This article reviews the recent trends, developments, and future applications of bio-based polymers produced from renewable resources. Bio-based polymers are attracting increased attention due to environmental concerns and the realization that global petroleum resources are finite. Bio-based polymers not only replace existing polymers in a number of applications but also provide new combinations of properties for new applications. A range of bio-based polymers are presented in this review, focusing on general methods of production, properties, and commercial applications. The review examines the technological and future challenges discussed in bringing these materials to a wide range of applications, together with potential solutions, as well as discusses the major industry players who are bringing these materials to the market.The online version of this article (doi:10.1186/2194-0517-2-8) contains supplementary material, which is available to authorized users. Bio-based polymers are materials which are produced from renewable resources. The terms bio-based polymers and biodegradable polymers are used extensively in the literature, but there is a key difference between the two types of polymers. Biodegradable polymers are defined as materials whose physical and chemical properties undergo deterioration and completely degrade when exposed to microorganisms, carbon dioxide (aerobic) processes, methane (anaerobic processes), and water (aerobic and anaerobic processes). Bio-based polymers can be biodegradable  or nondegradable . Similarly, while many bio-based polymers are biodegradable , not all biodegradable polymers are bio-based .Bio-based polymers still hold a tiny fraction of the total global plastic market. Currently, biopolymers share less than 1% of the total market. At the current growth rate, it is expected that biopolymers will account for just over 1% of polymers by 2015 Doug .The worldwide interest in bio-based polymers has accelerated in recent years due to the desire and need to find non-fossil fuel-based polymers. As indicated by ISI Web of Sciences and Thomas Innovations, there is a tremendous increase in the number of publication citations on bio-based polymers and applications in recent years, as shown in Figure Lead Market Initiative (European Union) and BioPreferred (USA). As a result, there is a worldwide demand for replacing petroleum-derived raw materials with renewable resource-based raw materials for the production of polymers.Bio-based polymers offer important contributions by reducing the dependence on fossil fuels and through the related positive environmental impacts such as reduced carbon dioxide emissions. The legislative landscape is also changing where bio-based products are being favored through initiatives such as the Using natural bio-based polymers with partial modification to meet the requirements Producing bio-based monomers by fermentation/conventional chemistry followed by polymerization Producing bio-based polymers directly by bacteria .The first generation of bio-based polymers focused on deriving polymers from agricultural feedstocks such as corn, potatoes, and other carbohydrate feedstocks. However, the focus has shifted in recent years due to a desire to move away from food-based resources and significant breakthroughs in biotechnology. Bio-based polymers similar to conventional polymers are produced by bacterial fermentation processes by synthesizing the building blocks (monomers) from renewable resources, including lignocellulosic biomass (starch and cellulose), fatty acids, and organic waste. Natural bio-based polymers are the other class of bio-based polymers which are found naturally, such as proteins, nucleic acids, and polysaccharides . These bio-based polymers have shown enormous growth in recent years in terms of technological developments and their commercial applications. There are three principal ways to produce bio-based polymers using renewable resources:In this paper, an overview of bio-based polymers made from renewable resources and natural polymers derived from plant and animal origins is presented. The review will focus on the preparation, properties, applications, and future trends for bio-based polymers. This paper discusses the use of renewable resources such as lignocellulosic biomass to create monomers and polymers that can replace petroleum-based polymers, such as polyester, polylactic acids, and other natural bio-based polymers, which are presented in Figure Polylactic acid (PLA) has been known since 1845 but not commercialized until early 1990. PLA belongs to the family of aliphatic polyesters with the basic constitutional unit lactic acid. The monomer lactic acid is the hydroxyl carboxylic acid which can be obtained via bacterial fermentation from corn (starch) or sugars obtained from renewable resources. Although other renewable resources can be used, corn has the advantage of providing a high-quality feedstock for fermentation which results in a high-purity lactic acid, which is required for an efficient synthetic process. l-lactic acid or d-lactic acid is obtained depending on the microbial strain used during the fermentation process.PLA can be synthesized from lactic acid by direct polycondensation reaction or ring-opening polymerization of lactide monomer. However, it is difficult to obtain high molecular weight PLA via polycondensation reaction because of water formation during the reaction. Nature Works LLC (previously Cargill Dow LLC) has developed a low-cost continuous process for the production of PLA . It has many unique characteristics, including good transparency, glossy appearance, high rigidity, and ability to tolerate various types of processing conditions.T g of 60°C. This problem can be overcome by changing the stereochemistry of the polymer and blending with other polymers and processing aids to improve the mechanical properties, e.g., varying the ratio of l and d isomer ratio strongly influences the crystallinity of the final polymer. However, much more work is required to improve the properties of PLA to suit various applications.PLA is a thermoplastic polymer which has the potential to replace traditional polymers such as PET, PS, and PC for packaging to electronic and automotive applications . Although PLA has one of the highest heat resistances and mechanical strengths of all bio-based polymers, it is still not suitable for use in electronic devices and other engineering applications. NEC Corporation (Japan) recently produced a PLA with carbon and kenaf fibers with improved thermal and flame retardancy properties. Fujitsu (Japan) developed a polycarbonate blend with PLA to make computer housings. In recent years, PLA has been employed as a membrane material for use in automotive and chemical industry.The ease of melt processing has led to the production of PLA fibers, which are increasingly accepted in a wide variety of textiles from dresses to sportswear, furnishing to drapes, and soft nonwoven baby wipes to tough landscape textiles. These textiles can outperform traditional textiles made from synthetic counterparts. Bioresorbable scaffolds produced with PLA and various PLA blends are used in implants for growing living cells. The US Food and Drug Administration (FDA) has approved the use of PLA for certain human clinical applications  are a family of polyesters produced by bacterial fermentation with the potential to replace conventional hydrocarbon-based polymers. PHAs occur naturally in a variety of organisms, but microorganisms can be employed to tailor their production in cells. Polyhydroxybutyrate (PHB), the simplest PHA, was discovered in 1926 by Maurice Lemoigne as a constituent of the bacterium Lemoigne .PHA can be produced by varieties of bacteria using several renewable waste feedstocks. A generic process to produce PHA by bacterial fermentation involves fermentation, isolation, and purification from fermentation broth. A large fermentation vessel is filled with mineral medium and inoculated with a seed culture that contains bacteria. The feedstocks include cellulosics, vegetable oils, organic waste, municipal solid waste, and fatty acids depending on the specific PHA required. The carbon source is fed into the vessel until it is consumed and cell growth and PHA accumulation is complete. In general, a minimum of 48 h is required for fermentation time. To isolate and purify PHA, cells are concentrated, dried, and extracted with solvents such as acetone or chloroform. The residual cell debris is removed from the solvent containing dissolved PHA by solid-liquid separation process. The PHA is then precipitated by the addition of an alcohol  and recovered by a precipitation process -3-hydroxybutyric acid monomer and 5% to 20% of a second monomer in order to improve the properties of PHAs. Some specific examples of PHAs include the following:More than 150 PHA monomers have been identified as the constituents of PHAs : Poly(3-hydroxybutyrate)co-3HV): Poly, PHBVPoly(3HB-co-4HB): Poly(3-hydroxybutyrate-co-4-hydroxybutyrate)Poly(3-HB-co-3HH): Poly(3-hydroxyoctanoate-co-hydroxyhexanoate)Poly(3HB-co-3HH): Poly(3-hydroxyoctanoate-co-hydroxyhexanoate)Poly(3HO-Poly (4-HB): Poly(4-hydroxybutyrate).co-3HV) has a much lower crystallinity, decreased stiffness and brittleness, and increased tensile strength and toughness compared to poly(3HB) while remaining biodegradable. It also has a higher melt viscosity, which is a desirable property for extrusion and blow molding  is an aliphatic polyester with similar properties to those of PET. PBS is produced by condensation of succinic acid and 1,4-butanediol. PBS can be produced by either monomers derived from petroleum-based systems or the bacterial fermentation route. There are several processes for producing succinic acid from fossil fuels. Among them, electrochemical synthesis is a common process with high yield and low cost. However, the fermentation production of succinic acid has numerous advantages compared to the chemical process. Fermentation process uses renewable resources and consumes less energy compared to chemical process. Several companies (solely or in partnership) are now scaling bio-succinate production processes which have traditionally suffered from poor productivity and high downstream processing costs. Mitsubishi Chemical (Japan) has developed biomass-derived succinic acid in collaboration with Ajinomoto to commercialize bio-based PBS. DSM and Roquette are developing a commercially feasible fermentation process for the production of succinic acid 1,4-butanediol and subsequent production of PBS. Myriant and Bioamber have developed a fermentation technology to produce monomers. There are several companies around the world developing technologies for the production of PBS, as listed in Table Conventional processes for the production of 1,4-butanediol use fossil fuel feedstocks such as acetylene and formaldehyde. The bio-based process involves the use of glucose from renewable resources to produce succinic acid followed by a chemical reduction to produce butanediol. PBS is produced by transesterification, direct polymerization, and condensation polymerization reactions. PBS copolymers can be produced by adding a third monomer such as sebacic acid, adipic acid, and succinic acid which is also produced by renewable resources  is an important engineering polymer traditionally produced from fossil resources. PE is produced by polymerization of ethylene under pressure, temperature, in the presence of a catalyst. Traditionally, ethylene is produced through steam cracking of naphtha or heavy oils or ethanol dehydration. With increases in oil prices, microbial PE or green PE is now being manufactured from dehydration of ethanol produced by microbial fermentation. The concept of producing PE from bioethanol is not a particularly new one. In the 1980s, Braskem made bio-PE and bio-PVC from bioethanol. However, low oil prices and the limitations of the biotechnology processes made the technology unattractive at that time  is the largest producer of bio-PE with 52% market share, and this is the first certified bio-PE in the world. Similarly, Braskem is developing other bio-based polymers such as bio-polyvinyl chloride, bio-polypropylene, and their copolymers with similar industrial technologies. The current Braskem bio-based PE grades are mainly targeted towards food packing, cosmetics, personal care, automotive parts, and toys. Dow Chemical (USA) in cooperation with Crystalsev is the second largest producer of bio-PE with 12% market share. Solvay (Belgium), another producer of bio-PE, has 10% share in the current market. However, Solvay is a leader in the production of bio-PVC with similar industrial technologies. China Petrochemical Corporation also plans to set up production facilities in China to produce bio-PE from bioethanol  are the paper, cardboard, and corrugating industries  and β-d-mannuronic acid residues (M blocks), as well as segments of alternating guluronic and mannuronic acids.Alginate is a linear polysaccharide that is abundant in nature as it is synthesized by brown seaweeds and by soil bacteria  logistics for biomass feedstocks, (2) new manufacturing routes by replacing existing methods with high yields, (3) new microbial strains/enzymes, and (4) efficient downstream processing methods for recovery of bio-based products.The current bio-based industry focus is mainly on making bio-versions of existing monomers and polymers. Performance of these products is well known, and it is relatively easy to replace the existing product with similar performance of bio-versions. All the polymers mentioned above often display similar properties of current fossil-based polymers. Recently, many efforts are seen towards introducing new bio-based polymers with higher performance and value. For example, Nature Works LLC has introduced new grades of PLA with higher thermal and mechanical properties. New PLA-tri block copolymers have been reported to behave like thermoplastic elastomer. Many developments are currently underway to develop various polyamides, polyesters, polyhydroxyaloknates, etc. with a high differentiation in their final properties for use in automotive, electronics, and biomedical applications.The disadvantage of some of the new bio-based polymers is that they cannot be processed in all current processing equipment. There is vast knowledge on additive-based chemistry developed for improving the performance and processing of fossil fuel-based polymers, and this knowledge can be used to develop new additive chemistry to improve the performance and properties of bio-based polymers (Ray and Bousmina The use of nanoparticles as additives to enhance polymer performance has long been established for petroleum-based polymers. Various nano-reinforcements currently being developed include carbon nanotubes, graphene, nanoclays, 2-D layered materials, and cellulose nanowhiskers. Combining these nanofillers with bio-based polymers could enhance a large number of physical properties, including barrier, flame resistance, thermal stability, solvent uptake, and rate of biodegradability, relative to unmodified polymer resin. These improvements are generally attained at low filler content, and this nano-reinforcement is a very attractive route to generate new functional biomaterials for various applications.Even though new bio-based polymers are produced on an industrial scale, there are still several factors which need to be determined for the long-term viability of bio-based polymers. It is expected that there will be feedstock competition as global demand for food and energy increases over time. Currently, renewable feedstocks used for manufacturing bio-based monomers and polymers often compete with requirements for food-based products. The expansion of first-generation bio-based fuel production will place unsustainable demands on biomass resources and is as much a threat to the sustainability of biochemical and biopolymer production as it is to food production (Michael et al. Bio-based polymers are closer to the reality of replacing conventional polymers than ever before. Nowadays, bio-based polymers are commonly found in many applications from commodity to hi-tech applications due to advancement in biotechnologies and public awareness. However, despite these advancements, there are still some drawbacks which prevent the wider commercialization of bio-based polymers in many applications. This is mainly due to performance and price when compared with their conventional counterparts, which remains a significant challenge for bio-based polymers.


Lung cancer is the second most common cancer and the leading cause of cancer death for both men and women. Although low-dose CT (LDCT) is recommended for lung cancer screening in high-risk populations and may decrease lung cancer mortality, there is a need to improve the accuracy of lung cancer screening to decrease over-diagnosis and morbidity. Blood and serum-based biomarkers, including EarlyCDT-lung and microRNA based biomarkers, are promising adjuncts to LDCT in lung cancer screening.We evaluated the diagnostic performance of EarlyCDT-lung, micro-RNA signature classifier (MSC), and miR-test, and their impact on lung cancer-related mortality and all-cause mortality.References were identified using searches of PubMed, EMBASE, and Ovid Medline® from January 2000 to November 2015. Phase three or greater studies in the English language evaluating the diagnostic performance of EarlyCDT-lung, MSC, and miR-test were selected for inclusion.Three phase 3 studies were identified, one evaluating EarlyCDT-lung, one evaluating miR-Test, and one evaluating MSC respectively. No phase 4 or 5 studies were identified. All three biomarker assays show promise for the detection of lung cancer. MSC shows promise when used in conjunction with LDCT for lung cancer detection, achieving a positive likelihood ratio of 18.6 if both LDCT and MSC are positive, and a negative likelihood ratio of 0.03 if both LDCT and MSC are negative. However, there is a paucity of high-quality studies that can guide clinical implementation.There is currently no high quality evidence to support or guide the implementation of these biomarkers in clinical practice. Reports of further research at stages four and five for these, and other promising methods, is required.The online version of this article (10.1186/s12885-018-4024-3) contains supplementary material, which is available to authorized users. Lung cancer is the second most common cancer and the leading cause of cancer death for both men and women –3. In 20In 2010, the National Lung Screening Trial (NLST) demonstrated a 20% reduction in lung cancer mortality and 7% reduction in all-cause mortality by screening patients at high risk of lung cancer with low-dose chest CT (LDCT) scans (NNS = 320) . HoweverMolecular biomarkers are potentially useful adjuncts to LDCT for lung cancer screening, either by further delineating patient risk prior to LDCT, or assessing malignant risk of positive LDCT findings , 9, 10. The EarlyCDT-Lung test is a commercially available blood test based on ELISA principles that measures a panel of seven tumor-associated autoantibodies: p53, NY-ESO-1, CAGE, GBU4–5, SOX2, HuD, and MAGE A4 . The miRWhat is the individual diagnostic performance of each of EarlyCDT-Lung, miR-test, and MSC for the detection of lung cancer?What is the diagnostic performance of EarlyCDT-Lung, miR-test, and MSC used in conjunction with LDCT for the detection of lung cancer?Does screening with EarlyCDT-Lung, miR-test, and MSC with or without LDCT improve lung-cancer mortality and all-cause mortality?This literature review describes the diagnostic performance of EarlyCDT-Lung, miR-test, and MSC as adjunctive biomarkers to LDCT for the diagnosis of lung cancer. The key questions considered for this review are:A literature review was conducted at North York General Hospital, a suburban academic teaching hospital in Toronto, Canada. We searched Ovid MEDLINE ®, EMBASE, and PUBMED from 2000 up to November 2015 for any lung cancer diagnostic trials involving EarlyCDT-Lung, miR-test, and MSC published in English. We also checked reference lists of included studies and relevant systematic reviews. The full search strategy is available in Additional file After removing duplicates, all citations titles were evaluated for relevance utilizing inclusion criteria for this review. Citation titles were evaluated independently by GS and FS, with consensus amongst both PIs required for inclusion. Articles marked for inclusion by either team member went on to abstract relevance testing. Abstract screening was done independently by GS and FS, with consensus required for inclusion or exclusion.The published results of studies had to be available in English.The population of interest for the review was asymptomatic adults age 18 and older who were at high risk but were not suspected of having lung cancer. Patients known to have lung cancer or were previously diagnosed with lung cancer were excluded from the study population.EarlyCDT-Lung, an antibody based biomarker screening panelmiR-test, a serum-based 13 miRNA signaturemicro-RNA signature classifier (MSC), a plasma-based 24 miRNA risk scoreThe three screening interventions of interest were:To answer the key questions, only Phase 3 or Phase 4 studies that included one or more measures of diagnostic performance  in the abstract were included. All studies that were Phase 1, Phase 2, or did not mention any diagnostic performance measure were excluded.Diagnostic performance for detection of lung cancerOutcome performance in reducing lung cancer-related mortality and all-cause mortalityThe key outcomes evaluated in this review included:For each included study, we extracted data about the population, study design, intervention, inclusion criteria, exclusion criteria, the analysis, and results for the outcome of interest. To evaluate for validity and bias, each included study was evaluated against the STARD 2015 checklist . Any conOur search for studies examining the diagnostic and outcome performance of EarlyCDT-lung, miR-test, and MSC with and without LDCT located 99 unique citations Fig. . From thThe reference lists of included studies and identified review articles were examined, but no additional studies that met inclusion criteria were identified. Therefore, 3 identified studies met inclusion criteria and were included in the review.Three phase 3 studies evaluated the diagnostic performance of various blood-based biomarkers for lung cancer detection, one evaluating EarlyCDT-lung , one evaJett et al. evaluated the use and diagnostic performance of EarlyCDT-lung in 1613 patients presenting to 810 unique physicians in 720 different practices in 48 states . The EarSozzi et al. evaluated the diagnostic performance of the MSC in 1000 consecutive plasma samples from 4099 participants enrolled in the Multicenter Italian Lung Detection (MILD) Trial . The MILMontani et al. evaluated the diagnostic performance of the miR-test in a “validation set” of 1008 patients enrolled in the Continuous Observation of Smoking Subjects (COSMOS) trial and lung cancer patients diagnosed outside of the screening trial . The COSThe diagnostic performance of each biomarker test used alone for the detection of lung cancer is summarized in Table The MSC was evaluated for its diagnostic performance in conjunction with LDCT. If positive results for both MSC and LDCT were needed for a positive screen, a sensitivity, specificity, PPV, NPV, and positive likelihood ratio of 69%, 96%, 65%, 97%, and 18.6 was achieved. If only one of MSC or LDCT needed to be positive to result in a positive screen, a sensitivity, specificity, PPV, NPV, and negative likelihood ratio of 98%, 66%, 22%, 99%, and 0.03 was achieved.miR-test and MSC were evaluated for the important outcome of lung-cancer related mortality Table . The miRThe MSC was evaluated for overall mortality. However, no death occurred due to other causes in lung cancer–free participants.EarlyCDT-lung, miR-test, and MSC were chosen as the focus for this review as they are reported as the biomarkers at the most advanced phase of development for the detection of lung cancer . This reAll three biomarkers show promise in their diagnostic ability to detect lung cancer. The plasma-based micro-RNA signature classifier (MSC) trended towards the highest sensitivity, specificity, and positive likelihood ratio for the detection of lung cancer. However, a direct comparison between the three biomarker signatures cannot be made at this time as sample sizes are small, confidence intervals for performance measures are wide, no trials have directly compared the three biomarker signatures, and the number of trials evaluating each biomarker is singular.The only trial that directly evaluated the diagnostic ability of a blood-based biomarker in conjunction with LDCT shows promise that biomarkers can be useful adjuncts to LDCT in screening for lung cancer. When using MSC in conjunction with LDCT, a positive likelihood ratio of 18.6 was achieved if both MSC and LDCT were positive, while a negative likelihood ratio of 0.03 was achieved if both MSC and LDCT were negative. This suggests that biomarker signatures may potentially be a means to risk stratify at-risk patients for the development of lung cancer.ClinicalTrials.gov ID: NCT01925625) [ClinicalTrials.gov ID: NCT02247453) [Although blood-based biomarkers show promise, there currently is no high quality prospective literature to guide the implementation of blood-based biomarkers in clinical practice for lung cancer detection. Prospective phase 4 studies are currently ongoing to assess the value of the above biomarkers for their value as a pre-CT screening tool. The Early Lung Cancer Detection Study (ECLS) is currently ongoing in Scotland, randomizing approximately 12,000 people from the Greater Glasgow and Clyde area to the EarlyCDT-lung test or routine care (1925625) . Patient1925625) . Similar2247453) .Limitations of this work include the small number of studies identified and the substantial variability across studies in terms of inclusion criteria, methodology, follow-up, timing, and comparators. The number of patients enrolled was small and follow up period for each study was relatively short. It is important to note that the inclusion criteria for these studies varied regarding pack-years of smoking and how patients were enrolled from their larger parent trials. These trials were conducted in different countries where attitudes, laws, and public health policies regarding smoking differed. As our search focused on the three biomarker signatures , studies regarding other biomarker signatures would not have been included. Finally, studies published in languages apart from English would not have been included.Although blood and serum-based biomarkers are promising adjuncts to LDCT for the detection lung cancer, there is currently no high quality evidence to support or guide the implementation of these biomarkers in clinical practice. Prospective studies are ongoing to evaluate the diagnostic performance and impact of biomarkers on clinically relevant outcomes. Further research is required to guide clinical implementation.Additional file 1:Appendix 1 - Search strategy; Appendix 2 - Data collection template; Appendix 3 -Summary of included studies. (DOC 146 kb)


Availability of directly-acting antivirals (DAAs) has changed the treatment landscape of hepatitis C virus (HCV) infection. The high price of DAAs has restricted their use in several countries. However, in some countries such as India, generic DAAs are available at much cheaper price. This study examined whether generic DAAs could be cost-saving and how long it would take for the treatment to become cost-saving/effective.A previously-validated, mathematical model was adapted to the HCV-infected population in India to compare the outcomes of no treatment versus treatment with DAAs. Model parameters were estimated from published studies. Cost-effectiveness of HCV treatment using available DAAs was calculated, using a payer’s perspective. We estimated quality-adjusted life years (QALYs), disability-adjusted life years (DALYs), total costs, and incremental cost-effectiveness ratio of DAAs versus no treatment. One-way and probabilistic sensitivity analyses were conducted.Compared with no treatment, the use of generic DAAs in Indian HCV patients would increase the life expectancy by 8.02 years, increase QALYs by 3.89, avert 19.07 DALYs, and reduce the lifetime healthcare costs by $1,309 per-person treated. Treatment became cost-effective within 2 years, and cost-saving within 10 years of its initiation overall and within 5 years in persons with cirrhosis. Treating 10,000 HCV-infected persons could prevent 3400–3850 decompensated cirrhosis, 1800–2500 HCC, and 4000–4550 liver-related deaths. The results were sensitive to the costs of DAAs, pre- and post-treatment diagnostic tests and management of cirrhosis, and quality of life after sustained virologic response.Treatment with generic DAAs available in India will improve patient outcomes, provide a good value for money within 2 years, and be ultimately cost-saving. Therefore, in this and similar settings, HCV treatment should be a priority from a public health as well an economic perspective. Hepatitis C virus (HCV) infects more than 70 million people worldwide and between 6–11 million in India . In IndiNew directly-acting antivirals (DAAs) for HCV treatment are highly effective, with DAA-based regimens providing rates of sustained virological response (SVR) exceeding 95%. These regimens are also very safe and convenient, needing administration of oral drugs once or twice daily for 12–24 weeks [cost-effective at low prices prevalent in India, it is not known how long it would take them to become cost-effective, and if DAAs could also be cost-saving; i.e. improve life expectancy and reduce costs at the same time. If it were indeed so, this would encourage advocacy by various stakeholders including the patient groups, physicians and public health professionals towards public funding of HCV treatment, and may make it easier for health administrators and political leaders to take such a decision.However, in India, three DAAs  are available from several generic manufacturers at a price as low as $300 . DespiteWe therefore estimated the cost-effectiveness of treatment of HCV-infected persons in India using low-priced DAAs, and evaluated if/when the upfront cost of treatment for HCV infection could result in cost-savings. This question is also of interest for other countries where it may be possible to obtain DAAs at low prices.Markov-based Analyses of Treatments for Chronic Hepatitis C (MATCH) [MATCH-India), following the principles recommended by the World Health Organization (WHO) on economic analyses in the field of viral hepatitis [We have previously developed and validated an individual-level Markov state-transition model, called the  (MATCH) , using C (MATCH) –16. For epatitis .Our base case population included HCV-infected person, aged 35 years, in India. We defined a total of 30 unique patient profiles based on HCV genotype , and the patient’s sex  and METAVIR fibrosis score  . The relThe treatment regimens used were based on the DAAs available in India, depending on HCV genotype and fibrosis stage  , and couWe used data from a previously-published meta-regression analysis to model fibrosis progression rates from F0 to F4 , and froThe model represented a healthcare payer’s perspective. The cost of sofosbuvir-ledipasvir (with or without ribavirin), or sofosbuvir-daclatasvir combination treatment was taken as Indian Rupees (INR) 6711 (USD 100) for every 28 days’ supply [For effectiveness outcomes, we estimated quality-adjusted life years (QALYs), a commonly used metric in cost-effectiveness analysis, and disability-adjusted life years (DALYs), as recommended by the WHO . For QALThe MATCH-India model was used to simulate the clinical course of HCV-infected persons in India with and without DAA-based treatment. We ran 10,000 iterations for each profile and projected the expected life-years, discounted QALYs, DALYs and discounted costs. From these, we estimated the incremental cost-effectiveness ratio  of DAA-based treatment in comparison with no treatment. We used a lifetime horizon, and discounted both future costs and QALYs at 3% per year, with additional sensitivity analyses with 0% and 5% rates. In addition, we projected the cumulative incidence of decompensated cirrhosis and HCC, and liver-related deaths.Since HCV progresses slowly, the full benefits of successful HCV treatment may appear several years later. Therefore, we also estimated the ICERs over time. Specifically, we estimated how long would it take for the cost offsets resulting from prevention of advanced disease to exceed the upfront cost of DAA-based treatment.).We performed one-way sensitivity analyses to estimate the effects of changes in transition probabilities, QOL weights, disability weights, cost inputs and patient’s age on the cost-effectiveness of treatment. Since our estimates of outcomes of various disease states were derived from developed countries, we conducted a sensitivity analysis considering that mortality rates for various liver conditions in India could be 1.0 to 3.0-fold the baseline rates, and rates of progression of liver fibrosis in HCV infection could be 0.6 to 1.2-fold the baseline. We also performed probabilistic sensitivity analysis using 10,000 first-order and 5000 second-order samples by simultaneously varying all key model inputs using the recommended statistical distributions .Compared with no treatment, the use of DAAs in Indian patients with HCV infection was estimated to increase overall life expectancy by 8.02 years and discounted QALYs by 3.89. The improvement in outcomes was more marked in patients with cirrhosis than those without, and was similar across viral genotypes . The no-Further, we found that HCV treatment with low-cost DAAs in India would avert 19.07 DALYs per-person treated . This gaCompared with the no-treatment arm, treating 10,000 persons without cirrhosis using DAAs could prevent ~3850 decompensated cirrhosis, ~2500 HCC, and ~4550 liver-related deaths. In cirrhotic patients, treatment could prevent ~3400 decompensated cirrhosis, ~1800 HCC and ~4000 liver-related deaths .cost-effective within 2 years and cost-saving within 10 years, irrespective of the age at treatment.HCV treatment became cost-effective  within 2 years of starting treatment . FurtherThe 10 model parameters to which ICER per QALY was most sensitive are presented in a tornado diagram . TreatmeHepatitis C is a major cause of morbidity globally, with estimated 495,000 deaths and loss of 12.6 million DALYs per year . The avaPrevious studies on cost-effectiveness of DAA-based treatments for HCV have all focused on the situations in developed countries, such as United States and European Union, where the drug costs are high . In thesBy contrast, in several low-income countries, DAAs are available at highly discounted prices. Our cost-effectiveness analysis showed that the treatment of HCV infection with DAAs at the prices prevalent in India was not only cost-effective, but was in fact cost-saving, i.e., the cost of treatment is offset by the savings in future healthcare costs, thus leading to an overall monetary saving while at the same time increasing QALYs. Situations such as this, where pharmacological treatments have been found to be cost-saving, are rare. Thus, HCV treatment with low-priced DAAs is a win-win situation, warranting the use of public money to fund it.Our results provide a compelling case for India to invest in HCV treatment. Unlike most other pharmacological interventions, HCV treatment with generic DAAs is not merely cost-effective, but also cost-saving. Therefore, investment in HCV treatment paying back for itself over time could be a very rewarding public health investment. For that reason, we estimated the duration in which the upfront cost of DAAs will be offset by the resultant health benefits—a useful parameter for policymakers who prioritize allocation of funds across sectors and diseases. Our analysis found this ‘pay-back’ time to be as short as 10 years, making the public funding of DAA-based treatment of HCV in India quite attractive. In this context, it seems particularly worthwhile to fund the treatment of patients with compensated cirrhosis, since the expenditure would be recouped even faster, i.e. within 5 years.We recognize that our study had some limitations. First, we did not include patients with HCV genotypes 2, 5 and 6 because their prevalence rate is less than 1% in India. Second, as with most of the previously published models of HCV treatment, we ignored the benefits and costs of re-treatment of patients who failed DAAs. With recent advancements in DAAs, newer compounds that are effective in patients who had not responded to the drugs considered in our analysis. However, these newer drugs, which should be useful for retreatment, are not yet available in India; also, these drugs too are expected to be available at low prices in India. Third, the costs of treatment of HCV sequelae in our study were based on expert opinion than on real data, because of lack of published information. However, our conservative assumptions, if anything, biased the analysis against the DAA-based treatment; further, sensitivity analyses over a wide range of costs showed that our results were robust. Finally, we excluded patients with HIV or hepatitis B virus co-infection, or those at higher risk of HCV reinfection. However, this should not detract from our conclusions since such patients account for only a small proportion of the total HCV-infected pool in the Indian population. On the positive side, our analysis and report follow the principles recommended by a WHO group, aimed at enhancing transparency of economic analyses in the field of viral hepatitis . Of courHealth planners would be interested in knowing whether the treatment is more cost-effective or cost-saving in some particular subgroups, which could then receive priority for treatment. We found that gender and viral genotype did not influence the cost-effectiveness of DAA-based HCV treatment much. However, patient’s disease stage and age at treatment influenced the response, with a much greater cost-effectiveness in those with advanced liver disease. Hence, the governments with limited resources may consider prioritizing treatment of such groups, to maximize the public health impact within their limited resources . Such prThough the cost of DAAs has come down, the cost of diagnosis and testing remain high. Thus, with the availability of pan-genotypic DAA-based regimens, it would be important for public-health programs to develop and implement simplified treatment guidelines that obviate the use of pre-treatment HCV genotype testing. Similarly, it would be useful to limit the post-treatment testing to only one occasion, i.e. 12 weeks after completing treatment . Also, iThe licensing agreements that have made low-cost generic DAAs available in India, allow for sale of these drugs in several other low- and low-middle-income countries at low prices. Hence, our results should generally apply to these other countries too, both for individual case treatment and for public-funded treatment programs.In conclusion, we found that low-cost generic DAAs available in India can improve patient outcomes and also result in cost-savings in a fairly short time-frame. Therefore, HCV treatment should be a priority for health planners of this country, and other countries where low-cost DAAs are available, not only from the public health viewpoint, but also from the economic perspective.S1 Appendix(DOCX)Click here for additional data file.


Ten chikungunya virus isolates from human plasma collected in Haiti from May to August 2014, in the midst of a chikungunya fever outbreak, were fully sequenced. The resulting genomic sequences are nearly identical, and phylogenetic analyses indicate they belong to the Asian lineage of the virus. Alphavirus, family Togaviridae) is a mosquito-borne virus that is the cause of chikungunya fever (CF) in humans. Although infections by CHIKV may be asymptomatic, up to 97% of those infected develop CF, which is a fever-rash-arthralgia syndrome often associated with debilitating pain that may last up to several years (Chikungunya virus (CHIKV) -PCR; cDNA synthesis from extracted RNA was performed using a Moloney murine leukemia virus reverse transcriptase (MMLV-RT) and sequence-specific reverse primers, and PCR was performed as described by Cherabuddi et al. . For seqAedes aegyptii  and also have 99% identity with CHIKV strain WHCHK9, which was also collected from Haiti in May 2014 . Presently, three distinct CHIKV lineages have been identified: African, East/Central/South African (ECSA), and Asian –8. Phy strains , but thiKX702401, KX702402, and KY415978 to KY415985.The 10 complete CHIKV genome sequences of this study have been deposited in the GenBank database under the accession numbers


The treatment effects and safety of Ma-Huang-Fu-Zi-Xi-Xin decoction for patients with allergic rhinitis have yet to be clarified. The aim of this study is to evaluate the effects and safety of Ma-Huang-Fu-Zi-Xi-Xin decoction in patients with allergic rhinitis. We searched PubMed, EMBASE , Cochrane Library, Chinese Cochrane Centre's Controlled Trials Register Platform, Wanfang Chinese Digital Periodical and Conference Database, China National Knowledge Infrastructure (CNKI) Database, and VIP Chinese Science and Technique Journals Database to collect randomized controlled trials of Ma-Huang-Fu-Zi-Xi-Xin decoction (MHFZXXD) for allergic rhinitis (AR) prior to May 8, 2017. RevMan 5.3 software was used to conduct a meta-analysis. GRADE methodology was applied to evaluate the evidence quality for each outcome.P = 0.0001) for all included studies. However, the evidence quality of these western medical intervention studies was low or very low due to a high risk of bias, small sample sizes, and poor-quality design. Six randomized controlled trials (RCTs) involving 576 participants (10–78 years old) were included. A meta-analysis revealed that the overall effect of MHFZXXD for AR was not better than western medical treatment (RR: 0.41; 95% CI: 0.26–0.65;  Allergic rhinitis (AR) is defined as chronic inflammation of the nasal mucous membrane, typically induced by immunoglobulin E- (IgE-) mediated sensitization to environmental allergens. These include dust, domestic animals, pollens, and molds. AR is defined by the onset of two or more of the following symptoms: nasal discharge, sneezing, nasal itching, and congestion, all of which interfere with activities of daily living, disrupt regular sleep patterns, or exert a negative influence on the patient's social life or intellectual performance.The incidence of AR is approximately 20%–40% in the US population . A surveAs a classical herbal medicine formula for AR, Ma-Huang-Fu-Zi-Xi-Xin decoction (MHFZXXD) and other herbal medicine formulas as effective interventions have been recommended in a Clinical Guideline for alleviation of symptoms of AR in 2015 . AccordiMHFZXXD is described in a TCM classical document called the Treatise on Febrile Disease, written at the beginning of the third century. According to the Treatise, MHFZXXD contains three herbal medicines, Mahuang (Herba Ephedrae), Fuzi (Radix Aconiti Praeparata), and Xixin (Herba Asari). Many believe in the long-term clinical effects of MHFZXXD for AR . An animAt least three reviews of herbal medicine therapy for AR have been located –9. HowevA systematic search for related published and ongoing trials was performed on May 8, 2017. The languages of the studies were limited to Chinese or English.A total of six databases were searched: PubMed , EMBASE  , Cochrane Library , Chinese Cochrane Centre's Controlled Trials Register Platform , Wanfang Chinese Digital Periodical and Conference Database , China National Knowledge Infrastructure (CNKI) Database , and VIP Chinese Science and Technique Journals Database . Besides, Chinese Clinical Trial Registry Center was also retrieved for ongoing trials.Ma Huang Fu Zi Xi Xin decoctionMa-Huang-Fu-Zi-Xi-Xin decoctionMHFZXXDChinese Herbal MedicineIntegrated Chinese and Western medicinesIntegrated traditional and Western medicine(1)–(6)/ORAllergic rhinitisRhinallergosisAR(8)–(10)/OR(7) AND (11)Search terms were as follows:References of related identified publications were checked for additional trials, and we contacted authors by e-mail or telephone for additional data where necessary.Prospective randomized controlled trials (RCTs) of Ma-Huang-Fu-Zi-Xi-Xin decoction versus placebo or conventional medicine were included in this review. Observational studies, case reports, case series, qualitative studies, uncontrolled studies, and studies with no randomization-control design were excluded.Patients presenting with seasonal AR or perennial AR were all included. Allergic rhinitis merged with allergic asthma or allergic conjunctivitis and other allergic diseases were excluded. This was done because targeted drug combination methods in these studies could not be used to compare effects.We compared MHFZXXD with conventional medicine or placebo regimens. MHFZXXD compared with other types of Chinese herbal medicine formulas such as Gui-Zhi decoction, Bu-Zhong-Yi-Qi decoction, and Yu-Ping-Feng decoction was excluded.Interventions considered for experimental groups versus control groups were as follows:(1) MHFZXXD versus conventional medicine, including chlorpheniramine, 1% ephedrine nose drops, cortisone, budesonide nasal spray, ebastine tablets, loratadine tablets, or other commonly used efficacy drugs.(2) MHFZXXD combined with conventional medicine versus conventional medicine.(3) MHFZXXD combined with other complementary therapies versus other complementary therapies.(4) MHFZXXD versus placebo.We excluded studies or trials with MHFZXXD performed as a part of complex interventions versus other types of regimens, for example, Ma-Huang-Fu-Zi-Xi-Xin decoction plus another herbal medicine formula versus acupuncture therapies.Trials were required to include as outcome measures either relief of symptoms of AR or evaluation of the efficacy of MHFZXXD in AR. Other important clinical outcomes included recurrence rate, influence on quality of life, improvement in symptom scoring, and adverse events.The efficacy of MHFZXXD for AR, improvement in quality of life, and improvement of symptom scoring were set as primary outcomes. Recurrence rate and adverse events  were set as secondary outcomes.Two authors (Juan Zhong and Dan Lai) scanned titles and abstracts of all papers. A determination was then made as to whether the studies met our inclusion criteria. Conflicts were resolved by discussion.Raw data of included papers containing the details of authors, the publication information, and design information of the original study were separately extracted by three authors .http://www.handbook.cochrane.org/) [The risk of bias was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. The latest version of this tool was updated in March 2011, version 5.1.0 (ne.org/) . Two autReview Manager (RevMan) software version 5.3 was applied to pool our data to perform the meta-analysis. GRADE profile software was used to record the results of the GRADE evidence rating.P < 0.05 was defined as statistically significant. I2 values were used to assess interstudy heterogeneity. When I2 > 75%, considerable heterogeneity was conformed, whereupon a random-effects model was applied [Risk ratio (RR) was chosen for dichotomous data . Confidence interval (CI) was set at 95%, and  applied . We poolWe initially identified a total of 53 trials using the specific search strategy in our protocol. No unpublished or ongoing studies were found. After reviewing titles, abstracts, and keywords, twenty-six papers were excluded for failure to conform to inclusion criteria. Eighteen duplicated texts were excluded, as well as nine studies that had initially appeared to meet our inclusion criteria. After the full text was read, six studies finally met our inclusion criteria. The study selection process is outlined in There were six Chinese language studies comprising 576 participants aged 10–78 years –17, publIn Zhu's work (2009) , particiSix studies were designed as randomized controlled trials –16, of wNo blinding method was mentioned in any of the six included studies. There might present a high risk of performance and detection bias.There might be unclear attrition bias in the six studies due to absence of sample size calculation. No cases lost case or withdrawal information was provided in these studies.Unclear reporting bias was detected in the six trials due to absence of protocol. None of the trials declared a clinical trial registration number.No other potential sources of bias were found.The risk of bias graph of authors' judgements concerning included studies is displayed in The risk of bias summary of authors' judgements concerning included studies is displayed in Six studies –16 comprThe efficacy of six RCTs comparing particular interventions and MHFZXXD is presented in P = 0.02; Three RCTs , 14, 16 P = 0.65; One clinical trial published in 2006  assessedP = 0.03; One trial  publisheP = 0.02; Yao and Li's work  publisheP = 0.02; Two studies , 14 repoP = 0.12; One study published in 2015 (Ye and Lin ) reporteThe quality of evidence for outcome measures according to the GRADE system is displayed in Tables To the best of our knowledge, this is the first meta-analysis of MHFZXXD therapy for AR patients. Six trials were included in our review. All control group interventions can be characterized as western medical therapy. MHFZXXD was not inferior to western medicine in improving patients' AR symptoms. However, the data extracted from six trials had small simple size and poor quality measures, according to the GRADE methodologyTables , andS4.None of our included studies used validated questionnaire and scales, including rhinoconjunctivitis, Quality Of Life Questionnaire (RQLQ), and visual analogue scale (VAS), to measure melioration of AR severity or disability, despite the fact that these scales are recommended by the 2015 Clinical Guideline . RQLQ isDespite our use of validated documents supporting diagnostic criteria and effectiveness assessment criteria in this review, nonuniform diagnostic approach or standard of efficacy evaluation might influence outcomes and results. It might be difficult to employ the same diagnosis and effectiveness assessment criteria for each trial, as these criteria vary with each update. Nevertheless, we employed the latest or most recently published criteria.Prior to our study, there have been at least three systematic reviews –9 focusiThe six included studies were prospective, randomized, placebo-controlled studies. However, just three studies , 15, 16 It was not clear whether incomplete outcome data were adequately addressed, as no trial reported drop-out rates. The risk of incomplete outcome data bias in these six studies is therefore unclear. The risk of selective reporting bias is unclear as we do not know whether these six trials reported all prespecified, expected results. Therefore, the quality of evidence for the outcome measurement was low for one outcome and very low for six outcomes, according to the GRADE system.No ongoing trials were found. The conclusion of this review was drawn from the six trials, which comprised a limited number of participants. More studies and high-quality trials should be included in future reviews.In addition, dexamethasone plus gentamicin and chymotrypsin are not used for treatment of allergic rhinitis alone. The diagnosis of allergic rhinitis in Yao and Li's study was questionable, even though we have already contacted the authors of that paper to confirm that this clinical experiment was real and reliable. Another crucial issue is that investigation duration varies in those studies. The treatment course in those studies varies from 3 weeks to 3 months. These critical differences might be an important factor with direct influence on the efficacy assessment and might be a factor leading to bias.In conclusion, current evidence suggests that MHFZXXD alone cannot be recommended for the treatment of AR. This conclusion might rest on a negative summary proof of MHFZXXD or on publication bias or study-design limitations of the included studies. There are insufficient data to state that MHFZXXD is safe and reliable due to the small number of trials reporting adverse events. Therefore, larger sample size and rigorously designed studies are necessary to determine conclusively a definitive association between MHFZXXD and AR.There is no support for the use of MHFZXXD for the treatment of AR.There is an urgent need for double-blind, prospective, randomized, placebo-control trials of MHFZXXD as a treatment for AR. Such studies should employ uniform and validated diagnostic criteria, efficacy evaluation criteria, recommended questionnaire, and measurement scales. Long-term follow-up effectiveness and safety studies for MHFFXXD in AR are necessary as well.


The effectiveness of S/S treatment was evaluated by determining diffusion coefficients (De) and leachability indices (LX). The standard toxicity characteristic leaching procedure (TCLP) was applied to evaluate the extraction potential of Pb and Cd. A diffusion-based model was used to elucidate the controlling leaching mechanisms. Generally, the test results indicated that all applied S/S treatments were effective in immobilizing Pb and Cd, and the treated sediments may be considered acceptable for “controlled utilization” based on LX values, irrespective of their different availability in the untreated samples. In the majority of samples, the controlling leaching mechanism appeared to be diffusion, which indicates that a slow leaching of Cd and Pb could be expected when the above S/S agents were applied. The TCLP results showed that all S/S samples were nonhazardous.The assessment of the quality of sediment from the Great Backi Canal (Serbia), based on the pseudo-total lead (Pb) and cadmium (Cd) content according to the corresponding Dutch standards and Canadian guidelines, showed its severe contamination with these two metals. A microwave-assisted BCR (Community Bureau of Reference of the Commission of the European Union) sequential extraction procedure was employed to assess their potential mobility and risk to the aquatic environment. Comparison of the results of sequential extraction and different criteria for sediment quality assessment has led to somewhat contradictory conclusions. Namely, while the results of sequential extraction showed that Cd comes under the high-risk category, Pb shows low risk to the environment, despite its high pseudo-total content. The contaminated sediment, irrespective of the different speciation of Pb and Cd, was subjected to the same immobilization, stabilization/solidification (S/S) treatments using kaolinite, montmorillonite, kaolinite-quicklime, montmorillonite-quicklime, fly ash, zeolite, or zeolite-fly ash combination. Semi-dynamic leaching tests were conducted for Pb- and Cd-contaminated sediment in order to assess the long-term leaching behavior of these metals. In order to simulate “worst case” leaching conditions, the semi-dynamic leaching test was modified using 0.014 M acetic acid (pH = 3.25) and humic acid solutions (20 mg TOC l


White matter (WM) degeneration has been found during the course of cognitive decline in both Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), however, it is unclear whether there are different WM microstructural abnormalities between two subtypes of aMCI, including single domain aMCI (aMCI-s) and multiple domain aMCI (aMCI-m). Thirty-two patients of aMCI single-domain (aMCI-s), twenty-three patients of aMCI multiple-domain (aMCI-m) and twenty-three healthy normal controls (NC) participated in this study. Neuropsychological measures and diffusion tensor imaging (DTI) data were acquired from each subject and tract-based spatial statistics (TBSS) was implemented. It was found that both aMCI groups showed significantly reduced fractional anisotropy (FA) in the right superior longitudinal fasciculus (SLF) than NC. It was also identified that, as compared to aMCI-m, aMCI-s showed significantly decreased FA in the left SLF, left uncinate fasciculus (UF) and left inferior longitudinal fasciculus (ILF), while significantly increased FA in the left anterior thalamic radiation (ATR). The correlation analysis showed that FA values in the regions with group difference were significantly correlated with cognitive functions as measured by Boston naming test and trail making test. These results suggested that the variations of aMCI may be differentiated by FA indexes and DTI may help to understand why specific signs and symptoms occur in patients. Alzheimer’s disease (AD) is a common dementia in elderly populations, and amnestic mild cognitive impairment (aMCI) often represents a transitional stage between normal aging and early dementia ,2. PatieAD was widely reported to have the neurodegenerative effects on cerebral white matter (WM) microstructure ,6. DiffuThe main goal of this study is to investigate the difference of diffusion indices between aMCI-s and aMCI-m by using tract-based spatial statistics (TBSS), which could improve the sensitivity, objectivity and interpretability of diffusion imaging results at group level . Given aThirty-two aMCI-s  and 23 aMCI-m  patients were screened from the Department of Neurology of Xuanwu Hospital, Capital Medical University from January 2011 to March 2015. Twenty-three NC  were recruited from local residents. Written informed consents were obtained from all participants or their relatives before the MRI scan. This study was approved by the Institutional Review Board of Xuanwu Hospital, Capital Medical University.The patients with aMCI were diagnosed according to Petersen’s criteria  and NatiParticipants of NC were cognitively normal and had a CDR of 0. Subjects were excluded if they met the following clinical characteristics: (a) those who have a clear history of stroke > 7 points); (b) severe depression  > 24 points); (c) cognitive impairment caused by traumatic brain injury; (d) other nervous system diseases, which could cause cognitive impairment; (e) systemic diseases, which could cause cognitive impairment; (f) a history of psychosis or congenital mental growth retardation; and (g) those who cannot corporate with neuropsychological tests or have any contraindication to Magnetic Resonance Imaging (MRI).All participants underwent a series of neurological tests and a battery of neuropsychological assessments by two experienced neurologists (JL and YH), including mini-mental state examination (MMSE) , Montrea3. DTI parameters were: 12 non-linear directions  with 1 non-diffusion weighting acquisition, TR/TE = 6000 ms /85 ms, 30 axial slices, slice thickness = 5 mm, FOV = 256 × 256 mm2, acquisition matrix = 128×128, number of averages = 4.MRI data acquisition was performed on a 3-Tesla scanner . MRI data were collected the day after the subjects finished the cognitive testing. Sedation was forbidden during the MRI scanning. Foam padding and headphones were used to limit head motion and reduce scanner noise. The 3D T1-weighted anatomical image was acquired with a magnetization-prepared rapid gradient echo (MPRAGE) method in the following parameters: repetition time (TR)/echo time (TE)/inversion time (TI) / flip angle (FA) = 1900 ms/2.2 ms/900 ms/9°, acquisition matrix = 224 × 256 × 176, voxel size = 1 × 1 × 1 mmhttp://www.fmrib.ox.ac.uk/fsl) [DTI data were pre-processed and analyzed using the FMRIB's Diffusion Toolbox in FSL software  . First, .uk/fsl) . Then, tTract-based spatial statistics of FA and MD images were adopted by using TBSS in FSL software . FA imagGroup statistical analysis was conducted only on voxels within the white-matter skeleton. Differences in FA and MD between aMCI-s, aMCI-m and NC were assessed by using analysis of covariance (ANCOVA), with age, gender and education level as covariates of no-interest. Nonparametric permutation test was used based on 5000 random permutations to generate a null distribution for each contrast. Threshold-free cluster enhancement (TFCE) was used in all comparisons to correct for multiple comparisons. The clusters with a TFCE-corrected P-value of less than 0.01 and a minimum cluster size of 50 contiguous voxels were reported. The John Hopkinson University (JHU) white-matter atlas  was applAs shown in ANCOVA results showed that there were significant FA differences among the three groups including NC, aMCI-s and aMCI-m in the bilateral superior longitudinal fasciculus (SLF), left uncinate fasciculus (UF), left anterior thalamic radiation (ATR) and left inferior longitudinal fasciculus (ILF) . No clusTo further specify the variations in FA index, the activated clusters were defined as the regions of interest (ROI) and then post-hoc pair-wise comparisons were performed on mean FA values of each ROI . It was The partial correlation analyses with gender, age and education level as covariates were performed between mean FA of each ROI and neuropsychological measures including MMSE, MoCA, AVLT, BNT, TMT and CDT. It was found that BNT was negatively correlated with FA in the left UF, SLF and ILF, while positively correlated with FA in the left ATR . It was To our knowledge, this is the first study to examine the WM difference between the subtypes of aMCI. Our results showed that aMCI-s significantly differed from aMCI-m in some WM tracts, and the FA differences were associated with the cognitive deficits of patients. Particularly, some possible compensation effects were also identified. These results have added new evidence to the disconnection mechanism of aMCI –35, and A larger cluster including the right SLF showed significant decreased FA in both aMCI-s and aMCI-m as compared to NC. This has added new evidences to the disconnection mechanism of MCI/AD. However, it was also found that a cluster in the left SLF indicated the different pattern that, in contrast to NC, aMCI-m showed increased FA while aMCI-s showed decreased FA. Specifically, FA values in the left SLF were significantly correlated with BNT and TMT, which suggested that the abnormality in the left SLF associated with the language and attention ability of aMCI patients. In particular, both the positive correlation between FA of the left SLF and TMT and the negative correlation between FA of the left SLF and BNT might indicate an effort of functional compensation  in aMCI-m patients, although the language and attention ability of aMCI-m have been substantial damaged. This is totally congruent with the facts that SLF has a broad neuroanatomical extent, connecting the frontal, parietal, and temporal lobes , and plaThis study found no significant alterations in the UF between NC and the two types of aMCI, although the UF was reported to be impaired in AD ,41. PartThe left ILF showed significant higher FA in aMCI-m as compared to aMCI-s and NC. It should be noted that the pattern in the left ILF was similar to that of the left UF. Actually, this might be explained by the facts that the ILF anteriorly joins the UF to relay information to the orbitofrontal brain , which mThe ATR consists of fibers connecting mediodorsal and anterior thalamic nuclei to the prefrontal cortex and the anterior cingulate cortex. The left ATR in this study showed the different abnormal pattern from the other identified bundles. In contrast to NC, aMCI-m showed decreased FA while aMCI-s indicated increased FA. Further, the correlation between FA in the left ATR and BNT as well as TMT provided the possible explanation that the impairment of the left ATR contributes to the cognitive dysfunction in aMCI-m. Based on the identical logic to the aforementioned discussion, the relative higher FA in aMCI-s might indicate the compensation mechanism. These explanations were totally consist with the previous reports of the role of the ATR in cognition that the ATR is involved in working memory, executive function and planning complex behaviors ,50. ThisThere were still some limitations in this study. First, the WMH within the white matter tracts assessed may substantially affect FA values. However, in this study, the WM lesions were not evaluated quantitatively and used as covariates to control for their effects when estimating the burden of FA on cognitive decline. Thus, it should be acknowledged that the findings are not necessarily independent of what is already known concerning the effects of WMH on cognitive performance. Second, given that the diffusion was 12 directions and 5mm thickness, which is not a optimized DTI protocol for high diffusion typically applied via TBSS. New experiment should be made to further validate the current findings with the optimized protocol. Third, this study was a cross-sectional design, and thus could not reveal the possible different progress characteristics of aMCI-s and aMCI-m. Furthermore, it was reported that, a novel technique, diffusion kurtosis imaging (DKI), enables characterization of non-Gaussian water diffusion behavior, and is considered to be more sensitive than DTI . Given tAlthough there are common FA abnormalities between aMCI-s and aMCI-m in contrast to NC, the two types of aMCI own their own DTI characteristics separately. The findings in this study suggest that DTI might  serve as a sensitive technique for the differential diagnosis of aMCI-s and aMCI-m.


Large vessel vasculitis (LVV) is defined as a disease mainly affecting the large arteries, with two major variants, Takayasu arteritis (TA) and giant cell arteritis (GCA). GCA often coexists with polymyalgia rheumatica (PMR) in the same patient, since both belong to the same disease spectrum. FDG-PET/CT is a functional imaging technique which is an established tool in oncology, and has also demonstrated a role in the field of inflammatory diseases. Functional FDG-PET combined with anatomical CT angiography, FDG-PET/CT(A), may be of synergistic value for optimal diagnosis, monitoring of disease activity, and evaluating damage progression in LVV. There are currently no guidelines regarding PET imaging acquisition for LVV and PMR, even though standardization is of the utmost importance in order to facilitate clinical studies and for daily clinical practice. This work constitutes a joint procedural recommendation on FDG-PET/CT(A) imaging in large vessel vasculitis (LVV) and PMR from the Cardiovascular and Inflammation & Infection Committees of the European Association of Nuclear Medicine (EANM), the Cardiovascular Council of the Society of Nuclear Medicine and Molecular Imaging (SNMMI), and the PET Interest Group (PIG), and endorsed by the American Society of Nuclear Cardiology (ASNC). The aim of this joint paper is to provide recommendations and statements, based on the available evidence in the literature and consensus of experts in the field, for patient preparation, and FDG-PET/CT(A) acquisition and interpretation for the diagnosis and follow-up of patients with suspected or diagnosed LVV and/or PMR. This position paper aims to set an internationally accepted standard for FDG-PET/CT(A) imaging and reporting of LVV and PMR.The online version of this article (10.1007/s00259-018-3973-8) contains supplementary material, which is available to authorized users. Large vessel vasculitis (LVV) is defined as a disease mainly affecting the large arteries, with two major variants, Takayasu arteritis (TA) and giant cell arteritis (GCA) . VasculiFDG-PET/CT is a functional imaging technique which is an established tool in oncology, and has also demonstrated a role in the field of inflammatory diseases. FDG-PET is based on the ability to detect enhanced glucose uptake from high glycolytic activity of inflammatory cells in inflamed arterial walls and synovia/bursa . TherebyIn nuclear medicine, procedural guidelines for FDG-PET imaging have been published for both cancer  and infeThere are currently no guidelines regarding PET imaging acquisition for LVV and PMR, even though standardization is of the utmost importance for facilitating clinical studies and for daily clinical practice.The aim of this joint paper is to provide recommendations and statements, based on the available evidence in the literature and consensus of experts in the field, for patient preparation and FDG-PET/CT(A) acquisition and interpretation in the diagnosis and follow-up of patients with suspected or diagnosed LVV and/or PMR. This position paper aims to set an internationally accepted standard for FDG-PET/CT(A) imaging and reporting of LVV and PMR. An additional aim is to facilitate prospective clinical studies and pooling of future multi-center data. Other imaging modalities applied in LVV diagnostics, such as MRI angiography and ultrasound, are beyond the scope of this document.The main goal of adequate patient preparation is to reduce physiologic tracer uptake in normal tissues  while maintaining uptake in diseased tissues and organs. Patients are instructed to fast for at least 6 h prior to FDG administration although intake of non-caloric beverages is allowed during that period . In addiPrevious studies have shown that FDG uptake is reduced if serum glucose levels exceed 7 mmol/L (126 mg/dL) –35, therThe impact of glucose levels on FDG uptake in inflammatory lesions is less well investigated. A study by Rabkin et al. in 123 patients with suspected infection demonstrated that hyperglycemia at the time of study had no significant impact on the false-negative rate . HoweverGlucocorticoids (GC) may reduce vascular wall uptake of FDG; the available data regarding the effect of GC withdrawal on FDG uptake are scarce. Nielsen et al. recently confirmed that diagnostic accuracy of LVV with FDG-PET remained for 3 days after initiation of GC, after which the signal decreased significantly –39. ThusA brief withdrawal of GC could “restore” pathological FDG uptake and reduce the likelihood of a false-negative result, but this is not known. At the same time, GC withdrawal may pose risks to the patient. In the case of GCA, especially if temporal artery or ocular involvement is suspected, administration of GC cannot be delayed or withdrawn due to possible ischemic complications. In other conditions such as PMR or TA, withdrawing or delaying therapy until after PET can be permitted unless there is risk of ischemic complications Table .Table 1RThe use of GC may also increase FDG uptake in the liver, resulting in underestimation and/or under-scoring of vascular FDG uptake .A minimum of 60 min between intravenous FDG administration and acquisition has been recommended for adequate tracer biodistribution . DelayedThere are currently no guidelines for image acquisition in LVV or PMR, but whole-body acquisition from head to knee  in the supine position with the arms next to the body is recommended, because (PMR) patients are generally unable to hold their arms above their head. For FDG-PET/CT imaging, a low-dose non-contrast CT must be performed for attenuation correction and anatomical localization. Alternatively, a diagnostic contrast-enhanced CT may be performed according to applicable local or national protocols and guidelines. A contrast-enhanced CTA is useful for identifying stenotic lesions in TA, but data are insufficient to support its routine use for GCA LVV . When usSeveral factors may significantly influence the arterial wall FDG uptake, and must be taken into consideration for interpretation of FDG-PET in LVV and PMR. For clinical routine, interpretation criteria must be uniform, reproducible, and easy to use. Many PET interpretation criteria have been proposed Table , and eviAs PMR and GCA frequently overlap, typical FDG joint uptake patterns should be reported, including uptake in glenohumeral synovia, subacromial-subdeltoid bursa, supraspinatus tendinitis and biceps synovitis (shoulder), trochanteric/ischial bursa, hip synovia, interspinous regions of the cervical and lumbar vertebrae, or the synovial tissue of the knees if present, including the use of a standardized 0-to-3 grading system , 75 Fig.Fig. 2FDAtherosclerotic vascular uptake , 77, freSeveral semiquantitative methods have also been proposed, from simple SUV metrics to target-to-background ratios (TBR) Table . The cliThe normalization of the arterial wall uptake to the background activity of venous blood pool provides a good reference for assessing vascular inflammation . Also, gRegions of interest (ROIs) are drawn around the majority of the target arterial structure, while the chance of including surrounding FDG uptake within the ROI needs to be minimized . For bacTBR varies as a function of blood pool activity, which can be affected by many factors, including (1) FDG uptake in circulating blood cells, (2) chronic renal insufficiency, and (3) blood glucose levels , 80. A sp < 0.0001) [In general, the diagnostic performance of FDG-PET for the detection of LVV is good; individual studies are summarized in Table  0.0001) , 86, but 0.0001) . Of note 0.0001) . These f 0.0001) . In TA,  0.0001) . These f 0.0001) . The spe 0.0001)  as the d 0.0001) . Visual  0.0001) .Table 4SThe precise evaluation of diagnostic accuracy of FDG-PET for the diagnosis of LVV faces several hurdles. First, in some patients, FDG-PET represents the only modality that allows for the diagnosis of LVV, and therefore cannot be compared to a gold standard. For GCA, the diagnosis is usually classified according to the American College of Rheumatology (ACR) criteria , which iLittle data has been published concerning the additional value of CTA for the diagnosis of LVV. Such evaluation could be of interest by providing morphological information on the vasculature in a “one-stop shop” procedure when using hybrid PET/CTA imaging Fig. . In acutCTA scanning parameters should be adapted to the specific capabilities of the local scanner specifications Table . In 2014Generally, these guidelines recommend, if available, the use of a multi-detector-row CT (MSCT) scanner with wide z-axis or volume coverage. The scans should be performed with ECG triggering to avoid motion or pulsation artifacts of the ascending aorta .Contrast material is administered through a venous catheter using an automated contrast material injector. The contrast material dose depends on the patient's body weight, body mass index, and kidney function (recent estimated glomerular filtration rate) .CTA images should be reconstructed in thin slices (e.g. 1 mm thick) to allow for additional multiplanar reformation (MPR) and 3D image post-processing. Preferably, isotropic voxels should be achieved. Both filtered back-projection and iterative reconstruction algorithms can be used, with the latter providing improved image quality due to noise removal, and dose-saving potential . Medium-According to American College of Radiology guidelines, CTA is indicated to “diagnose and localize diseases with primary manifestations in the arterial wall, including vasculitis, infection, and degenerative disorders” . ArteriaAlthough CTA itself is helpful for diagnosing LVV, the diagnostic accuracy of combined FDG-PET/CTA scans remains undefined. While the inflammatory activity within the vessel wall is displayed with high sensitivity on FDG-PET images, combining FDG-PET with CTA enhances specificity by providing high-resolution anatomical details.CTA also helps to differentiate different pathologic FDG-PET findings, as both vasculitis and atherosclerosis can demonstrate increased FDG wall uptake. Equally important in the contribution of CTA to the diagnostic accuracy of combined FDG-PET/CTA is its role in detecting structural changes and potential complications of vasculitis . During For monitoring of LVV activity during and after treatment, related biomarker measurements would be helpful. Unfortunately, both the cranial GCA and the extracranial large vessel type of GCA or TA lack disease-specific serum biomarkers.Although FDG-PET/CT(A) has proven to be an important imaging modality for diagnosis of non-temporal GCA, very limited data are available on the role of FDG-PET/CT(A) for patient management once treatment has started. With regard to the utility of FDG-PET for assessing changes in arterial wall inflammation in response to GC and methotrexate, the results are mixed, and represent only small patient cohorts.p < 0.0005), but no further decrease was seen at 6 months. In patients who experienced a relapse , FDG-PET was performed within 5 days. The authors found no difference in the predictive value of FDG uptake between relapsing and non-relapsing patients.In the only prospective study, which was conducted by Blockmans et al. Table , whole-bA retrospective study by Bertagna et al. Table  includedIn a study of five patients by Camellino et al. Table , FDG-PETInterestingly, a recent abstract by Nielsen et al.  reportedRecent studies have shown that at the temporal artery level, granulomatous infiltrates can persist even up to 1 year following the start of GC treatment , 101. MaThis is in agreement with a study by Brack et al., in which macrophages persisted in the vessel walls of severe combined immunodeficiency disorder (SCID) mice engrafted with TAB after 1 week of GC treatment . These fPrieto-González et al. prospectively assessed GC-induced changes in CTA findings of LVV in patients with GCA . Forty pFor PMR, there is one study with sequential PET/CT, by Blockmans et al. Table , using tThe optimal length of time before performing FDG-PET in PMR after treatment with GC is unclear. A recent study by Palard-Novello et al. evaluated the use of FDG-PET/CT(A) for the assessment of tocilizumab as first-line treatment in patients with PMR . They foFurther establish the role of FDG-PET/CT in patient management and evaluate its role in treatment monitoring. When to use FDG-PET/CT in the diagnosis, in the follow-up, and how often?Development of guidelines in LVV and PMR imaging with FDG-PET/CT(A) similar to those previously developed for FDG-PET/CT in oncology (EARL) criteria . RandomiIncluding imaging biomarkers with the current diagnostic criteria to be considered for TA, GCA, and/or PMR.Finding a consensus in the clinical support for performing imaging as early as possible and before starting GC therapy if treatment delay can be justified due to non-critical symptoms.Further investigation of the GC effect on vascular FDG uptake.Theranostics (diagnostics for selected therapy) for LVV/PMR, which may open more paths to targeted therapy, resulting in personal/precision medicine. Radiolabeled tocilizumab or other monoclonal antibody PET tracers are potential candidates for this.Circumstances of when there may be myocardial involvement in patients with LVV should be further investigated , including the risk of cardiovascular events due to drug therapy in LVV .Worldwide reimbursement for application of FDG-PET/CT(A) in LVV/PMR is needed.Standardization of visual scoring and (semi)quantification in FDG-PET in LVV and PMR is essential for interpretation, for optimal comparison among centers, especially in future multicenter trials.Decide how much thickening is mild, moderate, or severe (not established in literature). Based on our expertise, we think that ≥2 mm (up to 2.9) may be mild, ≥ 3 mm (up to 3.9) moderate, and ≥4 mm severe.Consensus needed on which quantification method to apply in LVV.An uptake interval of 60 min after FDG injection is recommended, but 90–120 min intervals can be evaluated for better image quality.Dual-time-point imaging may improve the target-to-background ratio, resulting in better image quality due to greater FDG blood pool clearance, particularly in patients with reduced kidney function. However, evidence-based data are lacking.New techniques for imaging and reconstruction of the skull that enable visualization of the superficial temporal artery, which will result in better comparison of local LVV with TAB.Value of combining FDG-PET with CTA as a standard procedure in LVV and PMR, single modalities or hybrid.Value of FDG-PET/MRI in monitoring LVV and PMR, i.e. reduction of radiation dose .Development of online training modalities for interpretation.Optimization of the application of hybrid imaging in monitoring  vascular wall disease in LVV.The use of vasculitis-specific tracers, directed against cells/proteins involved in and unique for the pathophysiology of LVV and PMR, should be investigated.New developments in camera systems, such as PET/MRI, enable us to combine metabolism or other molecular targets (PET) with vascular tissue layer characterization (MRI), including a reduction in radiation dose and improved cranial visualization. The value of these new multi-modality imaging systems may be of interest for LVV assessment and monitoring.Optimal use of (low-dose) CT to distinguish active atherosclerosis from active vasculitis by pattern recognition, visually as well as with the use of dedicated software methodologies .Several open issues are also in line with the recommendation for the use of imaging in large vessel vasculitis in clinical practice of the European League Against Rheumatism (EULAR) .The present procedural recommendation paper provides recommendations to assist imaging specialists and clinicians in requesting, performing, and interpreting the results of FDG-PET in patients with suspected LVV and PMR.Based on the present clinical data, FDG-PET/CT(A) has an important role in the diagnosis of extracranial vascular involvement in patients with LVV/PMR, but additional randomized studies are needed to support this.Improvements in FDG-PET/CT(A) procedures will help to optimize the diagnostic and monitoring value of this technique in LVV/PMR.Visual qualitative methods are most commonly used, but semiquantitative methods such as the vascular/blood ratio and vascular/liver ratio using SUVs are increasingly being used.The addition of CTA to FDG-PET provides high-resolution imaging of vascular morphology that can potentially improve diagnostic accuracy, but more importantly provides information on the presence of possible complications such as stenosis, organ ischemia, aneurysm formation, and dissection.Further prospective studies involving large cohorts of GCA/PMR patients are needed to investigate and validate the role of semiquantitative methods for the assessment of LVV.Several other open issues, as stated above, need to be studied for optimal performance of FDG-PET/CT(A) in the diagnosis, (treatment) monitoring, and future theranostics in LVV/PMR, further improving the levels of evidence and grades of recommendations.ESM 1(DOCX 16 kb)


Extracellular vesicles (EVs) are small membranous vesicles secreted from numerous cell types and have been found involved in cell-to-cell communication by transferring noncoding RNAs (ncRNAs) including microRNAs, long noncoding RNAs, and circular RNAs. Emerging evidence shows that EV-associated ncRNAs play important roles in a wide range of diseases, particularly in cancer where they function through regulating protein expression of the pivotal genes that make contributions to tumorigenesis. Given their stability and abundance in serum, EV-associated ncRNAs can act as new diagnostic biomarkers and new therapeutic targets for cancer. Herein, we review the properties of EV-associated ncRNAs, their functions, and potential significance in cancer. Extracellular vesicles (EVs) are small lipid bilayered vesicles released by a wide range of normal or diseased cells. Three main types of EVs are exosomes, microvesicles, and apoptotic bodies which are distinguished on the basis of their size and biogenesis , 2. ExosNoncoding RNAs (ncRNAs) refer to RNAs that cannot be translated into proteins. MicroRNAs (miRNAs) are the most widely studied class of ncRNAs with length of ~22 nucleotides, which mediate post-transcriptional gene silencing by controlling the translation of mRNA into proteins in animals , 8. LongEVs that were initially considered as garbage bags for abandoned membrane parcels and molecular fragments were first recognized as being closely related to the function of the immune system with the finding of the role of exosomes in the presentation of B lymphocyte antigens in 1996 by Raposo et al. . In the Herein, we will discuss how ncRNAs derived from EVs participate in tumorigenesis, invasion, metastasis, and drug resistance and how to use them as new diagnostic biomarkers and therapeutic targets Fig. .Fig. 1EVMiRNAs are a class of small noncoding RNA molecules that can regulate many genes by binding to noncoding regions of target mRNAs, post-transcriptionally lowering mRNAs and proteins . SecreteP < 0.0001/P = 0.0066). Similar results have been observed for OS .Tab.Tab68].TLncRNAs can influence regulation of gene expression and have an impact on many different cancerous processes, where they can influence tumorigenesis, invasion, and metastasis.The study of EV-associated lncRNAs begins with collecting tumor tissues and matched adjacent nontumor tissues. Then, lncRNA exposure levels are determined using RT-PCR and in situ hybridization and the exposure levels of the proteins are measured by western blot. In addition, dual-luciferase report assay can be performed to verify the target effect of lncRNAs on miRNAs. The proliferation, invasion, and migration ability of target cells after being infected were tested by MTT assay, wound healing assay, and transwell assays. Finally, researchers can utilize nude mouse xenograft models to measure lncRNA effects on tumor growth in vivo .LncRNA-p21 and lncRNA-GAS5 are tumor suppressor molecules in the cellular machinery , 71. SigEV-associated lncRNAs can foster tumor development through diverse mechanisms. Accumulating evidence has demonstrated that lncRNA-HOTAIR has the capability of facilitating tumor initiation and progression and is associated with poor prognosis in several cancers . ImportaLncRNA-MALAT1 is also involved in modulating EMT through regulating the expression of proteins concerning EMT, including E-cadherin, ZO-1, b-catenin, vimentin, and snail . AnotherLincRNAs MONC and MIR100HG are mainly localized in the nucleus and highly expressed in acute megakaryoblastic leukemia (AMKL) blasts, whose expression is correlated with corresponding miR-99a/100~125b clusters, resulting in tumorigenesis and tumor development. It has been shown that MONC or MIR100HG knockdown inhibits leukemic growth of AMKL cell lines and cells from primary patient samples through a shRNA-induced loss-of-function study .CD90 is a 25–37 kDa glycophosphatidylinositol-anchored protein involved in cell-to-cell and cell-matrix interaction, apoptosis, adhesion, migration, fibrosis, and cancer development [U]. Concerning the liver, CD90 is expressed by hepatic stem/progenitor cells [V] and is correlated with an aggressive phenotype during tumor growth, low differentiated HCC, and poor prognosis –85. LncRLinc-RoR is enriched in tumor cell-derived EVs during hypoxia and can modulate cellular signaling and cell survival in recipient cells as a stress-responsive lncRNA . Linc-RoAnother example of lncRNAs that enhance chemoresistance is linc-VLDLR. Takahashi and colleagues  have proCircRNAs are a class of novel endogenous ncRNAs that form a covalently closed continuous loop unlike linear ncRNAs  and provAs described above, the rapid development of EV-associated ncRNAs has contributed to reveal underlying mechanisms of cancer initiation and progression. However, there remain a large number of challenges.The first issue is that since the current method is incapable of distinguishing between exosomes and microvesicles , it is cSecondly, we should pay special attention to the tissue type being studied. The ncRNAs might serve as a tumor suppressor in one cell type and an oncogene in another. For example, in general, let-7 miRNAs act as a tumor suppressor by targeting oncogenes such as RAS and HMGA2 and let-7 miRNAs are downregulated in many cancers from solid organs , while tThe third issue is lacking of a universal method to analyze EV-associated ncRNAs which often leads to discrepancies between studies performed by different groups. Besides, occurrence of EMV-mediated ncRNA transfer has been indirectly confirmed by detecting the altered expression levels of internal miRNAs in both donor and recipient cells. In the future, fluorescence signal amplification by a confocal imaging system may open new avenues for studying EMV transfer directly .EVs are secreted by most cell types and exist in various body fluids including the blood, urine, and saliva. NcRNAs contained in EVs represented the biological or pathological states of cells. Because of their resistance to endogenous RNase and high stability under different storage conditions, EV-associated ncRNAs can serve as valuable noninvasive biomarkers for the diagnosis and prognosis of cancers including glioblastoma melanoma, liver cancer, gastric cancer, ovarian cancer, breast cancer, lung carcinoma, and so on Table  100–107107. ImpoEV-associated ncRNAs have also provided new opportunities for the treatment of cancer. EVs are in small size and capable of crossing biological membranes and protect their cargo from degradation, which suggests that they are ideal delivery systems for the transfer of specific molecules such as miRNAs or anti-miRNAs .For example, it has been discovered that miR-122-transfected adipose tissue-derived MSC (AMSC) can effectively package miR-122 into secreted exosomes rendering cancer cells sensitive to chemotherapeutic agents through alteration of miR-122-target gene expression in HCC cells by mediating miR-122 communication between AMSCs and HCC cells. Furthermore, intra-tumor injection of 122-Exo significantly increased the antitumor efficacy of sorafenib on HCC in vivo which suggests that the export of miR-122 via AMSC exosomes represents a novel strategy to enhance HCC chemosensitivity and can be used for HCC therapy .Recently, microvesicles have also been used as the shuttle of delivering antisense RNA targeted to miR-150 that is proved as an oncomir by regulating the VEGF secretion of TAMs into mice to treat tumors, leading to a new avenue for the transfer of antineoplastic drugs .However, the therapeutic potential of EV-associated ncRNAs in cancer is largely unknown. The intracellular delivery of EV-associated proteins can be fulfilled by a new tool named “exosomes for protein loading via optically reversible protein–protein interactions” (EXPLORs) . SimilarEVs, previously largely thought to function like garbage bags to remove excess or unnecessary constituents from the cells, have now been discovered to be mediators in specific cell-to-cell communication via transferring proteins, RNAs and DNAs. Exosomes are the most widely studied EVs. They can transfer information to the target cells through three main ways: receptor-ligand interaction, direct fusion with plasma membrane, and endocytosis by phagocytosis . Amongst