Summary Since the mid-1990s, dendritic cells have been used in clinical trials as cellular mediators for therapeutic vaccination of patients with cancer. Dendritic cell-based immunotherapy is safe ...and can induce antitumour immunity, even in patients with advanced disease. However, clinical responses have been disappointing, with classic objective tumour response rates rarely exceeding 15%. Paradoxically, findings from emerging research indicate that dendritic cell-based vaccination might improve survival, advocating implementation of alternative endpoints to assess the true clinical potency of dendritic cell-based vaccination. We review the clinical effectiveness of dendritic cell-based vaccine therapy in melanoma, prostate cancer, malignant glioma, and renal cell carcinoma, and summarise the most important lessons from almost two decades of clinical studies of dendritic cell-based immunotherapy in these malignant disorders. We also address how the specialty is evolving, and which new therapeutic concepts are being translated into clinical trials to leverage the clinical effectiveness of dendritic cell-based cancer immunotherapy. Specifically, we discuss two main trends: the implementation of the next-generation dendritic cell vaccines that have improved immunogenicity, and the emerging paradigm of combination of dendritic cell vaccination with other cancer therapies.
Over the past years, the phenotypic and functional boundaries distinguishing the main cell subsets of the immune system have become increasingly blurred. In this respect, CD56 (also known as neural ...cell adhesion molecule) is a very good example. CD56 is the archetypal phenotypic marker of natural killer cells but can actually be expressed by many more immune cells, including alpha beta T cells, gamma delta T cells, dendritic cells, and monocytes. Common to all these CD56-expressing cell types are strong immunostimulatory effector functions, including T helper 1 cytokine production and an efficient cytotoxic capacity. Interestingly, both numerical and functional deficiencies and phenotypic alterations of the CD56
immune cell fraction have been reported in patients with various infectious, autoimmune, or malignant diseases. In this review, we will discuss our current knowledge on the expression and function of CD56 in the hematopoietic system, both in health and disease.
Summary Background A new betacoronavirus—Middle East respiratory syndrome coronavirus (MERS-CoV)—has been identified in patients with severe acute respiratory infection. Although related viruses ...infect bats, molecular clock analyses have been unable to identify direct ancestors of MERS-CoV. Anecdotal exposure histories suggest that patients had been in contact with dromedary camels or goats. We investigated possible animal reservoirs of MERS-CoV by assessing specific serum antibodies in livestock. Methods We took sera from animals in the Middle East (Oman) and from elsewhere (Spain, Netherlands, Chile). Cattle (n=80), sheep (n=40), goats (n=40), dromedary camels (n=155), and various other camelid species (n=34) were tested for specific serum IgG by protein microarray using the receptor-binding S1 subunits of spike proteins of MERS-CoV, severe acute respiratory syndrome coronavirus, and human coronavirus OC43. Results were confirmed by virus neutralisation tests for MERS-CoV and bovine coronavirus. Findings 50 of 50 (100%) sera from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against MERS-CoV spike. Sera from European sheep, goats, cattle, and other camelids had no such antibodies. MERS-CoV neutralising antibody titres varied between 1/320 and 1/2560 for the Omani camel sera and between 1/20 and 1/320 for the Spanish camel sera. There was no evidence for cross-neutralisation by bovine coronavirus antibodies. Interpretation MERS-CoV or a related virus has infected camel populations. Both titres and seroprevalences in sera from different locations in Oman suggest widespread infection. Funding European Union, European Centre For Disease Prevention and Control, Deutsche Forschungsgemeinschaft.
In pursuit of optimal performance, athletes and physical exercisers alike have to make decisions about how and when to invest their energy. The process of pacing has been associated with the ...goal-directed regulation of exercise intensity across an exercise bout. The current review explores divergent views on understanding underlying mechanisms of decision making in pacing. Current pacing literature provides a wide range of aspects that might be involved in the determination of an athlete's pacing strategy, but lacks in explaining how perception and action are coupled in establishing behaviour. In contrast, decision-making literature rooted in the understanding that perception and action are coupled provides refreshing perspectives on explaining the mechanisms that underlie natural interactive behaviour. Contrary to the assumption of behaviour that is managed by a higher-order governor that passively constructs internal representations of the world, an ecological approach is considered. According to this approach, knowledge is rooted in the direct experience of meaningful environmental objects and events in individual environmental processes. To assist a neuropsychological explanation of decision making in exercise regulation, the relevance of the affordance competition hypothesis is explored. By considering pacing as a behavioural expression of continuous decision making, new insights on underlying mechanisms in pacing and optimal performance can be developed.
Immunotherapy is currently under intensive investigation as a potential breakthrough treatment option for glioblastoma. Given the anatomical and immunological complexities surrounding glioblastoma, ...lymphocytes that infiltrate the brain to develop durable immunity with memory will be key. Polyinosinic:polycytidylic acid, or poly(I:C), and its derivative poly-ICLC could serve as a priming or boosting therapy to unleash lymphocytes and other factors in the (immuno)therapeutic armory against glioblastoma. Here, we present a systematic review on the effects and efficacy of poly(I:C)/poly-ICLC for glioblastoma treatment, ranging from preclinical work on cellular and murine glioblastoma models to reported and ongoing clinical studies. MEDLINE was searched until 15 May 2021 to identify preclinical (glioblastoma cells, murine models) and clinical studies that investigated poly(I:C) or poly-ICLC in glioblastoma. A systematic review approach was conducted according to PRISMA guidelines. ClinicalTrials.gov was queried for ongoing clinical studies. Direct pro-tumorigenic effects of poly(I:C) on glioblastoma cells have not been described. On the contrary, poly(I:C) changes the immunological profile of glioblastoma cells and can also kill them directly. In murine glioblastoma models, poly(I:C) has shown therapeutic relevance as an adjuvant therapy to several treatment modalities, including vaccination and immune checkpoint blockade. Clinically, mostly as an adjuvant to dendritic cell or peptide vaccines, poly-ICLC has been demonstrated to be safe and capable of eliciting immunological activity to boost therapeutic responses. Poly-ICLC could be a valuable tool to enhance immunotherapeutic approaches for glioblastoma. We conclude by proposing several promising combination strategies that might advance glioblastoma immunotherapy and discuss key pre-clinical aspects to improve clinical translation. Keywords: Poly(I:C), Poly-ICLC (Hiltonol), Glioblastoma, Immunotherapy, Immune checkpoint, Vaccination, Combination therapy, Toll-like receptor 3, Adjuvant, Glioma
The relation between pathology and cognitive dysfunction in dementia is still poorly understood, although disturbed communication between different brain regions is almost certainly involved. In this ...study we combine magneto-encephalography (MEG) and network analysis to investigate the role of functional sub-networks (modules) in the brain with regard to cognitive failure in Alzheimer's disease. Whole-head resting-state (MEG) was performed in 18 Alzheimer patients (age 67±9, 6 females, MMSE 23±5) and 18 healthy controls (age 66±9, 11 females, MMSE 29±1). We constructed functional brain networks based on interregional synchronization measurements, and performed graph theoretical analysis with a focus on modular organization. The overall modular strength and the number of modules changed significantly in Alzheimer patients. The parietal cortex was the most highly connected network area, but showed the strongest intramodular losses. Nonetheless, weakening of intermodular connectivity was even more outspoken, and more strongly related to cognitive impairment. The results of this study demonstrate that particularly the loss of communication between different functional brain regions reflects cognitive decline in Alzheimer's disease. These findings imply the relevance of regarding dementia as a functional network disorder.
► Network analysis applied to MEG data to study functional sub-networks (modules). ► In Alzheimer's disease, altered modular organization relates to cognitive symptoms. ► Intermodular connectivity is damaged most, parietal region has highest local damage.
Most human coronaviruses cause mild upper respiratory tract disease but may be associated with more severe pulmonary disease in immunocompromised individuals. However, SARS coronavirus caused severe ...lower respiratory disease with nearly 10% mortality and evidence of systemic spread. Recently, another coronavirus (human coronavirus-Erasmus Medical Center (hCoV-EMC)) was identified in patients with severe and sometimes lethal lower respiratory tract infection. Viral genome analysis revealed close relatedness to coronaviruses found in bats. Here we identify dipeptidyl peptidase 4 (DPP4; also known as CD26) as a functional receptor for hCoV-EMC. DPP4 specifically co-purified with the receptor-binding S1 domain of the hCoV-EMC spike protein from lysates of susceptible Huh-7 cells. Antibodies directed against DPP4 inhibited hCoV-EMC infection of primary human bronchial epithelial cells and Huh-7 cells. Expression of human and bat (Pipistrellus pipistrellus) DPP4 in non-susceptible COS-7 cells enabled infection by hCoV-EMC. The use of the evolutionarily conserved DPP4 protein from different species as a functional receptor provides clues about the host range potential of hCoV-EMC. In addition, it will contribute critically to our understanding of the pathogenesis and epidemiology of this emerging human coronavirus, and may facilitate the development of intervention strategies.
The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their ...pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-kappaB as central player, whereas expression of type I interferon (IFN)-beta is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI.
Abstract
Background and Aims
There is paucity of data on safety and efficacy of anti-tumour necrosis factor TNF in elderly inflammatory bowel disease IBD patients. We aimed to compare the long-term ...treatment failure rates and safety of a first anti-TNF agent in IBD patients between different age groups <40 years/40–59 years/≥60 years.
Methods
IBD patients who started a first anti-TNF agent were identified through IBDREAM, a multicentre prospective IBD registry. Competing risk regression was used to study treatment failure, defined as time to drug discontinuation due to adverse events AEs or lack of effectiveness, with discontinuation due to remission as a competing risk.
Results
A total of 895 IBD patients were included; 546 started anti-TNF at age <40 61.0%, 268 at age 40–59 29.9%, and 81 at age ≥60 9.1%. Treatment failure rate was higher in the two older groups (subhazard rate SHR age ≥60 1.46, SHR age 40–59 1.21; p = 0.03). The SHR in the elderly >60 was 1.52 for discontinuation due to AEs and 1.11 for lack of effectiveness. Concomitant thiopurine use was associated with a lower treatment failure rate (SHR 0.78, 95% confidence interval CI 0.62–0.98, p = 0.031). Serious adverse event SAE rate, as well as serious infection rate, were significantly higher in elderly IBD patients 61.2 versus 16.0 and 12.4 per 1000 patient-years, respectively whereas the malignancy rate was low in all age groups.
Conclusions
Elderly IBD patients starting a first anti-TNF agent showed higher treatment failure rates, but concomitant thiopurine use at baseline was associated with lower failure rates. Elderly IBD patients demonstrated higher rates of SAEs and serious infections.
STUDY QUESTION
To what extent are endometriosis and its related physical and mental symptoms associated with the perceived level of sexual functioning in women and their male partners?
SUMMARY ANSWER
...Dyspareunia and depressive symptoms are associated with impaired sexual functioning in women with endometriosis, whereas sexual functioning in their male partners is not affected.
WHAT IS KNOWN ALREADY
Women with endometriosis suffer from more dyspareunia, lower sexual functioning, and lower quality of life. In qualitative studies, partners of women with endometriosis report that endometriosis affected their quality of life and produced relational distress.
STUDY DESIGN SIZE, DURATION
In this cross-sectional study, sexual functioning in women with endometriosis (n = 83) and their partners (n = 74) was compared with sexual functioning in a control group of women attending the outpatient department for issues related to contraception (n = 40), and their partners (n = 26).
PARTICIPANTS/MATERIALS, SETTING, METHODS
Women and partners were recruited in the Maastricht University Medical Centre (MUMC) and the VieCuri Medical Centre Venlo between June 2011 and December 2012. All participants were asked to complete a set of online questionnaires.
MAIN RESULTS AND THE ROLE OF CHANCE
Response rates were 59.3% (83/140) for women with endometriosis and 52.3% (74/140) for their partners. Response rates in the control group were respectively 43.2% and 27.4% (41/95 and 27/95), of whom 40 women and 26 partners could be included in the study. Women with endometriosis as compared with the control group, reported significantly more frequent pain during intercourse (53% versus 15%, P < 0.001); higher levels of chronic pain (median VAS 2.0 cm versus 0.0 cm, P < 0.001); more impairment of sexual functioning (median Female Sexual Function Index 25.4 versus 30.6, P < 0.001); more impairment of quality of life (median Short Form-12 66.3 versus 87.2, P < 0.001); more pain catastrophizing (mean Pain Catastrophizing Scale 17.8 versus 8.5, P < 0.001), more depression and anxiety symptoms (median Hospital Anxiety and Depression Scale for depression 7 versus 4, P < 0.001 and for anxiety 4 versus 1, P < 0.001). Sexual functioning was comparable between male partners of women with endometriosis and male partners of the control group based on the International Index of Erectile Function. Logistic regression analyses showed that dyspareunia (OR 0.54; 95% CI 0.39–0.75) and depressive symptoms (OR 0.761; 95% CI 0.58–0.99) were independent and significant negative predictors for sexual functioning. Chronic pelvic pain (OR 0.53; 95% CI 0.35–0.81) and depressive symptoms (OR 0.65; 95% CI 0.44–0.96) were independent and significant negative predictors for quality of life.
LIMITATIONS, REASONS FOR CAUTION
Patient recruitment was performed in one tertiary care centre and to a lesser extent one general hospital, possibly leading to an over-representation of patients with more severe endometriosis. All participating women had a partner and are therefore ‘survivors’ in relationship terms. This may have led to an underestimation of the impact of endometriosis on sexual functioning.
WIDER IMPLICATIONS OF THE FINDINGS
It would be worthwhile to further explore the role of depressive symptoms in women with symptomatic endometriosis and to assess the effect of treatment of depressive symptoms on sexual functioning and quality of life. The fact that the partners did not report impaired sexual functioning could be a reassuring thought to women that might be discussed in the consulting room.
STUDY FUNDING/COMPETING INTEREST(S)
The study was funded by the MUMC. An unconditional research grant was given by the Dutch Society of Psychosomatic Obstetrics and Gynaecology (21 June 2011).
TRIAL REGISTRATION NUMBER
Not applicable.
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