Cancer theranostics is a new concept of medical approach that attempts to combine in a unique nanoplatform diagnosis, monitoring and therapy so as to provide eradication of a solid tumor in a non-invasive fashion. There are many available solutions to tackle cancer using theranostic agents such as photothermal therapy (PTT) and photodynamic therapy (PDT) under the guidance of imaging techniques . Additionally, there are several potential theranostic nanoplatforms able to combine diagnosis and therapy at once, such as gold nanoparticles (GNPs), graphene oxide (GO), superparamagnetic iron oxide nanoparticles (SPIONs) and carbon nanodots (CDs). Currently, surface functionalization of these nanoplatforms is an extremely useful protocol for effectively tuning their structures, interface features and physicochemical properties. This approach is much more reliable and amenable to fine adjustment, reaching both physicochemical and regulatory requirements as a function of the specific field of application. Here, we summarize and compare the most promising metal- and carbon-based theranostic tools reported as potential candidates in precision cancer theranostics. We focused our review on the latest developments in surface functionalization strategies for these nanosystems, or hybrid nanocomposites consisting of their combination, and discuss their main characteristics and potential applications in precision cancer medicine. Cancer theranostics is an emerging field of nanotechnology that combines therapy and diagnosis in a single smart tool, providing real-time monitoring of treatment progress and efficacy ,2. The pAmong the most promising theranostic tools proposed in recent literature panorama, gold nanoparticles (GNPs), superparamagnetic iron oxide nanoparticles (SPIONs), carbon nanodots (CDs) and graphene oxide (GO) have shown intriguing characteristics exploitable in biomedicine and especially in cancer theranostics.GNPs are a varied class of colloidal gold with a controllable shape and characteristics ,33. As aSPIONs have been explored as efficient contrast agents in cancer magnetic resonance imaging (MRI) combined to chemo- and magnetotherapy. The viewpoint is that SPIONs can be accumulated into the tumor mass through magnetic targeting under the guidance of external static magnetic fields, and simultaneously used to release anti-cancer drugs and heat by using alternated magnetic fields directly in the site of action. However, the MRI efficacy of SPIONs remains much lower if compared with Gd-based drugs (the gold standard in clinics), and further efforts should be made to overcome these limitations ,36.To date, carbon-based nanomaterials such as GO and CDs have attracted considerable attention, since they are cost-effective, stable, biodegradable and possess excellent photothermal conversion in the near infrared (NIR) region, which make them potential candidates as nanoheaters useful in photoacoustic imaging and PTT applications. In particular, nano-GO has been exploited for biosensing applications, and to simultaneously release local heat and photothermal-induced release of huge amounts of anticancer drugs under the guidance of PA. However, their batch-to-batch size and structural characteristics are hardly controllable and thus a real-world medical application for GO is difficult. On the contrary, CDs are emerging 0-D nanomaterials with established size and surface functionalization, endowed with a smart combination of optical  and biological  properties, that seem to overcome the GO-related drawbacks, thus paving the way for future studies to develop promising theranostic agents for precision cancer therapy and diagnosis ,38,39.Although there are many examples of surface functionalization of nanomaterials for cancer theranostic applications, the proposed approaches are quite complex, and mainly yield to heterogeneous nanoplatforms whose industrial production for a real-world use is precluded. Considering the high-level of complexity as well as the difficulty to obtain properties with a suitable batch to batch consistency, this kind of nanotool usually do not meet the regulatory and translational criteria for commercialization. On the contrary, the application of carefully controlled synthesis and functionalization procedures may lead to highly ordered architectures exhibiting the desired properties in an extremely reproducible fashion. Bearing in mind that theranostic nanostructure features are typically tailorable with a high grade of precision during the synthesis stage, the uniformity of the starting material plays a critical role, the reason why bottom-up approaches are generally preferred addressing the production of most reliable tools, and are concurrently more suitable for translational theranostic research ,41,42.In this context, this review displays a comparative overview of the current state of the art, examining the characteristics and potentials of some of the most promising classes of theranostic nanomaterials, aiming to give a panoramic view that might be helpful for the researcher approaching the study of functionalized theranostic nanotools in cancer precision medicine.Noble metal nanoparticles, among which the main family is represented by gold nanoparticles (GNPs), have fascinated researchers in the field of nanomedicine for decades and are being extensively used owing to their well-established biocompatibility and physicochemical properties, which warrant their use in medical applications  15,43,4,443,44.Among all, GNPs are considered as potential candidates for clinical applications in cancer theranostics due to their chemical inertness, the unique optoelectronic properties such as Raman scattering, fluorescence and surface plasmonic resonance (SPR), and the high versatility in terms of surface engineering, thus leading to nanosystems with tunable biological properties  ,46. SPR The numerous varieties of GNPs comprise nanospheres (GNSs), nanorods (GNRs), nanoshells (GNShs), nanocubes (GNCs), nanostars (GNSts), nanocages (GNCgs), nanobipyramids (GNBPys) and many other simple or composite structures ,33. It iDespite GNPs have a huge potential in the biomedical field, the lyophobic nature of these colloids requires a hydrophilic/amphiphilic decoration that can prevent aggregation and increase biocompatibility to enable in vivo application . For thiThe versatility of the synthetic procedures of GNPs, along with the possibility to tailor the optical properties, makes GNPs useful nanomaterials for a plethora of applications in nanomedicine such as drug delivery, biosensing, diagnostics, and theranostics.Due to the extremely heterogeneous nature of cancer, antineoplastic therapies would take great benefit from precise and personalized approaches. The first step to plan a targeted strategy is the better understanding of the target itself from different points of view. Therefore, the accurate visualization of the tumor spatial hindrance, boundaries, and sometimes of the events occurring at the molecular level are the main objectives of nanoparticle-based diagnostics. The high electronic density combined with the SPR phenomenon allows the use of GNPs in assorted bioimaging methods capable of analyzing the tumor milieu from the nanoscopic to the macroscopic perspective.Dark field microscopy (DFM), also called optical imaging, exploits the ability of some contrast agents to cause intense scattering of incident light . GNPs’ hGNPs’ interaction with fluorescent molecules can be exploited in manifold ways to build bioimaging sensors based on FRET (Förster Resonance Energy Transfer). The application of FRET in biosensing is founded on the ability of GNPs to act as energy acceptors of electronically excited fluorescent donors . It has The strong electromagnetic field surrounding the gold nanoparticles allows amplifying the Raman diffusion of molecules conjugated or adsorbed on the noble metal surface, resulting in increased sensitivity of SERS (Surface Enhanced Raman Scattering) imaging. This scattering technique, generally used for the study of bio-nano interactions , was alsIn the two-photon luminescence imaging (TPL) the contrast agent is stimulated simultaneously by two photons emitted by a high-power laser, focused by the objective of a multiphoton microscope. The energy absorbed as a result of stimulation is then emitted as fluorescence . GNPs, aAnother widely used gold-based imaging method is photoacoustic imaging (PA), a high-resolution hybrid technique that allows the visualization of cells and tissues located in “deep” layers combining laser irradiation and ultrasound detection . Due to Gold-based bioimaging can furthermore be performed through photothermal imaging (PTI). GNPs usage in PTI is a direct consequence of their photothermal effect exhibited after irradiation at wavelength matching (or close to) the plasmonic band . As a reAlthough the youngest gold-based imaging techniques are very promising and fascinating due to their high resolution and minimally invasive character, computed tomography (CT) remains among the most reliable imaging methods in tumor detection. Since it is based on the different X-ray attenuation between soft and dense tissues, the administration of a contrast agent that can enhance the visualization of the desired district is often necessary. Their high electron density, along with the possibility to achieve passive and/or active tumor targeting, makes GNPs a quite useful boon in contrast-CT . In virtGold nanoparticles might be powerful allies in tumor precision medicine, a field whose efforts in recent years have been focused on achieving patient-sewn solutions to tailor real-time therapeutic plans. Although the use of GNPs as contrast agents is in itself an advantageous opportunity to detect tumors in a minimally invasive manner, the possibility of availing us of gold-driven bioimaging to guide and gain a simultaneous therapeutic effect appears considerably more appealing. Although numerous examples of theranostic gold have already been reported in the literature, herein will be provided a slice of recent research focused on in vivo applications of GNPs image-guided phototherapy (IG-PT).Jang et al. proposed multitherapeutic FRET nanoplatforms for the photothermal/photodynamic (PT/PD) treatment of SCC7 tumor xenografts. PEG thiol/peptide-coated GNRs were used to electrostatically load the fluorescent and photoactive molecule AlPcS4 so as to achieve gold-driven PT or PDT after 810 nm or 670 nm laser irradiation, respectively . The detThe value of IG-PT is not only limited to the real-time monitoring of the treatment, as it also offers the possibility of using predictive models that allow regulating treatment regimens according to the patient conditions in order to model the therapy in a personalized manner. This concept has been interestingly demonstrated by Von Maltzahn et al. who proposed the combination of GNRs CT imaging and computational sciences to predict the heat distribution in cancer . In theiAlthough IG-PT can lead to efficient in vivo tumor ablation, in view to obtain more energetic treatments with reduced risks of cancer recurrence, gold PT can be reinforced by supplementary antineoplastic strategies. A fascinating example can be found in a very recent work of Dai et al. Here, chitosan coated GNRs with highly controlled architectures were employed to synergistically treat breast cancer xenografts by combining PT and gene therapy. The biodistribution of the nanosystems, accomplished by PA imaging, was used as guidance to select the photothermal settings, achieving photothermal imaging-guided PT. Data furthermore showed that the efficacy of gold PT in slowing down the tumor progression was enhanced by gene therapy, reaching a considerable reduction of tumor volumes .The use of GNPs along with other contrast agents was also explored to obtain a multi-modal IG-PT. By hybridizing gold-based nano constructs, researchers managed to produce platforms that can rely on different kinds of imaging approaches for the detection and the personalized therapy of solid tumors. In recent times, Li et al. proved that by encapsulating indocyanine green into the silica coating of gold nano bipyramids, dual-mode imaging (fluorescence/PA) of cancer can be realized. In this study, fluorescence acquisitions were merged with photoacoustic outputs to establish the most convenient PT time point as a function of the biodistribution data observed . PhotothThe examples reported are only a few among the many promising results realized in gold IG-PT. The possibility to combine the optoelectronic properties of GNPs with the advantages of passive and active targeting might lead to further progress in this field. Moreover, the hybridization of GNPs with other contrast agents, as well as the chance to use gold nanoparticles as reliable drug delivery systems, might pave the way to multi-modal theranostic tools for the image-guided multi-therapy of cancer.3O4  oxide nanocrystals that have aroused great interest and exceptional achievements in targeted drug therapy . T. T1-weigreceptor .moleculCarbon nanodots (CDs), discovered in the early 21st century, are 0D carbonaceous nanomaterials smaller than 10 nm, typically composed by carbon, oxygen, and hydrogen. CDs emerge as a promising nanoplatform for different applications, including drug delivery , bioimag2/sp3-hybridized carbons . I. I2 hybrmembrane ,197,198.Remarkable features of GO are mainly due to its chemical modification to give rise to nanocomposite materials with a combination of properties owing to various entities such as polymers and metal nanoparticles  ,200,201.8-related signaling pathways [50 being up to 12 times lower than that observed for healthy fibroblasts. Other polymers has been employed to improve colloidal stability of GO, its biocompatibility and to confer thermos/stimuli responsiveness —PNIPAM) [N-isopropylacrylamide) (PNIPAM) via click chemistry, thus loading by π–π stacking interactions a water-insoluble anticancer drug, camptothecin (CPT), with a superior loading capacity of 15.6 wt % [block-poly(propylene glycol)-block-poly(ethylene glycol) moieties and maltodextrin so as to load a high amount of poorly soluble anticancer drugs such as ellagic acid by π–π stacking adsorption [Luo et al. have indeed demonstrated that PEGylated nano-GO sheets trigger massive cytokine responses in peritoneal macrophages, despite not being internalized. They also showed that GO preferentially adsorbs onto cell membranes, thereby amplifying interactions with stimulatory surface receptors and provoking cytokine secretion by enhancing integrin βpathways . PEGylatpathways . GO-PEG-—PNIPAM) ,215,216.5.6 wt % . Kakran sorption . Using tOn the other hand, metal/GO nanocomposites provide the proper combination of magnet ,220,221,Graphene oxide-based nanosystems are a class of biomaterial amenable of many functionalizations, since GO nanosheets have reactive polar surface groups , which make them available for several conjugation strategies. The potential combination of many biological and physicochemical properties due to the chemical versatility of this nanomaterial have attracted unprecedented attention in theranostics. However, whether GO and parent compounds are cytocompatible, or they may elicit a toxic effect both at cellular and tissue levels, remains open to debate.−1 body weight for 14 days. Besides, even if a lot of in vitro effects of GO have been reported using 2D cultures of fibroblasts [Many works have shown that GO-based nanocarriers do not exhibit cytotoxicity, and thus they are commonly considered as safe materials. Recently, researchers have made efforts to systematically study the GO cytotoxicity both in vitro and in vivo . They teroblasts , endotheroblasts  and neurroblasts , there aOn the contrary, Wang et al. suggest that when GO is explored for in vivo applications in humans, its biocompatibility should be carefully considered because it can exhibit dose-dependent toxicity to cells and animals, such as inducing cell apoptosis and lung granuloma formation . In addiIn recent years, the hypothesis of GO degradation upon in vivo administration has shed light on the possible fate of GO after biodistribution in the human body, thus spicing up the debate on the rule of GO in real world medical applications. Currently, research examining the biodegradability of GO sheets is limited to a few studies . This thGraphene oxide has been used to design advanced nanomaterials for biosensing applications because of the possibility to adsorb both electron donor and electron acceptor dyes along the surface plane, thus making GO a suitable slab for efficient long-range photo-quenching. Indeed, Resonance Energy Transfer (RET) is a mechanism of energy transfer between a donor chromophore transfers energy to an acceptor through non-radiative dipole–dipole coupling, which requires spatial proximity. Hence, GO can be assumed as a superior acceptor for DNA-containing fluorescent probes in RET. The bases of this mechanism is that these probes can be caught by the GO surface by π–π stacking, which leads to fluorescence quenching by RET and then, after the DNA probes bind to the target sequence, fluorescence is switched on due to separation of the DNA from the GO surface in situ .Very promising applications of functionalized GO probes reported so far include their use in protein and DNA sensing applications ,236. WanIn another study, GO has been used as peptide biosensor exploiting the GO complexing abilities toward a pyrene-RGD conjugate . CooperaUtilizing GO as a biosensor tool in liquid biopsy of cancer has effectively improved the sensitivity and specificity of biosensors for cancer detection. Mei Heb and co-workers have modified GO nanosheets with a layer of polydopamine and used protein G to immobilize antibodies on GO for exosome capture useful for liquid biopsy applications .Various reports proposed elsewhere show that GO can be diligently functionalized to be employed not only for the selective delivery of anticancer agents into tumors, but also for mini-invasive photo-induced therapy of solid tumors such as phototherapy (PTT) and photodynamic therapy (PDT). Combinational strategies applying PTT and PDT at once have been extensively studied, while simultaneously exciting with a single laser in the biologically transparent window (NIR wavelength) remains challenging. Ideally, GO can act as a photosensitizer aimed at achieving cell death through the generation of reactive oxygen species (ROS) inside cancer cells. This will result in localized oxidative photodamage, consisting in the oxidation of cellular bio-elements, including nucleic acids, lipids, and proteins, thus leading to selective cytotoxicity mainly due to severe alterations in cell signaling cascades and gene expression regulation ,241,242.2 hybridization of graphene comb-like structures and high NIR photothermal conversion. BSA provided high stability under physiological conditions and high cytocompatibility. In particular, they showed that these nanomaterials had no cytotoxic effect on the MCF-7 cell lines at concentrations up to 40 mg mL−1. The resulting nanosized BSA-GO conjugate displayed PA and ultrasonic dual-imaging potential useful for image-guided PTT in living mice [However, the application of GO in cancer theranostics is mostly precluded owing to the lack of specific contrast properties. As a consequence, many attempts have been made to exploit GO/metal and GO/CDs nanocomposites for combined multimodal diagnosis and photothermal therapy. In principle, this peculiar theranostics application implies high selectivity and efficacy through image-guided ablation techniques  ,248,249.ing mice . In anoting mice . Surfaceing mice . They fuVarious kinds of metal- and carbon-based nanoparticles or hybrid nanomaterials have been designed and developed, and among these are some expected to provide significant improvements in the field of precision cancer therapies, diagnosis and monitoring of solid tumors. In this review, we systematically disclose the potential applications of the most advanced gold-, iron oxide superparamagnetic-, graphene oxide- and carbon nanodots-based theranostic agents useful in precision and personalized cancer therapy as well as in bioimaging and biosensing applications. Recent works have shown that well-designed nanosystems with tunable interfacial, physical-chemical and optical features could be obtained in order to display multimodal imaging and selective non-invasive eradication of tumors. There is also a growing interest in developing photoactivatable theranostic nanosystems for even-smarter cancer therapy and imaging. Each type of nanosystem seems to have some characteristic advantage, but it might be noticed that better results could be obtained by designing multimodal nanohybrid “machines” capable in a single platform of imaging, monitoring and sensing tumors  while treating cancer cells. This promises to predict therapeutic responses together with a selective cancer cells eradication under continuous monitoring. Overall, hybrid nanotheranostics represent the future of personalized cancer treatments and require more in-depth knowledge of basic information about tissue/nanomaterial interactions to develop safe nanomedicines. Besides, further efforts should be made to design smart nanomaterials with well-established architectures  using highly tunable, industrially scalable and cost-effective synthetic routes to overcome the existing regulatory barriers that have limited their translation into the clinic.


Augmentation with second-generation antipsychotics (SGAs) represents an evidence-based psychopharmacotherapeutic strategy recommended in case of insufficient response to the first-line antidepressant (AD) treatment in major depressive disorder (MDD). Comparative evidence regarding efficacy and prescription preferences of the individual SGAs is scarce.In the scope of this European, multi-site, naturalistic cross-sectional investigation with retrospective assessment of treatment outcome, we compared sociodemographic and clinical characteristics of 187 MDD patients receiving either quetiapine (n = 150) or aripiprazole (n = 37) as augmentation of their first-line AD psychopharmacotherapy.Comorbid posttraumatic stress disorder and diabetes were significantly associated with aripiprazole augmentation in our primary and post-hoc binary logistic regression analyses. Furthermore, we identified an association between aripiprazole co-administration and the presence of additional psychotic features, higher rates of AD combination treatment, and a longer duration of psychiatric hospitalizations during the lifetime, which, however, lost significance after correcting for multiple comparisons. Regarding treatment outcome, we found a trend of higher response rates and greater reductions in severity of depressive symptoms in MDD patients dispensed quetiapine.Factors associated with a more chronic and severe profile of MDD seem to encourage clinicians to choose aripiprazole over quetiapine, that was, however, administered in the majority of our MDD patients, which might reflect the current approval situation allowing to prescribe exclusively quetiapine as on-label augmentation in MDD in Europe. Given the retrospective assessment of treatment response, the markedly smaller proportion of patients receiving aripiprazole augmentation generally showing an unfavorable disease profile, and the partially heterogeneous statistical robustness of our findings, further studies are required to elaborate on our observation and to generate unambiguous recommendations regarding the choice of first-line SGA augmentation in MDD. In line with recommendations of most clinical practice guidelines (CPG), second-generation antipsychotics (SGAs) are frequently administered as additional psychopharmacotherapeutic approach in case of insufficient treatment outcome with the first-line antidepressant therapy in major depressive disorder (MDD). However, there is a paucity of evidence revealing which individual SGA suits best for a given patient. Our naturalistic, cross-sectional multicenter data of 187 MDD patients revealed that the majority (n = 150) was prescribed quetiapine, which was associated with a more beneficial disease profile. Concurrently, a more chronic and severe illness profile, especially the presence of psychiatric and somatic comorbidities and trend-wise additional psychotic features, higher depression severity, the requirement of polypharmacy, worse treatment outcome during the current MDE, as well as a longer lifetime-period spent in psychiatric inpatient-care, may represent factors that encourage clinicians to prefer aripiprazole. The aforementioned contrasts may serve as basis for future longitudinal research aiming at individually tailored MDD treatments.Approximately two-thirds of the patients suffering from major depressive disorder (MDD) fail to adequately respond and/or achieve remission with their first-line antidepressant (AD) psychopharmacotherapy and require additional treatment strategies . The admThe XR formulation of quetiapine has not only been shown to be potent in augmenting first-line AD therapy in MDD  but has In light of the dearth of studies comparing augmentation of the first-line AD psychopharmacotherapy with either quetiapine or aripiprazole in MDD, we sought to enrich the existing evidence by specifically addressing 2 clinically relevant research questions in the course of the present study. Firstly, we aimed to elucidate factors potentially mediating the clinicians’ decision of prescribing either quetiapine or aripiprazole augmentation by systematically comparing the socio-demographic and clinical characteristics of MDD patients dispensed either compound. Our second goal was to elucidate differences in treatment outcome patterns related to the prescription of quetiapine or aripiprazole, respectively.The present work represents a secondary analysis of an international, multicenter, observational, cross-sectional, and non-interventional study with a retrospective evaluation of treatment outcome that was performed by the European Group for the Study of Resistant Depression (GSRD) . These pThe recruitment of adult, male and female in- and outpatients was performed in both university as well as non-academic clinical routine centers in 8 European countries that are mentioned above. Patients who were eligible to study participation signed written informed consent after a thorough explanation of the study procedures. A present single or recurrent major depressive episode (MDE) occurring in the course of MDD that was diagnosed based on the DSM-IV-TR criteria  and reprSocio-demographic, clinical, and treatment patterns of MDD patients were evaluated exclusively by experienced and specifically trained psychiatrists. In the course of this comprehensive clinical assessment, medical records of the patients were considered and the Mini International Neuropsychiatric Interview  was perfBased on the GSRD staging model for treatment outcome, the MADRS total score change (retrospective MADRS – cMADRS) was gathered after at least 1 adequate AD trial administered at sufficient daily dosages for at least 4 weeks . BrieflyAll eligible MDD patients derived from a subject pool of the GSRD  were subP ≤ .05, binary logistic regression analyses with the relevant independent variables were conducted to analyze their relation to the employed augmentation treatment with either quetiapine or aripiprazole representing the dichotomous dependent variable, whereby the recruitment center served as covariate  in ovariate .In total, the analyzed sample included 187 MDD patients, whereby 150 (80.2%) received augmentation with quetiapine and 37 (19.8%) with aripiprazole, both of which were administered together with the first-line AD psychopharmacotherapy . The socP = .003) and diabetes mellitus  occurred more frequently in individuals with aripiprazole augmentation treatment who were hospitalized in psychiatric inpatient units longer during their lifetime . During the current MDE, additional psychotic features appeared more frequently in MDD patients augmented with aripiprazole  who were also administered an overall higher number of AD agents in the course of an AD combination treatment . In terms of treatment outcome, a trend-wise higher proportion of responders to AD treatment was identified in MDD patients receiving quetiapine augmentation (23.3% vs 10.8%), while resistance to AD treatment occurred more commonly in MDD patients augmented with aripiprazole  was observed in the group of patients augmented with aripiprazole.Compared with MDD patients treated with quetiapine augmentation, comorbid posttraumatic stress disorder . Because the aforementioned clinical characteristics were repeatedly related to disease severity and chronicity and, hence, TRD  and a higher number of MDEs during the lifetime (4.1 vs 3.2 in cases of augmentation with quetiapine), even though the latter finding did not reach statistical significance (nce, TRD  and the nce, TRD , aripiprConsidering comparable international evidence, it is relevant that investigations directly contrasting quetiapine and aripiprazole have not yet been executed in MDD. Results derived from a network meta-analysis showed very similar AD potency and tolerability of the examined agents, whereby quetiapine performed slightly better regarding treatment outcome but had higher discontinuation rates . In termSummarizing the methodological strengths and limitations in detail, the real-world patient population derived from in- and outpatient units of academic as well as non-academic centers in 8 European countries should be highlighted. The resultant heterogeneous clinical manifestations of MDD including the presence of additional melancholic, psychotic, atypical, and/or catatonic features, suicidality, psychiatric and somatic comorbidities, and the varying illness severity and course ranging from single to recurrent MDEs with mild, moderate, or severe extent of current depressive symptoms are very much in contrast to those of MDD patients investigated in the course of RCTs. Such clinical heterogeneity might best possibly reflect the international everyday routine and, hence, represents a major strength. Potential cross-site differences that might have arisen in the course of recruitments in different European countries and cannot be fully ruled out were, however, considered in our statistical analyses. It should be noticed in this context that the present large multi-site project conducted by the GSRD  was not To warrant unrestricted comparability with already existing evidence, the psychopharmacotherapeutic terminology used in the present work is based on the traditional indication-based nomenclature that is, however, increasingly being replaced by a new classification system driven by the pharmacological profiles of the individual substances. According to the so-called neuroscience-based nomenclature that was developed to support rational and lucid prescribing with the aim to increase therapeutic adherence , the terMost importantly, the retrospective assessment of treatment outcome performed in the course of a cross-sectional investigation should be critically considered because it is less accurate than prospective and longitudinal approaches. However, it is essential in this context that supporting international data, showing that MDD patients are able to adequately and consistently recall and report their previous depressive symptoms even 2 years thereafter , exist. According to the present results, factors associated with a more chronic and severe profile of MDD reflected by the presence of psychiatric and somatic comorbidities and trend-wise additional psychotic features, a higher extent of depressive symptoms, the requirement of more complex psychopharmacotherapy, and worse treatment outcome during the current MDE, as well as a longer time-period spent in psychiatric inpatient-care during the lifetime, seem to encourage clinicians to choose aripiprazole over quetiapine. Theoretically, the fact that quetiapine, which was administered in the majority of our MDD patients and was generally linked to rather beneficial disease and treatment outcome patterns, currently represents the only SGA that is approved by the European Medicines Agency for augmentation in MDD might have moderated European clinicians’ readiness to enrich their psychopharmacotherapeutic armamentarium with aripiprazole, a substance beyond the current approval, preferably in MDD patients who are more severely ill. Although existing evidence similarly supports the employment of aripiprazole in TRD on the one hand , 2019, tGiven the mixed results in general and considering that the most current CPGs recommend augmentation with SGAs as first choice in case of insufficient treatment response in MDD  but do n


We found that only BDNF was consistent with the DNAm changes detected in four independent studies for MDD. It was positively correlated with clinical improvement in MDD. To develop better predictive DNAm factors for drug response, we also discussed future research strategies, including experimental, analytical procedures and statistical criteria. Our review shows promising possibilities for using BDNF DNAm as a predictor of antidepressant treatment response for MDD, while more pharmacoepigenetic studies are needed for treatments of various diseases. Future research should take advantage of a system-wide analysis with a strict and standard analytical procedure.Pharmacotherapy is the most common treatment for schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). Pharmacogenetic studies have achieved results with limited clinical utility. DNA methylation (DNAm), an epigenetic modification, has been proposed to be involved in both the pathology and drug treatment of these disorders. Emerging data indicates that DNAm could be used as a predictor of drug response for psychiatric disorders. In this study, we performed a systematic review to evaluate the reproducibility of published changes of drug response-related DNAm in SCZ, BD and MDD. A total of 37 publications were included. Since the studies involved patients of different treatment stages, we partitioned them into three groups based on their primary focuses: (1) medication-induced DNAm changes ( A majorreatment . This ilPharmacogenetic approaches for guiding the treatment of psychiatric disorders has been a rapidly expanding area of research in the last two decades . The maiEmerging evidence suggests that epigenetic marks could be used as a predictor of drug response for psychiatric disorders . DysreguThe recent advent of interest in pharmacoepigenetics of psychiatric disorders is an alternative research avenue. The epigenetic modification known as DNA methylation (DNAm), one of major epigenetic modifications, is the product of the interaction between genetic variants and environmental influence, and for this reason might be a better predictor of treatment outcomes . MeasuraWe systematically reviewed the literature on DNAm and drug response in SCZ, MDD, and BD to determine if epigenetic markers have produced any reproducible finding as predictors of drug response. In this review, we focused on studies providing information about the effect of medications on DNAm and the utility of DNAm as a predictor of drug treatment for major psychiatric disorders . First, We systematically reviewed published studies that examined DNAm in relation to drug response in SCZ, BD, or MDD, using the PubMed, Web of Science, and MEDLINE with the following search builder: (((((((pharmacogenetic) OR pharmacogenomic) OR pharmacoepigenetic) OR drug response) OR treatment) OR drug efficiency) OR #DRUG#) AND ((((DNA methylation) OR methylation) OR epigenetic) OR EWAS) AND (#DISORDER#). #DRUG# is the major drug for each disorder: antipsychotic, mood stabilizer, lithium, antidepressant, selective serotonin reuptake inhibitor (SSRI) and selective norepinephrine reuptake inhibitor (SNRI). #DISORDER# is one of the major psychiatric disorders: SCZ, BD and MDD. The inclusion criteria were the following: (1) published in English before April 2020; (2) assessed drug response on DNAm levels; (3) sample size larger than 10. Studies on animal and cell culture models were excluded. We discarded one study testing for drug-related co-methylation modules for BD, since it did not directly compare the efficacy of the individual drugs and was incompatible with the other studies. The literature selection followed the standard by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) .n = 7), BD (n = 6), MDD (n = 18), and cross-disorder studies . Since the studies involved patients of different treatment stages, we partitioned them into three groups based on their primary focuses (p < 0.05) that were consistent in more than one independent study. We also evaluated whether the results of candidate gene studies could be reproduced in genome-wide studies.We included 37 publications about drug response-related DNAm in SCZ, BD, and MDD . Studies focuses : (1) medPharmacoepigenetics research in psychiatry focuses on the effects of treatments on DNAm and their potential influences on treatment response. The main aim of pharmacoepigenetics is the identification of DNAm of specific genes that are associated with treatment outcomes of psychiatric disorders, with the ultimate goal of translating this information into strategies that can support personalized medicine.DNA methylation is the epigenetic modification by which methyl groups are added to DNA nucleotides, primarily cytosine, and adenine. DNAm is thought to have a prominent influence on the structure and functions of DNA, particularly in the regulation of gene expression. However, DNAm regulates gene expression differently according to its genomic context. Previous studies revealed that DNAm levels of CpG sites near the transcription start sites could repress gene expression levels, while DNAm levels of gene body CpGs could activate the expression of their target genes . ConflicTissues from postmortem samples, preserved clinical specimens from humans, can be used to study DNAm. For study pharmacoepigenetics for psychiatric disorders, peripheral tissues, such as blood, saliva, and buccal cells, are useful for developing clinically informative biomarkers. Psychiatric disorders are considered primarily a brain dysregulation. Therefore, we prefer to investigate genomic or epigenomic features in peripheral tissues that are similar to brain. Given that DNAm signals can be tissue-specific, it is important to establish the pros and cons of different types of tissue for investigation .in vivo human tissue for clinical application.Several studies investigated correlations of DNAm in blood and multiple regions of the brain, with inconsistent results . Studies® Array (HM27K) (® HumanMethylation450 BeadChips (HM450K) (® MethylationEPIC BeadChip (EPIC)  , Infiniu(HM450K) , 2014 anp (EPIC) , have bep (EPIC) . Whole-gp < 0.05). These candidate gene studies only focus on a limited number of genes, based on their established association with a disorders’ pathogenesis or hypothesized relation to response to drug treatment. Although previous candidate gene studies have identified target genes that may predict or reflect the clinical effect of drug response, most studies had limited statistical power, a concern especially for dense array data. Because of this limitation, the candidate gene method can provide little comprehensive understanding regarding the mechanism of action of drugs, but can only confirm previous knowledge or test relevance of a particular gene methylation  reached nominal significance , the use of a previously validated protocol of Linear Interspersed Nuclear Element 1 (LINE- 1) and the use of restriction enzymes . HoweverThe included pharmacoepigenetic studies were divided into three types: (1) medication-induced DNAm changes; (2) relationships between DNAm and clinical improvement, and (3) comparison of DNAm status across different medications . In thisThe changes of DNAm after a period of drug treatment were examined in studies comparing DNAm changes between pre- and post-treatment, which could reflect the effects of drug treatment directly. There were eight studies (p < 0.05). Of those five, only brain-derived neurotrophic factor (BDNF) was analyzed for MDD patients in 2 independent studies  that were significantly differentially methylated after 1 year of treatment with clozapine for 21 SCZ patients based on blood samples, using HM450K assays . Patients are separated into remission, non-remission, response or non-response based on changes of scale scores. Remission, the symptom of virtual absence of disease, is the goal of treatment . Responsp < 0.05). Only BDNF . Another study compared the DNAm changes in blood between responders and non-responders with 8 weeks of escitalopram treatment for 177 MDD patients, using the EPIC assays (p < 0.05) sites with nominally significant differences between responders and non-responders, but none were significantly different after correction for multiple comparisons. Since these two drugs, paroxetine and escitalopram, are both SSRIs, we compared the reproducibility of the nominally significant results between these two studies. We found that none of the significant loci found to be associated with paroxetine could be replicated in the escitalopram treatment analysis. This failure at replication has to be considered in the context of differences in the platforms used, limitations in statistical power, and the 303 escitalopram-related sites detected by EPIC analysis were not included in HM450K assays. In evaluating whether results of candidate gene studies for MDD could be reproduced in genome-wide studies, we did not detect any overlap.Three studies used a genome-wide approach to evaluate the correlation between baseline DNAm and clinical improvement. C assays . They idWe did find one study involving schizophrenia, which evaluated the correlation between DNAm changes in blood after 1-year of clozapine treatment and changes of PANSS scores for 21 SCZ patients . They foMajor medications for SCZ, BD, and MDD included antipsychotics, mood stabilizers and antidepressants. Antipsychotic medications are one of the primary treatments for the acute phases and the long-term prevention of recurrence for SCZ patients . Mood stIn this review, we evaluated 14 studies that compared DNAm after treatment with different medications, including 11 studies that used a candidate gene method and 3 that analyzed global methylation . We founInsufficient statistical power is a major challenge for pharmacoepigenetic studies in psychiatric disorders. The cost of using methylation panels, the high cost of clinical trials where drug therapy is controlled along with diverse drugs used across studies, and the large number of sites for methylation investigation, together conspire to limit sample sizes and statistical power to detect effects of interest. These factors limit our ability to evaluate reproducibility of current pharmacoepigenetic findings. Although several interesting associations between DNAm and drug treatment outcomes occurred in relatively small sample sizes, findings from these studies should be considered preliminary until replication in a larger sample size is pursued. So, given that collecting clinical data with a large-sample is challenging and costly, small-sample studies remain the focus of most investigators in this area via hypothesis-generating studies.∗D project  for insomnia or some side effects, which themselves can also exert epigenetic effects.Choice of duration for drug treatment trials is also important, yet variable across prior work. Treatment-resistance, non-adherence, late-emerging side effects and relapse are frequent events in clinical practice, some of which are seen only in longer term protocol participation. Aside from these factors, DNAm status is dynamic and can be affected by various environmental events during treatment that are unrelated to drug effects .in vivo assessment of brain physiology and treatment  . These mCandidate gene studies contributed to answering specific questions in biology, but they do not provide system-wide information. In this review, we noticed that the assessed candidate genes were generally not the top signals in genome-wide studies, and could not even reach a genome-wide significance. The genes that change the most between pre- and post-treatment, or are most strongly associated with clinical improvement, remain to be discovered. Also, pathway-based research rather than gene-based approaches may be more efficient. Different genes that converge on the same pathway may each contribute modestly, but together may robustly co-influence the functional abnormality. Therefore, system-wide research could provide better biomarkers than individual candidate genes.Regulation of drug responses occurs at various levels including genetics, epigenetics, transcriptional, and protein modification, and also involves many functional pathways . To dateStrict statistical criteria and sufficient attention to covariances are critical for reducing false-positive rates. DNAm status is not a constant like DNA sequence are therefore is subject to influences from more confounders. Further, approaches for DNAm assessment can be easily confounded by technical artifacts. DNAm levels are also affected by factors including age , sex Ma, circadiMethylation profiling could be easily confounded by batch effects. Systematic error can be introduced when samples are processed in multiple batches , which cannot be eliminated unless all samples are run in a single batch . It is eConsidering the influence of demographic information  is also important. In this review, nearly 49% of studies did not control for covariates in their analyses. When there was a correction for covariates, typically only sex and age was controlled. Since DNAm is highly cell-type-specific, cellular heterogeneity of blood may skew DNAm patterns, influencing findings in drug response for psychiatric disorders . All stup < 0.05 to be the threshold for statistical significance, even when multiple genes or CpG sites were tested. We noticed that only 59% of the previous studies did the correction for multiple testing. False-positive results likely occurred in published work (Additionally, strict and consistent statistical criteria for defining significance need to be applied that correct for multiple comparisons. Most published studies considered a nominal hed work .In this review, we found that only DNAm of BDNF was consistently related to clinical outcomes, an effect observed in four independent studies of MDD patients. Although pharmacoepigenetic studies to date are still limited in number and sample size, preliminary studies to date that evaluated changes in drug response-related DNAm across major psychiatric disorders provide evidence for an intriguing possibility of predictive DNAm biomarkers for drug treatment. A system-wide study using strict analytical and statistical procedures in large multisite studies may best advance identification of useful DNAm predictors for drug response in psychiatric disorders.JZ, ML, XW, and YH did the manuscript collection. JZ did the manuscript writing. JZ and ML designed and generated the manuscript figures and tables. YX, JS, and RK helped with manuscript writing. CC and CL helped with study design and manuscript writing. All authors contributed to the article and approved the submitted version.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.


Extended knowledge of pathophysiological mechanisms in cancer-related VTE may lead to targeted prevention in the future.Even though unprovoked VTE is associated with occult cancer, extensive cancer screening in these patients have not lead to detection of earlier stage cancers or improved prognosis.Recent RCTs comparing LMWHs and DOACs for treatment of cancer-related VTE have shown that DOAC treatment had less VTE recurrences and higher incidences of major bleedings. The clinical implications are uncertain.Venous thromboembolism (VTE) is often the first sign of cancer, and cancer patients have a 4-7 fold higher risk of VTE compared to the general population. The VTE risk in cancer is dependent on cancer type and severity. Extended knowledge on mechanisms of cancer-related VTE would potentially lead to targeted prevention. Even though the underlying mechanisms of thrombosis risk in cancer is only partly known, tissue factor (TF), cancer cell-derived microvesicles (MV), and podoplanin, a sialoglycoprotein upregulated in several cancer cells able to induce platelet activation, are important actors in the pathophysiology of cancer-related VTE. As 5% to 10% of unprovoked VTE events are diagnosed with cancer during the following year, it has been assumed that extensive cancer screening would lead to earlier cancer diagnosis and improved prognosis. However, many studies have failed to show that extensive screening leads to detection of earlier stage cancers and improved cancer prognosis. Furthermore, clinical scores have been developed, but are not yet validated for clinical practice. Currently, guidelines recommend LMWHs for treatment of cancer-related VTE. Two independent RCTs have recently reported less VTE recurrences and higher incidences of major bleeding by DOACs compared to LMWHs for treatment of cancer-related VTE. The clinical implications are uncertain.


Pronounced differences across individuals (interpatient variability) and cell–cell heterogeneity within a tumor  severely hinder effective brain tumor treatment. To overcome these challenges, a personalized precision medicine approach that considers the uniqueness of an individual patient’s tumor and its cellular composition is required. A systems biology approach is needed to develop a multiscale understanding of the mechanistic drivers of disease etiology and progression to realize this vision. A systems-level understanding of disease characteristics can facilitate precise patient stratification into clinically meaningful subtypes and inform on potential druggable targets that can enhance treatment. Here, we synthesize and review various methodologies that can be integrated into a framework designed to achieve a personalized precision medicine approach for treating brain tumors. Finally, we provide a practical example in the context of analyzing an individual glioblastoma (GBM) patient at various stages of disease progression.Brain tumors are among the most lethal tumors. Glioblastoma, the most frequent primary brain tumor in adults, has a median survival time of approximately 15 months after diagnosis or a five-year survival rate of 10%; the recurrence rate is nearly 90%. Unfortunately, this prognosis has not improved for several decades. The lack of progress in the treatment of brain tumors has been attributed to their high rate of primary therapy resistance. Challenges such as pronounced inter-patient variability, intratumoral heterogeneity, and drug delivery across the blood–brain barrier hinder progress. A comprehensive, multiscale understanding of the disease, from the molecular to the whole tumor level, is needed to address the intratumor heterogeneity resulting from the coexistence of a diversity of neoplastic and non-neoplastic cell types in the tumor tissue. By contrast, inter-patient variability must be addressed by subtyping brain tumors to stratify patients and identify the best-matched drug(s) and therapies for a particular patient or cohort of patients. Accomplishing these diverse tasks will require a new framework, one involving a systems perspective in assessing the immense complexity of brain tumors. This would in turn entail a shift in how clinical medicine interfaces with the rapidly advancing high-throughput (HTP) technologies that have enabled the omics-scale profiling of molecular features of brain tumors from the single-cell to the tissue level. However, several gaps must be closed before such a framework can fulfill the promise of precision and personalized medicine for brain tumors. Ultimately, the goal is to integrate seamlessly multiscale systems analyses of patient tumors and clinical medicine. Accomplishing this goal would facilitate the rational design of therapeutic strategies matched to the characteristics of patients and their tumors. Here, we discuss some of the technologies, methodologies, and computational tools that will facilitate the realization of this vision to practice.  Brain tumors are difficult to treat because inter-patient and intratumoral heterogeneity are particularly pronounced. Moreover, the blood–brain barrier (BBB) presents an impediment to drug delivery.Technological advancements now allow robust profiling of genomic, epigenomic, transcriptomic, proteomic, and metabolomic changes in brain tumors.In parallel, efficient computational approaches to probe multi-modal data extensively and to infer regulatory mechanisms distinguishing tumor cell subpopulations have fostered novel intervention strategies  to treat brain tumors effectively. N-of-1 therapy selection.To address the current gaps preventing the translation of these advancements into clinical practice, a procedural framework that incorporates sensitive diagnostic and prognostic tests and computational methodologies must be developed to analyze clinical molecular profiles, enable relevant patient stratification, and identify appropriate treatments for Brain tumors contribute to tens of thousands of deaths per year, with an estimated 17,760 deaths in 2019 in the U.S.A. . The prointratumoral heterogeneity and inter-patient variability. The latter is sometimes inappropriately called “inter-tumor heterogeneity” fluoro-2-deoxy-d-glucose (18F-FDG), which cannot be metabolized and thus accumulates in cells . U. U184]. ®) or Visium (10x Genomics) would provide spatial transcriptomic information that would help identify biomarkers or other potentially targetable, spatially distinct, transcriptional phenotypes. Ultimately, integrating single-cell technologies with computational methodologies to infer regulatory network mechanisms, identify tumor-cell states, and predict drug–target combinations for a patient offers an approach that would inform brain tumor treatment on an individual patient level.As this framework is a proof-of-concept, we acknowledge that there are opportunities for refinement. For instance, the lead-time in generating PDX models may not be suitable for some patients due to the rapid progression of GBM. Despite this issue, PDX models are still of value for multiple reasons. Beyond the fact that they are patient-specific and capture the effects of tumor architecture, data generated from multiple PDX models from multiple patients would provide valuable insight into what potential tumor-cell states arise post-treatment and what potential targets associated with these states may be manipulated to augment clinical treatment for future patients that may exhibit similar tumor cell subpopulations. Another gap in this framework is the inability of immunocompromised PDX models to capture the effects of immune system interactions on tumor cell evolution. Immunocompetent mouse models do exist, however, and can mimic various aspects of the brain tumor–immune response spectrum . The useSystems approaches have facilitated the discovery of new insights into the complexity and potential vulnerabilities in brain tumors. While many challenges remain and require a concerted effort across multiple disciplines and institutions, an integrated systems approach can provide immediate benefits to those suffering from brain tumors. Given the improvements in accuracy and precision of HTP technologies and advances in computational and experimental modeling approaches, improving treatment for brain tumors is an achievable goal. Creating an environment where in-depth molecular profiling and longitudinal assessment of a patient’s response to drugs would foster the generation of valuable insight into the molecular underpinnings of drug distribution, tumor response kinetics, and tumor progression. We remain optimistic, encouraged by the continual technological advances made and insights gained about the mechanisms underlying brain tumor structure and pathology, which will ultimately enable longer-term management of these tumor types.


Drug resistance is the most significant causes of cancer chemotherapy failure. Various mechanisms of drug resistance include tumor heterogeneity, tumor microenvironment, changes at cellular levels, genetic factors, and other mechanisms. In recent years, more attention has been paid to tumor resistance mechanisms and countermeasures. Nanomedicine is an emerging treatment platform, focusing on alternative drug delivery and improved therapeutic effectiveness while reducing side effects on normal tissues. Here, we reviewed the principal forms of drug resistance and the new possibilities that nanomaterials offer for overcoming these therapeutic barriers. Novel nanomaterials based on tumor types are an excellent modality to equalize drug resistance that enables gain more rational and flexible drug selectivity for individual patient treatment. With the emergence of advanced designs and alternative drug delivery strategies with different nanomaterials, overcome of multidrug resistance shows promising and opens new horizons for cancer therapy. This review discussed different mechanisms of drug resistance and recent advances in nanotechnology-based therapeutic strategies to improve the sensitivity and effectiveness of chemotherapeutic drugs, aiming to show the advantages of nanomaterials in overcoming of drug resistance for tumor chemotherapy, which could accelerate the development of personalized medicine. The biggest barrier to cancer therapy is the inevitable emergence of drug resistance. Drug resistance can be divided into two categories according to the behind factors: primary and secondary . PrimaryConsidering the drug resistance is a complex mechanism, many dexterous solutions appeared in anticancer therapies to overcome drug resistance and increase the efficacy of treatment. Among these, nanomaterials as a promising drug delivery are being investigated for solving several forms of drug resistance . CompareHere, in this review, we mainly described the mechanisms of drug resistance and focused on recent innovation of dexterous and sophisticated nano-strategies in overcoming drug resistance, providing ideas for tumor chemotherapy and related combination therapies .The mechanism of drug resistance at tumor tissue level is extremely complicated. Commonly, tumor heterogeneity, tumor microenvironment (TME), drug transporter and multidrug resistance, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and tumor metastasis are known as the major drug resistance factors , which cHeterogeneity is a distinct characteristic of tumor tissues from normal tissues and is represented by different morphological profiles. The heterogeneity may cause discrepant distribution of tumor cell subpopulations across different regions of the primary tumor  or variations in the molecular makeup of a single lesion over time . Cancer cells have the powerful capacity of self-renewal and differentiation, which give rise to abundant tumor types causing heterogeneity of the tumors . The driThe reprogramming of cellular metabolism is a common feature of cancer cells, one of which is known as the Warburg effect . Cancer Hypoxia is another common microenvironment feature in nearly all solid tumors. The uncontrolled proliferation of tumors limits the availability of oxygen supplied from the tumor vascular system, thus exposing them to low oxygen environments. On average, the oxygen level in tumor tissues is around 1–2% or below . HypoxiaDrug transporters are integral membrane proteins that are involved in drug disposition by affecting absorption, distribution, metabolism, and excretion (ADME). Clinical pharmacokinetic drug-drug interactions (DDIs) studies have shown that transporters mainly participate in the drug ADME process together with metabolic enzymes . Based oIt is widely accepted that cancers develop from a small subset of stem cells with exclusive ability to self-renew and differentiate into the heterogeneous cancer cell types . These iEpithelial-mesenchymal transition (EMT) is a process that epithelial cells lose their apical-basal polarity and cell-cell adhesive properties, acquire migratory and invasive properties of mesenchymal cells. These undergoing EMT cells exhibit decreased expression levels of epithelial markers (E-cadherin) and increased expression levels of mesenchymal genes (N-cadherin and vimentin) . In mostNanotechnology is initially defined as the “intentional design, characterization, production, and applications of materials, structures, devices, and systems by controlling their size and shape in the nanoscale from 1 to 100 nm range.” :2434–43) Nanotechnology has potential applications in medical applications because nanomaterials are similar in scale to biomolecules and systems, and can be designed to perform different functions. In cancer treatment, nanomaterials are mainly designed to aid in the transport of anticancer drugs through biological barriers. The aims of cancer nanomedicine are to use the properties and physical characteristics of nanomaterials for achieving more effective and safer cancer treatment :20–37). In recent years, emerging evidence demonstrated that some nanomaterials have distinct advantages in reducing side effects and overcoming drug resistance. The following will focus on recent advancements in nanotherapeutic approaches to tackle drug resistance.Tumor heterogeneity is an important hallmark for some cancers, which contribute to the unsatisfactory treatment outcome . TraditiRecognizing that tumors tend to be acidic environments, a class of pH-responsive nano-structures is developed and such systems could enhance uptake by tumor cells through acidic microenvironment-triggered drug release. These nanoparticles were reported as following. Self-assembled PEG-detachable polymeric micelles DOX-PMs , zwitterEvidence has revealed that hypoxia in the tumor microenvironment has a crucial role in the clinical resistance of chemotherapy through a variety of signal transduction pathways and molecular changes . The devWith the development of nanotechnology, more and more new-style nanostructures were discovered. Among these, gold nanoparticles (AuNPs) are being widely used to deliver small molecules due to their unique optical properties and surface plasmon resonance effect. And PEG can be attached to the surface of gold nanoparticles to increase the stability and circulation time of chemotherapy drugs. Moreover, the surface plasmon band (SPR) of the nanoparticle will be modified by changing the shape of AuNPs from spheres to rods. One of the advantages of gold nanorods is the shift of the SPR allows for near-infrared (NIR) absorption at the cross-sections permitting a deeper penetration into living tissues . Many rel-arginine (l-Arg)/Dox-loaded gold@copper sulfide yolk-shell nanoparticles (ADAu@CuS YSNPs) to programmable release Dox in Dox-resistant cancer. Various faceted Au NRs were embedded in CuS HNPs to optimize Au@CuS YSNPs. The finally formed ADLAu@CuS YSNPs can convert L-Arg into NO upon NIR laser irradiation, leading to hydrolysis of o-phenylenediamine-containing lipid and programmable release of NO and Dox. Once internalized into MCF-7/ADR cells, the early stage NO release of ADLAu@CuS YSNPs can inhibit P-gp expression and create a favorable microenvironment for the latter stage Dox accumulation, beneficial for MDR cancer therapy -stimulated nanosystem for multidrug resistance cancer therapy. This system reversing the MDR effect attribute to the principle that gaseous signaling molecules nitric oxide (NO) can be used as ABC transporter inhibitors to downregulate the expression level of P-gp, thus creating a favorable microenvironment for the treatment of drug-resistant cancer cells . Interes therapy . This NO therapy .The combination of chemotherapy and photothermal therapy is a promising strategy for cancer treatment. Despite the advantages in overcoming drug resistance, more studies have demonstrated the promising applications of these gold nanoparticles or NO-releasing nanomaterials in combined chemo-photothermal therapy .in vivo  is a common chemotherapeutical drug targeting vascular endothelial growth factor receptor (VEGFR), which is universally overexpressed in many tumors . The theThe combinatorial strategy of chemo-chemo, chemo-immune, and chemo-photothermal treatments, usually called “cocktail therapy”, have been reported to be effective solutions to overcome drug resistance. For example, Zhang et al. developed an iRGD peptide-modified lipid-polymer hybrid nanosystem (LPN), co-loaded with paclitaxel (PTX) and tetrandrine (TET). As expected, the PTX + TET/iRGD LPNs significantly suppressed P-gp expression, promoted ROS production and apoptosis in PTX-resistant tumors . Like “DHerein, the following picture simply illustrated a case that chemo-photothermal treatment applied in overcoming drug resistance . Wang etTumor metastasis is a major risk factor for poor prognosis of cancer patients, which is the most concerned issue in surgical treatment. Moreover, chemotherapy has little benefit in the treatment of multiple metastasis . Herein,Tumors are composed of mutually interacting tumor cells and tumor microenvironment. Consequently, internal cancer cells along with external environmental factors, extracellular matrix (ECM), and immune cells eventually determine the tumor fate. Tumor heterogeneity, the existence of CSCs, and the occurrence of EMT process in tumor cells are the inner driving force in chemotherapy resistance. However, alterative external pressure including hypoxia, acidic environment, and tumor-associated macrophage (TAM) directly affect drug kinetics and favor the selection of more malignant, therapy-resistant tumor cell subpopulations. Since the complexity of tumor heterogeneity and microenvironment, the causes of drug resistance may differ from individual patients and within a single tumor. Thus, the therapeutic strategies based on a single and fixed chemotherapy drug are inevitably suboptimal. In contrast, flexible and diverse drug delivery materials provided a window into the availability of better treatment. What’s more, multiple nanoparticles applied in chemotherapy regimens could be effectively combined with photothermal therapy, immunotherapy, and CRISPR-mediated gene edit, thus synergistically acquiring better therapeutic efficacy in cancer treatment . ConsideIn recent years, immunotherapy-combined nanoformulations have been developed based on studies of tumor escape mechanism, transforms immunosuppressive tumors into immunostimulatory phenotypes and overcomes the pathways leading to tumor escape. The therapeutic strategy has the potential to induce durable antitumor immune responses in hematologic and solid malignancies and thus has become treatment algorithms for multiple tumor types . Cancer in vivo and its interaction with biological system at the tissue, cellular, and molecular levels are always ignored. We strongly suggest that researchers should pay more attention on the material itself biological functions and its pharmacokinetics in vivo. What’s more, many efforts should be made to provide definitive evidence for its functional mechanism instead of creating many new complicated nanoparticle systems for similar concept.It is challenging to design nanomaterials to share all desirable characteristics for overcoming all barriers. A concrete design should mainly depend on the specific drug cargo and tumor target. An ideal drug delivery system should adequately protect drug cargo, minimize nonspecific interactions with biological species, and allow efficient aggregation to target sites. In addition, the drug delivery system, once accumulated in tumor tissue, should provide sufficient penetration to deliver the drug throughout the tumor tissue, resulting in mass apoptosis of tumor cells . For a lAt present, nanoparticles are trying to open a new era for tumor treatment. Though nanomedicine is still at an early stage, the reported results in cancer treatment especially in reversing drug resistance are surprising, and importantly, these advanced antitumor concepts are of great references for chemists, materials scientists, biologists, and may provide new insights into cancer and even a breakthrough in other fields.


Background: Adequate perfusion of a bone flap is essential for successful reconstruction of osseous defects. Unfortunately, complications related to inadequate bone perfusion are common. Near-infrared fluorescence (NIRF) imaging enables intraoperative visualization of perfusion. NIRF has been investigated in reconstructive surgery to aid the surgeon in clinical perioperative assessment of soft tissue perfusion. However, little is known on the beneficial use of NIRF to assess bone perfusion. Therefore, the aim of this review was to search for studies evaluating NIRF to assess bone perfusion. Methods: A systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, was performed. Studies up to October 2021 were included. We extracted data regarding the study population, size and design, reported objective fluorescence parameters and the methodology used for fluorescence imaging and processing. Results: Ten articles were included. Studies reported unevenly on the protocol used for NIRF imaging. Five studies reported objective parameters. Absolute and relative perfusion parameters and parameters derived from maximum fluorescence were reported. The clinical significance of these parameters has not been evaluated in humans. Conclusion: The evidence on bone perfusion as measured with NIRF is limited. More clinical studies are required. Adequate perfusion of tissue is a prerequisite for successful reconstructive surgery. The gold standard for tissue perfusion assessment in reconstructive surgery is based on perioperative clinical judgment of traditional parameters  ,2. Bone A systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, was performed to assess current concepts regarding the perfusion assessment of bone with fluorescence imaging. A PubMed database search was conducted with the following search strategy:(“indocyanine green”[MeSH Terms]) OR (“indocyanine green”[Title/Abstract]) OR (“ICG”[Title/Abstract]) OR (fluorescence imaging*[tiab]) OR (wofaverdin[tiab]) OR (vophaverdin[tiab]) OR (vofaverdin[tiab]) OR (cardio green[tiab]) OR (cardiogreen[tiab])) AND  screened through the abstracts and selected articles relevant to this review. In case of discordance, a third reviewer (CD) was consulted until consensus was reached. Inclusion criteria were human, cadaveric or animal studies with an evidence level ranging from 1 to 5, investigating bone perfusion by ICG . There was no minimum number of participants. In vitro studies were excluded. Methodological quality and risk of bias of the included case series were assessed using the “Joanna Briggs Institute” (JBI) checklist. Level of evidence of the studies was assessed by the American Society of Plastic Surgeons (ASPS) Evidence Rating Scale.From the included articles, we extracted data regarding study population, size and design, study end points, reported objective fluorescence parameters and the methodology used for fluorescence imaging and processing . To provide comparable results within studies, we contacted the authors to obtain additional information.We performed a descriptive and qualitative analysis of the data extracted; no meta-analysis was possible due to the heterogenicity of the studies included.The initial search in PubMed identified 481 articles. Of these, 464 were excluded because they were not relevant according to title or abstract. 17 articles were fully read, 10 articles met the inclusion criteria and were included into the study . One artThe characteristics of the included studies are presented in Not all studies reported clearly on the protocol used for NIRF imaging. Six different imaging systems were used combined with differing NIRF imaging processing software suites . PositioQuantification of NIRF imaging was reported only in five studies ,17,18,19Fichter et al. found that the maximum bone marrow fluorescence intensity before and after osteotomy decreased, but not significantly . ValerioNguyen et al. described an intensity ratio (fluorescence at region of interest/background fluorescence) for quantification of fluorescence . VasculaTwo derived perfusion parameters were reported by Fichter et al., namely the wash in rate (WiR) (defined as the maximum fluorescence slope) and wash in perfusion index (WiPI) (defined as the ratio between the wash in area under the curve (WiAUC), defined within the start of rise of the fluorescence slope and the maximum fluorescence and rise time). Both parameters were significantly decreased before and after osteotomy . No cut-Elliott et al. developed a kinetic analysis model to capture and describe the bipartite blood supply  to cortical bone . They apThis systematic review reports on studies that have explored the role of NIRF imaging with ICG in assessing bone perfusion. The studies evaluated in this review show that it is a promising way of visualizing bone perfusion, although there is a clear lack of data on this technique.The goal of real-time bone perfusion imaging in a clinical setting is primarily to differentiate between viable and non-viable tissue, to allow image-guided tailoring of osseous flaps or debridement of necrotic bone. An ideal imaging technique should allow clear differentiation between viable and non-viable tissue, be easy to set up, easy to use and interpret, be safe and minimally invasive for patients, provide consistent results between cases and ideally be cost-effective. Objective perfusion parameters could allow such differentiation, with a clear cut-off value indicating which tissue is deemed non-viable. While objective perfusion parameters derived from NIRF imaging have been reported previously for soft tissue, the evidence for objective levels of bone perfusion is scarce . There iIn cadaveric studies the feasibility of ICG to penetrate cancellous  portion of bone through penetrating periosteal capillaries has been shown ,22,23. NFive studies reported objective outcomes, including absolute, relative and extrapolated perfusion parameters. Some papers reported human studies and others animal research. Additionally, the NIRF imaging methodology used showed high heterogeneity between the studies included. For example, the studies used different camera systems with different camera chips and optics, resulting in varying camera sensitivities to pick up fluorescence. Moreover, several camera systems employ intensity optimization algorithms to boost the captured image data. Keeping these factors mind, there is a challenge to compare cut-off values between studies using different systems.Absolute perfusion values, defined as maximum fluorescence in number of units after ICG injection at a certain time point, were reported by Fichter et al. 2019), Valerio et al. (2015) and Gitajn et al. (2020). While Fichter et al. (2019) and Gitajn et al. (2020) looked at maximum fluorescence on a fluorescence perfusion curve over time, Valerio et al. (2015) looked at maximum fluorescence at a single not further specified time point. Fichter et al. (2019) looked at cancellous bone in a transverse view of a fibula flap and stated that maximum fluorescence did not differ significantly before and after osteotomy. No correlation to clinical outcome was made as they stated that the impact of decrease in bone perfusion, and consequently variation in perfusion parameters, on bone healing is difficult to assess. Biomechanical forces, wound bed configuration, adequacy of osteosynthesis, postoperative infections might all influence bone healing. Gitajn et al. (2020) found no significant difference in absolute perfusion between injured and healthy porcine bone. Valerio et al. (2015) used an absolute minimal fluorescence value of 6 as a cut off value for acceptable bone perfusion based on earlier studies in skin sparing mastectomy patients [19, ValerNguyen et al. (2012) reported a relative perfusion value; the fluorescence signal (fluorescence at region of interest) was divided by the background fluorescence. Vascularized bone marrow had a signal/background ratio of 2.30 and devascularized bone marrow of 1.03. This study therefore showed that avascular bone has a fluorescence signal almost equivalent to background fluorescence. The question remains how progressive injury of bone influences this ratio.Finally, the research groups of Gitajn et al. (2020) and Elliot et al. (2019), proposed and applied a new kinetic model to ICG fluorescence curves of regions of interest in bone under several injury conditions. The underlying concept of this model is that bone ICG fluorescence curve represents a combination of “late” and “early” bone perfusion, which in turn, reflects the bipartite blood supply network of bone. Bone has a bipartite blood supply, based on a periosteal and an endosteal network ,27,28. TRecent studies suggest that NIRF with ICG in breast reconstruction is cost effective . We did Future studies on NIRF assessment of bone perfusion should report objective outcome measures, including maximum and relative bone fluorescence intensity, after their use is confirmed in fundamental studies. When reporting absolute perfusion parameters, van den Hoven et al. propagated the normalization of the time-intensity curves to minimize the effect of multiple influencing factors, including camera distance and ICG dosage . BipartiIt is a challenge to implement the NIRF findings of bone perfusion in surgery. Regarding reconstructive surgery, NIRF assessment of the bone flap after osteotomy, drilling and plating, e.g., in a case of mandibular reconstruction, will often not lead to an adjustment of the flap itself. However, consequent data of NIRF and clinical follow up, may eventually be useful in assessing the maximal length/surface and number of osteotomies of a bone flap. The more NIRF data available on healthy bone perfusion, the better we will be at assessing inadequate perfusion due to infection, trauma or radiotherapy. Ultimately, it may facilitate in guiding the debridement of an acceptor site before reconstruction.One of the limitations of this systematic review was the limited amount and heterogeneity of studies included. Therefore, it was not feasible to perform a meta-analysis.Based on the results of this review, the evidence on NIRF assessment of bone perfusion is limited but promising. A few objective parameters have been reported, but their clinical significance has not been evaluated in humans. All the reported objective values are not yet available in real-time, limiting their applicability during surgery. More studies are required to assess clinical significance and cost effectiveness of NIRF with ICG to differentiate between viable and non-viable tissue, to allow image-guided tailoring of osseous flaps or debridement of necrotic bone.