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author:("gielkens, S")
1.  Wanting to attend isn’t just wanting to quit: why some disadvantaged smokers regularly attend smoking cessation behavioural therapy while others do not: a qualitative study 
BMC Public Health  2014;14:695.
Attendance of a behavioural support programme facilitates smoking cessation. Disadvantaged smokers have been shown to attend less than their more affluent peers. We need to gain in-depth insight into underlying reasons for differing attendance behaviour in disadvantaged smokers, to better address this issue. This study aims to explore the underlying motivations, barriers and social support of smokers exhibiting different patterns of attendance at a free smoking cessation behavioural support programme in a disadvantaged neighbourhood of The Netherlands.
In 29 smokers undertaking smoking cessation group therapy or telephone counselling in a disadvantaged neighbourhood, qualitative interviews were completed, coded and analysed. Major themes were motivations, barriers to attend and social support. Motivations and social support were analysed with reference to the self-determination theory.
Two distinct patterns of attendance emerged: those who missed up to two sessions (“frequent attenders”), and those who missed more than two sessions (“infrequent attenders”). The groups differed in their motivations to attend, barriers to attendance, and in the level of social support they received. In comparison with the infrequent attenders, frequent attenders more often had intrinsic motivation to attend (e.g. enjoyed attending), and named more self-determined extrinsic motivations to attend, such as commitment to attendance and wanting to quit. Most of those mentioning intrinsic motivation did not mention a desire to quit as a motivation for attendance. No organizational barriers to attendance were mentioned by frequent attenders, such as misunderstandings around details of appointments. Frequent attenders experienced more social support within and outside the course.
Motivation to attend behavioural support, as distinct from motivation to quit smoking, is an important factor in attendance of smoking cessation courses in disadvantaged areas. Some focus on increasing motivation to attend may help to prevent participants missing sessions.
PMCID: PMC4105168  PMID: 25002149
Smoking cessation; Group therapy; Telephone counselling; Attendance; Low socioeconomic status
2.  Dendritic Cell Therapy in an Allogeneic-Hematopoietic Cell Transplantation Setting: An Effective Strategy toward Better Disease Control? 
Hematopoietic cell transplantation (HCT) is a last treatment resort and only potentially curative treatment option for several hematological malignancies resistant to chemotherapy. The induction of profound immune regulation after allogeneic HCT is imperative to prevent graft-versus-host reactions and, at the same time, allow protective immune responses against pathogens and against tumor cells. Dendritic cells (DCs) are highly specialized antigen-presenting cells that are essential in regulating this balance and are of major interest as a tool to modulate immune responses in the complex and challenging phase of immune reconstitution early after allo-HCT. This review focuses on the use of DC vaccination to prevent cancer relapses early after allo-HCT. It describes the role of host and donor-DCs, various vaccination strategies, different DC subsets, antigen loading, DC maturation/activation, and injection sites and dose. At last, clinical trials using DC vaccination post-allo-HCT and the future perspectives of DC vaccination in combination with other cancer immunotherapies are discussed.
PMCID: PMC4032952  PMID: 24904573
DC-vaccination; hematopoietic cell transplantation; disease control; relapse; T-cell responses
4.  Interleukin-21 Receptor-mediated signals control autoreactive T cell infiltration in pancreatic islets 
Immunity  2012;36(6):10.1016/j.immuni.2012.04.005.
It remains unclear how interleukin-21 receptor (IL-21R) contributes to type 1 diabetes. Here we have shown that dendritic cells (DCs) in the pancreas required IL-21R, not for antigen uptake, but to acquire the chemokine receptor CCR7 and migrate into the draining lymph node. Consequently, less antigen, major histocompatibility complex (MHC) Class II and CD86 was provided to autoreactive effector cells in Il21r-/- mice, impairing CD4+ T cell activation, CD40:CD40L interactions and pancreatic infiltration by autoreactive T cells. CD40 cross-linking restored defective CD4+ cell expansion and CD4-independently expanded autoreactive CD8+ cells, but CD8+ cells still required CD4+ cells to reach the pancreas and induce diabetes. Diabetes induction by transferred T cells required IL-21R-sufficient host antigen presenting cells. Transferring IL-21R-sufficient DCs broke diabetes resistance in Il21r-/- mice. We conclude that IL-21R controls both antigen transport by DCs and the crucial beacon function of CD4+ cells for autoreactive CD8+ cells to reach the islets.
PMCID: PMC3810457  PMID: 22579473
5.  Antitumor immune responses mediated by dendritic cells 
Oncoimmunology  2013;2(11):e26403.
Dendritic cells (DCs) are essential for the induction of adaptive immune responses against malignant cells by virtue of their capacity to effectively cross-present exogenous antigens to T lymphocytes. Dying cancer cells are indeed a rich source of antigens that may be harnessed for the development of DC-based vaccines. In particular, malignant cells succumbing to apoptosis, rather than necrosis, appear to release antigens in a manner that allows for the elicitation of adaptive immune responses. In this review, we describe the processes that mediate the cross-presentation of antigens released by apoptotic cancer cells to CD8+ T lymphocytes, resulting in the activation of protective tumor-specific immune responses.
PMCID: PMC3894247  PMID: 24482744
DAMPs; apoptotic; cross-presentation; dendritic cells; necrotic; storage compartments; type 1 interferon
6.  Effectiveness of Cultural Adaptations of Interventions Aimed at Smoking Cessation, Diet, and/or Physical Activity in Ethnic Minorities. A Systematic Review 
PLoS ONE  2013;8(10):e73373.
The importance of cultural adaptations in behavioral interventions targeting ethnic minorities in high-income societies is widely recognized. Little is known, however, about the effectiveness of specific cultural adaptations in such interventions.
To systematically review the effectiveness of specific cultural adaptations in interventions that target smoking cessation, diet, and/or physical activity and to explore features of such adaptations that may account for their effectiveness.
Systematic review using MEDLINE, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials registers (1997–2009). Inclusion criteria: a) effectiveness study of a lifestyle intervention targeted to ethnic minority populations living in a high income society; b) interventions included cultural adaptations and a control group that was exposed to the intervention without the cultural adaptation under study; c) primary outcome measures included smoking cessation, diet, or physical activity.
Out of 44904 hits, we identified 17 studies, all conducted in the United States. In five studies, specific cultural adaptations had a statistically significant effect on primary outcomes. The remaining studies showed no significant effects on primary outcomes, but some presented trends favorable for cultural adaptations. We observed that interventions incorporating a package of cultural adaptations, cultural adaptations that implied higher intensity and those incorporating family values were more likely to report statistically significant effects. Adaptations in smoking cessation interventions seem to be more effective than adaptations in interventions aimed at diet and physical activity.
This review indicates that culturally targeted behavioral interventions may be more effective if cultural adaptations are implemented as a package of adaptations, the adaptation includes family level, and where the adaptation results in a higher intensity of the intervention. More systematic experiments are needed in which the aim is to gain insight in the best mix of cultural adaptations among diverse populations in various settings, particularly outside the US.
PMCID: PMC3792111  PMID: 24116000
7.  A process evaluation: Does recruitment for an exercise program through ethnically specific channels and key figures contribute to its reach and receptivity in ethnic minority mothers? 
BMC Public Health  2013;13:768.
Ethnic minority women from low-income countries who live in high-income countries are more physically inactive than ethnic majority women in those countries. At the same time, they can be harder to reach with health promotion programs. Targeting recruitment channels and execution to ethnic groups could increase reach and receptivity to program participation. We explored using ethnically specific channels and key figures to reach Ghanaian, Antillean, and Surinamese mothers with an invitation for an exercise program, and subsequently, to determine the mothers’ receptivity and participation.
We conducted a mixed methods process evaluation in Amsterdam, the Netherlands. To recruit mothers, we employed ethnically specific community organizations and ethnically matched key figures as recruiters over Dutch health educators. Reach and participation were measured using reply cards and the attendance records from the exercise programs. Observations were made of the recruitment process. We interviewed 14 key figures and 32 mothers to respond to the recruitment channel and recruiter used. Content analysis was used to analyze qualitative data.
Recruitment through ethnically specific community channels was successful among Ghanaian mothers, but less so among Antillean and Surinamese mothers. The more close-knit an ethnic community was, retaining their own culture and having poorer comprehension of the Dutch language, the more likely we were to reach mothers through ethnically specific organizations. Furthermore, we found that using ethnically matched recruiters resulted in higher receptivity to the program and, among the Ghanaian mothers in particular, in greater participation. This was because the ethnically matched recruiter was a familiar, trusted person, a translator, and a motivator who was enthusiastic, encouraging, and able to adapt her message (targeting/tailoring). Using a health expert was preferred in order to increase the credibility and professionalism of the recruitment.
Recruitment for an exercise program through ethnically specific organizations seems to contribute to its reach, particularly in close-knit, highly organized ethnic communities with limited fluency in the local language. Using ethnically matched recruiters as motivator, translator, and trusted person seems to enhance receptivity of a health promotion program. An expert is likely to be needed for effective information delivery.
PMCID: PMC3765122  PMID: 23957695
Recruitment; Recruiter; Channel segmentation; Community health worker; Ethnic minorities/migrants; Health promotion; Cultural targeting; Exercise/physical activity
8.  Intensive Lifestyle Intervention in General Practice to Prevent Type 2 Diabetes among 18 to 60-Year-Old South Asians: 1-Year Effects on the Weight Status and Metabolic Profile of Participants in a Randomized Controlled Trial 
PLoS ONE  2013;8(7):e68605.
To study 1-year effectiveness of an intensive, culturally targeted lifestyle intervention in general practice for weight status and metabolic profile of South-Asians at risk of type 2 diabetes.
536 South-Asians at risk of type 2 diabetes were randomized to an intervention (n = 283) or control (n = 253) group. The intervention, which was targeted culturally to the South-Asian population, consisted of individual lifestyle counselling, a family session, cooking classes, and supervised physical activity programme. All components of the intervention were carried out by professionals as part of their daily clinical practice. The control group received generic lifestyle advice. Change in weight status and metabolic profile were assessed after 1 year.
After 1 year, 201 participants were lost to follow-up. Remaining participants in intervention (n = 177) and control (n = 158) group had similar baseline characteristics. Weight loss in the intervention group was 0.2±3.3 kg, weight gain in the control group was 0.4±3.1 kg (p = 0.08). Changes in other weight-related measurements did not differ significantly between groups. Furthermore, there were no differences between groups in changes of metabolic profile. All results remained similar after repeating analyses in a multiple imputed dataset.
An intensive, culturally targeted, lifestyle intervention of 1 year did not improve weight status and metabolic profile of South-Asians at risk of type 2 diabetes. The laborious recruitment, high drop-out, and lack of effectiveness emphasise the difficulty of realising health benefits in practice and suggest that this strategy might not be the optimal approach for this population.
Trial Registration
Nederlands Trial Register NTR1499
PMCID: PMC3718785  PMID: 23894322
9.  Immune Adjuvant Efficacy of CpG Oligonucleotide in Cancer Treatment Is Founded Specifically upon TLR9 Function in Plasmacytoid Dendritic Cells 
Cancer research  2011;71(20):6428-6437.
The differences in function, location, and migratory pattern of conventional dendritic cells (cDC) and plasmacytoid DCs (pDC) not only point to specialized roles in immune responses but also signify additive and interdependent relationships required to clear pathogens. We studied the in vivo requirement of cross-talk between cDCs and pDCs for eliciting antitumor immunity against in situ released tumor antigens in the absence or presence of the Toll-like receptor (TLR) 9 agonist CpG. Previous data indicated that CpG boosted tumor-specific T-cell responses after in vivo tumor destruction and increased survival after tumor rechallenges. The present study shows that cDCs are indispensable for cross-presentation of ablation-released tumor antigens and for the induction of long-term antitumor immunity. Depletion of pDCs or applying this model in type I IFN receptor–deficient mice abrogated CpG-mediated responses. CD8α+ cDCs and the recently identified merocytic cDCs were dependent on pDCs for CpG-induced upregulation of CD80. Moreover, DC transfer studies revealed that merocytic cDCs and CD8α+ cDCs were most susceptible to pDC help and subsequently promoted tumor-free survival in a therapeutic setting. By transferring wild-type pDCs into TLR9-deficient mice, we finally showed that TLR9 expression in pDCs is sufficient to benefit from CpG as an adjuvant. These studies indicate that the efficacy of CpG in cancer immunotherapy is dependent on cross-talk between pDCs and specific subsets of cDCs.
PMCID: PMC3653311  PMID: 21788345
10.  Screening South Asians for type 2 diabetes and prediabetes: (1) comparing oral glucose tolerance and haemoglobin A1c test results and (2) comparing the two sets of metabolic profiles of individuals diagnosed with these two tests 
The glycated haemoglobin A1c (HbA1c) level may be used for screening for type 2 diabetes and prediabetes instead of a more burdensome oral glucose tolerance test (OGTT). However, among the high-risk South Asian population, little is known about the overlap of the methods or about the metabolic profiles of those disconcordantly diagnosed.
We included 944 South Asians (18–60 years old), whom we screened with the HbA1c level and the OGTT in The Hague, the Netherlands. We calculated the area under the receiver-operator characteristic curve (AUROC) with a 95% confidence interval of HbA1c using the American Diabetes Association classifications, and determined the sensitivity and specificity with 95% confidence intervals at different thresholds. Moreover, we studied differences in metabolic characteristics between those identified by HbA1c and by the OGTT alone.
The overlap between HbA1c and OGTT classifications was partial, both for diabetes and prediabetes. The AUROC of HbA1c for OGTT defined diabetes was 0.86 (0.79–0.93). The sensitivity was 0.46 (0.29–0.63); the specificity 0.98 (0.98–0.99). For prediabetes, the AUROC was 0.73 (0.69–0.77). Each of the 31 individuals with diabetes and 353 with prediabetes identified with the HbA1c level had a high body mass index, large waist circumference, high blood pressure, and low insulin sensitivity, all of which were similar to the values shown by those among the 19 with diabetes or 62 with prediabetes who only met the OGTT criteria, but not the HbA1c criteria.
The HbA1c level identified a partially different group than the OGTT did. However, both those identified with the HbA1c level and those identified with the OGTT alone were at increased metabolic risk.
Trial registration
Dutch Trial Register: NTR1499
PMCID: PMC3700889  PMID: 23442875
Type 2 Diabetes; Prediabetes; South Asian Populations; Screening; HbA1c; OGTT
11.  DiAlert: a prevention program for overweight first degree relatives of type 2 diabetes patients: results of a pilot study to test feasibility and acceptability 
Trials  2012;13:178.
Prevalence of type 2 diabetes mellitus is increasing due to lifestyle changes, particularly affecting those genetically at risk. We developed DiAlert as a targeted group-based intervention aimed to promote intrinsic motivation and action planning for lifestyle changes and weight loss in first degree relatives of patients with type 2 diabetes mellitus.
The main objective of the pilot of the DiAlert intervention was to assess fidelity, feasibility and acceptability prior to starting the randomized controlled trial.
Individuals with a family history of type 2 diabetes mellitus were self-identified and screened for eligibility. DiAlert consists of two group sessions. Feasibility, fidelity, acceptability and self-reported perceptions and behavioral determinants were evaluated in a pre-post study using questionnaires and observations. Determinants of behavior change were analyzed using paired-samples t tests and Wilcoxon signed rank tests.
DiAlert was delivered to two groups of first degree relatives of patients with type 2 diabetes mellitus (N = 9 and N = 12). Feasibility and fidelity were confirmed. Overall, the DiAlert group sessions were positively evaluated (8.0 on a scale of 1 to 10) by participants. The intervention did not impact perceived susceptibility or worry about personal diabetes risk. Action planning with regard to changing diet and physical activity increased.
DiAlert proved feasible and was well-accepted by participants. Positive trends in action planning indicate increased likelihood of actual behavior change following DiAlert. Testing the effectiveness in a randomized controlled trial is imperative.
Trial registration
Netherlands National Trial Register (NTR): NTR2036
PMCID: PMC3543339  PMID: 23013843
12.  Feasibility and effectiveness of a targeted diabetes prevention program for 18 to 60-year-old South Asian migrants: design and methods of the DH!AAN study 
BMC Public Health  2012;12:371.
South Asian migrants are at particularly high risk of type 2 diabetes. Previous studies have shown that intensive lifestyle interventions may prevent the onset of diabetes. Such interventions have not been culturally adapted and evaluated among South Asians in industrialized countries. Therefore, we have set up a randomized controlled trial to study the effectiveness of a targeted lifestyle intervention for the risk of type 2 diabetes and cardiovascular risk factors among 18 to 60-year-old Hindustani Surinamese (South Asians) in The Hague, the Netherlands. Here we present the study design and describe the characteristics of those recruited.
Between May 18, 2009 and October 11, 2010, we screened 2307 Hindustani Surinamese (18–60 years old) living in The Hague. We sent invitations to participate to those who had an impaired fasting glucose of 5.6-6.9 mmol/l, an impaired glucose tolerance of 7.8-11.0 mmol/L, a glycated hemoglobin level of 6.0% or more and/or a value of 2.39 or more for the homeostasis model assessment of estimated insulin resistance. In total, 536 people (56.1% of those eligible) participated. People with a higher level of education and a family history of type 2 diabetes were more likely to participate. The control and intervention groups were similar with regard to important background characteristics. The intervention group will receive a culturally targeted intervention consisting of dietary counseling using motivational interviewing and a supervised physical activity program. The control group will receive generic lifestyle advice. To determine the effectiveness, a physical examination (anthropometrics, cardiorespiratory test, lipid profile, and measures of oral glucose tolerance, glycated hemoglobin, and insulin) and interview (physical activity, diet, quality of life, and intermediate outcomes) were carried out at baseline and will be repeated at 1 year and 2 years. The process and the costs will be evaluated.
This trial will provide insight into the feasibility and effectiveness of a targeted, intensive, lifestyle intervention for the risk of type 2 diabetes and cardiovascular risk factors among 18 to 60-year-old South Asians.
Trial registration
Dutch Trial Register: NTR1499
PMCID: PMC3504520  PMID: 22621376
13.  The DISC (Diabetes in Social Context) Study-evaluation of a culturally sensitive social network intervention for diabetic patients in lower socioeconomic groups: a study protocol 
BMC Public Health  2012;12:199.
Compared to those in higher socioeconomic groups, diabetic patients in lower socioeconomic groups have less favourable metabolic control and experience more diabetes-related complications. They encounter specific barriers that hinder optimal diabetes self-management, including a lack of social support and other psychosocial mechanisms in their immediate social environments. Powerful Together with Diabetes is a culturally sensitive social network intervention specifically targeted to ethnic Dutch, Moroccan, Turkish, and Surinamese diabetic patients in lower socioeconomic groups. For ten months, patients will participate in peer support groups in which they will share experiences, support each other in maintaining healthy lifestyles, and learn skills to resist social pressure. At the same time, their significant others will also receive an intervention, aimed at maximizing support for and minimizing the negative social influences on diabetes self-management. This study aims to test the effectiveness of Powerful Together with Diabetes.
We will use a quasi-experimental design with an intervention group (Group 1) and two comparison groups (Groups 2 and 3), N = 128 in each group. Group 1 will receive Powerful Together with Diabetes. Group 2 will receive Know your Sugar, a six-week group intervention that does not focus on the participants' social environments. Group 3 receives standard care only. Participants in Groups 1 and 2 will be interviewed and physically examined at baseline, 3, 10, and 16 months. We will compare their haemoglobin A1C levels with the haemoglobin A1C levels of Group 3. Main outcome measures are haemoglobin A1C, diabetes-related quality of life, diabetes self-management, health-related, and intermediate outcome measures. We will conduct a process evaluation and a qualitative study to gain more insights into the intervention fidelity, feasibility, and changes in the psychosocial mechanism in the participants' immediate social environments.
With this study, we will assess the feasibility and effectiveness of a culturally sensitive social network intervention for lower socioeconomic groups. Furthermore, we will study how to enable these patients to optimally manage their diabetes. This trial is registered in the Dutch Trial Register: NTR1886
PMCID: PMC3337803  PMID: 22429263
Type 2 diabetes; Lower socioeconomic groups; Turkish; Moroccan; Surinamese patients; Social network intervention; Diabetes self-management
14.  Differential Toll-Like Receptor Recognition and Induction of Cytokine Profile by Bifidobacterium breve and Lactobacillus Strains of Probiotics ▿ 
The use of probiotics as a food supplement has gained tremendous interest in the last few years as beneficial effects were reported in gut homeostasis and nutrient absorption but also in immunocompromised patients, supporting protection from colonization or infection with pathogenic bacteria or fungi. As a treatment approach for inflammatory bowel diseases, a suitable probiotic strain would ideally be one with a low immunogenic potential. Insight into the immunogenicities and types of T-cell responses induced by potentially probiotic strains allows a more rational selection of a particular strain. In the present study, the bacterial strains Bifidobacterium breve (NumRes 204), Lactobacillus rhamnosus (NumRes1), and Lactobacillus casei (DN-114 001) were compared concerning their capacity to induce inflammatory responses in terms of cytokine production by human and mouse primary immune cells. It was demonstrated that the B. breve strain induced lower levels of the proinflammatory cytokine gamma interferon (IFN-γ) than the tested L. rhamnosus and L. casei strains. Both B. breve and lactobacilli induced cytokines in a Toll-like receptor 9 (TLR9)-dependent manner, while the lower inflammatory profile of B. breve was due to inhibitory effects of TLR2. No role for TLR4, NOD2, and C-type lectin receptors was apparent. In conclusion, TLR signaling is involved in the differentiation of inflammatory responses between probiotic strains used as food supplements.
PMCID: PMC3122558  PMID: 21288993
15.  DiAlert: a lifestyle education programme aimed at people with a positive family history of type 2 diabetes and overweight, study protocol of a randomised controlled trial 
BMC Public Health  2011;11:751.
Family history is a known risk factor for type 2 diabetes (T2DM), and more so in the presence of overweight. This study aims to develop and evaluate the effectiveness of a new lifestyle education programme 'DiAlert' targeted at 1st degree relatives of people with T2DM and overweight. In view of the high risk for diabetes and cardiovascular disease in immigrants from Turkish origin living in Western Europe, a culturally appropriate Turkish version of DiAlert will be developed and tested.
In this RCT, 268 (134 Dutch and 134 Turkish) overweight 1st degree relatives of patients with T2DM will be allocated to either the intervention or control group (leaflet). The intervention DiAlert aims to promote intrinsic motivation to change lifestyle, and sustain achieved behaviour changes during follow-up. Primary outcome is weight loss. Secondary outcomes include biological, behavioural and psychological indices, along with process indicators. Measurements will take place at baseline and after 3 and 9 months. Changes in outcomes are tested between intervention and control group at 3 months; effects over time are tested within and between both ethnic groups at 3 and 9 months.
The DiAlert intervention is expected to be more effective than the control condition in achieving significant weight loss at 3 months, in both Dutch and Turkish Dutch participants.
Trial registration
Netherlands National Trial Register (NTR): NTR2036
PMCID: PMC3191517  PMID: 21961949
16.  Prolonged antigen storage endows merocytic DC with enhanced capacity to prime anti-tumor responses in tumor-bearing mice 
Tumor-cell vaccination with irradiated autologous tumor cells is a promising approach to activate tumor-specific T cell responses without the need for tumor antigen identification. However, uptake of dying cells by DC is generally a non-inflammatory or tolerizing event in order to prevent the development of autoreactive immune responses. Here we describe the mechanisms that confer the potent T cell priming capacity of a recently identified a population of DC (merocyticDC, mcDC) that potently primes both CD8+ and CD4+ T cells to cell-associated antigens upon uptake of apoptotic cells.
mcDCs acquired cell-associated materials though a process of merocytosis that is defined by the uptake of small particles that are stored in non-acidic compartments for prolonged periods, sustained antigen presentation, and the induction of type I IFN. T cells primed by mcDC to cell-associated antigens exhibit increased primary expansion, enhanced effector function and increased memory formation. Using transgenic T cell transfer models and endogenous models, we show that treatment of tumor-bearing mice with mcDC that have been exposed to dying tumor cells results in tumor suppression and increased host survival through the activation of naïve tumor-specific CD8+ T cells as well as the revigoration of tumor-specific T cells that had been rendered non-responsive by the tumor in vivo.
The potent capacity of mcDCs to prime both CD4+ and CD8+ T cells to cell-associated antigens under immunosuppressive conditions makes this DC subset an attractive target for tumor therapies as well as interventional strategies for autoimmunity and transplantation.
PMCID: PMC3021914  PMID: 20720209
17.  Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice 
The Journal of Clinical Investigation  2011;121(8):3100-3108.
Tumor microenvironments feature immune inhibitory mechanisms that prevent T cells from generating effective antitumor immune responses. Therapeutic interventions aimed at disrupting these inhibitory mechanisms have been shown to enhance antitumor immunity, but they lack direct cytotoxic effects. Here, we investigated the effect of cytotoxic cancer chemotherapeutics on immune inhibitory pathways. We observed that exposure to platinum-based chemotherapeutics markedly reduced expression of the T cell inhibitory molecule programmed death receptor-ligand 2 (PD-L2) on both human DCs and human tumor cells. Downregulation of PD-L2 resulted in enhanced antigen-specific proliferation and Th1 cytokine secretion as well as enhanced recognition of tumor cells by T cells. Further analysis revealed that STAT6 controlled downregulation of PD-L2. Consistent with these data, patients with STAT6-expressing head and neck cancer displayed enhanced recurrence-free survival upon treatment with cisplatin-based chemoradiation compared with patients with STAT6-negative tumors, demonstrating the clinical relevance of platinum-induced STAT6 modulation. We therefore conclude that platinum-based anticancer drugs can enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capability of tumor cells. This dual action of platinum compounds may extend their therapeutic application in cancer patients and provides a rationale for their use in combination with immunostimulatory compounds.
PMCID: PMC3148725  PMID: 21765211
18.  How do psychosocial determinants in migrant women in the Netherlands differ from these among their counterparts in their country of origin? A cross-sectional study 
BMC Public Health  2011;11:397.
Migration of non-Western women into Western countries often results in an increase in smoking prevalence among migrant women. To gain more insight into how to prevent this increase, we compared psychosocial determinants of smoking between Surinamese women in Suriname and those in the Netherlands.
Data were obtained between 2000 and 2004 from two cross-sectional studies, the CVRFO study in Suriname (n = 702) and the SUNSET study in the Netherlands (n = 674). For analyses of determinants, we collected additional data in CVRFO study population (n = 85). Differences between the two groups were analysed by chi-square analyses and logistic regression analyses.
As was found in other studies among migrant women, more Surinamese migrant women in the Netherlands smoked (31%) than women in Suriname (16%). More Surinamese women in the Netherlands than in Suriname had a positive affective and cognitive attitude towards smoking (OR = 2.6 (95%CI 1.05;6.39) and OR = 3.3 (95%CI 1.31;8.41)). They perceived a positive norm within their partners and friends regarding smoking more frequently (OR = 6.5 (95%CI 2.7;15.6) and OR = 3.3 (95%CI 1.50;7.25)).
Migrant women are more positive towards smoking and perceived a more positive norm towards smoking when compared with women in the country of origin. Interventions targeted at the psychosocial determinants regarding smoking for newly migrated women, in particular the consequences of smoking and the norm towards smoking might help to prevent an increase in smoking in those populations.
PMCID: PMC3115863  PMID: 21615961
19.  Harnessing Dendritic Cells for Tumor Antigen Presentation 
Cancers  2011;3(2):2195-2213.
Dendritic cells (DC) are professional antigen presenting cells that are crucial for the induction of anti-tumor T cell responses. As a consequence, research has focused on the harnessing of DCs for therapeutic interventions. Although current strategies employing ex vivo-generated and tumor-antigen loaded DCs have been proven feasible, there are still many obstacles to overcome in order to improve clinical trial successes and offset the cost and complexity of customized cell therapy. This review focuses on one of these obstacles and a pivotal step for the priming of tumor-specific CD8+ and CD4+ T cells; the in vitro loading of DCs with tumor antigens.
PMCID: PMC3757412  PMID: 24212804
dendritic cell; tumor antigen; antigen presentation; antigen processing
20.  Multifaceted effects of synthetic TLR2 ligand and Legionella pneumophilia on Treg-mediated suppression of T cell activation 
BMC Immunology  2011;12:23.
Regulatory T cells (Treg) play a crucial role in maintaining immune homeostasis and self-tolerance. The immune suppressive effects of Tregs should however be limited in case effective immunity is required against pathogens or cancer cells. We previously found that the Toll-like receptor 2 (TLR2) agonist, Pam3CysSK4, directly stimulated Tregs to expand and temporarily abrogate their suppressive capabilities. In this study, we evaluate the effect of Pam3CysSK4 and Legionella pneumophila, a natural TLR2 containing infectious agent, on effector T (Teff) cells and dendritic cells (DCs) individually and in co-cultures with Tregs.
TLR2 agonists can directly provide a co-stimulatory signal inducing enhanced proliferation and cytokine production of naive CD4+ Teff cells. With respect to cytokine production, DCs appear to be most sensitive to low amounts of TLR agonists. Using wild type and TLR2-deficient cells in Treg suppression assays, we accordingly show that all cells (e.g. Treg, Teff cells and DCs) contributed to overcome Treg-mediated suppression of Teff cell proliferation. Furthermore, while TLR2-stimulated Tregs readily lost their ability to suppress Teff cell proliferation, cytokine production by Teff cells was still suppressed. Similar results were obtained upon stimulation with TLR2 ligand containing bacteria, Legionella pneumophila.
These findings indicate that both synthetic and natural TLR2 agonists affect DCs, Teff cells and Treg directly, resulting in multi-modal modulation of Treg-mediated suppression of Teff cells. Moreover, Treg-mediated suppression of Teff cell proliferation is functionally distinct from suppression of cytokine secretion.
PMCID: PMC3078900  PMID: 21435210
21.  Depressive symptoms and smoking among young Turkish and Moroccan ethnic minority groups in the Netherlands: a cross-sectional study 
Although evidence indicates a strong association between depressive symptoms and smoking among host and migrant adults, less is known about this relationship among young ethnic minority groups in Europe. This paper aims to assess the relationship between depressive symptoms and smoking among young Turkish and Moroccan migrants in the Netherlands.
Multiple logistic regression analyses was used to analyze cross-sectional data from a sample of 364 Turkish and Moroccan migrants aged 15 to 24 years. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to measure the presence of clinically significant depressive symptoms. Smoking behavior was measured by a number of questions.
Of the respondents, 22% were smokers and 33% had depressive symptoms. The prevalence of depressive symptoms was significantly higher in smokers (42.9%) than in nonsmokers (29.5%). Respondents with depressive symptoms had increased odds of smoking even after adjusting for socioeconomic and cultural factors (OR = 2.68, 95% CI = 1.45-4.97).
Depressive symptoms were significantly associated with smoking behavior in young Turkish and Moroccan migrants. In addition to other acknowledged factors, depressive symptoms should also be considered in relation to the smoking behavior of this group. Intervention programs for smoking behavior should take depressive symptoms into account for young Turkish and Moroccan migrants.
PMCID: PMC3064616  PMID: 21414199
22.  Social and cultural factors underlying generational differences in overweight: a cross-sectional study among ethnic minorities in the Netherlands 
BMC Public Health  2011;11:105.
The prevalence of overweight appears to vary in people of first and second generation ethnic minority groups. Insight into the factors that underlie these weight differences might help in understanding the health transition that is taking place across generations following migration. We studied the role of social and cultural factors associated with generational differences in overweight among young Turkish and Moroccan men and women in the Netherlands.
Cross-sectional data were derived from the LASER-study in which information on health-related behaviour and socio-demographic factors, level of education, occupational status, acculturation (cultural orientation and social contacts), religious and migration-related factors was gathered among Turkish and Moroccan men (n = 334) and women (n = 339) aged 15-30 years. Participants were interviewed during a home visit. Overweight was defined as a Body Mass Index ≥ 25 kg/m2. Using logistic regression analyses, we tested whether the measured social and cultural factors could explain differences in overweight between first and second generation ethnic groups.
Second generation women were less often overweight than first generation women (21.8% and 45.0% respectively), but this association was no longer significant when adjusting for the socioeconomic position (i.e. higher level of education) of second generation women (Odds Ratio (OR) = 0.77, 95%, Confidence Interval (CI) 0.40-1.46). In men, we observed a reversed pattern: second generation men were more often overweight than first generation men (32.7% and 27.8%). This association (OR = 1.89, 95% CI 1.09-3.24) could not be explained by the social and cultural factors because none of these factors were associated with overweight among men.
The higher socio-economic position of second generation Turkish and Moroccan women may partly account for the lower prevalence of overweight in this group compared to first generation women. Further research is necessary to elucidate whether any postulated socio-biological or other processes are relevant to the opposite pattern of overweight among men.
PMCID: PMC3048530  PMID: 21324156
23.  Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors 
Neuro-Oncology  2009;11(4):394-402.
The brain is a specialized immune site representing a unique tumor microenvironment. The availability of fresh brain tumor material for ex vivo analysis is often limited because large parts of many brain tumors are resected using ultrasonic aspiration. We analyzed ultrasonic tumor aspirates as a biosource to study immune suppressive mechanisms in 83 human brain tumors. Lymphocyte infiltrates in brain tumor tissues and ultrasonic aspirates were comparable with respect to lymphocyte content and viability. Applying ultrasonic aspirates, we detected massive infiltration of CD4+FoxP3+CD25high CD127low regulatory T cells (Tregs) in glioblastomas (n = 29) and metastatic brain tumors (n = 20). No Treg accumulation was observed in benign tumors such as meningiomas (n = 10) and pituitary adenomas (n = 5). A significant Treg increase in blood was seen only in patients with metastatic brain tumors. Tregs in high-grade tumors exhibited an activated phenotype as indicated by decreased proliferation and elevated CTLA-4 and FoxP3 expression relative to blood Tregs. Functional analysis showed that the tumor-derived Tregs efficiently suppressed cytokine secretion and proliferation of autologous intratumoral lymphocytes. Most tumor-infiltrating Tregs were localized in close proximity to effector T cells, as visualized by immunohistochemistry. Furthermore, 61% of the malignant brain tumors expressed programmed death ligand-1 (PD-L1), while the inhibitory PD-1 receptor was expressed on CD4+ effector cells present in 26% of tumors. In conclusion, using ultrasonic tumor aspirates as a biosource we identified Tregs and the PD-L1/PD-1 pathway as immune suppressive mechanisms in malignant but not benign human brain tumors.
PMCID: PMC2743219  PMID: 19028999
brain tumor; immunotherapy; PD-L1; regulatory T cell; tumor-infiltrating lymphocyte
24.  Route of Administration of the TLR9 Agonist CpG Critically Determines the Efficacy of Cancer Immunotherapy in Mice 
PLoS ONE  2009;4(12):e8368.
The TLR9 agonist CpG is increasingly applied in preclinical and clinical studies as a therapeutic modality to enhance tumor immunity. The clinical application of CpG appears, however, less successful than would be predicted from animal studies. One reason might be the different administration routes applied in most mouse studies and clinical trials. We studied whether the efficacy of CpG as an adjuvant in cancer immunotherapy is dependent on the route of CpG administration, in particular when the tumor is destructed in situ.
Methodology/Principal Findings
In situ tumor destruction techniques are minimally invasive therapeutic alternatives for the treatment of (nonresectable) solid tumors. In contrast to surgical resection, tumor destruction leads to the induction of weak but tumor-specific immunity that can be enhanced by coapplication of CpG. As in situ tumor destruction by cryosurgery creates an instant local release of antigens, we applied this model to study the efficacy of CpG to enhance antitumor immunity when administrated via different routes: peritumoral, intravenous, and subcutaneous but distant from the tumor. We show that peritumoral administration is superior in the activation of dendritic cells, induction of tumor-specific CTL, and long-lasting tumor protection. Although the intravenous and subcutaneous (at distant site) exposures are commonly used in clinical trials, they only provided partial protection or even failed to enhance antitumor responses as induced by cryosurgery alone.
CpG administration greatly enhances the efficacy of in situ tumor destruction techniques, provided that CpG is administered in close proximity of the released antigens. Hence, this study helps to provide directions to fully benefit from CpG as immune stimulant in a clinical setting.
PMCID: PMC2791230  PMID: 20020049
25.  Behavioural risk factors in two generations of non-Western migrants: do trends converge towards the host population? 
European Journal of Epidemiology  2007;22(3):163-172.
Migrant mortality does not conform to a single pattern of convergence towards prevalence rates in the host population. To understand better how migrant mortality develops, it is necessary to further investigate how the underlying behavioural determinants change following migration. We studied whether the prevalence of behavioural risk factors over two generations of Turkish and Moroccan migrants converge towards the prevalence rates in the Dutch population. From a random sample from the population register of Amsterdam, 291 Moroccan and 505 Turkish migrants, aged 15–30, participated in a structured interview that included questions on smoking, alcohol consumption, physical inactivity and weight/height. Data from the Dutch population were available from Statistics Netherlands. By calculating age-adjusted Odds Ratio’s, prevalence rates among both generations were compared with prevalence rates in the host population for men and women separately. We found indications of convergence across generations towards the prevalence rates in the host population for smoking in Turkish men, for overweight in Turkish and Moroccan women and for physical inactivity in Turkish women. Alcohol consumption, however, remained low in all subgroups and did not converge towards the higher rates in the host population. In addition, we found a reversed trend among Turkish women regarding smoking: the second generation smoked significantly more, while the first generation did not differ from ethnic Dutch. In general, behavioural risk factors in two generations of non-Western migrants in the Netherlands seem to converge towards the prevalence rates in the Dutch population. However, some subgroups and risk factors showed a different pattern.
PMCID: PMC2781098  PMID: 17334819
Behavioural risk factors; Convergence; Generation; Non-Western migrants; Western-Europe

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