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Objectives: Decision‐making for patients with a locally advanced laryngeal carcinoma (T3 and T4) is challenging due to the treatment choice between organ preservation and laryngectomy, both with different and high impact on function and quality of life (QoL). The complexity of these treatment decisions and their possible consequences might lead to decisional conflict (DC). This study aimed to explore the level of DC in locally advanced laryngeal carcinoma patients facing curative decision‐making, and to identify possible associated factors. Methods: In this multicenter prospective cohort study, participants completed questionnaires on DC, level of shared decision‐making (SDM), and a knowledge test directly after counseling and 6 months after treatment. Descriptive statistics and Spearman correlation tests were used to analyze the data. Results: Directly after counseling, almost all participants (44/45; 98%) experienced Clinically Significant DC score (CSDC >25, scale 0–100). On average, patients scored 47% (SD 20%) correct on the knowledge test. Questions related to radiotherapy were answered best (69%, SD 29%), whilst only 35% (SD 29%) of the questions related to laryngectomy were answered correctly. Patients' perceived level of SDM (scale 0–100) was 70 (mean, SD 16.2), and for physicians this was 70 (SD 1.7). Conclusion: Most patients with advanced larynx cancer experience high levels of DC. Low knowledge levels regarding treatment aspects indicate a need for better patient counseling. Level of Evidence: 4 Laryngoscope, 134:3604–3610, 2024 [ABSTRACT FROM AUTHOR]

Objective: Voice prosthesis leakage significantly affects the quality of life of patients undergoing laryngectomy, causing insecurity and frequent unplanned hospital visits and costs. In this study, the concept of prophylactic voice prosthesis replacement was explored to prevent leakages. Study Design: Retrospective cohort study. Setting: Tertiary hospital. Methods: This study included all patients who underwent laryngectomy between 2000 and 2012 in the Netherlands Cancer Institute. Device lifetimes and voice prosthesis replacements of a retrospective cohort were used to calculate the number of needed voice prostheses per patient per year to prevent 70% of the leakages by prophylactic replacement. Various strategies for the timing of prophylactic replacement were considered: adaptive strategies based on the individual patient's history of replacement and fixed strategies based on the results of patients with similar voice prosthesis or treatment characteristics. Results: Patients used a median 3.4 voice prostheses per year (range, 0.1‐48.1). We found high inter‐ and intrapatient variability in device lifetime. When prophylactic replacement is applied, this would become a median 9.4 voice prostheses per year, which means replacement every 38 days, implying >6 additional voice prostheses per patient per year. The individual adaptive model showed that preventing 70% of the leakages was impossible for most patients and only a median 25% can be prevented. Monte‐Carlo simulations showed that prophylactic replacement is not feasible due to the high coefficient of variation (SD/mean) in device lifetime. Conclusion: Based on our simulations, prophylactic replacement of voice prostheses is not feasible due to high inter‐ and intrapatient variation in device lifetime. [ABSTRACT FROM AUTHOR]

Mobile health (mHealth) technologies have the potential to capture dense patient data on the background of real‐life behavior. Merck & Co., Inc. (Kenilworth, NJ), in collaboration with Koneksa Health, conducted a phase I clinical trial to validate cardiovascular mHealth technologies for concordance with traditional approaches and to establish sensitivity to detect effects of pharmacological intervention. This two‐part study enrolled 18 healthy male subjects. Part I, a 5‐day study, compared mHealth measures of heart rate (HR) and blood pressure (BP) to those from traditional methods. Hypotheses of similarity, in the clinic and at home, were tested individually for HR, systolic BP, and diastolic BP, at a 2‐sided 0.05 alpha level, with a prespecified criterion for similarity being the percentage differences between the 2 measurements within 15%. Part II, a 7‐day, 3‐period randomized balanced crossover study, evaluated the mHealth technology's ability to detect effects of bisoprolol and salbutamol. Hypotheses that the changes from baseline in HR were greater in the bisoprolol (reduction in HR) and salbutamol (increase in HR) groups compared with no treatment were tested, at a 1‐sided 0.05 alpha level. Linear mixed‐effects models, Pearson's correlation coefficients, summary statistics, and exploratory plots were applied to analyze the data. The mHealth measures of HR and BP were demonstrated to be similar to those from traditional methods, and sensitive to changes in cardiovascular parameters induced by bisoprolol and salbutamol. [ABSTRACT FROM AUTHOR]

No curative treatment options are available for advanced hepatocellular carcinoma (HCC). Anti‐PD1 antibody therapy can induce tumor regression in 20% of advanced HCC patients, demonstrating that co‐inhibitory immune checkpoint blockade has therapeutic potential for this type of cancer. However, whether agonistic targeting of co‐stimulatory receptors might be able to stimulate anti‐tumor immunity in HCC is as yet unknown. We investigated whether agonistic targeting of the co‐stimulatory receptor GITR could reinvigorate ex vivo functional responses of tumor‐infiltrating lymphocytes (TIL) freshly isolated from resected tumors of HCC patients. In addition, we compared GITR expression between TIL and paired samples of leukocytes isolated from blood and tumor‐free liver tissues, and studied the effects of combined GITR and PD1 targeting on ex vivo TIL responses. In all three tissue compartments, CD4+FoxP3+ regulatory T cells (Treg) showed higher GITR−expression than effector T‐cell subsets. The highest expression of GITR was found on CD4+FoxP3hiCD45RA− activated Treg in tumors. Recombinant GITR‐ligand as well as a humanized agonistic anti‐GITR antibody enhanced ex vivo proliferative responses of CD4+ and CD8+ TIL to tumor antigens presented by mRNA‐transfected autologous B‐cell blasts, and also reinforced proliferation, IFN‐γ secretion and granzyme B production in stimulations of TIL with CD3/CD28 antibodies. Combining GITR ligation with anti‐PD1 antibody nivolumab further enhanced tumor antigen‐specific responses of TIL in some, but not all, HCC patients, compared to either single treatment. In conclusion, agonistic targeting of GITR can enhance functionality of HCC TIL, and may therefore be a promising strategy for single or combinatorial immunotherapy in HCC. What's new? Therapeutic antibodies that block interaction of the T cell co‐inhibitory receptor PD1 can unleash pre‐existing anti‐cancer T cell responses in hepatocellular carcinoma (HCC). However, whether agonistic targeting of co‐stimulatory receptors could stimulate anti‐tumor immunity remains unknown. This study is the first to show that agonistic targeting of the co‐stimulatory receptor GITR can reinforce the functionality of tumor‐infiltrating T cells isolated from human tumors. Combined targeting of PD1 and GITR exerts additive stimulatory effects on ex vivo functionality of tumor‐infiltrating T cells from HCC patients. Targeting of GITR thus emerges as a promising strategy for single or combinatorial immunotherapy in HCC. [ABSTRACT FROM AUTHOR]

BACKGROUND Although the biopharmaceutical market grows rapidly, the environmental impacts of biopharmaceutical manufacturing have been hardly evaluated. The aim of the study is to comprehensively assess the environmental sustainability of a biologically‐produced active pharmaceutical ingredient (API) manufacturing process. For this purpose, an exergy analysis and an (exergetic) life cycle assessment were performed using primary (foreground system) and modeled data (background system). Infliximab, a monoclonal antibody, was considered. RESULTS: The fermentation and its raw materials' supply chain was determined to have the highest environmental impact, since the culture media requires chemicals and complex compounds such as animal‐derived materials (ADMs). The total impact per 100 mg of API produced ranged between 18.6 and 101.8 MJex and 2.0–3.1 kg CO2‐eq, mainly as a function of the ADMs' source. A comparison of infliximab and ustekinumab, a biopharmaceutical produced without ADMs, showed that eliminating these materials can reduce the cumulative resource consumption of monoclonal antibody manufacturing by up to 7.5 times. The fermentation is the process taking the longest and the heating, ventilation and air conditioning system which support fermentation areas consumes approximately 75% of all plant electricity use. CONCLUSIONS: Culture media nutrients and cleanroom requirements are driving factors in the environmental impact of biological API manufacturing. Obtaining more precise data of the bioprocesses behind these nutrients' supply chain is crucial to corroborating this study's results. © 2019 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include but are not limited to (i) adaptive expression of inhibitory checkpoint molecules in response to the proinflammatory environment and (ii) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self‐renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission. Several individual therapeutic agents have so far been developed to revert T‐cell exhaustion or disrupt the cross‐talk between cancer stem cells and the tumor‐promoting microenvironment. Here, we demonstrate that a three‐arm combination therapy—consisting of an mRNA‐based vaccine to induce antigen‐specific T‐cell responses, monoclonal antibodies blocking inhibitory checkpoint molecules (PD‐1, TIM‐3, LAG‐3), and antibodies targeting IL‐6 and TGF‐β—improves the therapeutic outcome in subcutaneous TC‐1 tumors and significantly prolongs survival of treated mice. Our findings point to a need for a rational development of multidimensional anticancer therapies, aiming at the induction of tumor‐specific immunity and simultaneously targeting multiple resistance mechanisms. [ABSTRACT FROM AUTHOR]

In situ modification of antigen-presenting cells garnered interest in cancer immunotherapy. Therefore, we developed APC-targeted lentiviral vectors (LVs). Unexpectedly, these LVs were inferior vaccines to broad tropism LVs. Since IL-12 is a potent mediator of antitumor immunity, we evaluated whether this proinflammatory cytokine could enhance antitumor immunity of an APC-targeted LV-based vaccine. Therefore, we compared subcutaneous administration of broad tropism LVs (VSV-G-LV) with APC-targeted LVs (DC2.1-LV)-encoding enhanced GFP and ovalbumin, or IL-12 and ovalbumin in mice. We show that codelivery of IL-12 by VSV-G-LVs or DC2.1-LVs augments CD4+ or CD8+ T-cell proliferation, respectively. Furthermore, we demonstrate that codelivery of IL-12 enhances the CD4+ TH1 profile irrespective of its delivery mode, while an increase in cytotoxic and therapeutic CD8+ T cells was only induced upon VSV-G-LV injection. While codelivery of IL-12 by DC2.1-LVs did not enhance CD8+ T-cell performance, it increased expression of inhibitory checkpoint markers Lag3, Tim3, and PD-1. Finally, the discrepancy between CD4+ T-cell stimulation with and without functional CD8+ T-cell stimulation by VSV-G- and DC2.1-LVs is partly explained by the observation that IL-12 relieves CD8+ T cells from CD4+ T-cell help, implying that a TH1 profile is of minor importance for antitumor immunotherapy if IL-12 is exogenously delivered. [ABSTRACT FROM AUTHOR]

Seismically-induced event deposits embedded in the sedimentary infill of lacustrine basins are highly useful for palaeoseismic reconstructions. Recent, well-documented, great megathrust earthquakes provide an ideal opportunity to calibrate seismically-induced event deposits for lakes with different characteristics and located in different settings. This study used 107 short sediment cores to investigate the sedimentary impact of the 1960 Mw 9·5 Valdivia and the 2010 Mw 8·8 Maule earthquakes in 17 lakes in South-Central Chile (i.e. lakes Negra, Lo Encañado, Aculeo, Vichuquén, Laja, Villarrica, Calafquén, Pullinque, Pellaifa, Panguipulli, Neltume, Riñihue, Ranco, Maihue, Puyehue, Rupanco and Llanquihue). A combination of image analysis, magnetic susceptibility and grain-size analysis allows identification of five types of seismically-induced event deposits: (i) mass-transport deposits; (ii) in situ deformations; (iii) lacustrine turbidites with a composition similar to the hemipelagic background sediments (lacustrine turbidites type 1); (iv) lacustrine turbidites with a composition different from the background sediments (lacustrine turbidites type 2) and (v) megaturbidites. These seismically-induced event deposits were compared to local seismic intensities of the causative earthquakes, eyewitness reports, post-earthquake observations, and vegetation and geomorphology of the catchment and the lake. Megaturbidites occur where lake seiches took place. Lacustrine turbidites type 2 can be the result of: (i) local near-shore mass wasting; (ii) delta collapse; (iii) onshore landslides; (iv) debris flows or mudflows; or (v) fluvial reworking of landslide debris. On the contrary, lacustrine turbidites type 1 are the result of shallow mass wasting on sublacustrine slopes covered by hemipelagic sediments. Due to their more constrained origin, lacustrine turbidites type 1 are the most reliable type of seismically-induced event deposits in quantitative palaeoseismology, because they are almost exclusively triggered by earthquake shaking. Moreover, they most sensitively record varying seismic shaking intensities. The number of lacustrine turbidites type 1 linearly increases with increasing seismic intensity, starting with no lacustrine turbidites type 1 at intensities between V½ and VI and reaching 100% when intensities are higher than VII½. Combining different types of seismically-induced event deposits allows the reconstruction of the complete impact of an earthquake. [ABSTRACT FROM AUTHOR]

The thymus is the organ devoted to T-cell production. The thymus undergoes multiple rounds of atrophy and redevelopment before degenerating with age in a process known as involution. This process is poorly understood, despite the influence the phenomenon has on peripheral T-cell numbers. Here we have investigated the FVB/N mouse strain, which displays premature thymic involution. We find multiple architectural and cellular features that precede thymic involution, including disruption of the epithelial-endothelial relationship and a progressive loss of pro-T cells. The architectural features, reminiscent of the human thymus, are intrinsic to the nonhematopoietic compartment and are neither necessary nor sufficient for thymic involution. By contrast, the loss of pro-T cells is intrinsic to the hematopoietic compartment, and is sufficient to drive premature involution. These results identify pro-T-cell loss as the main driver of premature thymic involution, and highlight the plasticity of the thymic stroma, capable of maintaining function across diverse interstrain architectures. [ABSTRACT FROM AUTHOR]

The present study aims at exploring which factors predict the willingness of adolescents to disclose personal information in response to online marketing requests. Our analyses show that especially privacy concerns and perceived benefits explain a considerable portion of variance in both willingness to disclose profile data (e.g. age, hobbies, favourite products) and contact data (e.g. phone number, e-mail address, home address). An interesting interrelationship was found between profile data and contact data disclosure. Contrary to our expectations, parental mediation strategies were only a weak predictor of teenagers' willingness to disclose contact information. Policy implications that emerge from the central findings of this study are discussed. [ABSTRACT FROM AUTHOR]

Dendritic cell therapy has been optimized a lot aiming to induce a strong and broad immune response in terms of the recognized epitopes by both CD8+ and CD4+ T cells and the use of the patients' complete unique set of HLA molecules. We here give an overview of our approach for antigen loading and maturation of dendritic cells and describe the consequences to evaluate the immune response after treatment as well as the Brussels experience in clinical trials. [ABSTRACT FROM AUTHOR]

Treatment of melanoma patients with mRNA electroporated dendritic cells (TriMixDC-MEL) stimulates T-cell responses against the presented tumor-associated antigens (TAAs). In the current clinical trials, melanoma patients with systemic metastases are treated, requiring priming and/or expansion of preexisting TAA-specific T cells that are able to migrate to both the skin and internal organs. We monitored the presence of TAA-specific CD8+ T cells infiltrating the skin at sites of intradermal TriMixDCMEL injection (SKILs) and within the circulation of melanoma patients treated in two clinical trials. In 10 out of fourteen (71%) patients screened, CD8+ T cells recognizing any of the four TAA presented by TriMixDC-MEL cellular vaccine were found in both compartments. In total, 30 TAA-specific T-cell responses were detected among the SKILs and 29 among peripheral blood T cells, of which 24 in common. A detailed characterization of the antigen specificity of CD8+ T-cell populations in four patients indicates that the majority of the epitopes detected were only recognized by CD8+ T cells derived from either skin biopsies or peripheral blood, indicating that some compartmentalization occurs after TriMix-DC therapy To conclude, functional TAA-specific CD8+ T cells distribute both to the skin and peripheral blood of patients after TriMixDC-MEL therapy. [ABSTRACT FROM AUTHOR]

Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at Tmax (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than −60 s. There were no significant between-treatment differences in TET (mean treatment difference: −6.90 (90% CI: −17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose. [ABSTRACT FROM AUTHOR]

Antigen-specific immunity is crucially important for containing viral replication in human immunodeficiency virus (HIV)-1-infected hosts. Several epitopes have been predicted for the early expressed HIV-1 proteins Tat and Rev, but few have been studied in detail. We characterized the human leukocyte antigen (HLA)-B44-restricted Rev epitope EELLKTVRL (EL9) in an HIV-1-infected subject treated with antiretroviral therapy. Interestingly, a high sequence similarity was found between the EL9 epitope and the human nucleolar protein 6 (NOL6). However, this similarity does not seem to impede immunogenicity as CD8+ T-cells, previously stimulated with EL9-pulsed dendritic cells, were able to specifically recognize the HIV-1 Rev epitope without cross-recognizing the human self-antigen NOL6. After the subject interrupted antiretroviral therapy and virus rebounded, mutations within the EL9 epitope were identified. Although the emerging mutations resulted in decreased or abolished T-cell recognition, they did not impair Rev protein function. Mutations leading to escape from T-cell recognition persisted for up to 124 weeks following treatment interruption. This study shows that the HLA-B44-restricted Rev CD8+ T-cell epitope EL9 is immunogenic notwithstanding its close resemblance to a human peptide. The epitope mutates as a consequence of dynamic interaction between T-cells and HIV-1. Clinical status, CD4+ T-cell count and viral load remained stable despite escape from T-cell recognition. [ABSTRACT FROM AUTHOR]

The double-edged nature of modern technology, continuously balancing between risks and opportunities, manifests itself clearly in an emerging societal problem known as cyberbullying. To analyse the extent and nature of the issue in Belgium, 1318 adolescents were questioned explicitly about their involvement in cyberbullying, as well as implicitly about their experience with specific types of cyberbullying-related behaviour. This alternate questioning revealed higher victimisation and perpetration rates. The study also provides better insight into predictors associated with victimisation or perpetration in cyberbullying. Especially past involvement in cyberbullying and engaging in online risk behaviour increase the likelihood of victimisation; non-rejection of cyberbullying and online identity experimentation augment the likelihood of perpetration. Girls are more likely to become victims of cyberbullying, whereas boys are more inclined to engage in electronic bullying. Moreover, the incidence of cyberbullying increases slightly with age. Finally, teens spending much time on the Internet, reporting higher ICT expertise and owning a computer with privileged online access share an increased likelihood of online bullying behaviour. [ABSTRACT FROM AUTHOR]

The launch of the first product is an important event for start-ups, because it takes the new venture closer to growth, profitability, and financial independence. The new product development (NPD) literature mainly focuses its attention on NPD processes in large firms. In this article insights on the antecedents on innovation speed in large firms are combined with resource-based theory and insights from the entrepreneurship literature to develop hypotheses concerning the antecedents of innovation speed in start-ups. In particular, tangible assets such as starting capital and the stage of product development at founding and intangible assets such as team tenure, experience of founders, and collaborations with third parties are considered as important antecedents for innovation speed in start-ups. A unique data set on research-based start-ups (RBSUs) was collected, and event-history analyses were used to test the hypotheses. The rich qualitative data on the individual companies are used to explain the statistical findings. This article shows that RBSUs differ significantly in their starting conditions. The impact of starting conditions on innovation speed differs between software and other companies. Although intuition suggests that start-ups that are further in the product development cycle at founding launch their first product faster, our data indicate that software firms starting with a beta version experience slower product launch. The amount of initial financing has no significant effect on innovation speed. Next, it is shown that team tenure and experience of founders leads to faster product launch. Contrary to expectations, alliances with other firms do not significantly affect innovation speed, and collaborations with universities are associated with longer development times. [ABSTRACT FROM AUTHOR]

Recently, it has become more and more obvious that not only CD8+ cytotoxic T lymphocytes, but also CD4+ T helper cells are required for the induction of an optimal, long-lasting anti-tumor immune response. CD4+ T helper cells, and in particular IFN-γ-secreting type 1 T helper cells, have been shown to fulfill a critical function in the mounting of a cancer-specific response. Consequently, targeting antigens into MHC class II molecules would greatly enhance the efficacy of an anti-cancer vaccine. The dissection of the MHC class II presentation pathway has paved the way for rational approaches to achieve this goal: novel systems have been developed to genetically manipulate the MHC class II presentation pathway. First, different genetic approaches have been used for the delivery of known epitopes into the MHC class II processing pathway or directly onto the peptide-binding groove of the MHC molecules. Second, several strategies exist for the targeting of whole tumor antigens, containing both MHC class I and class II restricted epitopes, to the MHC class II processing pathway. We review these data and describe how this knowledge is currently applied in vaccine development. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are pivotal regulators of immune reactivity and immune tolerance. The observation that DCs can recruit naive T cells has invigorated cancer immunology and led to the proposal of DCs as the basis for vaccines designed for the treatment of cancer. Designing effective strategies to load DCs with antigens is a challenging field of research. The successful realization of gene transfer to DCs will be highly dependent on the employed vector system. Here, we review various viral and non-viral gene transfer systems, and discuss their distinct characteristics and possible advantages and disadvantages in respect to their use in DC-based immunotherapy. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) are the professional antigen-presenting cells of the immune system, fully equipped to prime naive T cells and thus essential components for cancer immunotherapy. We tested the influence of several elements (cPPT, trip, WPRE, SIN) on the transduction efficiency of human DC. Human and murine DC were transduced with tNGFR-encoding lentiviruses to assess the effect of transduction on phenotype and function. Human DC were transduced with lentiviruses encoding huIi80MAGE-A3 and murine DC with huIi80tOVA to test antigen presentation. A self-inactivating (SIN) lentiviral vector containing the trip element was most efficient in transducing human DC. The transduction of DC with trip/SIN tNGFR encoding lentiviral vectors at MOI 15 resulted in stable gene expression in up to 94.6% (murine) and 88.2% (human) of the mature DC, without perturbing viability, phenotype and function. Human huIi80MAGE-A3-transduced DC were able to stimulate MAGE-A3-specific CD4+ and CD8+ T cell clones and could prime both MAGE-A3-specific CD4+ and CD8+ T cells in vitro. Murine huIi80tOVA-transduced DC were able to present OVA peptides in the context of MHC class I and class II in vitro and induced a strong OVA-specific cytotoxic T lymphocyte response in vivo, that was protective against subsequent challenge with OVA-expressing tumor cells. We show that, using lentiviral vectors, efficient gene transfer in human and murine DC can be obtained and that these DC can elicit antigen-specific immune responses in vitro and in vivo. The composition of the transfer vector has a major impact on the transduction efficiency. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) cells have inherited an activated hypermutation mechanism from their origin of germinal centre B cells. Based on today's knowledge of the intrinsic properties related to this mechanism and the VH base composition, reconsideration of previous reports should be made on a broader range of samples. The present study examined the mutation pattern of the VH genes expressed by 55 cases of FL. FL VH genes showed evidence of antigenic selection in 30% of cases with 88% carrying a functional sIg and 78.2% showing intraclonal variation. VH family and gene segment utilization was found to be roughly similar to that of normal B lymphocytes. FL VH genes revealed extensive variations. 17% of the VH exons harboured a total of five deletions, three duplications and two insertions as compared to the most homologous germline counterpart. The VH genes of one tumour displayed three populations with varying CDR3 length at diagnosis. At relapse, emergence of a differently mutated gene, additional mutations reminiscent of ongoing mutations or no variation was prominent. From this study the heterogeneity of FLs is well established and ongoing mutations are seen in the scope of the activated status of the hypermutation mechanism rather than antigen-stimulated tumour growth. [ABSTRACT FROM AUTHOR]

Recently it was reported that Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) infects bone marrow (BM) dendritic cells (DC) in multiple myeloma (MM) patients and therefore might play a role in MM development. Because of the use of myeloid growth factors like GM-CSF and G-CSF for the mobilization of peripheral blood progenitor cells (PBPC), the subsequent increase of DC precursors might imply a risk for KSHV contamination in PBPC grafts. Therefore, in this study leukapheresis products and ex vivo cultured CD34+ cell suspensions were analysed. KSHV DNA could not be amplified in any of them. [ABSTRACT FROM AUTHOR]

Presents a study which examined the role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin-mediated photodynamic therapy (PDT). Factor that precedes the onset of intrinsic apoptosis in photodamaged cells; Consequence of PDT-mediated loss of native SERCA2 protein; Execution of photokilling through an autophagic cell death pathway; Conclusions and significance of the study.

Treatment of melanoma patients with mRNA electroporated dendritic cells (TriMixDC-MEL) stimulates T-cell responses against the presented tumor-associated antigens (TAAs). In the current clinical trials, melanoma patients with systemic metastases are treated, requiring priming and/or expansion of preexisting TAA-specific T cells that are able to migrate to both the skin and internal organs. We monitored the presence of TAA-specific CD8(+) T cells infiltrating the skin at sites of intradermal TriMixDC-MEL injection (SKILs) and within the circulation of melanoma patients treated in two clinical trials. In 10 out of fourteen (71%) patients screened, CD8(+) T cells recognizing any of the four TAA presented by TriMixDC-MEL cellular vaccine were found in both compartments. In total, 30 TAA-specific T-cell responses were detected among the SKILs and 29 among peripheral blood T cells, of which 24 in common. A detailed characterization of the antigen specificity of CD8(+) T-cell populations in four patients indicates that the majority of the epitopes detected were only recognized by CD8(+) T cells derived from either skin biopsies or peripheral blood, indicating that some compartmentalization occurs after TriMix-DC therapy. To conclude, functional TAA-specific CD8(+) T cells distribute both to the skin and peripheral blood of patients after TriMixDC-MEL therapy. [ABSTRACT FROM AUTHOR]