Over a wide range of systemic arterial pressures, cerebral blood flow (CBF) is regulated fairly constantly by the cerebral vessels in a process termed cerebral autoregulation (CA), which is depicted by the Lassen autoregulatory curve. After traumatic brain injury (TBI), CA can get impaired and these impairments manifest in changes of the Lassen autoregulatory curve. Continuous surrogate metrics of pressure-based CA, termed cerebrovascular reactivity (CVR) metrics, evaluate the relationship between slow vasogenic fluctuations in a driving pressure for cerebral blood flow, and the most commonly studied and utilized measures are based in the time domain and have been increasingly applied in bedside TBI care and have sparked the investigation of individualized cerebral perfusion pressure targets. However, not all CVR metrics have been validated as true measures of autoregulation in the pre-clinical setting. We reviewed all available pre-clinical animal literature that assessed the association between continuous time-domain metrics of CVR and some aspect of the Lassen autoregulatory curve. All 15 articles found associated the evaluated continuous metrics to the lower limit of autoregulation curve whereas none looked at the upper limit. Most of the evaluated metrics showed the ability to discriminate the lower limit of autoregulation with various methods of perturbation. Further work is required to evaluate the utility of such surrogate measures against the upper limit of autoregulation, while also providing validation to the existing literature supporting specific indices and their ability to discriminate the lower limit. The Lassen autoregulatory curve is plotted with cerebral perfusion pressure (CPP) or mean arterial pressure (MAP) along the x-axis, and CBF along the y-axis, where CBF has classically been invasively measured.3The innate ability of the cerebral vessels to maintain cerebral blood flow (CBF), relatively constantly, over a wide range of systemic arterial pressures, is termed cerebral autoregulation (CA).4–7 and after traumatic brain injury (TBI),8–14 across the spectrum of injury severity. Such impairment manifests in changes in the position of the LLA or ULA on the Lassen autoregulatory curve or, in the worst instance, absence of the autoregulatory curve altogether.15 These alterations in the autoregulatory curve expose the brain to pressure-passive flow states, where low MAP or CPP leads to hypoperfusion, whereas high MAP or CPP leads to hyperperfusion. Recent literature suggests that the exposure burden of impaired CA is a significant driver of poor long-term outcomes in various neurological conditions.16–18 Subsequently, to avoid subjecting the brain to hypo- or hyperperfusion conditions, it is imperative that we have the capacity to continuously and accurately monitor CA at the bedside.Impairment in CA has been documented in various neuropathological states, including post-stroke19 Continuous indices that have not been fully validated as measures of the Lassen autoregulatory curve have been given the term CVR metrics. The clinical realm has made a concerted effort to refer to these indices as CVR metrics to avoid misrepresenting them as a completely validated measure of autoregulation. We will maintain such consistent nomenclature throughout this article in keeping with this designation within the field. Such continuous CVR metrics evaluate the relationship between slow vasogenic fluctuations in a driving pressure for CBF  and a surrogate for pulsatile cerebral blood volume (CBV) or CBF. The table in Direct measurement of CA is not possible at the bedside, given that continuous and accurate measures of CBF are not readily available to the treating clinician. As such, we must rely on surrogate metrics of CA, termed cerebrovascular reactivity (CVR) metrics, involving changes in gas levels, pressure, or flow velocity to drive alterations in vascular caliber.2), thermal diffusion flowmetry (TDF) CBF, and laser Doppler flowmetry (LDF) CBF.20 With these devices, various CVR indices can be derived at the bedside in humans, with most literature to date focused on TBI patient cohorts. We mainly focused on time-domain metrics given that these measures have seen widespread adoption by clinicians at the bedside because they give greater simplicity in continuous derivation and interpretation over frequency-domain measures. However, not all indices have been explored in pre-clinical models as measures of the Lassen autoregulatory curve, and, as such, we conducted this study.The most readily studied and utilized measures are based in the time domain and are derived as moving Pearson's correlation coefficients between raw physiological signals, with negative values denoting “intact” autoregulation and positive values denoting “impaired” autoregulation. Cerebral monitoring devices utilized to obtain surrogate measures for pulsatile CBV/CBF derived from raw continuous physiological signals include both invasive and non-invasive modalities, such as: intracranial pressure (ICP), near-infrared spectroscopy (NIRS), transcranial Doppler (TCD), brain tissue oxygen .3031–33 Review questions and search strategy were decided upon by the supervisor (F.A.Z.) and the primary author (A.S.S.).A systematically conducted scoping review of the available literature was conducted using the methodology outlined in the Cochrane Handbook for Systematic Reviews.The question posed for this scoping systematic review was: What pre-clinical animal literature exists to validate continuous measures of CVR as true measures of the Lassen autoregulatory curve? All studies, either prospective or retrospective, of any size were included.3 Continuous CVR measures were defined as those which are moving Pearson's correlation coefficients between slow-wave fluctuations in a driving pressure for CBF  and a surrogate for pulsatile CBV/CBF, as defined in the existing literature body.20 The following cerebral monitoring techniques were considered eligible for the derivation of continuous CVR metrics: ICP, NIRS, TCD, PbtO2, TDF CBF, or LDF CBF. The primary outcome measure was the association between continuous CVR measures and the Lassen autoregulatory curve.2 reactivity testing).All studies, whether prospective or retrospective, of all sizes, including any animal model type that evaluated time-domain continuous metrics of pressure-based CVR and documented an association between the continuous metric and some aspect of the Lassen autoregulatory curve were eligible for inclusion in this review. Exclusion criteria were the following: being non-English-language studies, human studies, non-continuous CVR assessments, and non-pressure-based CVR measures , a two-step review of all articles returned by our search strategies was performed. First, the reviewers independently screened all titles and abstracts of the returned articles to decide whether they met the inclusion criteria. Second, the full text of the chosen articles was assessed to confirm whether they met the inclusion criteria, and that the primary outcome of CVR was documented. Finally, any discrepancies between the two reviewers were resolved by a third party (F.A.Z.).Data fields included the following: animal model details, the study's goal, aspects of Lassen autoregulatory curve assessed, primary/secondary outcomes, limitations, CVR indices measured, method of perturbation, and conclusions regarding continuous indices.Given that the goal of this review was to provide a comprehensive scoping overview of the available literature, a formal bias assessment was not conducted.A meta-analysis was not performed in this study because of the heterogeneity of study designs and data.Results of the search strategy across all databases and other sources are summarized in 34–4534–41 ICP perturbation,45 and other methods of inducing perturbation ,45 respectively. Articles that used mixed methods will be found in more than one of 38–44 two studies used laser Doppler index (LDx),37 and one study used a diffusion coefficient measured with a custom-built diffusion coefficient spectroscopy.45 All eligible studies reported the association between time-domain continuous metrics and the LLA aspect of the Lassen's autoregulatory curve. Only one study fully reconstructed the Lassen autoregulatory curve with both the LLA and ULA, but only related the continuous metrics to the curve's plateau (the region between LLA and ULA).452] and CPP),40 one measured COx-a (correlation between rSO2 and MAP),36 one measured wavelet COx ,25 seven studies measured hemoglobin volume index ,44 one measured wavelet HVx ,25 two measured LDx (correlation between laser-Doppler flux and MAP),35 one measured mean flow index (correlation between mean flow velocity and CPP),20 two measured pulse amplitude index ,20 10 studies measured pressure-reactivity index ,42–45 one measured induced PRx ,37 two measured wavelet PRx ,42 two measured the correlation between pulse amplitude of ICP and CPP (RAC),20 one measured systolic flow index (correlation between systolic flow velocity and CPP),20 and one measured MAP-ICP phase shift (ΔϕAI).3734–42 as their animal model whereas two studies used juvenile domestic pigs,44 one study used rhesus macaque,45 and one study used New Zealand rabbits.20Eleven studies used neonatal swine38–41 except for one where hypotension occurred with the gradual hemorrhage by syringe-pump withdrawal at a calculated rate of blood volume per hour.37 From the 10 studies that induced hypotension, only three of them also induced hypertension by slowly inflating an aortic balloon catheter.41 Overall, all the CVR indices that were measured in the hypotension model were able to distinguish whether CPP was above or below the LLA, and these indices included: COx,41 COx-a,36 wCOx,25 HVx,38–41 wHVx,25 LDx,35 PAx,19 PRx,39 iPRx,37 wPRx,25 RAC,19 and ΔϕAI.37Most of the studies that induced hypotension did it by gradually inflating the balloon catheter in the inferior vena cava ,19,25,3438–41 One study mentioned that LDx performed better than COx, and the agreement between these indices was limited but greatly improved with averaging values.34 The increase in PRx to more positive values (denoting impaired CVR) had a blunted response at CPP values around LLA, when compared with autoregulation curves derived from COx and LDx.35Results from studies show that during hypotension, PRx, COx, LDx, and HVx accurately detected CPP/MAP above and below LLA.39 In the same animal model, it has been shown that MAP-derived COx has an accuracy that is very much comparable to CPP-based COx, with COx-a having a slightly higher threshold for discriminating the LLA as compared to COx.36In corollary, one study had shown that HVx is an excellent alternative to PRx.AI were significantly lower as compared to normotension and hypotension above LLA where both iPRx and ΔϕAI were not different.37 Wavelet indices  did not increase as much as their corresponding correlation indices  did as MAP decreased below LLA. Also, all wavelet indices had lower variability than their correlation index counterparts given that the wavelet indices used a methodology to decrease signal noise.25Variants of PRx displayed varying performance with regard to their availability measure aspects of the Lassen autoregulatory curve. During hypotension with mean pressures below LLA, the iPRx and Δϕ19Finally, non-PRx ICP-derived CVR indices were only sparingly mentioned. Strong conclusions about PAx and RAC cannot be made given that only one study evaluated them against PRx with a small number of animals, but the preliminary evidence shows that both of these indices validate against LLA within a model of hypotension whereas PRx seemed to be superior.41 Of note, these studies did not successfully evaluate the ULA. Subsequently, we cannot comment on the ability of any of the described indices' ability to estimate aspects of the ULA at this time.The results from the handful of studies that induced hypertension showed that the values of CVR indices measured  were consistent with preserved autoregulation.35 gradual inflation of a latex balloon catheter in the superior vena cava,43 and influencing fluid to flow from a saline reservoir to lateral ventricle in the brain by lumbar catheter.45 Under both naïve and elevated ICP conditions, similar values were obtained above LLA using PRx, COx, HVx, and LDx,43 but two studies were able to relate high ICP to low CPP where CA becomes impaired45 and both PRx and PAx correlated well with LLA.20There were only four studies on ICP perturbation, as seen in 41 cardiac arrest with hypothermia,40 hypercarbia,44 and positive end-expiratory pressure (PEEP) oscillations as seen in 45 Cardiac arrest was induced by hypoxic-asphyxic in all the related studies41 whereas hypothermia was induced by cooling the temperature for a period of time or multiple short time periods.40 PRx, wPRx, COx, wCOx, HVx, and wHVx indices were able to discriminate CPP/MAP above and below the LLA in cardiac arrest and hypothermia,40 but it should be noted that the CPP/MAP change had to be driven to evaluate LLA taking the form of arterial hypotension or ICP increase in a brain-injured state attributable to cardiac arrest or hypothermia. One study reported that the accuracy of COx and HVx was slightly less in post-cardiac arrest animals.40Other methods of inducing perturbation in the studies included cardiac arrest,2 levels were elevated by bleeding CO2 from a cylinder into the gas mixture inspired by the piglets. Despite the presence of hypercarbia, PRx and HVx were able to accurately detect the LLA, and the elevated CO2 did not interfere with the NIRS readings.44There was only one study on hypercarbia, and CO45 and the precision of iPRx was improved compared to PRx.37 The wPRx produced a more stable result than PRx while distinguishing CPP above and below the LLA. However, both indices increased significantly while CPP was decreased below LLA in the PEEP group.42Finally, PRx variants were evaluated during PEEP modulation. With PEEP modulation, oscillations in MAP were inducedThrough comprehensive evaluation of the pre-clinical literature surrounding continuous CVR measures and their ability to measure aspects of the autoregulation curve, some interesting findings deserve highlighting.45 Traditionally, the region between LLA and ULA has been described as a plateau, but emerging evidence suggests that the intact autoregulation region of the curve is not a plateau.47First, the available literature lacked the inclusion of most of the CVR metrics of interest, provided in 45 showed that fentanyl-anesthetized non-human primates had an averaged negative trend between the LLA and ULA, which had been generally regarded as the plateau. This highlights the need for future validation work for both the LLA and new studies to evaluate the ULA along with exploring the intact autoregulation region, particularly in different large animals given that responses may vary. Similarly, with the ever-increasing number of metrics emerging based on continuous multi-modal monitoring of cerebral physiology, new pre-clinical studies encompassing all multi-modal metrics concurrently while evaluating the LLA and ULA are required to get a better perspective on their ability to estimate the Lassen autoregulatory curve.The study by Ruesch and colleagues34; however, this should not be a surprise given that LDx is derived from LDF and the LLA was defined at the intersection of two regression lines on the LDF versus CPP scatterplot. The results from studies show that during hypotension, all the CVR metrics evaluated were able to detect CPP/MAP above and below LLA accurately. Among these studies, the commonly evaluated CVR indices were COx, PRx, and HVx, where HVx was mentioned to be an excellent alternative to PRx39 and COx derived from either MAP or CPP had comparable accuracy.36 Also, it has been shown that the wavelet counterparts of the three commonly evaluated indices had lower variability attributable to decreased signal noise.25Second, regarding the NIRS-based potentially non-invasive metrics, some important aspects regarding their ability to discern the LLA were noted. A study comparing COx with LDx during arterial hypotension concluded that LDx performed better than COx41 whereas the rest only induced hypotension.39 The results from the hypertension studies showed that autoregulation was preserved, as indicated from COx and HVx values,41 but, as mentioned above, evaluation of these CVR indices to estimate aspects of ULA cannot be commented on because ULA was not successfully evaluated.Of the 10 studies categorized as arterial hypotension/hypertension, only three of them induced hypertension along with hypotension19 However, PRx appears to remain superior in measuring the LLA in arterial hypotension models.19 Similarly, PAx and PRx correlated well with LLA during intracranial hypertension, where RAC performed poorly.20 Two other studies obtained similar values above LLA using PRx, COx, HVx, and LDx under both naïve and elevated ICP conditions.43 Thus, despite some literature demonstrating the ability of PAx and RAC to estimate aspects of the LLA, their exact role beyond PRx in TBI monitoring remains unclear.Third, with respect to different ICP-derived measures, preliminary evidence shows that the newer ICP-derived CVR indices, PAx and RAC, can estimate the LLA.41 With PEEP oscillations to modulate MAP, iPRx and wPRx gave improved and stable results of distinguishing CPP above and below LLA as compared to PRx.42 There was only one study on hypercarbia where elevated CO2 did not affect the ability of PRx and HVx to detect the LLA during gradual arterial hypotension induced by continuous hemorrhage.44 Thus, it appears that the ability of PRx (and its variants), COx, and HVx to estimate the LLA is unaffected by the pathological state or co-manipulations of systemic physiology. Hence, it was important to review the pre-clinical literature given that such findings offer some confidence in their ability to perform as continuous measures at the bedside for TBI patients.Fourth, some studies used other models of inducing perturbation where specific pathological states were studied; common models were cardiac arrest with hypothermia and PEEP oscillations to ICP and/or MAP. PRx, COx, and HVx, along with their wavelet counterparts, accurately discriminated CPP/MAP above and below LLA in the model of cardiac arrest and hypothermia.46 This is in contrast to dynamic autoregulation, where autoregulatory capacity is assessed in a much shorter temporal scale, on the order of seconds to minutes, in response to rapid changes in a driving pressure to flow.46 However, despite most of the articles having evaluated static aspects of CA and some fundamental physiological differences between the techniques, the findings here carry potential importance for both static and dynamic autoregulation measurement techniques. There is evidence that points to the general agreement of static and dynamic aspects of CA in impaired autoregulation under challenges in ICP and blood pressure.48 In normal anesthetized adults with intact or impaired autoregulation,48 and in non-human primates under anesthesia-induced autoregulation impairment,45 it has been demonstrated that there is a good correlation between both techniques to assess CA, although dynamic CA seems to be initially more reduced than static CA. Such an agreement between static and dynamic CA would be consistent given that the more momentary physiological factors assessed by dynamic CA would be sufficiently identical to the longer methods of assessment in static CA. However, in situations where paroxysmal physiological responses occur, static autoregulation may be unaffected and thus a disagreement between dynamic and static CA assessments. This enforces the idea that determination of CA must be validated through continuous methods.Finally, most of the articles reviewed looked at static aspects of CA. Static autoregulation measures refer to those metrics that are derived when both aspects of physiological measures  have reached a steady state, where autoregulatory responses are assessed over a longer time frame of minutes to hours.20 our review highlights that only a few have been studied pre-clinically. Thus, we cannot definitively indicate the utility of TCD, PbtO2, and Hemedex™ CBF-based techniques in their ability to measure the autoregulatory curve.Despite the interesting findings outlined in this scoping review, there are some significant limitations that deserve highlighting. First, the uncovered literature was very heterogeneous in design, which means that there was limited ability to cross-sectionally evaluate the relationship between studies based on various combinations of CVR indices used in each method of perturbation. Further to this, the different animal models and species utilized limit the comparability between similar indices and perturbation results. Second, most studies used a small number of animals in their model design. This is likely secondary to the cost of such models and experiments. Such small numbers limit the definitiveness of the findings outlined and emphasize the need for further validation studies. Third, some models described used neonatal animals. This raises concerns of cerebrovascular immaturity and translatability of findings to adult animals or humans. Fourth, from the numerous multi-modal cerebral physiological monitoring devices noted in bedside monitoring to derive continuous CVR indices,50Fifth, we were unable to find literature documenting the ability of such continuous CVR metrics to estimate the ULA, which could be attributable to the occurrence of heart failure at higher CPP as mentioned by a couple of studies. As such, at this time, it is unknown whether such a metrics measure can discriminate more than just the LLA. Finally, and most important, the results from studies with animal models do not directly translate to human patients, though preliminary findings in humans support their ability to estimate the LLA.Moving forward, there are some important areas for future research. First, validation of the above findings is required, given that most are based on single-institution, single-study findings in a limited number of animals per study. Such work will require specialized centers for large animal research, dedicated to precision medicine in neural injury. These large animal models would be best positioned to facilitate translatability to adult human neurocritical care. Second, studying the performance of such indices in both healthy- and injury-state models is key to be able to differentiate between intact and dysfunctional autoregulation using each of the indices. Given that different neuropathological states may cause different changes to the shape and nature of the autoregulatory curve, having control pre-clinical models in the healthy state are critical to our understanding of fundamental changes in cerebral autoregulation that may occur in disease.51 Fourth, integrating physiological monitoring with histopathological correlations could improve our fundamental understanding of tissue consequences of impaired CA, based on different monitoring modalities, across different model ages and across the spectrum of neuropathological states. Finally, such large animal-model platforms would provide the ideal setting to explore directed therapeutics aimed at prevention and treatment of impaired CA, facilitating the needed pre-clinical investigation of precision therapeutics before application in humans.Further, in providing validation for a continuous surrogate measure of CA, we must have the utmost confidence in their ability to estimate various aspects of autoregulation during both the healthy and diseased states before they are adopted into routine clinical-care provision. This requires, again, specialized center expertise in model development, multi-modal cerebral physiological monitoring, and biomedical engineering capability. Such models would benefit from having both focal and diffuse injury patterns, including those modeling stroke, TBI, and anoxic brain injury. Third, work here would be bolstered by evaluating differences between both neonatal and adult models. Existing literature supports the use of pig models to facilitate such work.AI) showed the ability to distinguish CPP/MAP from above and below the LLA with various methods of perturbation in animal models. However, most studies focused on a small number of animal populations, with only a few simulating ICP elevations observed in TBI, so the conclusions drawn from these studies should be taken with caution. Also, none of the indices evaluated the ULA aspect of the Lassen autoregulatory curve. Therefore, further research is required to fully assess the relationship between both the LLA and ULA aspects of the Lassen autoregulatory curve to CVR indices in a larger pre-clinical population size.This literature demonstrates that most of the measured indices (COx, COx-a, wCOx, HVx, wHVx, LDx, PAx, PRx, iPRx, wPRx, RAC, and Δϕ


We suggest that pandemic-driven philanthropic and state funding flows have bolstered foodbanking and the food system logics that support it. By contextualising the complex and variegated politics of foodbanking in broader movements, from community food security to food sovereignty, we reframe simplistic narratives of charity and highlight the need for justice-oriented structural changes in wealth redistribution and food system organisation if we are to prevent the kinds of emergency-within-emergency that we witnessed as COVID-19 revealed the proximity of many to hunger.COVID-19 caused levels of household food insecurity to spike, but the precarity of so many people in wealthy countries is an outgrowth of decades of eroding public provisions and labour protections that once protected people from hunger, setting the stage for the virus’ unevenly-distributed harms. The prominence of corporate-sponsored foodbanking as a containment response to pandemic-aggravated food insecurity follows decades of replacing rights with charity. We review structural drivers of charity’s growth to prominence as a hunger solution in North America, and of its spread to countries including the UK. By highlighting pre-pandemic pressures shaping foodbanking, including charities’ efforts to retool themselves as health providers, we ask whether anti-hunger efforts during the pandemic serve to  Watching Donald Trump and Boris Johnson fail to preside over the unfolding tragedy of COVID-19, as millions lost their jobs and spectacular lines formed outside foodbanks, felt despairingly, dully predictable. Leaders’ ostrich approachcontain ongoing socioeconomic crises and the unjust living conditions they cause, or contest them through transformative pathways to a just food system.Those who cannot afford to meet their basic needs in increasingly marketised economies have been especially vulnerable to overcrowding, enforced mobility and destitution during COVID-19, rendering some people at far greater risk to the virus than others. Leaders’ heel-dragging responses portended a predictable response to the ever-larger numbers of people facing extreme hardships in the spring of 2020: an upswell in charity food provision in the US and UK, our respective home countries. This highlights a growing transnational trend of masking the failures of welfare systems through their voluntary sector appendages, including the use of food charity. While many scholars have noted upswells in foodbanking on the heels of recessions and crises since the 1970s Riches , the extDespite significant critique of food charity as anti-hunger response (Lohnes and Wilson We will show how US-style foodbanking’s (pre-pandemic) international expansion and normalisation was driven by four key trends: welfare retrenchment; the outsourcing of states’ responsibilities to uphold the Right to Food; food overproduction ‘balanced’ with aid; and the interests of ‘Big Food’ in charitable redistribution. These have solidified international foodbanking as a mode of ‘containment’ of system contradictions and injustices Heynen . CriticsThe pandemic has reinvigorated such debates and shifts. As states have re-asserted their capacities to respond to income crises through public assistance, the demands placed upon food charities and mutual aid providers have re-surfaced questions around the appropriateness of food-based versus income-based responses to the endemic food insecurity that preceded COVID-19. In this time of reckoning with systems of economic exploitation based on colonialism, patriarchy, misogyny, anti-Black racism, capitalist accumulation and ableism, demands have resurfaced that basic needs to be met not by well-meaning volunteers, but by universal income and service guarantees.This review paper is co-written by members of the Global Solidarity Alliance for Food, Health and Social Justice (#RightsNotCharity), thinking and acting to critique the international expansion of US-style foodbanking Cohen . It drawIn contrast to previous analyses of food charity’s relationship to economic crises, COVID-19 presents a unique opportunity to question links between food systems, infectious disease, and dietary inequality in ways that force us to examine the sustainability and equity dimensions of dominant responses; in this case, corporate foodbanking as a mode of managing food system contradictions. Globalised, industrial food systems have contributed to pandemic risks, including COVID-19 Smith . COVID-1The paper proceeds as follows: we first provide a snapshot of food insecurity during the pandemic, and the response. We analyse the rise of the dominant ‘containment’ response of internationally-expanding US-style foodbankingHere we provide an initial snapshot of pandemic impacts on household food security and the food charity response.COVID-19 and ensuing lockdowns unleashed rising demand for food assistance in the US and UK. UK advocates reported sharp rises in food aid demands, including a 110% rise in food parcel delivery reported by the Independent Food Aid Network (IFAN) from February to December 2020  of 1996 made substantial cuts to social welfare programs Allen . CampbeWelfare has been retooled as a means of disciplining labour forces . The charitable re-channelling of food surpluses and the replacement of cash entitlements with food transfers has been documented across OECD and countries experiencing the ‘supermarketisation’ and consolidation-corporatisation of food value chains Nally . Many suThe assumed responsibility of the charitable sector for communities’ food and other basic needs invites discussion of whose interests are best served by charitable food , a growing network of food providers, offer a series of potential narrative shifts to effect organisational transformation towards social justice-oriented modelsSuch re-framings offer ways to shift anti-hunger praxis towards countering economic and environmental injustice. While many efforts have been made to characterise the political complexity and multiple motivations of actors within both radical and charitable anti-hunger responses, we recall Allen’s  suggestiFoodbanks’ more progressive programmatic and policy changes can achieve certain justice-oriented outcomes, but do not necessarily overcome class, race and other inequities built into charitable food provision. Beyond ‘telling different stories’, the exit strategy narrative risks entrenching the palliative, reformist idea that hunger can be eliminated by making a few twinges without systemic change. We recognise the risk for co-optation of radical language and narratives that allow food charities to appear motivated by transformational goals while maintaining a status quo. However, we recognise the potential of (re)framing to widen the scope of what is seen as possible at different levels of intervention, from interactions within charity spaces to halls of power.Having described trends shaping foodbanking praxis in the UK and US, we consider how these have shaped responses to food insecurity since the pandemic began, and whether they can be seen as containing or contesting hunger, taking our cue from Heynen ’s comparState and private funding for foodbanking has been turbo-charged in response to COVID-19. Towards summer 2020, the UK government’s food and agriculture department (Defra) announced funds of £16m and $63m to support food distribution charitiesUS state funding for foodbanking preceded the pandemic, as we showed earlier. In 2018/9, the Trump administration committed to purchasing $2.6 billion-worth of commodities for foodbank distribution to help mitigate the impact of foreign tariffs on American farmers USDA . These fThese flows have intensified following COVID-19. In May 2020, USDA approved $1.2 billion in contracts for food providers to distribute boxes of produce, meat and dairy to emergency food providers UDSA 11, posinThe federal response has been matched, if not in scope but intent, by numerous US states which provided cash or facilitated purchases of surplus food by foodbanks. For example, the Oregon legislature granted $8 million to Oregon Food Bank to meet demand KGW , while CPrivate charitable donations skyrocketed. As-yet unpublished research by one author reviewed financial statements of the top 25 US foodbanks and found an overall rise of 349% in cash income from 2019-2020, translating to an average 59% gain in net assets, belying any pre-pandemic claims to be ‘putting ourselves out of business’. Net assets of the top 4 anti-hunger groups in the USCOVID-19 reduced the capacity of many foodbanks engaged in nutrition-focused, ‘client-choice’ models and other attempts to improve charitable provision. COVID-related pressures on food supplies and lockdown restriction have made it harder for charities to be discerning in their provision and have forced established food providers to scale down more ambitious programming in order to meet basic demands for food. Connors et al. , p.4 notThese pressures have also prompted reflection about wider food system sustainability and the need for radical transformations Goodwin , just asHere we ask whether COVID-19 may have also strengthened rationales and motivations for radical shifts away from food charity that contains, but does not prevent, precarity.We have seen renewed problematisation of food charity in media discourse since the pandemic . McKendrick and Campbell  necessary Fisher . Our disOur Alliance has debated whether the future of foodbanking could support transitions towards social and environmental justice. A key question remains as to whether ‘exit strategies’ from charitable expansion might entail foodbanks’ ‘retooling’ rather than their elimination. While foodbanking has been expanding globally as a way to manage contradictions of excess and hunger in industrial food systems, pressure from social movements have led some providers to reform their practice towards healthier and more dignified approaches, while others are questioning their role altogether. The complex politics at play among foodbanking spaces and actors Dixon  can be s


DNA double-strand breaks (DSBs) are a deleterious form of DNA damage, which must be robustly addressed to ensure genome stability. Defective repair can result in chromosome loss, point mutations, loss of heterozygosity or chromosomal rearrangements, which could lead to oncogenesis or cell death. We explore the requirements for the successful repair of DNA DSBs by non-homologous end joining and homology-directed repair (HDR) mechanisms in relation to genome folding and dynamics. On the occurrence of a DSB, local and global chromatin composition and dynamics, as well as 3D genome organization and break localization within the nuclear space, influence how repair proceeds. The cohesin complex is increasingly implicated as a key regulator of the genome, influencing chromatin composition and dynamics, and crucially genome organization through folding chromosomes by an active loop extrusion mechanism, and maintaining sister chromatid cohesion. Here, we consider how this complex is now emerging as a key player in the DNA damage response, influencing repair pathway choice and efficiency. To ensure genome stability, DNA damage by both endogenous and extrinsic sources must be dealt with robustly. Without effective mechanisms to detect and repair assaults on the genome, diseases such as cancer can arise . DNA douIn eukaryotes, including yeast and humans, DSBs are predominantly repaired by two mechanisms: non-homologous end joining (NHEJ), and homologous recombination HR; . NHEJ liCtIP complex, unmasking short 3′-single-stranded DNA (ssDNA) overhangs of 60–70 bp ..cis intrtrans interactions, further favoring repair with proximal sequences.Together, these data highlight the contribution of DSB-bound cohesin. Cohesin drives contact between DSB ends and proximal sequences through loop extrusion, participating in DNA damage signaling through γH2AX spreading and promoting intrachromosomal repair. Cohesin also restrains DSB motion, restricting Cohesin enrichment is also enhanced genome wide in response to DSB induction ,154. In S. cerevisiae demonstrated that HR repair occurs in a chromatin context spatially shaped at the global level by cohesin . . S. cereWhile the importance of chromatin composition and organization for DNA repair has become increasingly clear, more work is now required to precisely define the actors and molecular mechanisms at work in these processes. In particular, deciphering how chromatin compaction and the protein or DNA modifications associated with heterochromatin regulate DNA repair pathway choice is crucial, particularly in regard to the development of genome editing tools for therapeutic approaches.The cohesin complex and its activity as a molecular motor, capable of forming chromatin loops, has emerged as a key player in detecting and responding to DNA damage and, therefore, promoting DNA repair and genome stability. Recent advancements in our knowledge of how this complex works and the technology available for observing its functions at a molecular level, make it likely that we will continue to see novel roles attributed to cohesin for correct DNA repair in the near future. How cohesin interacts with heterochromatin and whether its role there is relevant for DNA repair has not yet been addressed and should be investigated.A better understanding of cohesin function in DNA repair could be particularly relevant for understanding how cohesin dysfunction affects tumorigenesis. Indeed, cohesin is frequently deregulated in cancer cells, notably in bladder cancer and myeloid neoplasms . The fac


Inspired by nature, the biomimetic approach has been incorporated into drug nanocarriers for cancer targeted chemotherapy. The nanocarriers are cloaked in cell membranes, which enables them to incorporate the functions of natural cells.Nanocarriers surface engineered with cell membranes have emerged as a fascinating source of materials for cancer targeted chemotherapy. A distinctive characteristic of cell membrane-coated nanocarriers (CMCNs) is that they include carbohydrates, proteins, and lipids, in addition to being biocompatible. CMCNs are capable of interacting with the complicated biological milieu of the tumor because they contain the signaling networks and intrinsic functions of their parent cells. Numerous cell membranes have been investigated for the purpose of masking nanocarriers with membranes, and various tumor-targeting methods have been devised to improve cancer targeted chemotherapy. Moreover, the diverse structure of the membrane from different cell sources broadens the spectrum of CMCNs and offers an entirely new class of drug-delivery systems.This review will describe the manufacturing processes for CMCNs and the therapeutic uses for different kinds of cell membrane-coated nanocarrier-based drug delivery systems, as well as addressing obstacles and future prospects. Cancer has been a worldwide concern for a long period of time and is the second largest cause of mortality . Conventco-glycolic acid) (PLGA) core and a red blood cell (RBC) membrane shell, using a co-extrusion process  and then the lipid tail was inserted into the cell membrane. Inserting a protein-conjugated lipid into the cell membrane enables protein affixing without disturbing membrane surface proteins, thereby increasing the likelihood of membrane proteins retaining their intact structure. However, chemical conjugation of lipid moieties with a protein may alter the configuration of associated proteins. Strategies for conjugating proteins with lipid moieties at specific sites must be carefully designed to minimize possible configurational changes. Another substance used to modify the vesicles derived from the cell membrane is nucleic acids. Aptamers are short single-strand oligonucleotides that may precisely attach to a target substrate. Peng et al. used the 26-mer G-quadruplex oligonucleotide AS1411, which binds to nucleolin, to modify the membrane of cancer cells  ester to improve tissue penetration [Modification of RBC membranes with specific ligands can improve delivery to target tissues. For example, when RGDyK peptide was inserted into the RBC membrane used for coating of drug nanocrystals, they had a better distribution to tumors and antitumor efficacy than nanocrystals coated with unmodified RBC membrane or plain nanocrystals . The CDXetration . The modWhite blood cells (WBCs) are colorless, nucleated spherical blood cells that influence disease progression. Nanocarriers surface engineered with a WBC membrane have been widely used as anticancer drug carriers in recent years due to their immune escape and active targeting abilities . The mosMacrophages are classified as M1 or M2 depending on their activation state. M2 macrophages reduce inflammation, suppress the immune system, and promote tumour growth, whereas M1 macrophages cause inflammation, stimulate the immune system, and extinguish tumour tissue . M1 macrPlatelets are nucleate cells of blood produced by megakaryocyte fragmentation and are involved in tumor metastasis, thrombosis, and blood coagulation . PlateleIn recent years, the number of platelet membrane coated drug delivery systems has increased rapidly due to their easy extraction, purification, and accumulation at cancer sites . Rong etCancer is described as abnormal cell growth that could lead to metastasis. Cancerous cells’ membrane display a variety of tumour-specific adhesion and antigen moieties. There are a wide range of molecules involved in cell–cell and cell–matrix adhesion, such as mucoprotein-1, epithelial adhesion moieties, lymphocyte-homing receptors, galectin-3, integrins, and cadherins , 136. CaMembranes of cancer cells have the feature of homologous targeting that can be used for targeting homologous toumors . In thisT cells play an important role in adaptive immune responses . T cellsT cell membranes were used to wrap PLGA nanocarriers loaded with dacarbazine . In thisDendritic cells (DCs) are immune cells that gather around cancer cells due to immune signals (such as pathogen-associated molecular patterns and proinflammatory cytokines). They transfer tumor-associated antigens to lymph nodes to establish communication with naive T cells for differentiation into attack cancer cells and mature T cells . For thiHybrid membranes can be used to combine the properties of a variety of cell membranes and optimize their function . In geneThe leukocyte membrane is considered a naturally occurring coating material with the biomimetic potential, capable of evading immune system capture and inflammatory targeting via inducing inflammation via specialized ligand-receptor interaction . VectorsSun et al. developed a cancer cell-RBC hybrid membrane coated gold nanocage loaded with doxorubicin to treat breast cancer via chemotherapy, photothermal therapy, and radiotherapy . HomologHe and Su’s group previously described the use of HMCNs based on RBC and retinal endotheliocyte membranes for non-invasive therapy of choroidal neovascularization . The RBCNumerous advantages have been reported for CMCNs, particularly in terms of biocompatibility and targeting. Synthetic DDSs currently available are basically foreign substances with the potential for immunogenicity and toxicity. Whereas cell membranes are endogenous, they are considered biocompatible and perform a variety of biological functions like the source cell. However, certain issues must be resolved before these carriers can continue to evolve and move from the laboratory to the clinic.The first and most important question to be addressed is about the yield of cell membranes and extracellular vesicles. Not only do existing separation technologies produce a negligible amount of cell membranes and extracellular vesicles, but they are also prohibitively expensive for large-scale production. As a result, more sophisticated large-scale manufacturing methods are required to continue expanding the application of cell membrane. In recent years, to address the yield issue, extensive work has been carried out on techniques which are used for generating artificial vesicles when the membrane is ruptured via extrusion. For example, the same number of THP-1 cells yield more than twice as many simulated exosomes as natural exosomes, and the drug encapsulating and releasing rates of the simulated exosomes are also higher . The extMoreover, a complete understanding of the mechanism of transporting cell membranes extracted from different sources in vivo is unknown and requires further research. For example, therapeutic molecules delivered by white cell membrane carriers may activate immune system components and cause inflammation . When caThe development of therapeutics derived from cell membrane material is a rapidly growing field of research that is particularly appealing because it involves an organic cellular networking system. Biomimetic technology has the advantage of taking advantage of the natural mechanisms of living matter, but it is also a double-edged sword. It is difficult to know which components, out of the multiple factors, confer membrane functionality, and so the ratio of each component needs to be modified as needed. To develop drug-containing membrane-coated carriers, a similarly and standardized manufacturing process will be required. Despite the difficulties associated with processing variables, manufacturing, and quality control, vesicles derived from natural cells have the advantage of being bioactive, reflecting the features of the parent cells. Although membrane-coated nanocarriers face numerous challenges, a powerful advantage of ‘mimicking nature’ overrides many disadvantages of traditional DDSs and offers a more efficient approach for cancer treatment. With the rapid advancement of nanotechnology, proteomics, bioinformatics, pharmacology, and material science, it is expected that the combination of DDSs and cells will overcome numerous obstacles, revolutionize current medical technology, and open up new avenues for targeted cancer therapy.


Breast cancer (BC) develops from breast tissue and is the most common aggressive malignant tumor in women worldwide. Although advanced treatment strategies have been applied and reduced current mortality rates, BC control remains unsatisfactory. It is essential to elucidate the underlying molecular mechanisms to assist clinical options. Exosomes are a type of extracellular vesicles and mediate cellular communications by delivering various biomolecules . These bioactive molecules can be transferred to change the transcriptome of target cells and influence tumor-related signaling pathways. Extensive studies have implicated exosomes in BC biology, including therapeutic resistance and the surrounding microenvironment. This review focuses on discussing the functions of exosomes in tumor treatment resistance, invasion and metastasis of BC. Moreover, we will also summarize multiple interactions between exosomes and the BC tumor microenvironment. Finally, we propose promising clinical applications of exosomes in BC. According to Globocan estimates, breast cancer (BC) is one of the most commonly diagnosed cancers in both sexes combined and is the leading cause of cancer death among females. New data published in 2020 suggest that 30% of women in United States will develop BC during their lifetime, and 15% of patients will die from it . In addiBreast cancer is a heterogeneous disease that exhibits extensive genomic, transcriptomic, and proteomic dysregulation. With diverse gene expression of steroid hormone receptors  and human epidermal growth factor receptor 2 (HER2), and BC is classified into four molecular subtypes. Such heterogeneity has resulted in marked differences in therapeutic options ; Table 1Exosomes are a separate type of endosome-released nanometer-sized extracellular vesicles released by all kinds of eukaryotic cells. Vesicles originating from various cells are classified into two main types, exosomes and ectosomes, all of which are cell-derived vesicles that are enclosed by lipid bilayers, with diameters ranging from 30 to 2,000 nm . The proExosomes are distributed through human body fluids to transport their cargos to cells in the vicinity or dwelling remotely, which brings notable advantages to detecting potential pathological conditions. The uptake mechanisms of exosomes are widely discussed, including direct plasma membrane fusion and endocytosis, such as micropinocytosis  and phagExosomes are secreted by almost every kind of cell and play an important role in cell-cell communication . They coThe tumor microenvironment often refers to a dynamic region intrinsic to the solid tumor. In addition to tumor cells, it also embodies multiple cell types and non-cancerous components such as fibroblasts, immune-related cells , adipocytes and endothelial cells. These cells each with diverse biological contributions constitute an integral part of the unique microenvironment for BC cells. Meanwhile, they have crucial roles in local interact with BC progression. For example, cancer-associated fibroblasts are believed to suppress BC microenvironment immunity and was exemplified in the work undertaken by Also, the tumor microenvironment provides a milieu for communication between cancer cells and surrounding immune cells, fibroblasts, endothelial cells, and adipocytes. Interactions between malignant cells and non-malignant cells in the tumor microenvironment occur via exosomes, soluble cytokines or signaling molecules that cancer cells are capable of manipulating to their own advantage in processes such as angiogenesis, immune evasion, migration, metastasis, and drug resistance . Under tIn this review, we summarize the multifaceted functions of exosomes in BC therapeutic resistance, invasion, and mediation of the tumor microenvironment to better understand and treat related malignant progression. In addition, their potential applications in diagnosing and providing novel clinical therapeutic options are also discussed in the section “Conclusion.”The tumor microenvironment is often described as the soil where tumor cells grow, which is formed by a variety of normal cells, signal-transmitting molecules, blood vessels, and extracellular matrix . ConsequImmunoediting in cancer is a dynamic process, which further determines tumor progression. The distinct modes between immune cells and cancer cells result in widely different outcomes. Immune cells like dendritic cells play a central role in immune responses against cancer. On the contrary, infiltration by plasmacytoid dendritic cells was found correlates with decreased overall survival and poor relapse-free survival in BC . BesidesMeanwhile, the function of exosomes that arise from the tumor microenvironment on the malignant progression of BC cells is also significant . It was Immunological surveillance plays a vital role in the generation and maintenance of the anti-tumor function of the immune system , and stuAs discussed above, the BC tumor microenvironment contains specific immune sub-populations such as immune surveillance evasion and immune regulation contributed to inhibited anti-tumor immune response of host cells. Several anti-inflammatory mechanisms presented by reciprocal interactions between BC cells and tumor microenvironment by utilizing exosomes as mediators have been summarized. In section “Conclusion,” the above findings demonstrated that blocking cancer-derived exosomes may have favorable impacts for treating BC.Fibroblasts are known as non-vascular, non-inflammatory, and non-epithelial cells in surrounding tissue. Their secretion of growth factors, various chemokines and extracellular matrix facilitates recruiting the endothelial cells and pericytes. They are also found activated into cancer-associated fibroblasts and become a key determinant in the malignant progression of tumor including metastasis, invasion, resistance, and imply an important target in cancer treatments . As pionAnother investigation found that exosomal miRNA-9 was transmitted from BC cells to normal fibroblasts and resulted in enhanced cell motility. Furthermore, this miRNA was also released by fibroblasts and was in turn capable of altering tumor cell behavior via extracellular matrix remodeling pathways . AdditioThe underlying mechanism of how normal fibroblasts were reached and transformed by cancer-associated fibroblasts-derived promoting cytokines is unclear. Closer investigation into this question found that promoting cytokines gained the ability to effectively break the extracellular matrix barrier after loading into exosomes and reached normal fibroblasts during the early stages of BC development. Diffusion of exosomes was enhanced with the aid of extracellular matrix fibril alignment in a force-dependent manner .in vitro and in vivo, probably by functioning as a specific receptor for both tPA and plasminogen , and circular RNA (circRNAs) . MasteriRecent evidence has revealed that exosomes play a major role not only in regulating drug resistance but also in transferring resistance to drug-sensitive BC cells. Furthermore, resistance can be inherent in the tumor cell itself or initiated by treatment with anticancer drugs (acquired resistance) and results in poor prognosis in cancer patients . Clear aVal was demonstrated capable of suppressing BC development through inhibiting FZD3/Wnt/β-Catenin signaling pathway, which could serve as a potential diagnostic biomarker (A growing volume of literature during the past decade indicates that non-coding RNAs are not the previously commonly deemed non-functional “junk” . Indeed,iomarker . AlthougExosome cargo includes several types of nucleic acids, including miRNAs, lncRNAs and mRNAs. Substantial evidence indicates that exosomes are crucially involved in the development of BC drug resistance by transmitting RNA. For instance, one finding indicated the possibility that drug-resistant BC cells conferred resistance to drug-sensitive BC cells partly by releasing specific exosomal miRNAs and thereby enhancing the general resistance of MCF-7/S after co-culture . SpecifiWhile BC cell malignant activities may be modulated by lncRNAs, the underlying drug resistance mechanisms within exosomes are still largely unknown. A recent study indicated that the lncRNA AFAP1-AS1 is highly expressed in trastuzumab-resistant BC cells. Notably, this specific lncRNA disseminated trastuzumab resistance to other BC cells through transmission in exosomes to further associate with AUF1 and activated ERBB2 translation, which did not influence mRNA expression . AnotherIn addition to the various microRNAs and lncRNAs discussed above, circRNAs have also been detected in exosomes. Although exosomal circRNA and its associated functions have been little studied in BC drug resistance, some articles have revealed exosomal circRNA roles in other types of cancers. For example, the metastatic ability of liver cancer cells was enhanced by transferring exosomal circRNA-100338, affecting human umbilical vein endothelial cells and their proangiogenic activity . Similar2 + and activated T-cell isoform c3-induced mechanism through accumulation and transfer in extracellular vesicles. In addition, upregulation of exosomal Trpc5 has a unique role in trapping Adriamycin and partially transferring chemoresistance from drug-resistant BC cells to non-resistant cells (Various oncogenic proteins and oncometabolites are prominent players in BC progression. Data provided by nt cells . Exosomant cells . In addint cells . Similarnt cells . Expressnt cells .Unfortunately, chemotherapy stimulates the creation of undesirable products while killing cancer cells. It was demonstrated that intensive chemoresistant therapeutic-induced senescent cells were generated after chemotherapy and helped form stem cell niches that contributed to metastasis. Importantly, increased extracellular vesicles and exosomes containing key proteins involved in tumor progression were harvested from and regulated by therapeutically induced senescent cells in TNBC cells. Additionally, expression of the multidrug resistance protein 1/p-glycoprotein was increased in therapeutically induced senescent cells. Taken together, these finding indicate that extracellular vesicles in therapeutically induced senescent cells TNBC cells are overexpressed and partially aid in conveying resistance to chemotherapy .Although various exosomal cargos are closely correlated with BC therapeutic resistance, exosomes themselves are also influenced and play vital roles in impairing BC therapy efficiency. For example, a previous investigation found that exosomes influenced the outcomes of antibody drugs by regulating their binding to tumor cells . BesidesRadiotherapy also provides an effective option for treating BC; however, resistance to radiotherapy has been identified in large-scale studies. Some findings indicated that exosomes engaged in this process. For example, a study investigating the effect of X-ray irradiation on differences in exosome activity in MCF-7 BC cells found that exosome biogenesis and secretion were activated in a dose-dependent manner, revealing the potential of exosomes to convey resistance to radiotherapy in BC cells . In addiWhile many drug-resistance incidents induced by exosomes and their contents in BC cells have been discussed above, it is noteworthy that some findings also revealed that exosomes have a role in relieving or reversing resistance in BC. A novel study identified an agent called d rhamnose β-hederin that attenuates resistance traits in docetaxel-resistant BC cells and reduces tumor burden by decreasing exosome secretion . In addiThese data indicated that BC exosomes mediate resistance via multiple different interventions and revealed conceivable values of exosomes as diagnostic and prognostic biomarkers. Nevertheless, clinical trials are needed to further demonstrate the ability to target exosomes and their effects in practical treatment.Although developing strategies have been applied to treat BC, including surgical intervention, chemotherapy, radiotherapy, and hormone therapy, challenges have also arisen . Drug reIn contrast to traditional “solid biopsies,” liquid biopsy provides a non-invasive method to both consistently monitoring and improving our knowledge about the BC metastatic process . By analin vitro (Not only exosomes, other extracellular vesicles are found to play a role in liquid biopsy. With clinical validation, a novel technology using nanopatterned microchips was reported to monitor tumor progression and metastasis. This technology demonstrated matrix metalloproteases-14 on extracellular vesicles to detect cell invasiveness in vitro . Howeverin vitro .To sum up, different content of bioliquid exosomes may applied in diagnosing and predicting treatment response of patients with BC.in vitro. Delivery of anti-miRNA-142-3p downregulated levels of miRNA-142-3p, which further increased the transcription of certain target genes and consequently led to reduced tumorigenicity (in vitro and in vivo (Exosomes are promising natural carriers of biomolecules or anti-tumor agents because they decrease clearance in the circular system and increase specificity toward target cells after modification by surface proteins and engineered targeting methods. For example, bone marrow-derived mesenchymal stem cell-released exosomes were designed to be loaded with anti-miRNA drugs and efficiently transferred into BC cells genicity . In addigenicity . One of  in vivo .Exosomes were also engineered to retarget recipient cells to increase the efficiency of delivery and improve anti-tumor ability. TNBC has a poor prognosis due to a lack of appropriate therapeutic targets, and clinical chemotherapeutics are often restricted by easy drug removal. As a result, exosomes that possess traits of delivering cargos without elimination in circular systems were designed to improve the efficacy of chemotherapeutics. In a recent study, macrophages released exosomes with coated nanoparticles engineered by a peptide that was capable of specifically targeting the mesenchymal-epithelial transition factor. As this transition factor was found to be overexpressed in TNBC cells, the cellular absorption efficiency was greatly improved and further led to enhanced inhibition of tumor growth and increased tumor apoptosis . In addiOwing to tumor evasion of the immune system, stimulating immune responses using an exosome-based vaccine represents a promising treatment for cancer. in vivo and in vitro, as antibody-tagged cancer-derived exosomes were internalized and eliminated by macrophages, leading to decreased metastatic incidence (Exosomes are thought to involved in multiple stages during invasive processes and likely contributed to early steps participated in metastasis. For example, it was collaborated that ASPH network regulated designated exosomes to enable deliver of pro-oncogenic secretome and disseminating for long-distance matastasis . Besidesncidence . Interesncidence . The aboncidence .As discussed in previous studies, modulated exosomal secretion is also involved in improving BC clinical treatment. For example, a specific drug called d Rhamnose β-hederin was investigated to explore its effects in treating BC. It was demonstrated that this novel drug reduced the formation and release of exosomes derived from docetaxel-resistant BC cells, which contributed to reversing docetaxel resistance . SulfisoWhile exosomes offer solutions to many challenges that are encountered by clinicians in the treatment of BC, they are not devoid of obstacles. Many mechanisms inhibit their successful therapeutic application, including potential immunogenicity, the risk of stimulating metastasis, and intracellular heterogeneity . With thExosomes are a range of nanosized extracellular vesicles that play pleiotropic roles in BC development and progression. By transferring various cargos, including proteins, lipids and RNA, they are capable of modulating intercellular interplay in the tumor microenvironment. This review brings together their roles in BC therapy resistance and their mediating and communicating functions in the tumor microenvironment.Exosomes may represent novel and accessible biomarkers of various cancers, as they are nearly ubiquitous in human cells. Moreover, there is rapidly growing evidence that exosomes are potential carriers of therapeutic agents or can be designed as vaccines to improve targeting and treatment efficiency in BC cells. Thus, the role of exosomes and their contents has become a promising research hotspot. However, which method is optimal for utilizing engineered exosomes is still unclear, and more efforts are warranted for safer and better clinical application of exosomes. Taken together, we summarize the pivotal roles of exosomes in orchestrating the tumor microenvironment and promoting BC pathological states. Fresh insights emphasizing treating BC with exosome-involved strategies are provided as well.XW: conceptualization and writing–original draft preparation. CS: writing–review and editing. XH: visualization. JL and ZF: supervision. WL: project administration. YY: funding acquisition. All authors read and agreed to the published version of 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The frequent involvement of the spine and sacroiliac joint has justified the classification of psoriatic arthritis (PsA) in the Spondyloarthritis group. Even if different classification criteria have been developed for PsA and Spondyloarthritis over the years, a well-defined distinction is still difficult. Although the majority of PsA patients present peripheral involvement, the axial involvement needs to be taken into account when considering disease management. Depending on the definition used, the prevalence of axial disease may vary from 25 to 70% in patients affected by PsA. To date, no consensus definition has been reached in the literature and the definition of axial involvement in PsA has varied from isolated sacroiliitis to criteria used in ankylosing spondylitis. This article reviews the unmet needs in the clinical and radiological assessment of axial PsA, reporting the various interpretations of axial involvement, which have changed over the years. Focusing on both imaging and clinical standpoints, we reported the prevalence of clinical and radiologic features, describing the characteristics of axial disease detectable by X-rays, magnetic resonance imaging, and PET-CT, and also describing the axial symptoms and outcome measures in patients affected by axial disease. Psoriatic arthritis (PsA) is a common chronic and potentially debilitating inflammatory arthropathy, affecting 0.4–2% of the general population , and froThe frequent involvement of the spine and sacroiliac joint has justified its classification in the Spondyloarthritis (SpA) group . The PsAFew studies compare axial PsA to ankylosing spondylitis (AS) and axial SpA , and simThe axial involvement in PsA was described more than 50 years ago, with the detection of changes in the sacroiliac joints, such as erosion and sclerosis . The defIn the Toronto PsA cohort, 15% of PsA patients without axial involvement at baseline are estimated to develop axial PsA during a follow-up period of 10 years ; the risCervical axial PsA occurs in 35–75% of cases ,15,16, mThe definition of sacroiliitis is still debatable. Battistone et al.  defined At present there is no clear distinction between axial involvement in PsA and the other spondyloarthritis (SpA). The current classification criteria for SpA (ASAS)  and PsA PsA has a polymorphic clinical phenotype, the majority of patients present peripheral disease as an early onset symptom and only the minority are diagnosed as having exclusive axial involvement . Often, IBP is the most typical symptom associated with axial disease, as well as AS , and is These data support the idea that clinical symptoms are not accurate predictors of cervical spine involvement, therefore erosive and progressive PsA might be screened for atlanto-axial instability, a potentially serious complication. Recently, the CORRONA registry database included data from 2330 PsA patients from 25 states in the United States. A sub-analysis about axial-PsA involvement was performed in the CORRONA registry among patients enrolled between March 2013 and March 2016. Axial involvement was defined as physician-reported spinal involvement at enrolment and/or when imaging showed sacroiliitis; patients without axial symptoms were defined as patients with no axial involvement. According to this definition, axial PsA was described in 12.5% of the 1530 PsA patients enrolled . PatientTo date, there is no specific and shared tool to measure clinical axial involvement in PsA. The more usual scoring measures have been borrowed from AS, such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Ankylosing Spondylitis Disease Activity Score (ASDAS), and the Bath Ankylosing Spondylitis Functional Index (BASFI). The INSPIRE study  tested whether the axial measures used in AS were also reproducible for axial PsA ,34. TheyRadiographic axial PsA was first reported in 1961 , when itNowadays, the modified New York criteria  are usedAlthough there are no clear discriminative radiographic scores differentiating axial PsA and AS, published data suggest that axial disease in AS has a worse clinical impairment compared to axial PsA. Radiographic sacroiliitis in PsA was reported more frequently unilateral and less severe than in AS ,38. TherA specific radiographic scoring system for axial PsA was developed by Lubrano et al., called PASRI (Psoriatic Arthritis Spondylitis Radiology Index) . This scIbrahim et al.  reportedMagnetic Resonance Imaging (MRI) allows a high-resolution visualization of the structures involved in arthritis. The knowledge of MRI in PsA derives from studies of SpA patients, including limited numbers of PsA patients . Signs oAxSpA MRI lesions of the spine mainly consist of bone marrow oedema/osteitis related to inflammation at the intervertebral disc’s enthesis. Typical locations of inflammation are the anterior and posterior vertebral body corners. The Assessment in Spondylarthritis international Society–Outcome Measures in Rheumatology (ASAS/OMERACT) MRI working group suggested that the presence of anterior/posterior spondylitis in three or more sites is highly suggestive of axial SpA, giving a minor role to other sites of inflammatory lesions . More reThe CANDEN scoring system requires a dedicated MRI protocol, with high-field scanners  using 4-mm-thickness T1-weighted turbo spin-echo and short tau inversion recovery (STIR) sequences on the sagittal plane. Separate cervical, thoracic, and lumbar spine acquisitions should compose the examination. Of note, sagittal slices must include the spinal canal  and the pedicles  . LateralWhole-body MRI is a useful screening tool to detect bone lesions in multiple myeloma as it can provide, in less than an hour, a complete assessment of the whole body . It alsoSince the syndesmophyte formation is not clearly identifiable on MRI, new techniques dedicated to bone remodelling, such as PET-CT, may play a role . In receSpine involvement in PsA is a frequent and underdiagnosed feature, particularly in the early phase of the disease . TypicalTo date, spine involvement in PsA is not clearly defined, neither from a clinical nor radiological standpoint, making it difficult to ensure a precise diagnosis and follow-up. In clinical practice, but also in clinical trials, spine assessment using imaging is not frequent, except for cases in which the spine involvement is predominant or drives the therapeutic decision. Thus, the presence of radiological axial involvement in patients who do not complain about axial symptoms may modify the therapeutic approach according to EULAR recommendations . FurtherThe clinical assessment of axial involvement in PsA relies on subjective or patient-reported measures of disease activity already in use in AS, such as ASDAS, BASDAI, BASFI. An important limitation is that many of the items are redundant . The therapeutic approach in axial PsA is currently of great interest. To date, according to the EULAR recommendations , if axiaNew imaging tools are needed to identify spinal PsA involvement for drive treatment strategy and to test the efficacy of new drugs. These tools, using MRI for early lesions or X-rays for established ones, should be easy and feasible as AS clinical tools, such as BASDAI, ASDAS and BASFI, do not seem specific enough. There is an increasing need to correctly define and identify axial PsA without using AS clinical and imaging tools. Nowadays, there is no specific clinical assessment for axial PsA; further research may consider a new tool based on PsA patients’ axial symptoms.A modified index for radiologic assessment of axial involvement in psoriatic arthritis (PASRI) was proposed in 2008 : it inclThe gold standard technique to identify early spine involvement and inflammatory alterations on posterior elements is MRI, but information on syndesmophytes morphology and sclerosis could be missed. A new integrated spine PsA assessment using X-rays and MRI should be tested to identify the underdiagnosed progressive axial disease. The aim may be to screen patients correctly at the onset of the disease. Further research in Nuclear Medicine imaging using a calcium metabolism tracer is needed to test the role of NaF18 in axial PsA identification and quantify its metabolic activity. Since data from PET imaging are quantitative, this technique adds a major dimension to assess disease activity and is a promising strategy to identify disease progressors. Prospective and longitudinal cohorts are needed to allow the characterization of axial involvement in PsA and to aim a consensus definition of axial PsA. Once a definition is formulated, an enhancement in the assessment tools and management strategies is desirable.


The tumor microenvironment (TME) is populated by abundant cancer-associated fibroblasts (CAFs) that radically influence the disease progression across many cancers, including the colorectal cancer (CRC). In theory, targeting CAFs holds great potential in optimizing CRC treatment. However, attempts to translate the therapeutic benefit of CAFs into clinic practice face many obstacles, largely due to our limited understanding of the heterogeneity in their origins, functions, and mechanisms. In recent years, accumulating evidence has uncovered some cellular precursors and molecular markers of CAFs and also revealed their versatility in impacting various hallmarks of CRC, together helping us to better define the population of CAFs and also paving the way toward their future therapeutic targeting for CRC treatment. In this review, we outline the emerging concept of CAFs in CRC, with an emphasis on their origins, biomarkers, prognostic significance, as well as their functional roles and underlying mechanisms in CRC biology. At last, we discuss the prospect of harnessing CAFs as promising therapeutic targets for the treatment of patients with CRC. Colorectal cancer (CRC), a term referring to colonic cancer and rectal cancer synonymously, ranks the third most common malignant disease across the world and accounts for 9.2% cancer-related mortality . DespiteIt is now becoming increasingly clear that CAFs can originate from diverse potential cellular precursors through distinct mechanisms. As known, normal resident tissue fibroblasts upregulate the expression of smooth muscle α-actin (α-SMA), the most common marker of myofibroblasts, and acquire a myofibroblast-like phenotype upon de novo activation by numerous soluble factors, such as the transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) secreted from the neighboring tumor cells . While lCancer-associated fibroblasts are present in high abundance in CRC . Althougin vitro and in vivo  stimulates the accumulation of CAFs within CRC tissues partly through transdifferentiation of resident fibroblasts . Additioin vivo needs more investigations. Analogous to activation process following liver damage, the quiescent hepatic stellate cells (HSCs), a subset of liver-specific pericytes, are activated and differentiated into myofibroblasts when tumor micrometastases are developed in liver lobules . It is known that bone marrow-derived MSCs can travel to tumor stroma, where they differentiate into CAFs. In an in vitro co-culture model, CRC cells have been reported to induce differentiation of MSCs into CAFs by cell–cell contacts, which is mediated by Notch-Jagged1 signaling and downstream activation of TGF-β/Smad pathway . This st lobules . A recen lobules . These f lobules . Neverth lobules . It woulIt has been established that the MSCs have the potential to differentiate into mesenchymal tissues like osteocytes, chondrocytes, and adipocytes. They also have a differentiation potential beyond the mesenchymal lineage, such as myogenic, cardiomyogenic, and neurogenic potentials . BesidesA number of markers that are highly expressed in CAFs, such as the α-SMA, fibroblast activation protein alpha (FAP), fibroblast-specific protein 1 (FSP-1), platelet-derived growth factor receptor-α (PDGFRα) and PDGFRβ, have already been widely used to identify or isolate CAFs from the pool of fibroblasts present in the whole body . HoweverAlong with the appearance of a growing body of potential markers of CAFs, accumulating evidence has also related some markers to the roles involved in CRC progression. Collagen I, PDGFR-β and α-SMA have been known as molecular markers of CAFs, and in advanced CRC, their expression varies in CAFs and is significantly associated with vessel markers CD31 and CD34, indicating that individual CAFs may have different expression patterns and effects on venous invasion of advanced CRC . In consAlthough the research approaches mentioned above have yielded a cohort of promising candidate markers for CAFs, novel selection methods based on cellular functions such as lineage tracing and single-cell sequencing will be preferable for improving the identification and targeting of CAFs in CRC in a more specific manner.Cancer-associated fibroblasts accumulated in large numbers in the TME are often associated with high-grade malignancies and poor prognosis across different human cancers. The prognostic impact of CAF-derived markers or gene signatures has also been demonstrated in CRC . For exaApart from CAF markers or gene signatures, accumulating studies also have revealed other prognostic markers that are expressed in CAFs of CRC. In an immunohistochemical evaluation of 110 CRC patient cases, the ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) in CAFs was shown to be an independent prognostic factor for predicting shorter survival and a higher incidence of recurrence and lymph node metastasis . AdditioCancer-associated fibroblasts are indispensable architects in the TME that play fundamental roles to radically influence multiple malignant behaviors. Over the recent decade, increasing lines of evidence have revealed the versatility of CAFs in CRC biology, including tumorigenesis, proliferation, angiogenesis, invasion and metastasis, stemness, therapy resistance, and tumor immunity . In thisin vivo, which depends on the activation of SOX2 that drives the generation of a CAF population  from CAF cultures was found to enhance the proliferation of CRC cells stronger than those from normal fibroblasts . CAFs inin vivo . The proin vivo , CAF-enhin vivo , and CAFin vivo . The mecin vivo , the lonin vivo , and somin vivo , FGF-1/-in vivo , HGF-METin vivo , and ERKin vivo , also acin vivo , possiblTumor angiogenesis establishes new microvessels that support cancer cell proliferation by providing nutrients and oxygen. During this complex process, many angiogenic factors, especially the vascular endothelial growth factor (VEGF), play a vital role . In CRC The malignant progression of cancer is a dynamic process depending not solely on genetic alterations, but also on additional regulations by the TME . A molecIn recent years, increasing studies has indicated that an intense biochemical cross-talk between CRC cells and CAFs is forged by the CAF-secreted numerous factors, which is critical for tumor progression into a metastatic malignancy. For example, the secreted glycoprotein stanniocalcin-1 (STC1) was identified to mediate the function of the platelet-derived growth factor (PDGF) receptor signaling in increasing the migration, invasion and metastasis of CRC . TypicalRecently, growing study efforts have been devoted to understanding how metabolic reprogramming is mechanistically involved in CAF-promoted CRC progression. In orthotopic CRC models, the activated CAFs have been discovered to promote a metabolic switch favoring glutamine consumption in CRC cells, which results in increased number of organ metastases . On the in vitro and decreases metastatic spread of CRC cells to the liver  are believed to be a driving force behind tumorigenesis and also play major roles in tumor resistance and recurrence. In CRC patients, a significant increase in the number of CAFs was observed after cytotoxic treatment, and CSCs were shown to be promoted by CAFs via augmented secretion of specific cytokines, including IL-17A, which in turn lead to increased resistance to chemotherapy . Coincid+ T-cell infiltration (The immunomodulatory effects of CAFs on CRC have been observed in a progressive rat model, in which T lymphocytes and monocytes were found outside the myofibroblast-surrounded tumors . Recent ltration , hence ultration . And morltration . These oMonocytes affect the TME and induce immune tolerance . CAFs haNotably, it has been reported that CAFs can regulate immune checkpoint in CRC. CAFs in human CRC tissues constitute the major population expressing CD73, a molecule acting as an immune checkpoint to suppress immune activation through the A2A receptor, and importantly, CD73 expression on CAFs is enhanced via A2B-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73 immune checkpoint and consequently counteracts the antitumor immunity in CAF-rich CRC . Taken tAs discussed above, the increasingly deep understanding into the CAFs’ exquisite regulation of CRC pathogenesis achieved over recent years by pioneering studies has sparked vast inspirations to develop some potential mechanism-based targeted therapies, which can be classified according to their respective effects directed to each functional role of CAFs in impacting CRC, as illustrated in in vivo by the deletion of CAFs’ PKCζ supports a revised paradigm holding a view that the PKC family acts as a tumor suppressor (A number of preclinical studies have described the tight control of CRC tumorigenesis by CAFs, implicating that there are some druggable targets in CAFs that possess the potentialities for CRC prevention or intervention. For example, MyD88 signaling in CAFs contributes crucially to colitis-associated CRC carcinogenesis via promoting macrophage M2 polarization . Interesppressor . As a reppressor , also reppressor .Cancer-associated fibroblasts-secreted IL-6 and ensuing STAT3 activation promote CRC proliferation and angiogenesis. Because targeting IL-6 are effective in some inflammatory diseases in clinical trials . It is vin vitro and in vivo (The PDGF receptor signaling functions to transduce the pro-metastatic signals from CAFs into CRC cells, and inhibition of this signaling has proven useful for treating patients with some tumors . Whether in vivo . These r in vivo . This su in vivo . These sThe CAF-increased chemoresistance in CRC can be achieved via CSC self-renewal that is promoted by CAF-derived IL-17A, and accordingly, targeting IL-17A signaling impairs CSC growth and overrides chemoresistance . The antAlthough the versatile pro-tumoral functions of CAFs performed during CRC development and progression make them to be attractive and promising therapeutic targets that can be harnessed for CRC treatment, the total depletion of CAFs unexpectedly results in more aggressive tumors , demonstCancer-associated fibroblasts are crucial components of the TME which interacts intensively with proliferating tumor cells, together creating a developing tumor, including CRC. Currently, the first-line treatment options for advanced CRC are chemotherapy combined with targeted therapy. Despite some achievements in improving patients’ survival rates, the success of treatment is limited by targeting tumor cells alone. This dilemma has redirected more research attentions into investigating on the roles of the TME in the progression of CRC and their underlying mechanisms, in an effort to discover novel and more effective therapeutic strategies and targets for improving the available therapies. With the CAFs becoming the study focus, many advancements in our understanding of the CAF biology in CRC pathogenesis have been obtained in recent decade. We now know that the CAFs in CRC have heterogeneous precursors and markers, and also show a clinical significance in predicting patients’ prognosis. Mounting analyses in preclinical models have unveiled versatile roles and distinct mechanisms of CAFs that profoundly promote many key malignant behaviors of CRC, including tumorigenesis, proliferation, angiogenesis, invasion and metastasis, stemness and therapy resistance, and simultaneously attenuate tumor immune responses. These findings indisputably support the notion that CAFs can be considered as a prominent therapeutic target of stroma-based therapy in CRC treatment. However, targeting specific CAF subpopulation that promote cancer progression encounters a huge challenge in clinic, as little is known about a myriad of functions of different CAF subsets originated from their high heterogenetic nature. To address this difficulty, novel techniques like the lineage tracing and single-cell sequencing should be applied in the future to distinguish targetable subpopulations from the whole pool of CAFs within tumors. As such, the selective eradication of the tumor-promoting CAF subsets will be realized and then implemented in combination with the current therapeutic rationales for the better treatment of CRC and even other cancers.LD and NJ conceived and wrote the manuscript. JZ helped with the table drawing. YW and HC reviewed and revised the manuscript. All the authors have read and agreed to the published version of 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This paper presents an empirical study of spatial origin and destination effects of European regional FDI dyads. Recent regional studies primarily focus on locational determinants, but ignore bilateral origin- and intervening factors, as well as associated spatial dependence. This paper fills this gap by using observations on interregional FDI flows within a spatially augmented Poisson interaction model. We explicitly distinguish FDI activities between three different stages of the value chain. Our results provide important insights on drivers of regional FDI activities, both from origin and destination perspectives. We moreover show that spatial dependence plays a key role in both dimensions. Recent decades have shown a rapid growth of worldwide foreign direct investment (FDI), which led to increased efforts in research to understand the economic determinants of FDI activities. Classical explanations focus on the factors driving firms to become multinational. The Ownership-Localization-Internalization theory , industry classifications, as well as the level of capital investment. Crescenzi et al.  FDI flows as well as regional growth empirics , as well as services (NACE G to U). We moreover include typical supply-side quantities such as regional endowments of human and knowledge capital. To proxy regional human capital endowments, we include two different variables. The first variable measures regional tertiary education attainment shares labelled higher education workers. A second variable labelled lower education workers is proxied by the share of the working age population with lower secondary education levels or less.i in period t. Specifically, we define i at time t.We use data on patent numbers to proxy regional knowledge capital endowments. Patent data exhibit particularly desirable characteristics for this purpose, since they can be viewed as a direct result of research and development activities .This subsection presents the empirical results obtained from 15,000 posterior draws after discarding the first 10,000 as burn-ins. Running multiple chains with alternating starting values did not affect the empirical results, which also provides evidence for sampler convergence.Posterior quantities for upstream-, downstream-, and production-related investment flows are presented in Tables market size and population density. In addition, the corresponding third-regional effects are significant and negative. For example, an increase in the market size restricted only to neighbouring regions thus decreases the amount of FDI outflows from a given region. The table also suggests a particularly accentuated importance of a well educated working age population (higher education workers) in the origin region. The estimated impact appears much more pronounced as compared to downstream and production FDI. Moreover, for upstream FDI the third region effect associated with the higher education workers variable also appears to be positive and highly significant. Own-regional knowledge capital endowments appear to be positively associated with the generation of upstream FDI outflows. However, the impacts of regional knowledge capital endowments for upstream FDI outflows appear rather muted as compared to the other types of FDI considered. Interestingly, Table knowledge capital. Unlike other types of FDI under scrutiny, the compensation per hour variable only appears to have a significant impact for own-regional upstream FDI outflows.Table market size and population density variables. Both destination-specific variables show a positive and highly significant own-regional impact, with negative (and significant) spatial lags. Similar to the origin specific determinants of upstream FDI, the corresponding host-specific impacts appear more pronounced as in other activity types. This finding is in line with Henderson and Ono (employment in services), relative to the agriculture sector (which serves as the benchmark in the specifications).Inspection of the regional determinants to attract upstream FDI inflows shows some interesting similarities to the origin-specific characteristics. This holds particularly true for the  and Ono , Defever and Ono , or Dura and Ono , who higcompensation per hours, to be an important determinant for attracting FDI inflows. This hypothesis is confirmed by inspecting the destination-specific results across all tables. Significant negative direct impacts of this variable can be observed throughout all stages of the value chain, both concerning the own region, as well as third regions. This corroborates the findings of Ascani et al.  for downstream FDI outflows appears less accentuated as compared to upstream FDI outflows. As opposed to the results for origin-specific upstream FDIs, the third-regional effects of tertiary education attainment are insignificant. Regional knowledge capital endowments, on the other hand, appear somewhat more important for generating downstream FDI as compared to upstream FDI, with positive direct, and negative third-regional effects.Overall, the results for downstream FDI reported in Table market size and population density variables as a means to attracting downstream-related FDI inflows. Similar to destination-specific upstream FDI, educational attainment (lower and higher education workers) and the compensation per hour variable appear as important pull-factors. Concerning the regional industry mix, Table employment in industry and services) appear to be significantly and positively associated with attracting downstream-related FDI inflows. An interesting result is given by a negative and statistically significant own-regional impact of the regional knowledge capital variable. The estimated impacts, however, appear rather offset by the positive third-regional impacts. Similar results can also be found in work by Dimitropoulou et al.  levels and regional knowledge capital endowments.Empirical results for production-related FDI are summarized in Table market size shows a similar importance, along with negative third-regional effects, the direct impact of the population density variable shows a negative and significant sign. Our estimation results thus show that production-oriented FDI activities are predominantly attracted by smaller regions in proximity to urban agglomerations. For upstream and downstream activities, however, urban agglomerations seem to play a more central role. Moreover, our results imply that regional human capital endowments are particularly important for explaining upstream and downstream-oriented investment decisions. For production activities, the importance of regional human capital endowments appears slightly less pronounced. These results corroborate the findings of Strauss-Kahn and Vives (employment in industry and services) further underpins these findings.Inspection of the destination-specific determinants of production-related FDI, however, reveals markedly different patterns as compared to upstream and downstream FDI. Albeit the nd Vives , and Defnd Vives  by highlcompensation per hour variable of the host region. The negative direct impact on inflows is the strongest with a posterior mean of For attracting production-related FDI, Table and Cook  and Cresand Cook , who botThis subsection discusses the results for the spatial autoregressive origin and destination random effects, as well as the estimates of intervening opportunities from the distance matrix mentclass2pt{minimA comparison of their corresponding posterior means and standard deviations shows that all spatial autoregressive parameters are estimated with a high precision. The intensity of spatial dependence in the upstream- and downstream-specific latent unobservable effects appear similarly pronounced, with values ranging from 0.42 to 0.58. For production-related investment activities, the difference between geographical distance are negative and significantly differ from zero for all types of investment activities. Moreover, the posterior standard deviations are comparatively small, indicating that the impact of geographic distance is estimated with a high precision. Higher geographic separation of two regions is thus associated with lower FDI activities, as increased distance often raises transportation, monitoring and thus investment costs. The negative impacts reported in Tables Rather similar results for upstream, downstream and production are also reported for the distance factors collected in matrix entclass1pt{minimacommon language proxies the cultural distance between regions in the sample. As expected, the reported posterior means show a positive sign and are significantly different from zero. The third distance variable in the matrix corporate tax rates between source and target regions. In line with theoretical and empirical literature on the location choice of multinationals, the tables report significant and positive impacts to regional FDI flows when corporate tax rates in the target region are lower than in the source region (see Bellak and Leibrecht Our dummy variable measuring whether a pair of regions shares an official This paper presents an empirical study on the spatial determinants of bilateral FDI flows among European regions. Due to data scarcity on the subnational level, previous papers typically adopt a national perspective when analysing FDI dyads (see, for example, Leibrecht and Riedl fDi Markets database, which contains detailed information on regional FDI activities using media sources and company data. The data from the fDi Markets database also contains detailed sectoral information on the functional form of the FDI activity, which allows us to explicitly focus on FDI flows across different stages of the value chain. Specifically, the paper studies the origin- and destination-specific determinants of upstream, downstream, and production activities.Our data comes from the Our empirical results clearly indicate that both source and destination spatial dependence plays a key role for all investment activities under scrutiny. In line with recent literature, we find that regional market size, corporate tax rates, as well as third region effects appear to be of particular importance for all stages in the value chain. We moreover find that production-oriented FDI activities are predominantly attracted by smaller regions in proximity to urban agglomerations. For upstream and downstream activities, however, being in the same region as urban agglomerations seem to play a key role. Moreover, our results imply that regional human capital endowments are particularly important for explaining upstream and downstream-oriented investment decisions. For production activities, the importance of regional human capital endowments are less accentuated. These results corroborate the findings of Strauss-Kahn and Vives , or Defe