*Edited by Ahmed Lasfar*

This book offers outstanding approaches to understanding the role of the tumor microenvironment (TME) in cancer development and metastasis. The TME, with its multifaced role, is fundamental in the control and exacerbation of almost all cancer types. The outcome of many solid tumors is dependent on the modulation of the TME. Local tumor immunity, which is crucial in the control of cancer promotion, is one of the leading compounds of the TME. This book presents new insights and provides detailed and updated descriptions of the role of the TME in the control and the development of almost all cancer types. This book is an authentic source of knowledge, useful for researchers, medical doctors, students, and all individuals interested in understanding the mechanisms of cancer control and development.

ISBN 978-1-83969-379-3

Tumor Microenvironment - New Insights

Published in London, UK © 2023 IntechOpen © Marcin Klapczynski / iStock

## Tumor Microenvironment New Insights

*Edited by Ahmed Lasfar*


*4.2.2 Tea consumption and NAFLD*

Tea intake modulates NAFLD by suppressing inflammation and lipogenesis while promoting fatty acid β-oxidation. *Camellia sinensis* leaves and buds are used to make green and black tea, however, due to variations in post-harvest processing, their polyphenol content varies. Catechins (flavan-3-ols), which make up about 20% of the total flavonoids in green tea leaves are the main polyphenols and EGCG (Epigallocatechin gallate) [2, 22]. In humans, between the ages of 10 and 16, drinking green tea has been shown to lower plasma levels of aminotransferases, triglycerides, and improve BMI, explaining that drinking tea helps protect against NAFLD is supported by the tight association between these factors and NAFLD. *In-vivo* research has previously demonstrated that green tea has antioxidant capabilities, it reduces the accumulation of lipids in the liver and adipose tissue and prevents intestinal absorption of dietary lipids. In the mouse model of NAFLD, green tea extract (GTE) has been discovered to protect against hepatic steatosis and related liver damage. Recent research suggests that GTE therapy reduces pro-inflammatory signals through TLR4 and TNFR1, which in turn reduces inflammation in steatohepatitis [22]. Green tea catechins have also been demonstrated to support hepatic lipid metabolism. It was suggested that oxidative degradation of fatty acids by catechins acts as a protective mechanism against NAFLD and also functioning as a natural iron chelator. It has been found that giving patients EGCG reduces non-heme iron absorption by 27%. Since elevated hepatic iron levels have been linked to NASH in patients, while catechins that block iron absorption may be a useful treatment for NAFLD. Similar to this, theaflavin from black tea reduced liver steatosis, oxidative stress, inflammation, and apoptosis in mice with NAFLD-induced ischemia-reperfusion injury [22].


**On the Role of a ZDDP in the Tribological Performance of Femtosecond Laser-Induced Periodic Surface Structures on Titanium Alloy against Di**ff**erent Counterbody Materials**

**Jon Joseba Ayerdi 1,2,\*, Nadine Slachciak 2, Iñigo Llavori 1, Alaitz Zabala 1, Andrea Aginagalde 1, Jörn Bonse 2 and Dirk Spaltmann 2**

Received: 3 July 2019; Accepted: 30 August 2019; Published: 3 September 2019

**Abstract:** Laser-induced periodic surface structures (LIPSS, ripples) with ~500–700 nm period were produced on titanium alloy (Ti6Al4V) surfaces upon scan processing in air by a Ti:sapphire femtosecond laser. The tribological performance of the surfaces were qualified in linear reciprocating sliding tribological tests against balls made of different materials using different oil-based lubricants. The corresponding wear tracks were characterized by optical and scanning electron microscopy and confocal profilometry. Extending our previous work, we studied the admixture of the additive *2-ethylhexyl-zinc-dithiophosphate* to a base oil containing only anti-oxidants and temperature stabilizers. The presence of this additive along with the variation of the chemical composition of the counterbodies allows us to explore the synergy of the additive with the laser-oxidized nanostructures.

**Keywords:** lubricant additives; laser-induced periodic surface structures (LIPSS); wear; friction


Preface

Chapter 6 **Multimodality Imaging to Detect Vulnerable Plaque in Coronary Arteries and Its Clinical Application 91**

Chapter 8 **Ethical Aspects of Vulnerable Group of Patients in**

Pablo Alejandro Millones Gómez

Sabe Sabesan and John Zalcberg

Aurora Occa and Susan E. Morgan

**Inventory (CTCI) 199**

**A Pilot Study 109** Katarzyna Rygiel

**Clinical Trials 125**

**Research 139**

**Section 4 Clinical Trials 123**

**VI** Contents

Pannipa Suwannasom, Yohei Sotomi, Yosuke Miyazaki, Erhan Tenekecioglu, Yoshinobu Onuma and Patrick W. Serruys

Chapter 7 **"Calendarium Vitae" for Hospice Patients and their Caregivers:**

Ekaterina Ivanova, Ilko Getov and Hristina Lebanova

Chapter 10 **Access to Clinical Trials Closer to Home Using Tele-health 157**

**Medical Research and Clinical Trials: A Systematic Review 177**

**Recruitment and Consent: The Clinical Trial Communication**

Soroya Julian McFarlane, Janice Krieger and JoNell E. Potter

Susan E. Morgan, Amber Finn, Jessica Raley, Wei Peng, Aurora Occa,

Chapter 9 **Nature of Vulnerability in Biomedical and Psychosocial**

Chapter 11 **Training Programs for Improving Communication about**

Chapter 12 **Assessing Communication Practice during Clinical Trial**

The book Clinical Trials in Vulnerable Populations has 12 chapters divided in four sections:

More than 30 authors came from different countries of the world, from Serbia to Turkey. The editor of this book is Professor Milica Prostran MD, Ph.D. Professor Prostran is a phar‐ macologist as well as a clinical pharmacologist with a subspecialty in clinical pharmacology - pharmacotherapy. This editorial task was due to her vast experience with publishing in respected international journals. She has published more than 200 *in extenso* papers in inter‐ national journals indexed in CC/SCI, and over 50 chapters in international and national books. Professor Prostran serves as a member (and referee) of the Editorial Board of several highly respected international journals - *Frontiers in Ageing Neuroscience*, where she is an As‐ sociate Editor, *Frontiers in Pharmacology*, *Current Medicinal Chemistry*, as well as several na‐ tional scientific and professional journals.

"Vulnerable subject - a subject who is at risk (from trialist rather than from disease). Exam‐ ples include patients with very serious diseases and with high expectations of the benefits of a new product, subjects who have a working relationship with investigators (medical stu‐ dents, nurses, employees of pharmaceutical companies, etc." (Day, 2007).

Some authors make a distinction between a vulnerable population and a special research population.

A vulnerable population includes children and minors, pregnant women, fetuses and human *in vitro* fertilization. Also, cognitive impaired persons and prisoners are included in this group.

On the other hand, a special population includes students, residents, employees, terminally ill patients and minorities (Prostran et al., 2012, Prostran et al., 2016).

The potential reader is shown the modern approach to clinical trials in vulnerable popula‐ tions, from different points of view (Medič et al., 2016). The chapters deal at length and clari‐ ty with their topics. Finally, I believe that this book I edited and reviewed with dedication will capture the attention of many readers, from medical students to practicing doctors and pharmacists. All of them must consider this very important field of medicine: clinical trial in vulnerable patients. Also, I believe that the answers to their questions may be found in this book and may make their practice at least more bearable.

Last but not least, I want to express my gratitude to Ms. Diana Olloni from InTechOpen, for her constant help during the editing of this book.

### **Professor Milica Prostran MD, Ph.D.**

**Minority Patients**

**Section 1**

Chair of Pharmacology Clinical Pharmacology and Toxicology University of Belgrade, Serbia

#### **References**

**Section 1**

**Minority Patients**

Last but not least, I want to express my gratitude to Ms. Diana Olloni from InTechOpen, for

[1] Day S. Dictionary of clinical trials, 2007.2nd edition, John Wiley & Sons, Ltd, Chi‐

[2] Prostran M, et al. Bioethics in clinical trials: vulnerable subjects. In: Bioethics and pharmacology: ethics in preclinical and clinical drug development, eds. Z Todor‐

[3] Prostran M, et al. Pharmacotherapy of pain in the older population: the place of

[4] Medić B, et al. Evaluation of novel biomarkers of acute kidney injury: the possi‐ bilities and limitations. Current Medicinal Chemistry, 2016, 23, 1981-1997.

ović, Milica Prostran and Karel Turza, 2012, 87-100.

opioids. Frontiers in Aging Neuroscience, 2016, 8, 144.

**Professor Milica Prostran MD, Ph.D.**

Clinical Pharmacology and Toxicology

Chair of Pharmacology

University of Belgrade, Serbia

her constant help during the editing of this book.

**References**

VIII Preface

chester.

**Chapter 1**

**Provisional chapter**

**Scientific and Ethical Considerations for Increasing**

Since its inception, a major weakness in clinical trial research has been an inability to recruit diverse populations into clinical trials. These under-represented populations are mostly comprised of the poor, the elderly, children, women, and racial/ethnic minorities (African Americans and Hispanics). This fundamental weakness is further exacerbated by the fact that these same groups are often disproportionately affected by the diseases being studied in clinical trials. There are various patient specific, provider specific, and policy related causes for the existence of these disparities. Regardless of the cause, the lack of participation of these groups in clinical trials raises important questions about the quality and ethics of clinical research. The goal of this document is to discuss the evidence and reasons behind disparities in clinical trial participation. We also provide a discourse on potential mechanisms to address disparities in clinical trial accrual including the ethical considerations of financial incentives, the impact of a more stringent policy and review process for product approval from the Food and Drug Administration (FDA) including a diversity mandate with an associated population black box warning.

**Keywords:** African American, hispanic, clinical trials, underrepresented, health disparities,

Since its inception, a major weakness in clinical trial research has been an inability to recruit diverse populations into clinical trials. These under-represented populations are mostly comprised of the poor, the elderly, children, women, and racial/ethnic minorities (African Americans and Hispanics). This fundamental weakness is further exacerbated by the fact that these same groups are often disproportionately affected by the diseases being studied in clinical trials. There are various patient specific, provider specific, and policy related causes for the existence

**Scientific and Ethical Considerations for Increasing**

DOI: 10.5772/intechopen.70181

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Minority Participation in Clinical Trials**

**Minority Participation in Clinical Trials**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70181

food and drug administration (FDA)

Julius M. Wilder

**Abstract**

**1. Introduction**

Julius M. Wilder

**Provisional chapter**


**3. Results**

**Figure 2** shows the PPIX formation after 3 h of cream incubation for human and porcine skin obtained by widefield fluorescence imaging. **Figure 3** shows the quantitative analysis of the PPIX formation by counting pixels of the images and spectroscopy collection acquired by fluorescence techniques. The result of this analysis was acquired by means of the average data collected from volunteers and animals. The results of the porcine skin model were also published previously [19]. The results in **Figure 3** show that the high amount of PPIX production in human and porcine skin occurs for all cream samples (ALA, M2, M3, M4, M5, M6, and MAL) after 3 h of cream application.

fluorescence techniques. From this study, it was possible to analyze which sample PPIX was produced quickest, and by means of a parameter called the index of fluorescence (IF50) it was possible to quantify the PPIX production in minutes. IF50 means 50% of maximum fluores-

**Figure 3.** Analysis of PPIX production in human and porcine skin models after 3 h of cream sample application evaluated

Correlation between Porcine and Human Skin Models by Optical Methods

http://dx.doi.org/10.5772/intechopen.75788

167

Although **Figure 4** presents the results of the human skin study, **Table 1** shows the IF50 results for the study in human and porcine skin. We have included it here for best comparison. The graphs of the kinetics study in porcine can be observed in previously published work [19].

The results for the kinetics study in the human skin model show that PPIX production is faster with ALA than MAL and cream samples (M3, M4, M5, and M6) for both fluorescence analyses. However, the mixtures M3, M4, and M5 presented better results for PPIX production than MAL in the kinetics study (IF50 values). These results suggest that these differences may be due to high variability in human skin experiments. Perhaps these differences can be reduced

The results for the kinetics study from **Table 1** show that PPIX production in 5 h (IF50) in human skin models is faster for ALA than MAL, and the opposite occurs for porcine skin models where PPIX production is faster for MAL than ALA. This can be explained by the previous preparation for porcine skin where we can suggest that PPIX production by MAL can be optimized. The other sample creams (M3, M4, M5, and M6) show the same behavior

The values found for IF50 through the widefield fluorescence imaging data were closer to human and porcine skin models than the IF50 values collected by fluorescence spectroscopy. We believe that this occurred because PPIX production is heterogeneous and the fluorescence spectroscopy measurements are punctual. This punctual fluorescence collection data of PPIX production can suggest false negative or false positive results. On the other hand, by using widefield fluorescence imaging, we can evaluate all PPIX production on the skin surface.

cence value obtained for 5 h.

by (a) widefield fluorescence imaging and (B) spectroscopy fluorescence.

by using a number of human volunteers.

considering the standard deviation.

Fluorescence imaging shows that PPIX production is heterogeneous for healthy skin in both skin models. Even so, it is possible to verify the differences in PPIX formation to ALA, MAL, and mixtures from both. The results suggest that PPIX formation is greater for ALA than for MAL for both models. In addition, PPIX formation of all sample cream mixtures from ALA and MAL (M2, M3, M4, M5, and M6) was more elevated than MAL and is similar to ALA.

In addition, it is important to mention that for porcine skin preparation it was necessary to shave the back, and for human skin preparation the area was cleaned with physiological serum. This previous skin preparation can interfere with cream sample penetration on the skin as well as PPIX production. This explains the lowest PPIX production for all samples in human skin models when compared to porcine skin models (**Figure 3**).

**Figure 4** shows the kinetics study on human skin only, wherein the monitoring of PPIX production was carried out during 5 h, and the measurements were carried out hourly for both

**Figure 2.** Widefield fluorescence imaging after 3 h of cream sample application (ALA, M2, M3, M4, M5, M6, and MAL): (A) PPIX production in human skin (inner arm) and (B) PPIX production in porcine skin back.

Correlation between Porcine and Human Skin Models by Optical Methods http://dx.doi.org/10.5772/intechopen.75788 167

the autofluorescence. The spectrum evaluations were performed using an Origin 9 program as previously described in our publication [2, 19]. A spectrometer and widefield fluorescence imaging equipment collected skin fluorescence at every full hour during 5 h. At the end of the fluorescence analysis, the cream mixtures were reapplied to the treatment area and covered

**Figure 2** shows the PPIX formation after 3 h of cream incubation for human and porcine skin obtained by widefield fluorescence imaging. **Figure 3** shows the quantitative analysis of the PPIX formation by counting pixels of the images and spectroscopy collection acquired by fluorescence techniques. The result of this analysis was acquired by means of the average data collected from volunteers and animals. The results of the porcine skin model were also published previously [19]. The results in **Figure 3** show that the high amount of PPIX production in human and porcine skin occurs for all cream samples (ALA, M2, M3, M4, M5, M6, and

Fluorescence imaging shows that PPIX production is heterogeneous for healthy skin in both skin models. Even so, it is possible to verify the differences in PPIX formation to ALA, MAL, and mixtures from both. The results suggest that PPIX formation is greater for ALA than for MAL for both models. In addition, PPIX formation of all sample cream mixtures from ALA and MAL (M2, M3, M4, M5, and M6) was more elevated than MAL and is similar to ALA.

In addition, it is important to mention that for porcine skin preparation it was necessary to shave the back, and for human skin preparation the area was cleaned with physiological serum. This previous skin preparation can interfere with cream sample penetration on the skin as well as PPIX production. This explains the lowest PPIX production for all samples in

**Figure 4** shows the kinetics study on human skin only, wherein the monitoring of PPIX production was carried out during 5 h, and the measurements were carried out hourly for both

**Figure 2.** Widefield fluorescence imaging after 3 h of cream sample application (ALA, M2, M3, M4, M5, M6, and MAL):

human skin models when compared to porcine skin models (**Figure 3**).

(A) PPIX production in human skin (inner arm) and (B) PPIX production in porcine skin back.

with an occlusive dressing.

166 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

MAL) after 3 h of cream application.

**3. Results**

**Figure 3.** Analysis of PPIX production in human and porcine skin models after 3 h of cream sample application evaluated by (a) widefield fluorescence imaging and (B) spectroscopy fluorescence.

fluorescence techniques. From this study, it was possible to analyze which sample PPIX was produced quickest, and by means of a parameter called the index of fluorescence (IF50) it was possible to quantify the PPIX production in minutes. IF50 means 50% of maximum fluorescence value obtained for 5 h.

Although **Figure 4** presents the results of the human skin study, **Table 1** shows the IF50 results for the study in human and porcine skin. We have included it here for best comparison. The graphs of the kinetics study in porcine can be observed in previously published work [19].

The results for the kinetics study in the human skin model show that PPIX production is faster with ALA than MAL and cream samples (M3, M4, M5, and M6) for both fluorescence analyses. However, the mixtures M3, M4, and M5 presented better results for PPIX production than MAL in the kinetics study (IF50 values). These results suggest that these differences may be due to high variability in human skin experiments. Perhaps these differences can be reduced by using a number of human volunteers.

The results for the kinetics study from **Table 1** show that PPIX production in 5 h (IF50) in human skin models is faster for ALA than MAL, and the opposite occurs for porcine skin models where PPIX production is faster for MAL than ALA. This can be explained by the previous preparation for porcine skin where we can suggest that PPIX production by MAL can be optimized. The other sample creams (M3, M4, M5, and M6) show the same behavior considering the standard deviation.

The values found for IF50 through the widefield fluorescence imaging data were closer to human and porcine skin models than the IF50 values collected by fluorescence spectroscopy. We believe that this occurred because PPIX production is heterogeneous and the fluorescence spectroscopy measurements are punctual. This punctual fluorescence collection data of PPIX production can suggest false negative or false positive results. On the other hand, by using widefield fluorescence imaging, we can evaluate all PPIX production on the skin surface.

**Figure 5** shows the correlation linear fitting to fluorescence measurements obtained through widefield fluorescence imaging and fluorescence spectroscopy. The fitting in **Figure 5** shows that the red fluorescence signal emitted by PPIX in the porcine and human skin was measured at 3 h following application of ALA and MAL cream mixtures. These results confirm that there is a correlation between both models since the equation line factor obtained was 0.9824,

**Table 1.** IF50 values for widefield fluorescence imaging and fluorescence spectroscopy collected over time (5 h) after

**Fluorescence spectroscopy**

Correlation between Porcine and Human Skin Models by Optical Methods

http://dx.doi.org/10.5772/intechopen.75788

169

**IF50 (min)**

**Human skin Porcine skin Human skin Porcine skin**

ALA 103 ± 15 120 ± 10 234 ± 18 230 ± 7

M3 154 ± 18 40 ± 60 312 ± 6 114 ± 16 M4 127 ± 14 128 ± 8 225 ± 13 17 ± 20 M5 122 ± 21 97 ± 7 280 ± 12 131 ± 17 M6 207 ± 38 120 ± 20 260 ± 15 187 ± 25 MAL 233 ± 18 70 ± 5 388 ± 37 131 ± 9

M2 138 ± 27 134 ± 6 315 ± 13

sample cream application on human and porcine skin model surfaces.

The same linear fitting was performed for fluorescence collected through fluorescence spectroscopy (results not presented here). However, we do not find a correlation between both models (human and porcine skin) by this optical technique due to high variability during

**Figure 5.** The best correlation analysis between human and porcine skin models by widefield fluorescence imaging.

bordering on 1.0, the ideal linear fitting number.

fluorescence spectroscopy collection.

**Samples Widefield fluorescence imaging**

**IF50 (min)**

**Figure 4.** Kinetics of the PPIX production in human skin models by fluorescence spectroscopy and widefield fluorescence imaging evaluations for all cream samples (ALA, M2, M3, M4, M5, M6, and MAL).

**Table 1.** IF50 values for widefield fluorescence imaging and fluorescence spectroscopy collected over time (5 h) after sample cream application on human and porcine skin model surfaces.

**Figure 5** shows the correlation linear fitting to fluorescence measurements obtained through widefield fluorescence imaging and fluorescence spectroscopy. The fitting in **Figure 5** shows that the red fluorescence signal emitted by PPIX in the porcine and human skin was measured at 3 h following application of ALA and MAL cream mixtures. These results confirm that there is a correlation between both models since the equation line factor obtained was 0.9824, bordering on 1.0, the ideal linear fitting number.

The same linear fitting was performed for fluorescence collected through fluorescence spectroscopy (results not presented here). However, we do not find a correlation between both models (human and porcine skin) by this optical technique due to high variability during fluorescence spectroscopy collection.

**Figure 5.** The best correlation analysis between human and porcine skin models by widefield fluorescence imaging.

**Figure 4.** Kinetics of the PPIX production in human skin models by fluorescence spectroscopy and widefield fluorescence

imaging evaluations for all cream samples (ALA, M2, M3, M4, M5, M6, and MAL).

168 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

The fitting results shown in **Figure 5** indicate the best correlation between porcine and human skin models by widefield fluorescence imaging measurements. The possibility of predicting drug behavior on transdermal skin application promotes the success of clinical topical PDT treatment.

The kinetics study observed that ALA, M4, and M5 indicated the least time of PPIX production (high PPIX production velocity) at the skin. Both studies, human and porcine skin, showed the same behavior. IF50 values acquired by widefield fluorescence imaging for both models were very close, with the exception of M3, M6, and MAL. Thereby, it is possible to appreciate the similarity of porcine skin with human skin by first performing clinical tests

Correlation between Porcine and Human Skin Models by Optical Methods

http://dx.doi.org/10.5772/intechopen.75788

171

However, it is known that *in vitro* and *in vivo* experiments using the same species show less variability than experiments using human volunteers. The authors suggest that human experiments are done using a greater number of volunteers. The measurement of the correlation coefficient proved that porcine and human skin models have the same behavior with respect to the production of PPIX in quantity as well as in speed of PPIX production through optical methods. The correlation coefficient is a measure of how well the predicted values from a forecast model fit with the real data. We suggest that the best correlation is between porcine and human skin by widefield fluorescence imaging, suggesting this optical method as an important tool to develop new clinical topical PDT protocols.

The correlation found between human and porcine skin models measured by widefield fluorescence imaging confirms that porcine skin can be used for establishing human protocols in clinical topical PDT using ALA, MAL, and mixtures from both. The capacity of porcine skin models to predict PDT results in humans can be beneficial to clinical studies optimizing PDT

The authors acknowledge the financial support of the National Council of Technological and Scientific Development (CNPq process 140370/2012-9) and São Paulo Research Foundation (FAPESP/CEPOF). Expressive thanks are extended to Ms. Michelle Requena and all the vol-

\*, Rozana Wendler da Rocha2

, Vanderlei Salvador Bagnato1

2 Department of Veterinary Clinic and Surgery, School of Agriculture and Veterinary

1 São Carlos Institute of Physics, University of São Paulo, São Carlos, SP, Brazil

, André Escobar2

and

,

on porcine skin.

**5. Conclusion**

treatment on patients.

**Acknowledgements**

**Author details**

Alessandra Keiko Lima Fujita1

Priscila Fernanda Campos de Menezes1

\*Address all correspondence to<EMAIL_ADDRESS>
Sciences, São Paulo State University (UNESP), Jaboticabal, SP, Brazil

Andrigo Barboza de Nardi2

unteers for their participation in this study.


**1. Introduction**

Anniversaries are one of the classical types of *lieux de mémoire* that the French historian Pierre Nora lists in his main work of the same name (Nora 1984–1992). Due to their value as representations of history, the power to define commemorations very directly represents instances of the production of history. They constitute multiple sites to which certain values, meanings, and emotions are attached and around which the struggle to define history takes place1. Over the past seven years, the celebration of the National Holiday of Catalonia on September 11, the *Diada*, has grown into a popular mass demonstration that has, once again, become a channel for political demands, as it was in the transition to democracy in the late 1970s after the death of Dictator Franco. During the more than 30 years between these two periods in time, the celebration of the *Diada* was taken over and institutionalised

1 For discussions of the process of creation of commemorations, see Trouillot (1995) and Zerubavel (2003). For a critical discussion of Nora's concept and of its relation to national master narratives, see Humlebæk (2018).

by the regional Government and the political parties in Catalonia. Thereby, the National Holiday, paradoxically, lost most of the popular support and mobilisation potential it had had just a few years before. The number of participants in the celebrations in Barcelona has thus fluctuated from over a million in 1977, dropping to a few tens of thousands over the period from the early 1980s to 2011, to again exceed one million participants several times since 2012.

In 1976, just over nine months after Franco's death, the *Diada* celebration was activated by a wide range of organisations and still illegal political parties, and it was linked to the central demands of the transition to democracy in the Catalan context, namely democracy and self-government. These thoughts were easily merged into the historical significance that the *Diada* had had since its invention as a memorial day in the late 1800s. Since 2012, the *Diada* has again been activated especially by the civil society organisations that have made secession from Spain their main goal, and the demands associated with the celebration are therefore their political demands for independence. They are thus not completely in line with the predominant interpretations of earlier periods of politicisation of *Diada*, yet the organisers chose this anniversary for their demonstrations of the movement's popular support. Giori argues that this is because civil society organisers did not want the demonstration to be a "reactive" event against any current political issue, but a proactive one that could cover mobilisations on a number of autonomy-related issues (Giori 2017, p. 289).

Now, the *Diada* has been celebrated eight times since its reinvention in 2012, and a certain fatigue seems to be spreading in relation to the mobilisation power because, among other things, the demands around which the celebration has been constructed have not materialised. The question remains how the organisations behind the successful mobilisation will try to maintain the popular mobilisation around the *Diada* or whether the celebration in a kind of bound cyclic movement returns to earlier participation levels. In this article, we will examine the apparent paradox that when civil society organisations are in charge of the *Diada* celebration, the result is a more politically charged event that mobilises a much larger proportion of the population than when politicians and political parties organise the celebration. Further, when political parties are in charge, the *Diada* not only mobilises far fewer people, but usually takes on a much more cultural and festive character compared with the explicitly political *Diada* demonstrations organised by civil society actors since 2012.

We investigate the recent period of activating the *Diada* since 2012 using qualitative interviews and ethnographic data in order to examine how activists and participants perceive the *Diada* and how the present perception is related to their memory of past commemorations. In particular, we want to gauge to what extent civil society organisations or political parties are driving the mobilisation around the *Diada*.

## **2. State of the Art**

Issues related to Catalan secessionism are central to current scholarship on European integration, nationalism, and territorial politics. Moreover, the debate about nationalities and nationalism is directly related to a more general debate about citizenship, diversity, and collective rights. The terminology used, however, is both unclear and heavily politicised, such as the distinction between a "nation" and a "region". Catalonia is thus sometimes described as a "nation without a state" (Keating 2001) and Catalan nationalism as "regional nationalist" (Keating 1988). The most common term in the literature, however, is "minority nationalism" (Lynch 1996; Elias 2009; Keating 2014; Griera 2016). This term works for two reasons. It shows how sub-state polities stand in a relationship to a larger whole, in this case the majority nation, and it tells us that the parties who support this ideology represent, or aim to represent, national collectives who desire statehood. Catalan politics is heavily impacted by Spanish politics; however, many of the Catalan political parties would want it to be otherwise. To some extent, the recognition of such regions as nations is predicated on the larger, majority nations' approval (Guibernau 2013, p. 369). However, as Burchardt notes, the question of who constitutes majority and who constitutes minority is quite ambiguous in stateless nations (Burchardt 2017, p. 699). Although the

people who identify as Catalans are certainly a minority within the Spanish state, they are a majority within their own territory.2

In fact, Keating has specifically described the independence movement in Catalonia as one of the "new nationalisms of Western Europe" due to its non-essentialist, inclusive, and staunchly non-ethnic character, clearly distinguishing them from far-right movements or ethno-nationalist politics (Keating 2008, p. 334). He has argued in favour of reconceptualising nationalities as "nonspatial cultural communities and endowed with various forms of nonterritorial rights" (Keating 2004, p. 373). Guibernau has even gone so far as to term the Catalan pro-independence movement "emancipatory nationalism" for its focus on democratic self-determination and progressive politics. Guibernau argues that those Western liberal democracies in which state and nation are not coextensive and where strong minority nationalist movements have emerged, such as Catalonia, Flanders, and Scotland, are examples of an emerging type of "deepening of democracy" (Guibernau 2013, p. 327). Although some authors, such as Thomas J. Miley, have argued for seeing Catalan linguistic identity as an ethnic component (Miley 2007), there is a wide consensus in the literature on Catalonia that ethnicity and ancestry have little to do with being Catalan (see for example Brandes 1990; Desfor Edles 1999; McCrone 2007; or Dardanelli and Mitchell 2014). The Catalan language can work both as an ethnolinguistic marker of inclusion or, as others have suggested, as a vehicle for the integration of foreigners and non-nationalists into a wider "Catalan culture" (Conversi 1997, p. 4). The dynamics of this socio-linguistic process are best explored in more specific texts (such as Woolard 2005; Conversi and Jeram 2017; or Wilson-Daily et al. 2018).

Specifically for the *Diada*, very little has been written on and, to our knowledge, this paper is the first attempt at a thorough empirical investigation of the most important political event in Catalonia, combining historical and ethnographic analysis that covers the current modern period. The *Diada* has been mentioned *en passant* in other works (such as Conversi 2002; Llobera 2004; or Crameri 2014, pp. 75–82), and Llobera made an analysis of the *Diada* from the 1970s to the early 1990s (Llobera 1996), but no sustained analysis of the political evolution of the event from its reinvention until the present epoch yet exists. Likewise, Michonneau has written an interesting historical account of the creation of the anniversary and its early celebration, and Anguera has written a couple of extensive accounts of the *Diada* from the origins in 1886, but none of them includes the period beyond the Civil War (Michonneau 2001, pp. 165–77, 229–51; Anguera 2003, 2008).

Nevertheless, Rubio has made an interesting comparative rhetorical-discursive analysis of the official speeches of the regional presidents on the respective national days in the Basque Country and Catalonia and, as such, comes close to our object of inquiry. However, the analysis only covers the period from 1980 to 2004 and thus omits precisely the important changes of the last decade and a half (Rubio 2015). Further, although Pablo Giori argues, as we do, that the *Diadas* since 2011 have clearly been taken over and organised by civil society actors, such as the Catalan National Assembly (ANC) and Òmnium Cultural (Giori 2017, p. 286), his analysis of the *Diada* goes a di fferent route than ours and focuses more on cultural elements such as Catalan human towers or *castellers* during the event. Lastly, Rodon et al. (2018) have performed a novel and illuminating social media analysis using Twitter data from the 2016 *Diada* but did not include a historical analysis of the evolution of the *Diada* or qualitative, ethnographic data on the contemporary understandings of the *Diada*.

Several authors such as Crameri (2015), Dowling (2017), and Della Porta et al. (2017) have noted the contemporary vitality of Catalan pro-independence civil society, although a minority of scholars have labelled the Catalan independence movement elite-driven and populist (Barrio et al. 2018). However, few have developed analyses specifically of the *Diada* and memory spaces. Kathryn Crameri (2015)

2 According to the Catalan bureau of statistics, *Centre d'Estudis d'Opinió* (CEO), 79.9% of the population of Catalonia identifies as Catalan, with 34.2% also identifying to some degree as Spanish. Exclusive Spanish identities are at only 6.5%. This is in contrast to Spain in general, where 24.7% consider themselves exclusively Spanish (Centre d'Estudis d'Opinió (CEO) 2019, p. 16).

has thus argued that civil pro-independence associations such as the ANC are playing an increasingly significant role in Catalan politics, e ffectively putting pressure on the Catalan government (Crameri 2015, p. 104), and Andrew Dowling (2017) notes that the 2012 *Diada* was organised outside the structures of political parties by the ANC. Similarly, social movements scholar Donatella Della Porta has argued that the Catalan independence movement is a "paradigmatic example" of a campaign initiated by civil society, which institutional actors and established politicians have later attempted to co-opt. (Della Porta et al. 2017, p. 31). This analysis corroborates our argument that a range of actors both institutional and coming from civil society are attempting to activate and control the *Diada*. These di ffering understandings of the purpose of the *Diada* significantly change the nature of the celebration between the more cultural and the more political. Our focus on this interplay between civil society and established politics nuances claims that the Catalan independence movement is either fully elite-driven or fully bottom-up.

Our study thus contributes to the incipient but flourishing study of the Catalan independence movement and to the more established study of commemorations and *lieux de memoire* in Spain, addressing both a methodological lacuna and a thematic one. The combination of historical analysis and ethnographic data provides us with ample data to both trace the evolution of the *Diada* as a cultural and political event, and to perform a thorough and multifaceted analysis of how leaders and activists in the Catalan independence movement perceive it and activate it in contemporary Catalan politics, focusing on the interplay between civil society and more established political actors.