwelling older adults' subjective sleep and whether these potential improvements are associated with the large-scale brain activity alterations recorded by functional magnetic resonance imaging. Thirty-one older adults were randomly allocated to the HD-tDCS group and the control group. HD-tDCS was applied for 25 min at 1.5 mA per day for two weeks. The anode electrode was placed over the left dorsolateral prefrontal cortex, surrounded by 4 cathodes at 7 cm radius. All participants completed sleep neuropsychological assessments and fMRI scans individually before and after intervention. Behaviorally, we observed a HD-tDCS-induced enhancement of older adults' sleep duration. On the aspect of the corresponding neural alterations, we observed that HD-tDCS decreased the functional connectivity between the default mode network (DMN) and subcortical network. More importantly, the decoupling connectivity of the DMN-subcortical network was correlated with the improvements of subjective sleep in the HD-tDCS group. Our findings add novel behavioral and neural evidences about tDCS-induced sleep improvement in community-dwelling older adults. With further development, tDCS may be used as an alternative treatment for sleep disorders and alleviate the dysfunction of brain networks induced by aging. [ABSTRACT FROM AUTHOR]

Background Primary liver cancer (PLC) is the third largest contributor to cancer mortality in the world. PLC is a heterogeneous disease that encompasses several biologically distinct subtypes including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). CHC is a distinct, albeit rare, subtype of PLC and is comprised of cells with histopathological features of both HCC and ICC. Several studies have focused on the mutation and expression landscapes of HCC and ICC. However, studies of CHC were rare. Objective The aim of the current study was to identify genetic and gene expression alterations in the carcinogenesis and development of CHC and ICC in the Chinese population. Unraveling both similar and differing patterns among these subtypes may help to identify personalized medicine approaches that could improve patient survival. Methods Whole genome sequencing (WGS), whole exome sequencing (WES) and RNA-seq were performed on 10 ICC and 10 CHC samples, matched with adjacent non-tumor liver tissue specimens. Comparative analysis was performed using HCC datasets from The Cancer Genome Atlas (TCGA). Results Mutational and transcriptional landscapes of CHC and ICC were clearly delineated. TP53 and CTNNB1 were identified as exhibiting mutations in CHC. ARID1A , PBRM1 , and IDH1 were frequently mutated in ICC. RYR3 , FBN2 , and KCNN3 are associated with cell migration and metastasis and might be driver genes in CHC. KCNN3 was identified as also exhibiting mutations in ICC. The ECM-receptor interaction pathway associated fibrogenic hepatic progenitor cell differentiation and liver fibrosis may play an important role in carcinogenesis of PLC. Chromatin remodeling and chromosome organization are key processes in carcinogenesis and development in PLC. P53 related pathways showed alterations in CHC and HCC. Inflammation may be a key factor involved in ICC carcinogenesis. Conclusion CHC and ICC are different subtypes of PLC. This study discusses predominantly the molecular genetic details of PLC subtypes and highlights the need for an accurate diagnosis and treatment of specific PLC subtypes to optimize patient management. [ABSTRACT FROM AUTHOR]

This study investigated whether beginning nonnative learners of Chinese can use phonological and semantic information of radicals to learn the sounds and meanings of new Chinese characters. Thirty-four seventh- and eighth-grade American adolescents, who received intensive Chinese instruction for one semester, were taught 16 compound pseudocharacters paired with novel pictures over three learning trials. After each learning trial, students were asked to produce the sounds and meanings of pseudocharacters in which semantic transparency and phonetic regularity of radicals were manipulated. Results showed a facilitation effect of transparent semantic radicals in learning character meanings in early trials. There was a trend that students learned to read regular and transparent characters better than irregular and opaque characters. The ability to learn orthography–pronunciation association uniquely predicted Chinese word reading after controlling for semantic and phonetic radical knowledge. These findings suggest a predominant use of semantic strategies and the importance of orthography to phonology mappings in learning to read Chinese for beginning nonnative learners of Chinese. [ABSTRACT FROM PUBLISHER]

Distinct regions harboring cancer stem cells (CSCs) have been identified within the microenvironment of various tumors, and as in the case of their healthy counterparts, these anatomical regions are termed "niche." Thus far, a large volume of studies have shown that CSC niches take part in the maintenance, regulation of renewal, differentiation and plasticity of CSCs. In this review, we summarize and discuss the latest findings regarding CSC niche morphology, physical terrain, main signaling pathways and interactions within them. The cellular and molecular components of CSCs also involve genetic and epigenetic modulations that mediate and support their maintenance, ultimately leading to cancer progression. It suggests that the crosstalk between CSCs and their niche plays an important role regarding therapy resistance and recurrence. In addition, we updated diverse therapeutic strategies in different cancers in basic research and clinical trials in this review. Understanding the complex heterogeneity of CSC niches is a necessary pre-requisite for designing superior therapeutic strategies to target CSC-specific factors and/or components of the CSC niche. [ABSTRACT FROM AUTHOR]

Transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) is currently considered a novel therapeutic strategy for diabetic nephropathy (DN). However, the mechanisms by which UC-MSCs ameliorate renal fibrosis in DN are not well understood. Herein, we firstly investigated the therapeutic effects of mouse UC-MSC infusion on kidney structural and functional impairment in streptozotocin- (STZ-) induced diabetic mice. We found that the repeated injection with mUC-MSCs alleviates albuminuria, glomerulus injury, and fibrosis in DN mouse models. Next, mesangial cells were exposed to 5.6 mM glucose, 30 mM glucose, or mUC-MSC-conditioned medium, and then we performed western blotting, immunofluorescence, wound healing assay, and cell proliferation assay to measure extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), myofibroblast transdifferentiation (MFT), and cell proliferation. We demonstrated that mUC-MSC paracrine decreased the deposition of fibronectin and collagen I by inhibiting TGF-β1-triggered MFT and cell proliferation mediated by PI3K/Akt and MAPK signaling pathways, and elevating the levels of MMP2 and MMP9. Importantly, we provided evidence that the antifibrosis role of mUC-MSC paracrine in DN might be determined by exosomes shed by MSCs. Together, these findings reveal the mechanisms underlying the therapeutic effects of UC-MSCs on renal fibrosis in DN and provide the evidence for DN cell-free therapy based on UC-MSCs in the future. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear.Methods: The mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo.Results: Mitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-D-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1.Conclusions: Our results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Abstract Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus (DM) and the main reason for end-stage renal diseases (ESRD). Based on the role of mesenchymal stem cells (MSCs) in regenerative medicine, the MSC therapy has been considered a promising strategy to ameliorate the progression of DN. In this article, we review the therapeutic potential of MSCs in DN, mainly involving MSC paracrine mechanism based on trophic factors and extracellular vesicles. Knowledge of mechanism underlying the therapeutic action of MSCs on DN can provide much needed new drug targets for this disease. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Background/Aims: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. Methods: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. Results: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. Conclusions: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment. [ABSTRACT FROM AUTHOR]

MicroRNAs play significant roles in the development of cancer and may serve as promising therapeutic targets. In our previous work, miR-219-5p was identified as one of the important metastasis-related microRNAs in HCC. Here we demonstrated that miR-219-5p expression was elevated in HCC tissues and was associated with vascular invasion and dismal prognosis. In multivariate analysis, miR-219-5p was identified as an independent prognostic indicator for HCC patients. Functional mechanism analyses showed that miR-219-5p promoted HCC cell proliferation and invasion in in vitro, as well as in vivo, tumor growth and metastasis in nude mice models bearing human HCC tumors. In addition, cadherin 1 (CDH1) was revealed to be a downstream target of miR-219-5p in HCC cells. In conclusion, miR-219-5p promotes tumor growth and metastasis of HCC by regulating CDH1 and can serve as a prognostic marker for HCC patients. [ABSTRACT FROM AUTHOR]

Cancer associated fibroblast (CAF) is a well-known microenvironment contributor for the development of hepatocellular carcinoma (HCC), while forkhead box (FOX) proteins are also critical to exacerbate HCC malignancy. However, whether FOX proteins are involved in the crosstalk between CAFs and HCC cells remains unclear. In the present study, we reveal that CAFs induce forkhead box Q1 (FOXQ1) expression, and N-myc downstream-regulated gene 1 (NDRG1) is therefore trans-activated to enhance HCC initiation. Intriguingly, pSTAT6/C-C motif chemokine ligand 26 (CCL26) signaling is induced by FOXQ1/NDRG1 axis, thus recruiting hepatic stellate cells (HSCs), the main cellular source of CAFs, to the tumor microenvironment. Thereby, tumor initiating properties are enhanced at least partly through a positive feedback loop between CAFs and HCC cells. Importantly, leflunomide, a pSTAT6 inhibitor that has been approved for the treatment of rheumatoid arthritis, significantly blocks the loop and HCC progression. High expression of CAF marker, ACTA2, and induced FOXQ1/NDRG1 axis in HCC tissues predict unfavorable prognosis. Collectively, our findings uncover a positive feedback loop between CAFs and FOXQ1/NDRG1 axis in neoplastic cells to drive HCC initiation, thus providing new potential therapeutic targets for HCC. [ABSTRACT FROM AUTHOR]

Samia cynthia ricini (Lepidoptera: Saturniidae) is an important commercial silk-producing insect; however, in contrast to the silkworm, mulberry leaves are toxic to this insect because the leaves contain the component 1-deoxynojirimycin (DNJ). A transcriptomic analysis of eri-silkworm haemolymph was conducted to examine the genes related to different metabolic pathways and to elucidate the molecular mechanism underlying eri-silkworm haemolymph responses to DNJ. Eight hundred sixty-five differentially expressed genes (DEGs) were identified, among which 577 DEGs were up-regulated and 288 DEGs were down-regulated in the 2% DNJ group compared to control (ddH2O) after 12h. Based on the results of the functional analysis, these DEGs were associated with ribosomes, glycolysis, N-glycan biosynthesis, and oxidative phosphorylation. In particular, according to the KEGG analysis, 138 DEGs were involved in energy metabolism, glycometabolism and lipid metabolism, and the changes in the expression of nine DEGs were confirmed by reverse transcription quantitative PCR (RT-qPCR). Thus, DNJ induced significant metabolic alterations in eri-silkworm haemolymph. These results will lay the foundation for research into the toxic effects of DNJ on eri-silkworm as a model and provide a reference for the exploitation of new drugs in humans. [ABSTRACT FROM AUTHOR]

Ferritins are conserved iron-binding proteins that are primarily involved in iron storage, detoxification and the immune response. Despite the importance of ferritin in organisms, little is known about their roles in the eri-silkworm (Samia cynthia ricini). We previously identified a ferritin heavy chain subunit named ScFerHCH in the S. c. ricini transcriptome database. The full-length S. c. ricini ferritin heavy chain subunit (ScFerHCH) was 1863 bp and encoded a protein of 231 amino acids with a deduced molecular weight of 25.89 kDa. Phylogenetic analysis revealed that ScFerHCH shared a high amino acid identity with the Bombyx mori and Danaus plexippus heavy chain subunits. Higher ScFerHCH expression levels were found in the silk gland, fat body and midgut of S. c. ricini by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Injection of Staphylococcus aureus and Pseudomonas aeruginosa was associated with an upregulation of ScFerHCH in the midgut, fat body and hemolymph, indicating that ScFerHCH may contribute to the host's defense against invading pathogens. In addition, the anti-oxidation activity and iron-binding capacity of recombinant ScFerHCH protein were examined. Taken together, our results suggest that the ferritin heavy chain subunit from eri-silkworm may play critical roles not only in innate immune defense, but also in organismic iron homeostasis. [ABSTRACT FROM AUTHOR]

Hispanic Americans comprise the largest and fastest-growing ethnic minority in the USA. In Houston, Texas, 44% of the population is of Hispanic descent, with the majority being Mexican Americans (78%). This population is under-represented in health-related research despite their high prevalence of obesity and diabetes, which may predispose them to cancer and other chronic conditions. Recognizing the need for a greater research effort into the health risks of Hispanic Americans, the population-based Mexican American (Mano a Mano) Cohort study was launched in 2001. This is an open cohort with enrolment ongoing to 2019, and as of 30 June 2014, 23 606 adult participants from over 16 600 households were enrolled. Bilingual interviewers elicit information in person on demographics, acculturation, lifestyle, occupation, medical history, family cancer history, self-reported and measured height and weight, and other exposures. Urine, blood and saliva samples have been collected at baseline from 43%, 56% and 63% of participants, respectively. DNA samples are available for about 90% of participants. Incident cancers and other chronic diseases are ascertained through annual telephone re-contact and linkage to the Texas Cancer Registry and/or medical records. Molecular data such as genetic ancestry markers, blood telomere length and HbA1c, a marker of impaired glucose tolerance, are available for a substantial proportion of the participants. Data access is provided on request [manoamano@mdanderson.org]. For further information please visit [www.mano-mano.us]. [ABSTRACT FROM AUTHOR]

The ATP-binding cassette (ABC) transporters belong to a superfamily of genes involved in the transport of specific molecules across lipid membranes, as well as insecticide resistance, present in all living organisms. In this study, we combined the Cnaphalocrocis medinals transcriptome database with a bioinformatics approach to identify four C. medinals ABCs (CmABCs), including CmABCG1, CmABCG4, CmABCC2 and CmABCC3. Tissue expression analysis showed that these genes had a tissue-specific expression pattern. CmABCG1 had significantly higher expression in the haemolymph and head compared to the other tissues. The expression of CmABCG4, CmABCC2 and CmABCC3 was highest in the midgut, followed by expression in the fat body. The developmental stage expression analysis showed that CmABCG1, CmABCG4, CmABCC2 and CmABCC3 were mainly expressed in adults. The transcription of CmABCG1, CmABCG4 and CmABCC2 was significantly induced by chlorpyrifos. Taken together, the results of our study provided useful information for understanding of the detoxification system of C. medinalis. [ABSTRACT FROM AUTHOR]

The ATP-binding cassette (ABC) transporters belong to a superfamily of genes involved in the transport of specific molecules across lipid membranes, as well as insecticide resistance, present in all living organisms. In this study, we combined the Cnaphalocrocis medinals transcriptome database with a bioinformatics approach to identify four C. medinals ABCs (CmABCs), including CmABCG1, CmABCG4, CmABCC2 and CmABCC3. Tissue expression analysis showed that these genes had a tissue-specific expression pattern. CmABCG1 had significantly higher expression in the haemolymph and head compared to the other tissues. The expression of CmABCG4, CmABCC2 and CmABCC3 was highest in the midgut, followed by expression in the fat body. The developmental stage expression analysis showed that CmABCG1, CmABCG4, CmABCC2 and CmABCC3 were mainly expressed in adults. The transcription of CmABCG1, CmABCG4 and CmABCC2 was significantly induced by chlorpyrifos. Taken together, the results of our study provided useful information for understanding of the detoxification system of C. medinalis. [ABSTRACT FROM AUTHOR]

Using a longitudinal sample of young Chinese students (fall and spring in grades 1 and 2: times 1-4, respectively) and growth curve analysis, this study examined whether the initial status and growth rates of compounding awareness from time 1 to time 4 uniquely contribute to reading comprehension at time 4 and whether word-reading efficiency at time 4 mediates the association between initial status and growth in compounding awareness and reading comprehension at time 4. The results indicated that initial status and growth rates of compounding awareness made a significant direct contribution to reading comprehension at the end of second grade after controlling for IQ, phonological awareness, and vocabulary knowledge. The relationship between initial status and growth rates of compounding awareness and reading comprehension were fully mediated by word-reading efficiency. The findings underscore the importance of growth in compounding awareness for reading comprehension and add to the literature about the nature of the morphological awareness and reading comprehension relationship in Chinese. [ABSTRACT FROM AUTHOR]

Deregulation of glycolysis was often observed in human cancer cells. In the present study, we reported resveratrol, a small polyphenol, which has been intensively studied in various tumor models, has a profound anti-tumor effect on human non-small cell lung cancer (NSCLC) via regulation of glycolysis. Resveratrol impaired hexokinase II (HK2)-mediated glycolysis, and markedly inhibited anchorage-dependent and –independent growth of NSCLC cells. Exposure to resveratrol decreased EGFR and downstream kinases Akt and ERK1/2 activation. Moreover, we revealed that resveratrol impaired glucose metabolism by mainly inhibiting expression of HK2 mediated by the Akt signaling pathway, and exogenous overexpression of constitutively activated Akt1 in NSCLC cells substantially rescued resveratrol-induced glycolysis suppression. The in vivo data indicated that resveratrol obviously suppressed tumor growth in a xenograft mouse model. Our results suggest targeting HK2 or metabolic enzymes appears to be a new approach for clinical NSCLC prevention or treatment. [ABSTRACT FROM AUTHOR]

Summary The mechanism of cancer metastasis remains poorly understood. Using gene profiling of hepatocellular carcinoma (HCC) tissues, we have identified GOLM1 as a leading gene relating to HCC metastasis. GOLM1 expression is correlated with early recurrence, metastasis, and poor survival of HCC patients. Both gain- and loss-of-function studies determine that GOLM1 acts as a key oncogene by promoting HCC growth and metastasis. It selectively interacts with epidermal growth factor receptor (EGFR) and serves as a specific cargo adaptor to assist EGFR/RTK anchoring on the trans -Golgi network (TGN) and recycling back to the plasma membrane, leading to prolonged activation of the downstream kinases. These findings reveal the functional role of GOLM1, a Golgi-related protein, in EGFR/RTK recycling and metastatic progression of HCC. [ABSTRACT FROM AUTHOR]

Bombyx mori nucleopolyhedrovirus (BmNPV) is one of the primary pathogens causing severe economic losses in sericulture. However, the molecular mechanism of silkworm resistance to BmNPV remains largely unknown. Here, the recurrent parent P50 (susceptible strain) and the near-isogenic line BC9 (resistance strain) were used in a comparative transcriptome study examining the response to infection with BmNPV. A total of 14,300 unigenes were obtained from two different resistant strains; of these, 869 differentially expressed genes (DEGs) were identified after comparing the four transcriptomes. Many DEGs associated with protein metabolism, cytoskeleton, and apoptosis may be involved in the host response to BmNPV infection. Moreover, some immunity related genes were also altered following BmNPV infection. Specifically, after removing genetic background and individual immune stress response genes, 22 genes were found to be potentially involved in repressing BmNPV infection. These genes were related to transport, virus replication, intracellular innate immune, and apoptosis. Our study provided an overview of the molecular mechanism of silkworm resistance to BmNPV infection and laid a foundation for controlling BmNPV in the future. [ABSTRACT FROM AUTHOR]

We previously reported that the intronic tagSNP +357G/C in the metastasis suppressor HTPAP is associated with metastasis and prognosis of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether SNPs in the HTPAP promoter modulate HTPAP expression and prognosis of HCC. Genomic DNA from 572 microdissected HCCs were genotyped by pyrosequencing and verified by direct sequencing. Haplotype blocks were analyzed. Reporter plasmids were constructed and transfected into HCC cell lines. Transcriptional activities of plasmids were analyzed by dual-luciferase reporter systems. HTPAP expression was measured by real-time quantitative PCR, western blots, and tissue microarrays. Invasion was assessed by Matrigel assays. The prognostic values of HTPAP promoter SNPs in HCC were evaluated by Kaplan-Meier and Cox regression analyses. We identified six SNPs, including -1053A/G and +64G/C, in the HTPAP promoter. The SNPs were in complete linkage disequilibrium, resulting in three promoter haplotypes (promoter I:-1053AA/+64GG, promoter II: -1053AG/+64GC, and promoter III: -1053GG/+64CC). Promoter I manifested the highest luciferase index (p<0.005). However, no significant difference was observed between promoters II and III. We consistently found that HTPAP mRNA and protein levels were significantly higher in promoter I than that of promoter II+III (p<0.001). Invasion was increased in HCC cells transfected with promoters II+III compared to those transfected with promoter I (p<0.05). The HTPAP promoter II+III haplotype was associated with significantly increased metastasis compared to that of promoter I (p = 0.023). The postoperative five-year overall survival of patients with promoters II+III was lower than that of patients with promoter I (p = 0.006). Multivariate analysis showed that the promoter II+III haplotype was an adverse prognostic marker in HCC. The genetic variants at loci –1053 and +64 of the HTPAP promoter affect the expression of HTPAP, which might be a novel determinant and target for HCC prognosis. [ABSTRACT FROM AUTHOR]

Genome-wide association studies of white persons with lung cancer have identified a region of extensive linkage disequilibrium on chromosome 15q25.1 that appears to be associated with both risk for lung cancer and smoking dependence. Because studying African American persons, who exhibit lower levels of linkage disequilibrium in this region, may identify additional loci that are associated with lung cancer, we genotyped 34 single-nucleotide polymorphisms (SNPs) in this region (including LOC123688, PSMA4, CHRNA5, CHRNA3, and CHRNB4 genes) in 467 African American patients with lung cancer and 388 frequency-matched African American control subjects. Associations of SNPs in LOC123688 (rs10519203; odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.25 to 2.05, P = .00016), CHRNA5 (rs2036527; OR = 1.67, 95% CI = 1.26 to 2.21, P = .00031), and CHRNA3 (rs1051730; OR = 1.81, 95% CI = 1.26 to 2.59, P = .00137) genes with lung cancer risk reached Bonferroni-corrected levels of statistical significance (all statistical tests were two-sided). Joint logistic regression analysis showed that rs684513 (OR = 0.47, 95% CI = 0.31 to 0.71, P = .0003) in CHRNA5 and rs8034191 (OR = 1.76, 95% CI = 1.23 to 2.52, P = .002) in LOC123688 were also associated with risk. The functional A variant of rs1696698 in CHRNA5 had the strongest association with lung cancer (OR = 1.98, 95% CI = 1.25 to 3.11, P = .003). These SNPs were primarily associated with increased risk for lung adenocarcinoma histology and were only weakly associated with smoking phenotypes. Thus, among African American persons, multiple loci in the region of chromosome 15q25.1 appear to be strongly associated with lung cancer risk. [ABSTRACT FROM AUTHOR]

Common variants in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25.1 were associated with lung cancer risk in three recently published independently conducted genome-wide association studies, with no consensus as to the relative impact of the variants on the propensity to smoke vs a direct carcinogenic effect. To further explore our hypothesis that these variants are indeed associated with both cancer causation and nicotine dependence, we performed a more detailed analysis of the association of these putative risk genotypes with smoking phenotype, as well as in lifetime never smokers, and in other smoking-related cancers. We demonstrate a statistically significant association of the variants with both nicotine dependence, as well as lung cancer phenotypes, including earlier age at lung cancer onset. The variants were associated with higher risks of lung cancer in lower smoking-exposed strata, and in individuals with a strong family history of lung or smoking-related cancers. In contrast, we found no evidence that the variants were associated with elevated risks in 547 lifetime never-smoking lung cancer case subjects, nor in other smoking-related cancers (bladder and renal). Thus, we conclude that the variants are implicated both in smoking behavior and more directly in lung cancer risk. [ABSTRACT FROM AUTHOR]

This study correlated the extent of induced in vitro chromosomal damage, assessed by the mutagen sensitivity assay, with genotypes of the X-ray repair cross complementing group 1 (XRCC1) gene, which encodes for a base excision repair protein. There are two common polymorphisms that cause amino acid substitutions in XRCC1, one at codon 194 in exon 6 and another at codon 399 in exon 10. We genotyped these two polymorphisms in 524 healthy subjects and performed mutagen sensitivity assays using both bleomycin and benzo[a]pyrene-diol-epoxide (BPDE) as challenge mutagens. Our results showed that individuals with the wildtype exon 6 Arg/Arg exhibited significantly higher values of chromosomal breaks per cell (b/c) than those with one or two variant Trp alleles (P=0.005 for bleomycin and P=0.05 for BPDE). For the exon 10 polymorphism, subjects who were Gln/Gln homozygotes had higher b/c than did those with other genotypes, with evidence of a gene dosage effect. When we combined the two polymorphic sites and used the exon 6 Arg/Trp and Trp/Trp and exon 10 Arg/Arg genotypes as the reference category, these differences were enhanced for bleomycin sensitivity (P for trend = 0.032), but not for BPDE sensitivity (P for trend = 0.821). These data are biologically plausible since codon 399 is located within the BRCA1 C-terminus functional domain and codon 194 is in the linker region of the XRCC1 N-terminal functional domain. To our knowledge, this is the largest study conducted evaluating the functional relevance of these polymorphisms. [Copyright &y& Elsevier]

Exosomes are a subset of extracellular vesicles that carry specific combinations of proteins, nucleic acids, metabolites, and lipids. Mounting evidence suggests that exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including cancer development. Exosomes are released by various cell types under both normal and pathological conditions, and they can be found in multiple bodily fluids. Moreover, exosomes carrying a wide variety of important macromolecules provide a window into altered cellular or tissue states. Their presence in biological fluids renders them an attractive, minimally invasive approach for liquid biopsies with potential biomarkers for cancer diagnosis, prediction, and surveillance. Due to their biocompatibility and low immunogenicity and cytotoxicity, exosomes have potential clinical applications in the development of innovative therapeutic approaches. Here, we summarize recent advances in various technologies for exosome isolation for cancer research. We outline the functions of exosomes in regulating tumor metastasis, drug resistance, and immune modulation in the context of cancer development. Finally, we discuss prospects and challenges for the clinical development of exosome-based liquid biopsies and therapeutics. [ABSTRACT FROM AUTHOR]