Background: Substance Use Disorder (SUD) and behavioral addictions are common and require a multidisciplinary approach. New technologies like Virtual Reality could have the potential to improve assessment and treatment of these disorders.Objective: In the present paper, we therefore present an overview of Virtual Reality (Head Mounted Devices) in the field of addiction medicine for craving assessment and treatment.Method: We conducted a systematic review by querying PubMed database for the titles of articles published up to March 2019 with the terms [virtual] AND [addictive] OR [addiction] OR [substance] OR [alcohol] OR [cocaine] OR [cannabis] OR [opioid] OR [tobacco] OR [nicotine] OR [methamphetamine] OR [gaming] OR [gambling].Results: We screened 319 abstracts and analyzed 37 articles, dividing them into two categories, the first for assessment of cue reactivity  and the second for intervention, each drug  being detailed within each category.Conclusions: This overview suggest that VR provide benefits in the assessment and treatment of substance use disorders and behavior addictions and achieve high levels of ecological validity. While, craving provocation in VR is effective across addiction disorders, treatments based exclusively on virtual exposure to drug related cues as shown heterogenous results. Substance Use Disorder (SUD) and behavioral addictions are prevalent in many countries , attention bias and drug seeking behaviors triggered by stimuli previously associated with drug use  or cognitive behavioral therapy (CBT)-driven techniques applied in real time. VR may also facilitate the link between clinician and patients and improve our understanding of addictive behavior.Until recently, VR was limited by its cost and by the quality of the multimedia content. There has been a recent democratization of these systems  concomitant with the video game industry's growing interest in this technology. Decreasing costs and increasing power are making it useful for performing an ecological assessment of cognition, emotions, and behavior in real-time.The purpose of this systematic review is to evaluate the usefulness and efficacy of immersive VR in cue reactivity assessment and craving management for patients undergoing SUD or behavioral addictions. To this end, the proposed systematic review will answer the following questions:- When compared to VR neutral stimuli, are VR cues able to elicit cue reactivity in adult patients suffering from addictive disorders? Is there an advantage of using VR cue reactivity over traditional cue reactivity methods?- Can VR be used as an effective tool for craving reduction compared to standard therapy in this aforementioned population?To identify appropriate resources and search for relevant evidence. We used a PICOS framework, to form a well-focused question and facilitate the literature search  and the second for treatment, each drug being detailed within each category.See PRISMA diagram .A brief description of the concepts underlying virtual reality (VR) and cue features in the field of addiction is summarized in Studies and results described below are summarized in n = 465) assessed cue reactivity after virtual nicotine-related cues in adult smokers. Nicotine addiction criteria were reported in 13 studies, using DSM 4  in VR showed craving induction in adult smokers. Various cues  were associated with craving induction.All studies investigating craving , complex cues were evaluated and often compared to other types of cues  . All studies reported a significant increase of attentional bias compared to virtual neutral environments. Adding olfactory nicotine cues were surprisingly not associated with greater attention to cue in Traylor et al.  or the Smoking Attention Scale (SAS)  assessed cue reactivity after presentation of virtual alcohol-related cues in adults suffering from alcohol use disorder  showed its induction after VR cue exposure   suffering from cocaine use disorder (DSM-IV)  Guze,  assessedCraving induction through virtual cues has been demonstrated with contextual and complex environments compared to neutral virtual environments in cocaine-dependent subjects. Craving assessment was performed using single-item VAS. Situations triggering highest craving are those related to cocaine use and interactions with a dealer.Physiological reactivity was also measured. Heart rate increased in a manner comparable to craving in scenes of cocaine use and interaction with a dealer compared to neutral scenes. Besides, there was no change in skin conductance measurements between virtual neutral exposure or virtual cocaine-related exposure.n = 20) suffering from cannabis use disorder (DSM-IV)  Guze,  assessedBordnick et al.  showed cIn this study  were induced after exposure to a virtual and real slot machine environments in Bouchard et al. . Cravingn = 34) suffering from internet gaming disorder [DSM-5 . One VET trial was effective on craving and cigarette consumption reduction  after 5 weekly sessions on 48 subjects with low to moderate nicotine dependence in association with a tobacco education group  studied VCBT in nicotine addiction reduction  in Korea evaluated virtual exposure therapy, including aversive exposure situations on alcohol craving reduction  suggest that greater craving can be triggered by complex environments. Moreover, recent interest in proximal stimuli has emerged  and new studies on other substance consumption behavior in virtual reality could further enrich the exposition realism.Social interaction with avatars can efficiently induce cravings for multiple substances, mainly assessed in cigarette smoking and alcohol studies. However, difficulties persist in separating social craving from context craving. Indeed, several questions remain regarding stimuli specification assessment in VR craving induction. A significant number of studies were exposed to carry over effect while a better understanding of craving stimuli characteristics could be obtained by using a two by two comparison protocols or by an effective carry over effect control .The lack of stimuli comparability resulting from the craving ceiling effect may have been increased by VAS widespread use by limiting the measurement to its intensity level, while a dimensional analysis of scales such as QSU could have revealed interesting qualitative differences (Rosenberg, in vivo scenarios. However, metanalyses report disappointing results (Mellentin et al., Traditional Cue Exposure Therapy studies' designs are mainly on substance-related cues detached from social environmental or In the future, attention to potential limits should be considered:Cost-effective studies are needed.Access to VR and therapists training need to be evaluated.Ethical considerations remain regarding the use of aversive exposures.Cybersickness could represent a threat to virtual reality usability and effectiveness and would also require integration in future studies (Gallagher and Ferrè, Patient's adherence should be accurately assessed before implementing aversion therapy in routine practice.Both positive and negative studies show numerous methodological biases: confusion bias due to the absence of control groups, selection bias due to the absence of randomization, attrition bias due to little intent to treat analysis, altogether indicating low internal validity and limiting the possibility of drawing clear conclusions.Future studies appear necessary and should evaluate dependence and abstinence maintenance as primary endpoint, offer more long-term follow-up, and include more control treatment groups to limit confusion bias.Efficacy of treatment based exclusively on virtual exposure to drug related cues appears to be limited, but interesting results point the great potential of implementing VR in CBT. Pericot-Valverde et al.  shows hoDespite these limitations, VR has the potential to offer new opportunities for treatment through its ability to provide a more ecological environment with more control and safety over exposition. The ability to fine-tune environments composition according to patient's preferences and most relevant data makes it a future tool for personalized medicine.Because VR has the potential to be disruptive [for review (Freeman et al., Besides its acceptability, its accessibility also raises questions. It could be limited due to the lack of financial support. The populations suffering from substance disorders being frequently in situation of social precariousness. The question of the cost of VR will also have to be evaluated in order to consider its wide implementation in health centers.The studies presented in this review suggest that VR provide benefits in the assessment and treatment of substance use disorders, behavior addictions and achieve high levels of ecological validity. While, craving provocation in VR is effective across addiction disorders, treatments based exclusively on virtual exposure to drug related cues as shown heterogenous result. The addition of learning coping strategies in VRCBT studies are promising, however more rigorous methodological studies are warranted.The datasets generated for this study are available on request to the corresponding author.TS and TB screening and abstract analysis, both authors contributed equally to the writing. AB, SM, and FF conceptual framework, supervised development of work, helped in data interpretation and manuscript evaluation. C-SP and J-VB helped to evaluate and edit the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To date, there is a dearth of interdisciplinary simulation education and research that involves LGBT older adults within schools of social work and nursing. The purpose of this mixed method study was to examine the use of an intervention among social work and nursing students to determine if lecture and simulations impacted their health-related knowledge and cultural sensitivity/awareness of health provisions with LGBT older adults. Interprofessional faculty created lecture and interdisciplinary simulations with actual members of the older LGBT communities using simulation clinic/lab and health care scenarios. An adapted survey with permission from Grubb et al (2013) was used to include quantitative and qualitative measures of cultural awareness with LGBT populations. Pre-Post test data were analyzed using Generalized Linear Models in SAS software. Results indicated that the intervention positively changed perceptions and increased knowledge among  allied health students. Statistically significant change experiences in their work with LGBT individuals were noted to positively alter their beliefs about sexuality, gender identity, and sexual development =26.51, p<0.001). Qualitative findings include four primary themes about how gender identity and sexual orientation influences health: (a) bias of health care providers, (b) access to quality care, (c) specific health care needs, and (d) health risks of LGBT older adults. As older adults continue to be the largest population needing health care, it is imperative that professionals are trained to give culturally sensitive health care and demonstrate this competency in their practice and interpersonal interactions with clients.


Here we highlight two areas of research where multiple talks provided new insights. POLE/POLD1 mutations resulting in hypermutation and response to immune therapy. Imielinski’s group presented 10 signatures that were based on the pattern of structural variation within tumors. The method utilized to generate SV signatures combined features derived from classic as well as motif-based patterns of structural variation. The expectation is that these patterns may also subsequently allow recognition of patterns that will implicate specific cancer treatments e.g. homology-directed repair deficiency and response to polyADP ribose polymerase (PARP) inhibition.In the Cancer and Medical Genomics session, Marcin Imielinski of the New York Genome Center highlighted the enormous complexity of structural rearrangements that can be found in individual cancer genomes. This complexity has challenged current genome presentations and Imielinksi described new tools for the generation of cancer genome graphs (gGraphs) and analysis of complex structural variation . Somatic mutation signatures based on single nucleotide variants (SNVs) have been previously described. Specific SNV signature patterns has provided insight to underlying genetic variation and, in some cases, these signatures identify tumors that may be responsive to specific cancer treatments, e.g. Similar to the focus on structural variation as opposed to SNV’s in protein coding genes, there were a number of excellent talks defining variation in non-coding regions from genome sequencing datasets of different patient populations. Patrick Short from Matthew Hurles’ group at the Wellcome Sanger Institute investigated the de novo mutation rate in regulatory elements using over 10,000 whole genome sequencing samples from the Deciphering Developmental Disorders (DDD) study and found that de novo mutations (DNMs) in these individuals are enriched within the ultra-conserved elements and these variants may contribute to 1–3% of subjects without a diagnostic finding. There was substantial overlap between DNMs identified in cohorts diagnosed with developmental delay and autism-spectrum disorders. To facilitate analysis of this type of non-coding variation dataset, the group is now developing a non-coding constraint metric .Taking a different approach based on gene expression, Pejman Mohammadi  presented work utilizing allele-specific gene expression data to identify genetic regulatory outliers in a cohort of patients with muscular dystrophy using Analysis of Expression Variance- Dosage Outlier Test (ANEVA-DOT). These talks and a number of posters at the meeting illustrate our need to develop consistent ways to describe clinically relevant regulatory “grammar”.The two keynote addresses provided new insights into chromosomal and chromatin regulation in normal and disease states. Wendy Bickmore (University of Edinburgh) described the role of regulatory variation in developmental genes in Mendelian diseases. Bickmore highlighted the central role of chromosomal decompaction in transcriptional regulation as mediated by PARP through phase separation or by Lmbr1 through chromosomal looping.In the second keynote address, David Page (Whitehead Institute) investigated overlapping sets of genes retained on sex chromosomes over the course of evolution from autosomes see Fig. . InteresWith regard to the “Biology” of genomes, several talks provided early results of elegant, yet massive, screens to better understand the biological and functional consequence of variation seen in either genomic disorders or cancer. Parisa Razaz from Michael Talkowski’s lab at Massachusetts General Hospital modeled isogenic 16p11.2 reciprocal gene disorder using CRISPR mediated deletions and duplications in induced pluripotent stem cells (iPSCs) and mouse models. These models were then used to investigate gene expression differences and the genes which altered expression due to copy number change were enriched in genes expressed at early and late developmental stages and for genes within autism spectrum disorder risk pathways.Trey Ideker of University of California San Diego described findings from the Cancer Cell Map Initiative (CCMI) designed to generate large protein interaction maps of tumor cells. By integration of somatic RNA expression, whole genome sequencing, and enhancer-gene networks, his group identified 193 somatic eQTLs. Additionally, using hierarchical structured data from yeast, the team developed a deep neural network model (DCell) to predict mechanistic genotype-phenotype relationships giving useful insights into cell structure and function.BRCA1 based on CRISPR mediated saturation genome editing. The functional screen identified pathogenic missense variants in BRCA1 with high accuracy. The increasing use of CRISPR methodologies to facilitate large-scale genetic screens or assist functional assessment of thousands of possible variants within clinically relevant genes is expected to have a high impact on clinical interpretation of variants identified through genetic testing, particularly for rare variants where there is not sufficient patient and/or population related data to determine the pathogenicity of the variant.Sidi Chen of Yale University presented work from functional cancer genome atlas project that used in vivo AAV-CRISPR screen to reveal a functional map of frequently mutated driver genes in hepatocellular carcinoma and glioblastomas. Gregory Findlay from Jay Shendure’s laboratory at the University of Washington described functional classification of nearly all possible SNVs  in functional domains of


Most individuals with dementia are undiagnosed or they/their families are unaware of the diagnosis. Implications of dementia diagnosis and awareness are poorly understood. Our objective was to determine whether undiagnosed dementia or unawareness increases risk of hospitalization or emergency department (ED) visits, outcomes with recognized risk in diagnosed dementia. We linked National Health and Aging Trends Study (NHATS) data to fee-for-service Medicare claims for 4,311 community-living participants in the nationally representative cohort. We assessed probable versus no dementia using validated NHATS dementia criteria, undiagnosed versus diagnosed using Medicare claims, and aware versus unaware using NHATS self or proxy report of diagnosis. Cox proportional hazards models evaluated hospitalization and ED visit risk by time-varying dementia diagnosis and awareness status, adjusting for sociodemographic characteristics, functional impairment, medical comorbidities, and prior hospitalization. Compared to no dementia, persons with dementia who were unaware but diagnosed had greater risk of hospitalization  and ED visits . Persons unaware but diagnosed also had greater risk compared to persons aware and diagnosed . Persons with undiagnosed dementia demonstrated hospitalization risk similar to persons with no dementia  and similar or potentially lower than persons aware and diagnosed ; ED visit findings were similar. Results suggest that being unaware of dementia diagnosis may affect healthcare utilization. Strategies to improve communication and understanding of dementia could potentially reduce hospitalizations and ED visits.


Persons living with dementia-related disorders (PwD) can experience challenging behavioural and psychological symptoms (BPSD) as their illness progresses. There is a continued reliance on antipsychotic drugs (APD) in long-term care to manage this issue despite the well-documented risks of adverse events and increased morbidity and mortality. This study examines the role of culture of care in relation to efforts at reducing inappropriate APD use in managing BPSD within long-term care. Culture of care consists of shared norms, beliefs, and cognitive frames which guide clinical practice and inform the development and implementation of care strategies. Findings were obtained from three Canadian long-term care facilities working on reducing inappropriate use of APD. Data came from interviews with 6 nurses, 18 licenced practical nurses, 14 health care assistants, 4 activity leaders, 4 directors of care, 1 chaplain, and 10 physicians. We found that direct care providers initially varied in their perceived ability to develop and use alternate care strategies with health care assistants being most concerned about safety and exposure to violence. Change involved detective work and innovative thinking in assessing possible causes of BPSD beyond psychosis, including pain and feelings of confusion. Informal reciprocal patterns of communication emerged among health care assistants to identify effective non-pharmaceutical strategies to manage BPSD. Overall, the study shows how shared beliefs in the need for and value of alternate care practices among direct care providers along with the existence of effective informal communication can contribute to successful reduction in APD use when managing BPSD in PwD.


In a post hoc study of the multicenter FINNAKI trial, Tverring et al. recently reported that measuring heparin-binding protein (HBP) on admission in the intensive care unit (ICU) improved prediction of sepsis-induced acute kidney injury (AKI). In addition, high plasma HBP levels were associated with a significantly higher fluid balance within 24 h, more organ failure within the first week, and increased 28-day mortality . These oHBP is stored in azurophilic granules and secretory vesicles of neutrophils and is quickly and abundantly secreted when neutrophils are activated and mobilized. Once released, HBP displays a strong proinflammatory activity. In the blood stream, HBP chemoattracts and activates more neutrophils but also T-lymphocytes and monocytes. Binding of HBP to β2-integrins of monocytic cells initiates intracellular signaling processes which evoke a release of chemokines and proinflammatory mediators . SheddinHBP proved to be a valuable diagnostic marker in suspected sepsis  and demoDevelopment and progression of sepsis-related AKI are determined by endothelial leakage, renal tubular cell inflammation, and an adaptive cell-cycle shutdown effect . These iTargeting HBP modulatory effects in sepsis could prove therapeutically useful. Either preventing HBP receptor binding or HBP release from neutrophils are theoretically attractive options. However, evidence that decreasing HBP plasma levels would improve global or renal outcome is still scarce. Moreover, a specific receptor for HBP has not been identified and unselective blocking of crucial immunologic effects of frontline neutrophils may expose patients to unexpected or unwanted side effects. HBP is highly positively charged and thus can be neutralized by negatively charged molecules such as heparin and colloid solutions. Unfractionated and low molecular weight heparin block HBP-induced endothelial cell permeability  and rena


Ficedula hypoleuca, collects information about nest predation risk from indirect cues of predators visiting nests of heterospecific birds. Furthermore, we investigated whether the migratory birds can associate such information with a specific nest site characteristic and generalize the information to their own nest site choice.Breeding site choice constitutes an important part of the species niche. Nest predation affects breeding site choice, and has been suggested to drive niche segregation and local coexistence of species. Interspecific social information use may, in turn, result in copying or rejection of heterospecific niche characteristics and thus affect realized niche overlap between species. We tested experimentally whether a migratory bird, the pied flycatcher Our results demonstrate that flycatchers can use the fate of heterospecific nesting attempts in their own nest site choice, but do so selectively. Young flycatcher females, when making the decision quickly, associated the fate of an artificial nest with nest-site characteristics and avoided the characteristic associated with higher nest predation risk.Copying nest site choices of successful heterospecifics, and avoiding choices which led to failed attempts, may amplify or counter effects of nest predation on niche overlap, with important consequences for between-species niche divergence-convergence dynamics, species coexistence and predator-prey interactions.The online version of this article (10.1186/s12862-018-1301-3) contains supplementary material, which is available to authorized users. The niche concept is a central tenet in the theory of species coexistence and community ecology, stating that two species cannot coexist without adequate niche differences –4. One iBreeding site choice driven by varying nest predation pressure has been shown to be an important mechanism affecting species coexistence –7. This Direct observations of often stealthy, widely ranging and quickly moving nest predators are relatively rare events for an observer, and therefore offer little information for decision-making. Encounters with nest predators may also threaten the observer itself e.g. , 15). Ye. Ye15]).and convergence of realized niches, and both could conceivably be amplified by social information use. Resulting dynamics can be complex, scale-sensitive, and highly dependent on local conditions and community composition.Heterospecific social information use is expected to be most useful between ecologically similar species , in thisFicedula hypoleuca), collects information about nest predation risk from indirect cues of predators visiting nests of a heterospecific resident bird, the great tit (Parus major). We then investigated whether the migratory bird can associate such information with a specific nest site characteristic, are able to generalize the perceived information and use it in guiding their own nest-site choice. Great tits and flycatchers are putative competitors )This study demonstrates that birds i) can detect indirect cues of predation risk from observing heterospecifics nesting attempts and ii) can associate nesting site characteristics with that predation risk infromation and iii) can – but only conditionally do – develop preference for “safer” characteristics in their own nest site choice. Such interspecific social information use in relation to nest predation risk may affect realized niche dynamics among coexisting species with important implications for species coexistence and community dynamics. These findings also add to the accumulating evidence of between-individual variation in social information use patterns; both due to age-related differences and also due to within-age-group variation. Given the substantial potential of individual level variation in behaviour to affect key ecological and demographic processes, also including species coexistence and community ecology and evolution –57, we sAdditional file 1:The data set supporting the article. (XLSX 16 kb)


Cigarette smoking and nicotine dependence commonly co-occur with alcohol dependence. However, treatment for tobacco dependence is not routinely included in alcohol treatment programs, largely because of concerns that addressing both addictions concurrently would be too difficult for patients and would adversely affect recovery from alcoholism. To the contrary, research shows that smoking cessation does not disrupt alcohol abstinence and may actually enhance the likelihood of longer-term sobriety. Smokers in alcohol treatment or recovery face particular challenges regarding smoking cessation. Researchers and clinicians should take these circumstances into account when determining how best to treat these patients’ tobacco dependence. Cigarette smoking and alcohol dependence co-occur at high rates. Research indicates that approximately 80 percent of people with alcoholism smoke cigarettes and that most of these smokers are nicotine dependent . ConversDespite the fact that 60 to 75 percent of patients in alcoholism treatment are tobacco dependent and about 40 to 50 percent are heavy smokers , treatmeSmoking is more benign than alcoholism. The short-term effects of alcoholism may appear more dangerous than those of cigarette smoking. However, mortality statistics suggest that more people with alcoholism die from smoking-related diseases than from alcohol- related diseases . In addicf.cf.Smokers with comorbid alcoholism have either no interest or no ability to quit smoking. It is interesting to note that although addiction treatment programs routinely address multiple substances of addiction , tobacco is frequently the sole excluded substance. The scientific literature also frequently describes treatment of multiple nontobacco substances simultaneously, making it difficult to evaluate the impact of smoking cessation on alcoholism treatment per se cf.. Still, Inclusion of smoking as a target for intervention does not appear to reduce patients’ commitment to broader addiction treatment. For example, incorporating smoking cessation treatment into inpatient addiction treatment centers has not substantially reduced longterm treatment completion  . In addicf.Evidence suggests that a history of alcohol use difficulties may not impede a specific smoking cessation attempt, though it does seem to reduce the likelihood of quitting smoking during one’s lifetime . ResearcMyth: Smoking is more benign than alcoholism.More people with alcoholism die from smoking-related diseases than from alcohol-related illness .Comorbid smoking and alcoholism result in synergistic exacerbation of health risks .Myth: Smokers with comorbid alcoholism have either no interest or no ability to quit smoking.cf.The majority (up to 80 percent) of individuals in addiction treatment are interested in quitting smoking cf..Inclusion of smoking cessation treatment into other addiction programs does not negatively affect rates of treatment completion or motivation for abstinence  that patients must choose between abstinence from cigarettes and abstinence from alcohol. In contrast to this concern, research suggests that treating tobacco dependence within broader addiction programs does not adversely influence recovery from alcoholism (or illicit substances). Although not universal e.g., , the majThe mechanisms of action responsible for the potential benefits of smoking cessation interventions provided during alcoholism treatment remain largely unexplored. However, possible explanatory factors may include greater clinical contact time, reduced exposure to substance use cues, relapse prevention and/or coping skills practice, increased mastery or self-efficacy, and broader healthy lifestyle choices . Self-inAlcohol-dependent patients who quit smoking while in recovery from alcohol problems also do so without negative consequences to their alcohol or drug abstinence . Data suNot only does the preponderance of evidence suggest that smoking cessation does not compromise alcohol abstinence, but multiple studies indirectly suggest that continued smoking may place alcohol-dependent smokers at risk for alcohol relapse . These dUnfortunately, even with today’s best interventions for tobacco cessation, smokers in alcohol treatment or recovery face particular challenges to their cessation efforts. On average, compared with smokers who do not abuse substances, alcoholic smokers are more addicted to nicotine, smoke higher nicotine cigarettes, smoke more per day, and score higher on nicotine dependence measures and on carbon monoxide assessment . Many smDespite concerns to the contrary, the majority of empirical evidence indicates that smoking cessation  does not pose a risk to successful alcoholism treatment. Not only does smoking cessation not disrupt alcohol abstinence, it actually may enhance the likelihood of longer-term sobriety. Although research has yet to determine the extent to which smoking cessation is impeded by active alcohol use difficulties, the presence of these difficulties does not prohibit achievement of tobacco abstinence. Given the substantial negative health consequences of co-occurring cigarette smoking and alcoholism, smoking cessation efforts in the context of treatment for alcoholism are likely to yield important benefits to patients physically, emotionally, socially, and economically.


Radiofrequency (RF) wire recanalization of short segments of central venous obstruction has been considered safe; however its use for recanalization of long segments of inferior vena cava (IVC) has not been reported.A 55-year-old female with recurrent massive hematemesis was found to have systemic venous upper esophageal varices on endoscopy and an extensive chronic IVC occlusion on CT. Using both a percutaneous transhepatic and transfemoral approach IVC recanalization was performed. A snare was advanced to the cavo-atrial junction via transhepatic venous access. From the groin utilizing RF wire steerable guide sheaths, endovascular reconstruction of the IVC was performed. Post recanalization venography demonstrated patent stented IVC and marked decrease in the intraabdominal-pelvic collaterals. No recurrence of hematemesis was noted. After 6 months, patient remained asymptomatic and had functioning right femoral arteriovenous hemodialysis graft.Using appropriate techniques, Power wire recanalization of long occlusive segments of IVC can be safe and effective. Recanalization of central venous obstruction with RF wire has been considered safe and effective based on outcomes of prior reports (Guimaraes et al., The patient is a 55-yo-female with past medical history of end stage renal failure on hemodialysis with chronic SVC and IVC occlusions from prior hemodialysis accesses. She also had a history of chronic pancreatitis, coronary artery disease. She presented with recurrent massive episodes of hematemesis. Upper GI endoscopy 3showed varices only in the upper esophagus but none in the lower esophagus. The patient did not have liver disease. Cross sectional imaging at that time revealed extensive IVC occlusion Fig.  and multOne month later, the patient returned for follow up venography, which demonstrated widely patent stented IVC and removal of the transhepatic permcath Fig. . NephrolRF wire recanalization has been successfully used to treat pulmonary atresia, to create atrial septal perforation, to recanalize completely occluded thoracic aorta and to recanalize chronic or malignant central venous obstructions after failure of conventional endovascular techniques (Guimaraes et al., In order to safeguard neighboring critical structures, we used following techniques. We placed indicator VCF-1 catheter in the aorta and constantly monitored Power wire tip to avoid deviation towards periaortic area. Unpredictable movement of the RF wire tip was a major concern while crossing long occlusive segment in caudal to cranial direction, especially when the flexible tip moves away from the power generator towards the beating heart. Use of steerable sheath allowed us to have better control of RF wire tip. Also by placing a 25 mm snare tip at the IVC-atrial junction, Power wire trajectory was given a precise target.Due to easy penetrability of heated tip of RF wire, prior studies used techniques such as short duration of RF energy delivery and very small advancements of RF wire tip (Guimaraes et al., Multiple cranial and/or femoral access approaches have been reported in the literature to treat chronic complex central venous occlusions (Massmann et al.,


The choices we make can have long-lasting effects on our health. Repetitive stress; diet; use of cigarettes, drugs, or alcohol; and work-related exposure to environmental toxins often exhibit no immediate effects. Symptoms can appear later on, sometimes many decades later, making it challenging to assign specific blame to behaviors that occurred in the past.Drosophila melanogaster males is caused by an early spermatogenesis arrest. Instead of proceeding through development normally, precursor germline and somatic cells accumulate as immature progenitors, causing a nearly complete block in spermatogenesis. Through careful investigation, the authors discovered that continuous mating causes developmental arrest indirectly, via induction of inflammation signals in the muscle sheath that surrounds the testes. Thus, it appears that muscle exhaustion or mating-associated muscle damage impacts cell fate determination nonautonomously.Most impactful are behaviors that cause irreversible changes to impair tissue function. The paper by Yi-Chieh Chang and colleagues  describeGamete quality is paramount for maintenance of species, with multiple mechanisms contributing to age-associated fertility arrest . The besChang and colleagues focus on the effects of aging on the non-self-renewing daughters of GSCs and CySCs . Reciprodpp by poorly differentiated cyst cells blocks germ cell differentiation. However, reducing dpp expression has no effect on accumulation of poorly differentiated cyst cells, indicating that a previously undiscovered mechanism must regulate cyst cell differentiation.Numerous studies have demonstrated the critical role of transforming growth factor beta (TGFβ) signaling in promoting GSC and CySC self-renewal by blocking differentiation . The autUsing clever deductive reasoning, Chang and colleagues determined that c-Jun N-terminal kinase (JNK) activity within cyst cells blocks their differentiation. They narrowed down the source of the JNK activating ligand to the muscle sheath surrounding the testes, finding that the tumor necrosis factor (TNF) ligand Eiger is both necessary and sufficient to inhibit cyst cell differentiation via JNK activation. The data support the model that excess muscle use leads to increasing Eiger production with age, with receipt of the signal by the TNF receptor Grindelwald on the cyst cell surface triggering JNK activity and the resulting differentiation block.For years, scientists have noted the inverse impact of reproduction on fertility. This study defines a novel mechanism in which inflammatory signals in tissue-associated muscle prevent gamete production, resulting in fertility arrest. The results are congruous with the disposable soma theory, in which the germline is protected at the expense of the soma . In thisWhy does this mechanism exist? One idea is that fertility arrest occurs because of increasing genetic mutations over time, resulting in gamete defects and unsuccessful reproduction. However, Chang and colleagues show that aged, never-mated males produce differentiated sperm and can productively mate to produce progeny. This calls into question the idea that passive mutation accumulation over time is the key mechanism driving fertility arrest. Perhaps TNF produced by damaged muscle induces mutations in developing germ cells. Eiger is expressed throughout the entire muscle sheath surrounding the testes in continuously mated males , suggest


Recently published article by Pieri’s group suggested that follicle-stimulating hormone (FSH) activates canine testicular spermatogonial stem cells (SSCs) and results in increased expression of pluripotent markers and formation of germ cell clumps possibly via indirect paracrine effect of Sertoli cells. We disagree with their interpretations and herewith provide a better explanation to their findings. We have earlier reported the presence of pluripotent, very small embryonic-like stem cells (VSELs) as a sub-group among the SSCs in human and mouse testes and that both VSELs and SSCs express FSH receptors. Thus, FSH exerts a direct stimulatory action on the testicular stem/progenitor cells whereby VSELs undergo asymmetrical cell divisions to self-renew (result in upregulation of pluripotent markers) and give rise to slightly bigger SSCs which undergo symmetrical cell divisions and “clonal expansion” (rapid proliferation with incomplete cytokinesis) which was noted by the authors as “clump” formation. This action of FSH is mediated via alternately spliced FSHR3 rather than the canonical FSHR1 receptor isoform, and FSH exerts similar action on ovarian and uterine stem/progenitor cells also. Being quiescent by nature, VSELs survive chemotherapy. Transplanted germ cells colonize chemoablated tubules but do not differentiate into sperm since the testicular stem cell niche comprising Sertoli cells gets functionally compromised by chemotherapy. Transplanting healthy niche cells  can restore spermatogenesis in chemoablated testes. Pieri et al.  have pubTestis harbors OCT-4-positive pluripotent stem cells in addition to SSCs: We have reported that both adult human and mouse testicular stem cells include a sub-group of pluripotent stem cells termed very small embryonic-like stem cells (VSELs) along with SSCs [ith SSCs –4. VSELsith SSCs , 5 and aith SSCs  and endoith SSCs  similar Effect of FSH on stem cells in adult mammalian testis: FSH treatment upregulated pluripotent markers in the testis. We have reported an increase in pluripotent OCT-4-positive stem cells after FSH treatment in mouse testis, ovaries, and uterus [d uterus –4, 7. InFSH stimulates SSCs to expand and form clumps or “colonies”: FSH activated the SSCs to undergo proliferation resulting in a clump formation, with paracrine influence by the Sertoli cells as suggested by the authors. Rather, the testicular stem cells including VSELs and SSCs express FSHR, and FSH has a direct effect as reported for the first time in the literature by our group for both the testis [e testis  and ovare testis . We havee testis . Similare testis . Pluripoe testis , 8, 9.Transplanted SSCs colonize and expand in response to FSH but fail to differentiate in chemoablated mouse testis: This needs to be clearly understood. We have reported that VSELs survive chemotherapy whereas the Sertoli cells get functionally compromised. The authors observed long-term survival and colonization of cSSCs in chemoablated mouse testis, but they did not differentiate since Sertoli cells become non-functional as a result of chemotherapy. Transplantation of mesenchymal cells directly in the chemoablated testis (not intratubular route through the rete testis) helped to achieve differentiation since they provided an improved paracrine support to the surviving VSELs to restore spermatogenesis [ogenesis , 10.Both bone marrow and testicular VSELs when cultured on a Sertoli cell bed and in the presence of Sertoli cell-conditioned medium differentiate into germ cells and sperm .The purpose to write this commentary is because major interpretations and conclusions reported by Pieri’s group need to be re-examined. Their findings are correct but still lack clarity on the role of FSH in adult testis that needs to be understood in proper perspective. We would like to discuss several facets of our findings to provide a novel understanding of the role of FSH on adult testicular stem cells.To conclude, FSH action is not limited to only the ovary and testis, and besides Sertoli and granulosa cells, it exerts a direct action on the stem cells to undergo self-renewal and clonal expansion. Alternately spliced FSH receptor isoform biology needs to be studied in greater details, and one needs to acknowledge both the stem cells and their niche to ensure regeneration of chemoablated testis.


Adenocarcinomas account for approximately 40% of small bowel cancers. They are typically mucosal lesions with distinctive features on endoscopy. We describe a rare case of duodenal adenocarcinoma presenting as a subepithelial lesion which posed a diagnostic challenge. An 85-year-old male patient presented for investigation of iron deficiency anaemia. Initial upper endoscopy found a subepithelial duodenal lesion with central depression but otherwise normal appearing mucosa. Superficial biopsies of the duodenal lesion were unremarkable. Subsequent antegrade single balloon enteroscopy revealed active bleeding from the lesion which was refractory to endoscopic treatment. A complete local excision of the lesion via laparotomy was necessary to achieve haemostasis. Histopathology from the lesion showed a moderately differentiated duodenal adenocarcinoma with invasion into the submucosa but no evidence of lymphovascular spread. Duodenal adenocarcinomas are rare gastrointestinal tumours associated with a poor prognosis. This case report outlines a rare presentation of duodenal adenocarcinoma and highlights the importance of judicious assessment of lesions found on endoscopy. Advances in endoscopic diagnostic modalities could facilitate early diagnosis and improve therapeutic outcomes. Adenocarcinomas account for 40% of cancers in the small intestine and the most common site of involvement is the duodenum . They arAn 85-year-old male patient was referred for investigation of iron deficiency anaemia. His comorbidities included ischemic heart disease and localized prostate cancer with previous transurethral resection (TURP) and external beam radiotherapy (EBRT). Gastroscopy found the presence of two Forrest grade III antral ulcers which were biopsied. Histopathology from the gastric antral biopsies showed moderate chronic gastritis and focal intestinal metaplasia. His colonoscopy was unremarkable. CT abdomen pelvis with oral and intravenous contrast did not find a source of bleeding, evidence bowel obstruction or mural thickening suspicious for malignancy. He subsequently underwent capsule endoscopy for investigation of occult gastrointestinal bleeding which found a non-bleeding lesion in the duodenum. Antegrade single balloon enteroscopy again identified the 1.5 cm polypoid, subepithelial lesion in the lateral wall of the second part of the duodenum, distal to the major papilla. The lesion had central depression and minor ulceration but otherwise normal appearing mucosa on endoscopy . Initialth edition, Stage I, T1bN0M0)  has demonstrated utility in the assessment of subepithelial lesions found on endoscopy. It provides a minimally invasive method of acquiring tumour characteristics such as size, layer of infiltration, and the presence of local lymphadenopathy which holds prognostic value and guides the use of biopsy techniques. EUS itself can be combined with fine needle aspiration (EUS-FNA) and fine needle biopsy (EUS-FNB) techniques for the sampling of lesions arising from the submucosa and muscularis propria . EUS-FNBThe treatment approach for duodenal adenocarcinoma differs from that of other subepithelial lesions in the small bowel. The American Society of Gastrointestinal Endoscopy (ASGE) outlines an approach for the management of subepithelial lesions, which takes into account histological features, size, layers involved, distal spread, symptomatology, and other patient factors . EndoscoAlthough rare, there have been previous reports of duodenal adenocarcinoma presenting as a subepithelial lesion. Kojima et al. reported this presentation in a 63-year-old female patient undergoing investigation for epigastric pain . The lesThis case report describes an unusual presentation of duodenal adenocarcinoma as a subepithelial lesion with initially unremarkable superficial biopsies. The diagnosis was only made retrospectively following complete excision of the lesion. The failure of initial biopsies to successfully diagnose the underlying lesion exposes the limitations of current techniques in the sampling of subepithelial lesions not accessible via endoscopic ultrasound. Improvements in endoscopic modalities for the assessment of subepithelial lesions could facilitate early diagnosis and improve therapeutic outcomes.


Although metabolic alterations are one of the hallmarks of cancer, there is a lack of understanding of how metabolic landscape is reconstituted according to cancer progression and which genetic alterations underlie its heterogeneity within cancer cells. Here, the configuration of the metabolic landscape according to genetic alteration is examined across 7648 subjects representing 29 cancers. The metabolic landscape and its reconfiguration according to the accumulated mutation maintained characteristics of their tissue of origin. However, there were some common patterns across cancers in terms of the association with cancer progression. Carbohydrate and pyrimidine metabolism showed the highest positive correlation with tumor metabolic burden and they were also common poor prognostic pathways in several cancer types. We additionally examined whether genetic alterations associated with the heterogeneity of metabolic landscape. Genetic alterations associated with each metabolic pathway differed between cancers, however, they were a part of cancer drivers in most cancer types.The online version of this article (10.1186/s12943-018-0895-9) contains supplementary material, which is available to authorized users. Cancer cells reorganize their metabolism to fulfill their biosynthetic requirements for tumor growth and proliferation . BesidesHere, we aim to investigate the metabolic landscape of multiple cancer types and its configuration according to the progression. We also aim to find answers for whether there are common features in genetic alterations related to the metabolic landscape across cancer types. An integrated analysis of genomic and transcriptomic profiles of 29 different solid cancers was performed. We demonstrate that some common metabolic pathways exhibit the close relationship with TMB and clinical outcome across several cancer types. We also show that genetic alterations associated with cancer metabolic heterogeneity were a part of cancer drivers in most cancer types.We compared the median values of metabolic signatures manually curated considering cancer-related pathways for each cancer type . Of note, glycolysis, the well-known cancer metabolic feature, showed relatively weak correlation with TMB. LUSC showed the highest carbohydrate metabolism and TMB among 29 cancer types . In general, carbohydrate and nucleotide metabolism were associated with poor prognosis. Specifically, poor prognostic metabolic signatures include carbohydrate metabolism, ribonucleotide synthesis, pyrimidine metabolism, purine metabolism, and glycolysis, whereas good prognostic signatures include peroxisomal lipid metabolism, fatty acid oxidation, and biological oxidation.Several metabolic signatures were associated with overall survival across all cancer samples  were included in cancer drivers Fig. . In otheAccording to the results, cancer transcripts and protein networks consisting of metabolic pathways may be changed by cancer drivers instead of alterations of genes participated in the networks. It corresponds to the Darwinian selection of cancer cells which carry driver mutations facilitate cellular survival and growth by changing a favorable metabolic landscape . The reshttps://choih.shinyapps.io/metabolicsignatures) according to cancer type and its reconstitution according to cancer progression can contribute to developing appropriate diagnostics and therapeutics targeting metabolism for cancer subtypes.Among several metabolic signatures, carbohydrate metabolism representing overall nutrient demand and nucleotide metabolism showed the closest association with TMB and clinical outcome. Genetic alterations closely associated with metabolic heterogeneity were a part of cancer drivers in most cancers rather than genes affiliated to metabolic pathways. It supports the role of cancer drivers in the evolution process in constituting metabolic landscape appropriate for tumor growth. Our database of the metabolic landscape


Television viewing is a risk factor for poor physical and cognitive health. Yet, we know little about associations between current health and frequency of television viewing throughout the day. This study examined associations between multiple assessments of physical and cognitive well-being and television viewing. Participants (N = 313) from the Daily Experiences and Well-being Study completed an initial interview assessing their health and well-being. They also wore an Electronically Activated Recorders (EAR) to capture sound in the environment and an Actical to measure physical activity for 5 days. Coders rated the audiofiles for television viewing. Multilevel models revealed that participants who spent a greater proportion of time tuned into television had: higher BMI, poorer health, expended less energy, were more sedentary, and reported drinking more alcohol and eating more junk food. We discuss findings with regard to potential reciprocal influences between television viewing and poor health.


Reperfusion injury follows ischemia/reperfusion events occurring during myocardial infarction, stroke, embolism, and other peripheral vascular diseases. Decreased blood flow and reduced oxygen tension during ischemic episodes activate cellular pathways that upregulate pro-inflammatory signaling and promote oxidant generation. Reperfusion after ischemia recruits inflammatory cells to the vascular wall, further exacerbating oxidant production and ultimately resulting in cell death, tissue injury, and organ dysfunction. Diving mammals tolerate repetitive episodes of peripheral ischemia/reperfusion as part of the cardiovascular adjustments supporting long duration dives. These adjustments allow marine mammals to optimize the use of their body oxygen stores while diving but can result in selectively reduced perfusion to peripheral tissues. Remarkably, diving mammals show no apparent detrimental effects associated with these ischemia/reperfusion events. Here, we review the current knowledge regarding the strategies marine mammals use to suppress inflammation and cope with oxidant generation potentially derived from diving-induced ischemia/reperfusion. The ability to manage body oxygen stores in the face of environmental hypoxia constrains the life history of many vertebrate taxa. In humans, oxygen management is critically important in clinical settings where both acute and chronic conditions such as organ transplantation and intermittent hypoxia contribute to ischemic injuries. Diving mammals, however, experience fluctuations in blood flow and oxygen saturation without sustaining such injuries. A range of physiological mechanisms for coping with finite oxygen availability has been identified to date  is considered the master regulator of the molecular response to hypoxia across taxa . Functiop apneas . MoreoveRecent phylogenomic studies have begun to uncover additional molecular mechanisms underpinning ischemia/reperfusion tolerance in marine mammals, including the expansion and positive selection of several gene families related to oxidative stress tolerance and oxygen management. Most work has considered cetacean species; pinniped genomes have generally been less available. In strong agreement with the current physiological understanding of antioxidants in both cetaceans and pinnipeds, several genes in the glutathione system – including glutathione reductase, glutathione peroxidases, and γ-glutamylcysteine ligase – are expanded, under positive selection, and/or have amino acid changes in cetaceans . Two perManaging body oxygen stores and tissue oxygen supply while diving is of paramount importance for marine mammals. Hemoglobin and myoglobin are central to this process; both are under positive selection in cetaceans . In the ex vivo systems that are amenable to physiological manipulation and molecular perturbation in an effort to provide the missing link between genomic- and organismal-level investigations. Identifying the drivers of ischemic and hypoxemic tolerance in marine mammals can provide a mechanistic understanding of natural tolerance to such conditions while aiding in translation to clinical applications.Marine mammals experience diving-induced hypoxemia and ischemia/reperfusion events without apparent detrimental effects. Physiological, biochemical, and genomic studies have begun to uncover the mechanisms underlying such extreme tolerance. Among those mechanisms, coordinated body-wide responses to delay the onset of tissue hypoxia, counteract oxidant generation and prevent inflammation are critical. Convergent genomic changes across marine mammal lineages hint at the evolutionary underpinnings of the physiological adaptations supporting mammalian diving . The incKA and JV-M wrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Adults who remain cognitively active may be protected from age-associated changes in white matter (WM) and cognitive decline. To determine if cognitive activity is a precursor for WM plasticity, the available literature was systematically searched for Region of Interest (ROI) and whole-brain studies assessing the efficacy of cognitive training (CT) on WM microstructure using Diffusion Tensor Imaging (DTI) in healthy adults (> 40 years). Seven studies were identified and included in this review. Results suggest there are beneficial effects to WM microstructure after CT in frontal and medial brain regions, with some studies showing improved performance in cognitive outcomes. Benefits of CT were shown to be protective against age-related WM microstructure decline by either maintaining or improving WM after training. These results have implications for determining the capacity for training-dependent WM plasticity in older adults and whether CT can be utilised to prevent age-associated cognitive decline. Additional studies with standardised training and imaging protocols are needed to confirm these outcomes.


Papio ursinus) and assesses their relative importance. Our results show that oestrous females initiate fewer copulations in the presence of adult male bystanders, irrespective of whether they are mate-guarded or not. This inhibitory effect probably reflects a response to indirect sexual coercion by males, whose close proximity may dissuade females to initiate copulations with rival males to avoid punishment and/or aggressive mating interference. By contrast, females initiate more matings with their mate-guard in the presence of higher-ranking female bystanders, which may reflect an attempt to secure bodyguard services from their mate when they feel threatened. These results emphasize the importance of intra- and intersexual conflicts in shaping female sexual behaviour in this promiscuous society.In social species, female mating strategies can be constrained by both male and female groupmates through sexual conflict and reproductive competition, respectively. This study tests if females adjust their sexual behaviour according to the presence of male and female bystanders in wild chacma baboons ( For example, dominant females often harass other females and interfere with their mating attempts, and monopolize resources that are necessary to breed, such as shelters, mates or offspring care . SimilarTheropithecus gelada) )


The combination of aging and losing an only adult child challenges an increasing number of older adults in China. Current literature primarily focuses on older parents’ bereavement but seldom examines how they restore their lives. Guided by the Dual Process Model, this study explores how older parents who lost their only adult child restore their lives and prepare for future care in Shanghai. Twenty-four older adults were purposively sampled and participated in face-to-face, in-depth interviews. The findings suggest that participants tried to restore their lives by rationalizing grief and expanding their social networks. Despite their losses, participants remained in favor of family caregiving and reluctantly prepared for future care. They showed ambivalent attitudes toward current government support while proposing their preferred services. This study informs social work practice to incorporate caregiving plan services and emotional support for this vulnerable group.


The current achievements in treating glioblastoma (GBM) patients are not sufficient because many challenges exist, such as tumor heterogeneity, the blood brain barrier, glioma stem cells, drug efflux pumps and DNA damage repair mechanisms. Drug combination therapies have shown increasing benefits against those challenges. With the help of nanocarriers, enhancement of the efficacy and safety could be gained using synergistic combinations of different therapeutic agents. In this review, we will discuss the major issues for GBM treatment, the rationales of drug combinations with or without nanocarriers and the principle of enhanced permeability and retention effect involved in nanomedicine-based tumor targeting and promising nanodiagnostics or -therapeutics. We will also summarize the recent progress and discuss the clinical perspectives of nanocarrier-based combination therapies. The goal of this article was to provide better understanding and key considerations to develop new nanomedicine combinations and nanotheranostics options to fight against GBM. GBM therapeutics need to be able to cross this barrier and penetrate the brain to reach the tumor. However, only small lipophilic chemotherapeutic agents with a molecular weight less 400 Da and 8 hydrogen bonds can passively pass through the BBB The blood brain barrier (BBB) is a particularly formidable challenge in developing therapeutics for brain tumors. Brain microvascular endothelial cells, pericytes, astrocytes, tight junctions, neurons and the basement membrane together form a physical barrier to protect the brain and maintain a well-defined intracranial environment Another difficulty is found in the heterogeneity of GBM. Genomic research has shown that GBM contains many different cell types depending on their origin or subsequent genetic and epigenetic conversions in vitro and in vivo. Consequently, populations of glioma stem cells remain alive after initial treatment and reinitiate tumor recurrence This genetic drift can result in self-renewing, tumorigenic glioblastoma stem cells (GSCs) that contribute to tumor initiation and therapeutic resistance MDR1 gene has been mostly considered as the cause of anti-cancer drug resistance. MDR1 P-gp is present in the brain capillaries of the BBB, as well as in many other tissues. Many drugs exhibit significantly improved brain penetration when drug efflux transporters are inhibited Multidrug resistance (MDR) presents another major barrier for chemotherapeutic drugs to get access to brain tumor cells effectively. Among the different mechanisms of MDR, ATP-binding cassette (ABC) transporter-mediated exocytosis was mostly noticed. The P-glycoprotein (P-gp) which is encoded by the human Because of these challenges, combining drugs with different working mechanisms has gained great attention in recent years. The right combination of compounds could enhance efficacy by targeting these issues in a synergistic or additive manner. However, the efficiency of many chemotherapeutic agents is also limited by their dose-related toxicities. As the BBB shields the brain from most systemically administrated compounds, high doses are given to achieve intracranial therapeutic drug levels. Increasing the dose of a specific anticancer drug will inevitably lead to significant toxicity. Many GBM chemotherapeutic drugs have demonstrated off-target toxicity at the doses needed to reach an intracranial effect. For example, TMZ is associated with lymphopenia, thrombocytopenia and neutropenia With growing investigation of the tumor microenvironment and by unravelling biological and molecular pathways, increasingly more potential drug combinations are emerging. However, just combining cytotoxic compounds does not address the problems associated with poor drug distribution at the desired tumor site. Different approaches have been raised to defeat unfavorable drug distribution in the brain In this review, we will discuss and address the advantages of drug combinations with or without nanocarriers, nanomedicine-based tumor targeting strategies, current preclinical drug combinations, and promising nanotherapeutics and nanodiagnostics. The aim of this review was to highlight the importance and potential of drug combinations and give a comprehensive understanding of different combination strategies for GBM therapy.Poor drug delivery, tumor heterogeneity and drug resistance pathways have prevented single compound therapies to show significant benefits for GBM patients Drug delivery to GBM is notoriously difficult due to the inability of most drugs to cross the BBB and penetrate the tumor tissue. Only few systemically administrated drugs reach the tumor site in a therapeutic dose. Various approaches, such as chemical modification of chemotherapeutic drugs, BBB altering strategies and efflux transporter inhibitors, are being investigated to enhance the systemic delivery of potential anti-GBM drugs. For instance, drugs can be modified to a more lipophilic form by adding lipid groups to the polar ends of therapeutic molecules. A log P (octanol-water) value ranging from 1.5 to 2.5 of lipophilic analogs has better brain permeability Alternatively, hyperosmotic agents, bioactive molecules, surfactants and ultrasound or electromagnetic waves have been used to alter the permeability of the BBB. Yet, such approaches are often associated with risks such as possible tumor diffusion to the periphery, and exposure of the brain to neurotoxins.In addition, inhibition of ABC efflux gene families can increase drug penetration into the brain without compromising the integrity of the tight junctions and endothelial layers. However, this approach will also reduce the efflux of potential neurotoxic compounds. In fact, many of these efflux pumps transporters could not be fully inhibited due to various reasons, including multifactorial multidrug resistance and genomically unstable tumor cells via convection enhanced delivery. The Ommaya reservoir is a reservoir capsule connected to a catheter located in the lateral ventricle. The capsule is embedded under the scalp and is easily accessible for cerebrospinal fluid (CSF) aspiration or drug delivery directly into the ventricular CSF and relies on the flow of CSF to distribute chemotherapeutics, radioactive compounds, antibodies, viruses or cells throughout the brain Local intracranial delivery not only overcomes BBB-associated drug delivery issues but also prevents systemic compound clearance and/or degradation and reduces systemic side effects. As such, much lower dosages are needed. Local drug delivery to the brain and further distribution within the brain can be mediated by simple diffusion using a reservoir-catheter system or positive pressure bulk flow via convection-enhanced delivery (CED). The positive pressure drives convective local transport of therapeutic concentrations of anti-tumor drugs into the interstitial tumor space. This technique achieved higher drug concentrations in the targeted tumor tissue compared with diffusion-limited delivery Alternatively, drugs are administered to the brain continuously with a positive pressure bulk flow ® wafer for newly diagnosed malignant and recurrent GBM. However, the success of Gliadel® wafers is restricted by the limited penetration of the active compound, carmustine, into the brain tumor tissue. Moreover, use of the wafers has been associated with several adverse events, including intracranial infections, wafer migration, cerebral edema, CSF leakage and seizures Locally implanted (biodegradable) drug delivery depots have increasingly gained interest. Currently, the only FDA-approved biodegradable implant is the GliadelNevertheless, the concept of local delivery by implanting drug-releasing depots in the tumor resection cavity remains intriguing for the treatment of GBM. Films, foams and gels have been investigated for their use in local drug delivery. Particularly hydrogels have gained much attention in recent years. In general, hydrogels are injectable, biocompatible, biodegradable and mechanically comparable to soft tissue, making them attractive for intracranial implantation. They provide a versatile drug delivery system because they can be loaded with small-molecule drugs, biomacromolecules (such as DNA or protein) or cells. The gels can be engineered to tune the release of their contents in a timeframe ranging from hours up to several months Different drug combination strategies have been explored in clinical trials to tackle known drawbacks of GBM treatment. A non-exhaustive summary of combination therapy trials is presented in table 6-methylguanine-DNA methyltransferase (MGMT inhibitor) O6-benzylguanine (O6-BG) to rebuild drug sensitivity in TMZ-resistant anaplastic glioma. Indeed, O6-BG was able to restore TMZ sensitivity in TMZ-resistant anaplastic glioma, but not in TMZ-resistant GBM Another phase II clinical trial combined TMZ with an OMore often than not, promising preclinical anti-tumor strategies disappoint in clinical trials due to various reasons. For example, a phase I/II trial to determine the efficacy of vorinostat + erlotinib versus vorinostat + erlotinib + TMZ in patients with recurrent GBM multiforme was terminated because of unanticipated toxicities (NCT01110876). A trial that combined the histone deacetylase inhibitor vorinostat and proteasome inhibitor bortezomib to treat recurrent GBM, reported that no patient achieved 6-month PFS and only one patient showed a partial response according to the Macdonald Criteria, probably due to brain delivery issues in vitro results can be explained by several factors  therapeutics, which has led to disappointing clinical outcomes table . For GBM®, Doxil®, DaunoXome®) mainly reduce toxicity of the parent compound and thereby improve its therapeutic index. Small interfering RNAs (siRNA) show great therapeutic promise but have disappointing clinical relevance due to stability and delivery issues. The only currently FDA approved siRNA therapeutic is Patisiran®, which is based on a lipid NP formulation that improves siRNA stability.Depending on the materials, nanoformulations are able to load hydrophilic and hydrophobic drugs, ensure sustained drug release and enhance the half-life of the drug in the circulation. For example, the half-life of TMZ was enhanced to 13.4 h compared to 1.8 h of the free drug by encapsulation in a chitosan-based nanoparticle Two decades have passed since the first NP-based cancer treatment was approved by the FDA, with an increasing number of clinical trials now ongoing, including many for GBM. A variety of systems based on polymers , inorganic materials  and/or lipids  have been investigated for drug delivery to the brain. The therapeutic drugs can be loaded in these particles by encapsulation, covalent linking or surface adsorption Passive tumor targeting is based on the observation that certain sized particles tend to accumulate in tumor tissue much more than they do in healthy tissues. This is known as the enhanced permeability and retention effect (EPR) effect, which was first described by Matsumura and Maeda in 1986 i) heterogeneity or lack of fenestrations in the tumor endothelium, (ii) presence of acidic and hypoxic areas (iii) lower or heterogeneous pericyte and basement membrane coverage, (iv) and high interstitial fluid pressure (IFP) induced by dense extracellular matrix, explaining the difficulty in translating the EPR effect from bench to bedside However, within the last couple of years, more and more researchers have realized that the EPR effect is highly heterogeneous both intra- and intertumorally, varies during tumor development and does not always hold up in clinical settings Figure . MoreoveInterestingly, GBM is characterized by robust endothelial proliferation resulting in tortuous, disorganized and highly permeable vasculature First of all, when comparing different imaging modalities, it becomes clear that T1-weighted MRI alone does not visualize the entire tumor. Beyond the contrast-enhancing region, essentially all of GBM show non-enhancing edema on T2-weighted or fluid attenuation inversion recovery imaging Other key pathological features of GBM are hypoxic areas surrounded by hypercellular rings of actively migrating tumor cells Due to the differences in EPR effect between and within tumors, approaches to still take advantage of it may vary. In certain situations, one might benefit from tumor vasculature normalization 64Cu-labeled long-circulating particles of different size were systemically administered and tracked via MRI and positron-emission tomography (PET) in an intracranial rat GBM model. It was demonstrated that 7 hours after systemic injection, the uptake of 20 nm NPs is significantly greater than those of 110 nm. It also showed that PET/MRI co-registration of brain images may contribute to the monitoring of disease progression and determining what drug delivery approach is feasible The extent of EPR in a tumor could be tested prior to treatment using imaging modalities. In a preclinical study, the relative blood volume was found to correlate with the tumor accumulation of polymeric drug carriers. With the help of contrast-enhanced ultrasound imaging, this vascular parameter proved useful in predicting EPR-mediated tumor accumulation of NPs and could possibly be used to preselect patients eligible for nanotherapeutic treatment The high variability of the EPR effect is considered as one of the major challenges for translating nanomedicine into the clinic. This issue can be addressed by indirect EPR imaging, utilizing companion diagnostics or developing systems with both diagnostic and therapeutic properties (theranostics). Indirect EPR imaging can non-invasively visualize and quantify the key EPR-determining parameters of the tumor vasculature, while theranostics or companion diagnostics can give insight in NPs distribution and tumor responses.via the secretion of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and CXC-chemokine ligand 2, paving the way for hypervascularity as seen in GBM et al. developed an albumin-based biomimetic NPs with transferrin receptor-binding peptide T12 and mannose as targeting ligands for codelivery of the disulfiram/copper complex and the macrophage modulator regorafenib. The T12 peptide can enhance BBB permeability and glioma cell uptake. The mannose ligand can bind to mannose receptors on TAM2. This system efficiently inhibited the glioma cell proliferation, successfully induced the protumor TAM2 towards antitumor TAM1 and triggered macrophage-directed anti-glioma immunotherapy via TAM, regulatory T cells, CD8+ T cells and cytokines Many cancers are preceded by infections or (chronic) inflammation and it is increasingly clear that the immune system plays a central role not only in cancer development but also in tumor progression et al. show that NPs predominantly accumulate in tumor associated immune cells rather than tumor cells. They used fluorescently labeled polymeric NP (100 nm) together with magnetic NP (20 nm) in several tumor mouse models to predict NP tumor accumulation and treatment outcome. It appeared that NP distribution was mainly determined by vascularization and permeability at early time points, but at later time points by cellular uptake. Both NPs were mostly taken up by host phagocytes (> 90%). High local TAM counts correlated with increased NP accumulation and as such proved an important component of the EPR effect In vitro studies show monocyte mediated transfer of NP over an endothelial monolayer In vivo, TAM with ingested NPs has been observed to cross the BBB and migrate to (distant) tumors. As such, NPs were shuttled between contralateral CNS tumors via migrating TAMs via these cells.The inflammatory response observed in GBM results in increased vascular permeability as well. In turn, this will not only allow for extravasation of immune cells, but also of therapeutics including NPs. Furthermore, extracellular matrix (ECM) remodeling can influence NPs transport through the interstitial space e.g. ATP, calreticulin, high-mobility group box 1(HMGB1) and chemokine ligand 10 (CL10), allowing dendritic cells to recognize the dying cell and initiate an anti-tumor immune response to clear tumor cells Another point that might influence the immune microenvironment-based therapy for GBM is the immunosuppressive effects of chemotherapy. Indeed, systemic chemotherapy might suppress the bone marrow and consequently impact the amount and activation state of immune cells When passive targeting is insufficient, active targeting of NPs can facilitate their transport over the BBB. With polymeric NPs this is often achieved by modifying their surface with surfactants or BBB- or glioma-specific ligands. For example, doxorubicin (DOX) loaded poly butyl-cyanoacrylate NPs were more effective when coated with the surfactant P80 and increased the survival time of GBM tumor bearing rats compared to the non-coated group ®) resulted in a significantly higher intratumoral concentration of DOX than normal brain tissue in GBM patients via RME and promote tumor specific uptake. Transferrin conjugated liposomes increased brain delivery of 5-fluorouracil by 13 times compared to non-conjugated liposomes Lipid NPs, liposomes in particular, are also widely investigated in the drug delivery field. Liposomes can encapsulate hydrophilic compounds in the aqueous compartment and hydrophobic compounds in the bilayer making it a versatile delivery vehicle. Covering the surface of these particles  with polyethylene glycol (PEG) neutralizes surface charge but thereby ensures prolonged circulation and increases the EPR effect. Radiotherapy supplemented with PEGylated liposomal DOX (CaelyxLipid nanocarriers (LNCs) are also able to load both hydrophilic and hydrophobic molecules in an aqueous core by formation of reversed micelles 131I-labeded CTX-functionalized polyethylenimine-entrapped gold nanoparticles as a multifunctional glioma-targeting nanoprobe was generated. After incubation with the NPs, C6 cells displayed much stronger fluorescence intensities than those treated with negative controls under the same conditions by confocal imaging. This CTX-loaded NP could also act as a nanoprobe for the targeted single photon emission computed tomography (SPECT)/ computed tomography (CT) imaging of glioma cells and in a subcutaneous tumor model Sometimes NPs are made by organic-inorganic hybrid materials as the magnetic and optical features of metallic NPs can be used to actively target to tumor site and monitor delivery non-invasively. In an U87MG orthotopic tumor model, magnetic targeting treatment with superparamagnetic iron oxide (SPIO) and PTX coloaded PLGA NPs significantly enhanced the median survival time compared with the passive targeting treatment group via passive targeting, while active targeting might be employed to increase this accumulation in hard to reach tumors such as GBM. Imaging (whether direct or indirect) can give an indication of the potential of certain tumors to be treated with NP formulations, thereby preselecting patients and possibly improving treatment success.Overall, NPs show great potential in preclinical studies. They often improve accumulation of therapeutic compounds Nanocarrier formulations additionally offer the opportunity to incorporate imaging features facilitating diagnostic as well as monitoring features. Accurate diagnosis is essential for adequate cancer treatment. For GBM, imaging is pivotal as the alternative diagnostics (e.g. biopsies or surgery) are highly invasive. As such, imaging is crucial for (preliminary) tumor characterization and localization, planning of surgical strategies and monitoring of treatment response.Generally, maximal gross resection is correlated with increased survival via compromised and leaky vasculature, amino acid linked PET tracers can transverse the intact BBB Where conventional contrast enhancers and tracers can only enter the brain Coupling the integrin targeting ligand RGD to PET tracers increased their tumor specificity in mouse models via fluorescence imaging ex vivoet al. designed a carbon-based QD that could emit red light. Intravenously injected dots accumulated in xenograft HeLa tumors via EPR and allowed in vivo fluorescent as well as PA imaging. Moreover, the dots could be used as photothermal inducers, as a large percentage of the absorbed energy is converted to heat, facilitating thermal ablation of tumor tissue Preclinically, novel materials and approaches are being investigated such as quantum dots (QDs), metallic NPs, protein conjugates and polymeric particles 64CuCl2. These particles could be imaged using PET scans in a xenograft GBM mouse model. The dots were self-luminescent via cerenkov resonance energy transfer, making it possible to visualize tumors via luminescence imaging as the EPR effect resulted in tumor accumulation of the PEGylated particles via PET imaging and showed promising fluorescence imaging opportunities in an earlier mouse study Alternatively, QDs can be coupled to other imaging agents such as radioactive tracers to allow deeper tissue imaging. PEGylated radioactive QDs were made using metal chlorides and via MRI allowing tracking of the particles and simultaneously present a way of directing the particles toward their goal via magnetic fields. A second biocompatible layer reduces toxicity and extends circulation via magnetic targeting, assisted by ultrasound-targeted microbubble destruction of the BBB. They were visualized by MRI (SPION) and fluorescent imaging (using the QD). The fluorescent signal was able to improve gross resection while the loaded cinglitide could inhibit tumor growth ® for hyperthermal treatment of primary and recurrent GBM. The particles are injected intratumorally, followed by applying alternating magnetic fields to produce cell killing heat. Combined with radiotherapy, NanoTherm® prolonged survival in 66 patients with recurrent GBM As mentioned in the section of active targeting, superparamagnetic iron oxide nanoparticles (SPIONs) are extensively investigated as standalone theranostic particles as well. The magnetic iron core can be visualized As more and more information is gathered on the presence of different cellular compositions in different tumor regions, subtype specific diagnostic/ theranostic NPs might be used to elucidate the tumor make up and provide tailored therapy e.g. Bortezomib and HDAC; O6-BG and TMZ) in vitro. Intravenous administration of NPs encapsulating the compounds in their optimal ratio significantly inhibited tumor growth in a U87 subcutaneous model in vivoDue to differences in BBB permeability, drug stability and pharmacokinetics, therapeutic efficacy may be disappointing when simply administering two or more theoretically synergistic compounds  in several tumor models Besides the optimal ratios, the timing and order in which drugs are administered can have significant effects on the treatment outcome. For instance, the complex tumor microenvironment can greatly impair drug distribution within the tumor p53 gene plasmid was loaded in a transferrin targeted liposome (SGT-53) which could sensitize human glioma cells to TMZ. Moreover, pretreatment of TMZ resistant tumors with SGT-53 reversed TMZ resistance, while co-delivery of SGT-53 and TMZ postponed the development of TMZ resistance in an intracranial mouse GBM model p53 inhibitors MDMX and MDM2 which was loaded in an RGD-targeted micelle. The micelles could reach an intracranial tumor and exert potent p53-dependent anti-proliferative activity. In addition, activating p53 sensitized the tumors for subsequent TMZ treatment The timing and order of treatments can also significantly affect the way tumors respond to certain insults on a cellular level, a factor that often seems overlooked. Knocking down epidermal growth factor receptor (EGFR) signaling in triple-negative breast cancer cells markedly increased their sensitivity to subsequent DOX treatment. Reverse order or simultaneous administration had no such effect and could even be inhibitory, emphasizing the importance of timing rather than just co-administration Intelligent designs of NPs As single drug therapies often seem insufficient for the treatment GBM, the focus has shifted to combination therapies. It is important to find combinations that act synergistically and preferably on different targets as tumor heterogeneity and emergence of resistance pathways need to be considered. Genetic profiling of tumors can help in finding the most promising approach. Incorporating established therapies in combination approaches will ensure faster translation to the clinic while adding compounds for novel targets such as the tumor immune microenvironment has shown promising results. However, simply administering two compounds systemically will most likely result in underwhelming results. Brain delivery of most compounds has proven challenging and seems to be insufficiently acknowledged as few clinical trials investigate or report brain concentrations of the used compounds.in vivo studies, results fail to translate to the clinic. This is partly due to too simplistic (murine) models that don't represent the complex human tumor heterogeneity.Intracranial delivery of therapeutics is promising but still needs significant optimization before it is sufficiently practical to be implemented in standard care. Systemic delivery is predominantly hampered by the BBB. There is increasing interest in nanoformulations for the delivery of drugs to the brain and has shown promising results in preclinical  animal studies. The ideal design of a nanosized delivery system depends predominantly on the encapsulated molecules, the preferred release profile of each compound (simultaneous or time staggered) and which cells are targeted. Nevertheless, certain characteristics seem to be universally beneficial. PEGylating the particle and keeping the size around 20-75nm ensures prolonged circulation and at the same time allows sufficient tissue penetration. Factors such as the partition coefficient, the molecular weight and the synergistic ratio of the payloads have to be considered as well. Although nanocarrier based brain delivery shows promising results in preclinical p53 and/or Rb knock-down and the activation of pro-survival RTK and Ras signaling to allow for de novo tumor formation. With GEMMs, it could be possible to investigate the function of tight junction proteins, transporters, or ECM components in BBB development and biology as well. On the other hand, GEMMs also failed to recapitulate the intratumoral heterogeneity seen in patients. Other limitations like expensive breeding and low tumor penetrance have to be considered In order to have a more accurate prediction of clinical outcome of novel therapeutic strategies, an ideal mouse glioma model should be orthotopic and highly reproducible with predictable tumor growth, bear a genetic similarity to human glioma, show cellular heterogeneity and angiogenic-like growth Additionally, EPR based passive brain targeting of NPs as seen in animal models fails to translate to the clinic. Active targeting is often suggested to improve tumor accumulation yet it is most likely more favorable to pre-select for patients that are suited for NP based treatment. Novel imaging modalities as well as the rise of nanotheranostics will provide the opportunity to pre-select patients with appropriate tumor characteristics such as high tumor perfusion and large relative blood volumes. Additionally, nanotheranostics will provide a way to monitor drug delivery and possibly visualize treatment outcome.The preclinical success of immunotherapy of GBM has not been replicated in human clinical trials. Both vaccines as single therapy and immune check point inhibitors have led to disappointing clinical results GBM is a complicated cancer that involves various sophisticated molecular pathways, gene mutations, and tumor microenvironments. Despite plentiful investigations, an unmet medical need persists for the treatment of invasive GBM. Here we have described the current strategies for nanomedicine-based drug combination therapies. With increasing knowledge of GBM molecular pathways, increasingly more intelligent drug combination strategies will be developed. Nanocarriers will be designed to improve delivery and allow targeting of different pathways within the tumor microenvironment. Future approaches will exploit different nanocarrier-based combinations, the most promising being immunotherapy and nanotheranostics, to enhance the therapeutic benefits for GBM. With the broad knowledge and efforts of researchers, nanocarrier-based combination therapies are expanding the way for success in the battle for GBM treatment.


Cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) improve survival of patients with colorectal peritoneal metastases (PM).,Therefore, identification of practical clinicopathologic prognostic variables is key to optimize treatment for patients with PM. Patients who experience PM despite previous adjuvant chemotherapy after primary tumor resection are thought to benefit less from cytoreduction and HIPEC, and several studies and guidelines exclude these patients from a potentially curative HIPEC treatment.3This study evaluated all relevant clinicopathologic variables potentially associated with oncologic outcome in a large prospectively obtained cohort of 175 patients who had colorectal PM and were treated with cytoreduction and HIPEC.Future guidelines should incorporate the identified clinicopathologic prognosticators into clinical practice. Before clinical implementation, however, these variables require further prospective validation. A combined effort, with prospectively collected consecutive data from patients with PM, is key for this purpose. Currently, ongoing clinical trials with patients who have colorectal PM are addressing perioperative systematic chemotherapy, the additional value of HIPEC versus cytoreduction alone, and novel chemotherapeutic HIPEC agents. Future research to optimize treatment of patients with PM should focus on identification of molecular tumor characteristics that could improve patient selection. In addition, the substantial progress regarding the use of blood samples as liquid biopsies could provide prognostic (epi-)genetic information. Knowledge of tumor biology not only could help in selecting the right patients, but also could provide guidance regarding the optimal chemotherapeutic drug for the HIPEC treatment. Ultimately, a personalized profile consisting of both clinical and molecular characteristics will provide a way toward tailored treatment for patients with colorectal PM.


Extrachromosomal gene amplification refers to copy number gains of DNA fragments that are not contiguous with the twenty-three canonical chromosomes. Unlike typical chromosomes, they are composed of circular DNA fragments without centromeric sequences . They arEGFR) is, by far, the most commonly altered oncogene in glioblastomas, the most common form of primary brain cancer. It is mutated or amplified in 60% of glioblastomas [EGFR gene. EGFRvIII-positive glioblastomas exhibit unique molecular physiologies associated with distinct therapeutic response profiles and an overall tumor aggressiveness [Epidermal growth factor receptor gene (lastomas . OncogenEGFR deletion variants.Breakpoint junctions in EGFRvIII are highly variable between tumor samples due to 120-kb-long intron one of this gene where one of the breaks take place. Breakpoint sequence analyses implicate contribution by multiple DNA strand-break repair mechanisms, including non-homologous end joining, micro-homology mediated end joining, and other forms of replication mediated repair . These fEGFRvIII is that a single tumor can harbor multiple, independent EGFRvIII variants -- each with distinct breakpoint junctions. These variants as well as the accompanied amplified full-length EGFR share common allelic profiles, suggesting that the deleted variants arose from a common ancestral amplified EGFR. A corollary of this hypothesis is that distinct additional genomic rearrangements of amplified full-length EGFR in glioblastoma subpopulations gave rise to polyclonal EGFRvIII breakpoint species (Figure Another interesting observation pertaining to s Figure .EGFR variant formation and EGFR amplification. Is extrachromosomal EGFR amplification a requisite precursor of EGFRvIII? For instance, this acquisition of glioblastoma specific EGFR deletion mutation might be associated with the fact that amplified EGFR in glioblastoma mostly resides in extrachromosomal DNA that is selectively captured in micronuclei [EGFRvIII.An important mechanistic question in this context involves the sequence of events that led to ronuclei , where cronuclei . In thisEGFRvIII is formed, not only do cells expressing this mutant transform to a more aggressive phenotype as mentioned above, but surrounding tumor cells without mutant EGFR are also benefited in terms of growth and cell survival by paracrine effects through cytokines such as interleukin-6 [EGFR yielding EGFRvIII that establishes an ecosystem supportive of aggressive tumor growth. Elucidation of this mechanisms of further rearrangements of extrachromosomal amplicons should yield opportunities for future therapeutic development and mechanistic insight.Once leukin-6 , or throleukin-6  (Figure


Drug targeting has opened a new paradigm in therapeutics with development of delivery vectors like liposomes and polymeric nanoparticles. Although their clinical application is crippled by limited biological adaptability. Off-target toxicity and biocompatibility still remains one of the critical problems in anticancer therapeutics that can be life-threatening. Here we report a quick, simple and facile method of engineering human platelets to generate drug loaded platelet-derived microparticles (PMPs) by top-down approach, which are biocompatible and naturally target leukemia cells. Drug loaded PMPs and cancer cell uptake were characterized by flow cytometry, confocal microscopy, Nanoparticle Tracking Analysis and fluorimetry. Effective drug delivery was tested in cancer cell lines as well as in clinical samples from leukemia patients. We explored that PMPs are capable of carrying multiple drug payloads, have long shelf life and can be harvested in large quantity in short period. Importantly, PMPs exhibited remarkably higher toxicity towards cancer cells than free drug and had lower escape into extravascular spaces. Transfer of drug to cancer cells of leukemia patients was significantly higher than free drug, when delivered through PMPs. Our experiments validated therapeutic application of PMPs as biocompatible drug delivery vector against cancer cells with minimal off-target delivery. Off-target toxicity is presently one of the main issues associated with drug administration, especially anticancer therapy . Being pTargeting drugs to specific sites of action through nano-sized vehicles has opened new paradigm in therapeutics . Despitein vivo, as well as overcoming biological barriers such as the blood-brain barrier  under informed consent. Leukemia diagnosis was confirmed by presence of >90% blast cells with high nuclear-cytoplasmic ratio in peripheral blood and bone marrow examinations. Aliquots (100 μl) of whole blood from each sample were treated either with vehicle (buffer without Dox), or free drug (0.15–0.2 μg/ml DoX), or equivalent PMPDox for 1 h. WBCs were separated using RBC lysis reagent (Puregene), fixed with 2% paraformaldehyde and Dox uptake was evaluated by flow cytometry. Comparison with normal leukocytes was carried out with blood obtained from healthy donors following similar procedure.t-test was used for evaluation of significance and values of p < 0.05 were considered significant. This study was approved by ethical committee of Institute of Medical Sciences, Banaras Hindu University.All data are representative of at least three independent experiments. Two-tailed Student’s In this report we discussed a quick and facile top-down approach of generating drug-loaded PMPs that behave as natural vectors targeted against leukemia and other cancers. PMPDox engineered from autologous human platelets are physiological, biocompatible, non-immunogenic and inherently targeted towards cancer cells, thus obviating the need for implantation of exogenous targeting molecules on the particle surface. PMPDox is also capable of carrying multiple therapeutic payloads. Platelets can be easily accessed from blood and harvested in large quantity. PMPDox can be generated in huge number from donor platelets, stored for several days without loss of stability and exhibit targeted delivery and higher toxicity against leukemia cells than free drug. Successful drug delivery and compatibility in whole blood samples from leukemia patients confirmed potential practical application of this approach. Multimodality is also feasible in our approach as multiple anticancer drugs and/or contrasting agent can be loaded into PMP. Reduced extravascular escape of drug from PMPDox would minimize off-target adverse effects including cardiac and hepato- toxicity, making it far safer approach for anticancer therapy.