General introduction

Nederlandse samenvatting
Nederlandse samenvatting
Het Hodgkin lymfoom (HL) is een maligniteit van B cellen die uit het kiemcentrum
afkomstig zijn. HL heeft een karakteristiek fenotype met een minderheid van
tumorcellen in een achtergrond van reactieve cellen. HL kan worden onderverdeeld
in twee subtypen, het klassieke HL en de nodulair lymfocyten predominante variant.
De tumor cellen van de klassieke variant staan bekend als Hodgkin Reed Sternberg
(HRS) cellen. Op basis van de kenmerken van de HRS cellen en de karakteristieken
van de reactieve cellen wordt de klassieke variant verder onderverdeeld in de
nodulair scleroserende (NS), gemengdcellige (MC), lymfocytenrijke en
lymfocytenarme subtypes.
In 30-40% van de klassieke HL gevallen in West Europa zijn de HRS cellen
positief voor het Epstein Barr virus (EBV). EBV+ HL is sterk geassocieerd met het MC
subtype, terwijl EBV- HL vooral voorkomt bij de NS variant. In tegenstelling tot de
meeste andere kankers, zien we bij HL een bimodale incidentie curve. De eerste piek
bij jong volwassenen in de leeftijd van 15 tot 30 jaar bestaat vooral uit EBV- HL van
het NS subtype. De tweede piek zien we na de leeftijd van 50 jaar en deze HL
patiënten hebben vaak EBV+ HRS cellen en een MC of NS subtype. Daarnaast
hebben jonge kinderen ook vaak EBV+ en MC subtype HL.
Op basis van eerder onderzoek is het duidelijk dat er een genetische
component is die het risico op het krijgen van HL beïnvloedt. Met name de HLA
regio en specifieke klassieke HLA allelen zijn geassocieerd met HL. Het doel van dit
promotie onderzoek is om het risico- of beschermingseffect van specifieke HLA
allelen op het ontwikkelen van HL verder te onderzoeken. Dit is gedaan voor de
totale HL populatie en ook voor specifieke subgroepen gebaseerd op EBV status en
leeftijd.
Hoofdstuk 2 is een samenvatting van de bestaande literatuur met betrekking
tot genetische varianten die geassocieerd zijn met HL of specifieke subgroepen.
Daarnaast wordt de literatuur over het effect van genetische varianten op prognose,
behandelrespons en secundaire toxiciteit samengevat. Ruwweg zijn er twee
benaderingen te onderscheiden, dit zijn de gen specifieke benaderingen en de
genoom brede studies. Bij de gen specifieke studies is er vooral veel onderzoek
gedaan naar de HLA genen en associaties in de HLA regio werden ook gevonden in
genoom brede studies. De HLA klasse I regio is sterk geassocieerd met EBV+ HL, en
de klasse II regio met EBV- HL en met de totale HL groep. De genetisch associaties
met andere gen loci op het genoom werden niet terug gevonden in de genoom
brede associaties studies. Studies over genetische varianten geassocieerd met
prognose, behandelrespons en secundaire toxiciteit lieten slechts enkele associaties
zien die over het algemeen nog niet gevalideerd zijn in onafhankelijke studies.
151
Nederlandse samenvatting
In hoofdstuk 3 hebben we gekeken welke HLA allelen geassocieerd zijn met
de hele, de EBV+ of de EBV- HL groepen. Twee allelen, HLA-B*51/52 (B5) en HLADRB1*07 waren geassocieerd met de totale HL groep. HLA-B5 dragers hadden een
verhoogd risico terwijl HLA-DRB1*07 dragers een verlaagd risico hadden op HL. In de
EBV- groep waren de allel frequenties van HLA-DRB1*11/12 (DR5) en van HLADRB1*15/16 (DR2) significant verhoogd in vergelijking met controles. In EBV+ HL
vonden we een verhoogde allel frequentie van HLA-A*01, HLA-B*37 en HLADRB1*10 ten opzichte van de controles. Deze drie allelen vormen een haplotype dat
relatief veel voorkomt in de westerse populatie en de gevonden associaties zijn dus
mogelijk van elkaar afhankelijk. De frequentie van het HLA-A*02 allel was significant
verlaagd in de EBV+ HL groep. Het risico effect van HLA-A*01 en het beschermende
effect van HLA-A*02 voor de ontwikkeling van EBV+ HL is consistent met het verschil
in affiniteit van deze twee allelen voor EBV afkomstige antigene peptiden.
In hoofdstuk 4 hebben we de HLA susceptibiliteit onderzocht in relatie tot de
leeftijd bij diagnose van de HL patiënten. De HLA-DRB1*15 HLA-DQB1*06 allel
frequenties waren significant verhoogd in patiënten ≤45 jaar ten opzichte van
controles. Ook de frequentie van het DQB1*06-DRB1*15 haplotype was significant
verhoogd in deze leeftijdsgroep. De HLA-DRB1*15 associatie komt overeen met de
bevindingen in de EBV- groep en dit kan verklaard worden doordat HL bij jonge
patiënten over het algemeen EBV- is. De HLA-B*08 en HLA-DRB1*03 allel frequenties
en de frequentie van het HLA-B*08-DRB1*03 haplotype waren significant verhoogd
in HL patiënten met een leeftijd van >45 jaar. De frequenties van het HLA-A*02 allel
dat onderdeel uitmaakt van het DQB1*06-DRB1*15 haplotype en dat van het HLAA*01 allel dat onderdeel uitmaakt van het B*08-DRB1*03 haplotype laten geen
leeftijd associaties zien.
Studies in de Chinese HL populatie lieten eerder al zien dat de associatie met
HLA-A allelen en EBV+ HL anders zijn. Het HLA-A*02:07 sub allel is een risico allel
terwijl de andere HLA-A*02 sub allelen geen risico of beschermend effect hebben.
HLA-A*01 is vrij zeldzaam in de Chinese populatie en er zijn geen aanwijzigen dat dit
allel een risico allel is. In hoofdstuk 5 hebben we HLA-A associaties in de Braziliaanse
HL populatie onderzocht. We vonden een risico profiel gelijk aan dat van de westerse
populatie. In hoeverre deze HL populatie representatief is voor de Braziliaanse
populatie is nog onzeker aangezien het percentage EBV+ HL veel lager was (34%)
dan verwacht. Normaal voor Zuid-Amerika zijn EBV+ percentages van 60 tot 70%.
Het kan zijn dat er in onze patiënten populatie relatief veel westerse patiënten zaten.
In dit promotie onderzoek hebben we de associatie tussen HLA allelen en
specifieke subgroepen van HL verder onderzocht. Het is duidelijk dat er sterke
152
Nederlandse samenvatting
associaties zijn met de totale populatie maar ook met EBV en leeftijdsspecifieke
subgroepen. Aangezien HLA moleculen belangrijke mediatoren zijn van de
immuunreactie en een specifieke subset van antigenen peptide presenteren aan het
immuunsysteem, is het aannemelijk dat de immuunreactie een essentiële component
is in de pathogenese van HL.
(Translated by Prof. Dr. Anke van den Berg and Dr. Arjan Diepstra)
153
Summary in Kannada
Kannada summary
Hodgkin lymphoma, HL)
B
B
HL
Hodgkin Reed Sternberg, HRS)
HL
,
classical Hodgkin lymphoma, cHL
Nodular lymphocyte predominant Hodgkin
lymphoma, NLPHL) HL
, cHL
Nodular sclerosis
(Mixed cellularity, MC ,
NS ,
(Lymphocyte rich, LR)
(Lymphocyte depleted, LD).
cHL
-
Epstein Barr virus, EBV)
HRS)
EBV
EBV+ cHL
cHL EBV- cHL)
NS
MC
, cHL
Bimodal age incidence)
EBV-, NS
cHL
cHL
,
EBV+
MC
EBV+
MC
cHL
(Human leukocyte
antigen, HLA)
,
,
cHL
, EBV
cHL
PhD
, EBV
HLA class II)
NS
HLA
HLA
HLA class I)
cHL
HLA
cHL
HLA
cHL
,
cHL
cHL
,
,
GWAS)
HLA
157
Kannada summary
-
HLA class I
EBV + cHL,
HLA class II
-
.
:
EBV- cHL
HLA
-
GWAS
HLA
,
NS cHL
-HLA
cHL
GWAS
,
PRDM
HLA
cHL
cHL
HLA I
cHL
HLA II
cHL
cHL
HLA
HLA
HLA-B*51/52 (B5)
EBV
cHL
HLA-DRB1*07
EBV- cHL
HLA-DRB1*11/12 (DR5)
EBV+ cHL
HLA-DRB1*15/16 (DR2)
HLA-A*01, HLA-B*37
A*01-B*37-DRB1*10
HLA-DRB1*10
, HLA-A*02, EBV+ cHL
. HLA-A*01
HLA-A*02
,
T
cHL
HLA
CHL
, HLA-DRB1*15
.
HLA-DQB1*06
.
, DQB1*06-DRB1*15
EBV- cHL
,
:
HLA-DRB1*15
EBV-
HLA-B*08, HLA-DRB1*03
B*08-DRB1*03
cHL
, HLA-A*02, EBV+ cHL
A*02-DQB1*06-DRB1*15
,
,
HLA-A*01, EBV+ cHL
A*01-B*08-DRB1*03
,
cHL
158
,
Kannada summary
, HLA-A*01
HLA-A*02
EBV+ cHL
cHL
.
EBV+ cHL
A*02:07
HLA
HLA-
EBV+ cHL
EBV- cHL
cHL
,
HLA-A
EBV+ cHL
HLA-A*01
HLA-
A*02
,
EBV+
EBV+
EBV+ cHL
HLA I
,
HLA II
cHL
cHL
HLA
cHL
HLA
T
cHL
,
(
)
159
160
Author’s affiliations
Anke van den Berg
Department of Pathology and Medical Biology
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
Arjan Diepstra
Department of Pathology and Medical Biology
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
Bianca Olver
Section of Cancer Genetics
Institute of Cancer Research
Sutton, United Kingdom
Bouke Hepkema
Department of Laboratory Medicine
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
Carlos E. Bacchi
Consultoria em Patologia
Botucatu-Sao Paulo, Brazil
Gabriela Gualco
Consultoria em Patologia
Botucatu-Sao Paulo, Brazil
Gustaaf van Imhoff
Department of Hematology
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
161
Authors affiliations
Henrik Hjalgrim
Department of Epidemiology Research
Statens Serum Institut
Copenhagen, Denmark
Huang Xin
Department of Pathology and Medical Biology
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
Ilby Bouwman
Department of Laboratory Medicine
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
Ilja Nolte
Department of Epidemiology
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
Karin E Smedby
Institute of Medical Epidemiology and Biostatistics
Karolinska Institute
Stockholm, Sweden
Klaus Rostgaard
Department of Epidemiology Research
Statens Serum Institut
Copenhagen, Denmark
Kushi Kushekhar
Department of Pathology and Medical Biology
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
162
Authors affiliations
Lydia Visser
Department of Pathology and Medical Biology
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
Niels Kouprie
Department of Laboratory Medicine
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
Pollyanna Domeney
Consultoria em Patologia
Botucatu-Sao Paulo, Brazil
Rianne Veenstra
Department of Pathology and Medical Biology
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
Richard S. Houlston
Section of Cancer Genetics
Institute of Cancer Research
Sutton, United Kingdom
Ruth Jarrett
MRC-University of Glasgow Centre for Virus Research
Glasgow, Scotland
Sibrand Poppema
Department of Pathology and Medical Biology
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
163
Authors affiliations
Wierd Kooistra
Department of Pathology and Medical Biology
University Medical Centre Groningen
University of Groningen
Groningen, the Netherlands
164
Publications
Genetic associations in classical Hodgkin lymphoma: a systematic review and insights
into susceptibility mechanisms. Kushekhar K, van den Berg A, Nolte I, Hepkema B,
Visser L, Diepstra A. Cancer Epidemiol Biomarkers Prev. 2014 Sep 9. pii: [Epub ahead
of print]. PMID: 25205514
HLA associations in classical Hodgkin lymphoma: EBV status matters. Huang X,
Kushekhar K, Nolte I, Kooistra W, Visser L, Bouwman I, Kouprie N, Veenstra R, van
Imhoff G, Olver B, Houlston RS, Poppema S, Diepstra A, Hepkema B, van den Berg A.
PLoS One. 2012;7(7). PMID: 22808081
HLA-A*02:07 is a protective allele for EBV negative and a susceptibility allele for EBV
positive classical Hodgkin lymphoma in China. Huang X, Hepkema B, Nolte I,
Kushekhar K, Jongsma T, Veenstra R, Poppema S, Gao Z, Visser L, Diepstra A, van den
Berg A. PLoS One. 2012;7(2):e31865. PMID: 22355400
165
166
Biography
Kushekhar was born on May 20th 1985 in Beedikere, a
small hamlet in the limits of Bangalore, India. He
attended his elementary school in Beedikere. At the age
of 10 he was selected to attend a central government
funded boarding school, Jawahar Navodaya Vidylaya in
Doddaballapur, Bangalore, India. This free boarding
school not only gives India’s best education but also
responsible overall personality growth of the students. As
a part of cultural exchange, he spent one year in Jawahar
Navodaya Vidylaya Alirajpur in Madhya Pradesh, India. After spending nearly 10
years in this school, he went to Vishweshwarapura College of science to pursue his
bachelors in Biotechnology. He did his bachelors research projects at Veterinary
College, Bangalore and Kemepegowda Institute of Medical Sciences, Bangalore. With
good grades in the bachelors, he opt Department of Biotechnology, Bangalore
University to pursue his masters in Biotechnology. He did research project on
isolation and characterization of metal degrading bacterial enzymes in Center for
Clean Environmental Technology, Bangalore University. In 2008 he moved to New
Delhi to pursue his research interest. He was a junior research fellow in Department
of Pediatrics, All India Institute of Medical Sciences. His research project was on
evaluation of Chikungunya infection in India. He also worked on T cell IFNγ response
to Rotavirus membrane proteins and global analysis of inflammatory cytokines in
Chikungunya patients. To get an international exposure, he wanted to move abroad
for PhD. He was selected as a PhD student in Lymphoma group led by Prof. Dr. Anke
van den Berg at Department of Pathology and Medical Biology University Medical
Center Groningen. In April 2010, he started his PhD project on Human leukocyte
antigen and classical Hodgkin lymphoma. After the defense of his PhD thesis in
January 2015, Kushekhar intend to pursue his academic research career in
immunology related field.
167
168
Acknowledgements
Whoever responsible for your present condition, obviously cares a great deal.
-Rubin Hurricane Carter
The trial and tribulations of PhD can overwhelm even the most collected of a person.
Given a chance, the feelings of insecurity and guilt are always right around the corner
waiting to entrap you within its sinister web. In such an environment, the scientific
and social support system becomes a crucial ingredient for the success of any
support system. Here, I would like to acknowledge the many faces that have been
part of my support system.
First of all, my promoter Prof. Dr. Anke van den Berg cuts a great deal. Anke, who has
the attitude and substance of a genius with no trappings of pride, she continually
and convincingly conveyed a spirit of adventure in regard to research and an
excitement in regard to teaching. Without her guidance this thesis would not have
been possible. Perhaps, Anke is the only promoter who “always” has time for her
students. Outside the work, she is a good friend you can have. I thank Anke with my
deepest gratitude.
Without Dr. Lydia Visser, I would not have written this anyway. Lydia, who recognized
my candidacy for this PhD position is responsible for my arrival to Groningen.
Importantly, she took a great care of me both professionally and personally with my
whole stay. She is always available for you as a teacher, as a close friend and as a
parent. One thing which I take home is her maternal care towards her students.
Dr. Arjan Diepstra, although you are one of my co-supervisor, you are rather a better
intellectual and helpful friend. These words are not enough express that how thankful
I am. With you I feel more comfortable and relaxed to express my thoughts, because
your calm listening. You are busy, until I just come inside your office, then discussion
goes for an hour. Dear Arjan, I thank you from my deepest heart, you shaped my PhD
thesis and my thought process as well.
Numbers are not my most favorite, working with Dr. Ilja Nolte I did not realize this
lacunae that much. Dear Ilja, thank you so much for you unparalleled help in analysis
of complex data. I never thought beyond p<0.05, however you shown me p<0.001
and still we are struggling give its biological sense.
169
Acknowledgements
HLA is the most complex region of human genome, until you get to know Dr. Bouke
Hepkema. Dear Bouke, you are always encouraging and your sparkling hints
provided enormous input to my HLA knowledge tank. I will thank you from the
deepest heart.
I would express my deepest appreciation for the members of the reading committee,
Prof. Ruth Jarrett, Prof. Edo Vellenga and Prof. Toos Deamen for reading and
approving my PhD dissertation. Dear Ruth, I also tank you for quality time we spent
during conferences. Dear Edo, thank you for your valuable discussions during our
Monday morning meetings.
I want to thank other peers who contributed to my scientific knowledge. Dr. Joost
Kluiver, a big brother to our group, for his help in all little things and fruitful scientific
discussions. I thank Prof. Wim Timmens head of the Dept. of Pathology. I thank Prof.
Sibrand Poppema for his peer check on my research and Dr. Gustaaf Imhoff for his
constant help in recruiting patients and collecting blood samples and his quality
discussions during our meetings. I also thank Dr. Johan Gibcus, Dr. Klaas Kok, Prof.
Annette Gouw, Prof. Philip Kluin, Prof. Ed Schuuring, Prof. Jan-Luuk Hilebrands, Prof.
Harry Hollema, Dr. Machteld Hylkema and Dr. Corry-Anke Brandsma for their
valuable discussions and ideas during refereran, which are important part of my
scientific growth.
Many thanks to all my co-authors and collaborators, Ilby Bouwman, Bianca Olver,
Richard S. Houlston, Zifen Gao, Henrik Hjalgrim, Karin E Smedby, Klaus Rostgaard,
Gabriela Gualco, Pollyanna Domeney and Carlos E. Bacchi who shared their
intellectual views and provided their valuable input in publishing my articles. My
special thanks to Niels Kouprie, Theo Jongsma and Richard Kuntzel who are coauthors as well as gave their immense help for HLA typing and collecting blood
samples for my experiments.
Rianne Veenstra, you are the first Dutch friend I met. With whom I had freedom to do
stupid technical mistakes in the experiments and still it’s OK. You thought me that
Lab O&O is better than my office, which is indeed true. Now, you are my welldeserved paranymfen, many thanks for all the efforts in organizing and making my
D-Day a memorable one, for you will be part of my memory down the lane.
I want to thank all the people whom I shared the office, lab, my thoughts, my
excitement or my sorrows during my course of PhD. Thank you Wouter for
introducing me to Dutch work culture and dealing with people and things. I thank
Huang for all the initial data and understandings of the project. Rae, thank you for all
the time you spent on our sometime stupid discussions. Ahmed, talking with you
170
Acknowledgements
opens up my brain. All your basic immunology discussions are worth spending time
for. Ali, thanks you recognizing my real talents and appreciating them. Iza, thank you,
for all those initial hints for a successful PhD. Yuxuan, I am going to miss your
charming and smiling face. Melanie, a sensible talker, I learnt a lot talking with you.
Marcel, I thank you for your constant check on my schedule and brotherly help. Mina,
I miss you kukus the most. Zheng, common man lets deal our D-Day together. Nato,
your smart dressing sense and fun talks are memorable forever. Ben, you are cool
guy, with very mature mindset. Those bold gestures of Reny best matches to her
personality. My big thanks to Geok, Yuan, Lotte, Sietse, Jan-Lukas for sharing their
friendly space and time.
Proud will be mine, for the things I learnt in the Lab O&O. I could not have learnt
these things without the help people. There is nothing you are lacked with in this lab,
the lab manager Hans Vos had make sure everything is in the reach of your hands.
Thank you Hans, for recognizing my volley ball talent. Many things were new at this
lab, I learnt many techniques with Bea Rutgers, Wierd Kooistra, Marian Bulthuis. It is
my pleasure to thank Debora de Jong, Nancy Helsema, Gertrud Kortman, Marrit
Otter, Theo Borghuis, Jantine Sietzema, Jasper Koerts, Lorian S Menkema, Tineke van
der Sluis, Bart Baake and Geert Harms for their immense support in conducting my
experiments. My special thanks to Ilia Vinchtian and Sulima Hoek with whom I shared
my first days in the Dept. of pathology.
With Xaver, Ben, Til, Chris and Wim, I both thought and learnt science and research
techniques. I also thank Rik, Silvana, Martijn, Patricia, Karolin, Hiro, Jing and Siobhan
whom I spared time in corridors at least to check on how are the things at our sides.
I take this opportunity to thank, Richard Jacobs, Ingrid van der Strate-Tmpert, Jenny
Fledderus, Ellen Kuijpers, Harriet Roffel and Marijke Gimberg who helped me in all
paper works pertaining to my PhD also constant update on ongoings in the
department. I also thank Roel Soesbeek and Peter Wagenaar from ICT department.
My special thanks to Freke Dijkhuis from tissue archives, for providing all the tissue
blocks for my research. I also thank people from Histology for helping me to cut all
the sections
I want to thank Maaike Bansema and Mieke Kapteyn from GUIDE for their continuous
help in organizing and structuring my PhD into a success.
For all bureaucratic solutions, I want to thank Marco van der Vinne and Swaeske de
Vries from ISD.
171
Acknowledgements
My special thanks to Dr. TN Atmaram, Dr. Devaiah, Prof. Sarangi, and Prof. Manjula
Kumari from Dept. of Biotechnology, Bangalore University for their continuous
support to reach heights in my academic career.
Work apart, during my stay in Groningen I spent quality time with many people
learning their culture, their sense of humor and sharing all the thoughts about
different cultures. All these people helped me to create and evolve myself into a
cosmopolitan man.
My life in Groningen started with mix of internationals at Winschoterdiep 46, where I
learnt to socialize. I will take this opportunity to mesmerize the moments I shared
with Michael, Marko, Mustafa, Nikos, Deniz, Mayer and Aiste. I moved from Diep to
Kade. At Winschoterkade18, I met Constanza, an Argentinian warm heart, Jenny,
caring and sharing, who become my good friends. Also I thank Inken, Sylwia, Hilke,
Andres, Nikola, Ben, Magnus, Bjorn, Claudius, Jason, Jakob and Tejas for allowing me
into their culture of being and sharing their personal space.
The best part of my life in Groningen is meeting Luis, Gry, Linde, Giancarlo, Stefano,
Neeraj andVikram and many more. Luis, a bloody good Mexican with intel, I learnt
how deal with life in tricky situations and positive thinking. I never met such a downto-earth person like Gry, I think everyone should have person like her in their life.
Giancarlo and Stefano, the best Italians I met, their hospitality at Rome will be my
one of the best nostalgic event. Neeraj filled my brain with some of his philosophical
thoughts and made me to think sometime beyond stars, I like it though. With Vikram,
I felt like staying at home but in Europe, those road trips and dinners at his place, a
very caring friend.
My special thanks to Gaurav, a good and very helpful friend and my paranymfen. If
there is a need, there are you. Those are the best times we spent in trips. I take this
opportunity to thank him with my full heart for his immense help in organizing my
success day at its best. I wish him success in his PhD and his future endeavours.
The only opportunity infiltrate into Dutch culture is to meet this student group HOST.
In HOST I met these beautiful people Hendrik, Arend, Sezar, Marije, Krina, Trix,
Danica, Anahi, Maaike, Maarten, Pieter, Joanne, Elsa, Yaroslav, Olaf, Ibrahim, Esther,
Jhonathan, Sjoukje, Henrieke, Margje, Michell, Dragous, Hans-Joann and many more.
A special regards to Angelica, for her innocent care and warm heart.
172
Acknowledgements
My best regards to Hink and his Boer family, for inviting me to their family and
showing how things work at farm. My warm regards to Magda, for her sweet
friendship. Minnah, for her enthusiastic conversations. Izabel, for her open and warm
heart. With Violeta, Ena and Funda I shared lough and with whom somehow Balkan
culture matches with Indian culture.
I also take this space to extend my regards to Iranian friends Mehran and his wife,
Fariba, Shiva Sajari and Narges with whom I felt no different from Indian culture.
Those are the best days I spent with Paria, you will be missed.
Having Indian friends abroad is always feels like coming home. I thank Eswar who
first received me to Groningen and those first days of hospitality. Khyum, never says
no, always ready to help. Pramod, Shiva, Siddu, Vijay, Rajinder & Chaitali, Suresh,
Gautam, Tushar, Raja, Akshay & Spoorthi, Abhishek, Paul, Swapnil, Rama, Praneeth,
Pranov, Lakshmi, Gopi, Saritha, Justin with who I spent a warmth homely Indian time.
Having old friends around is best feelings you can ever have in your life. My heartily
regards to my friends from Bangalore, Mahesh, Anand, Naveen, Srinivas, Rakesh,
Madhavi, Suryakala, Shobha and Pallavi. A talk for a minute with them suffices to get
rid of your all sorrows and weather imprisoned depressions at Northern hemisphere.
My parents and my sibs, I do not know how to thank them. I thank my three sisters
and their husbands, Sushilamma & Narayanaswami, Prabha & Srinivas and Indira &
Venkatesh and my brother Govindaraj & Suma for their unconditional love and
support. I wish all my niece and nephews a bright future. Having born in a typical
Indian nuclear family you have pre-directions to your life and career. But my parents
allow me to follow my heart and gave their unbiased support. I will thank them in all
my reincarnating lives.
My sincere apologies and many thanks for those I have missed here.
173
Notes
174
Notes
175
Notes
176