In color vision, the quantitative rules for mixing lights to make a target color are well understood. By contrast, the rules for mixing odorants to make a target odor remain elusive. A solution to ...this problem in vision relied on characterizing receptor responses to different wavelengths of light and subsequently relating these responses to perception. In olfaction, experimentally measuring receptor responses to a representative set of complex mixtures is intractable due to the vast number of possibilities. To meet this challenge, we develop a biophysical model that predicts mammalian receptor responses to complex mixtures using responses to single odorants. The dominant nonlinearity in our model is competitive binding (CB): Only one odorant molecule can attach to a receptor binding site at a time. This simple framework predicts receptor responses to mixtures of up to 12 monomolecular odorants to within 15% of experimental observations and provides a powerful method for leveraging limited experimental data. Simple extensions of our model describe phenomena such as synergy, overshadowing, and inhibition. We demonstrate that the presence of such interactions can be identified via systematic deviations from the competitive-binding model.
The hypothesis was tested that parameters of an aged T-cell compartment associate with the risk for late rejection after kidney transplantation.
Recipients of a kidney transplant in the period ...2007-2013 were (N = 365) were included. T cells were characterized prior to transplantation by flow cytometry as naive (CD45RO-CCR7+), central-memory (CD45RO+CCR7+), effector-memory (CD45RO-CCR7-) or terminally differentiated CD8+ Temra (CD45RO-/CCR7-/CD28-) cells. T cell telomere length and thymic output were assessed prior to transplantation in 202 recipients. Follow-up was until December 2018. The date of the first time of biopsy-proven late rejection (>6 months after transplantation) was used to calculate the rejection-free survival time.
Fifty cases of biopsy-proven rejection were recorded. Thymic output and T cell telomere length did not associate with late rejection-free survival. However, the percentage and absolute numbers of CD8+Temra and CD28null CD8+ T cells were significantly lower in patients with late rejection. Specifically, in the highest tertile of percentages of CD28null CD8+ T cells, the cumulative incidence of late rejection at 5 and 10 years was only 5% and 8% compared to 16% and 20% in the middle to lowest tertile (p = 0.002). Multivariate proportional hazard analysis showed that percentage and absolute number of CD28null CD8+ T cells remained significantly associated with late rejection and rejection-related graft loss.
High numbers of differentiated CD28null CD8+ T cells decrease the risk for late rejection and rejection-related graft loss after kidney transplantation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Different histological and molecular subtypes of pancreatic ductal adenocarcinoma (PDAC), with different molecular composition and survival statistics, have recently been recognised.
This review ...describes the currently available studies regarding molecular and histological subtypes in PDAC. Studies from major cohorts such as International Cancer Genome Consortium as well as smaller cohorts are reviewed. We discuss where the described subtypes overlap, where the discrepancies are and which paths forward could be taken regarding diagnosis, ontogeny and therapy.
Four molecular subtypes with strong overlap among the different studies can be found, next to a list of mixed findings. Two of the four subtypes (epithelial classical and mesenchymal basal-like) were represented in every study and were often discriminated in other solid tumours as well. These two subtypes differ substantially in prognosis. One biomarker has been discovered, only discriminating these two subtypes, and insights into subtype-specific therapeutic vulnerabilities are scarce.
Subtypes can be reproducibly detected in cohorts of PDAC patients and two of them directly relate with prognosis. A consensus on the subtypes is warranted. Further discovery and validation studies are needed to identify strong biomarkers, to comprehend subtype ontogeny and to define strategies for precision medicine.
Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The ...establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments.
Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated.
The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred− (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred−: 91.3 months 95% confidence interval (CI): 61.2-not reached versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value.
The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.
•An RNA signature of gemcitabine-sensitivity is developed from in vitro and in vivo models of pancreatic cancer.•The resulting GemPred signature identifies a subgroup of patients who are sensitive to adjuvant gemcitabine.•The predictive value of GemPred is validated in two cohorts on both OS and disease-free survival.
Progressive loss of renal function is associated with a dysregulation of circulating T cells that may underlie their impaired T-cell immunity. Here we tested whether end-stage renal disease ...(ESRD)-related T-cell alterations are compatible with the concept of premature immunological aging. Younger patients (25–45 years old) with ESRD were found to resemble older healthy controls (60–80 years old) as they had a significant loss of naive T cells and a relative increase of memory T cells showing progressive terminal differentiation. A significant decrease in the content of T-cell receptor excision circles and telomere length in patients with ESRD confirmed these phenotypic data. The loss of naive T cells in patients with ESRD was associated with an excessive age-related decrease of recent thymic emigrants, indicating a premature decline in thymic function. Additionally, increased homeostatic proliferation of naive T cells was found in patients with ESRD, similar to that of older healthy individuals, with an increased susceptibility for activation-induced apoptosis. Therefore, both decreased thymic output and increased susceptibility of naive T cells for apoptosis may play a role in the loss of naive T cells in ESRD patients. Thus, our results are compatible with premature aging of the T-cell system of patients with ESRD comparable with that of healthy individuals 20–30 years older.
Cytomegalovirus (CMV) infection can cause significant complications after transplantation, but recent emerging data suggest that CMV may paradoxically also exert beneficial effects in two specific ...allogeneic transplant settings. These potential benefits have been underappreciated and are therefore highlighted in this review. First, after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) using T-cell and natural killer (NK) cell-replete grafts, CMV reactivation is associated with protection from leukemic relapse. This association was not observed for other hematologic malignancies. This anti-leukemic effect might be mediated by CMV-driven expansion of donor-derived memory-like NKG2C
NK and Vδ2
T-cells. Donor-derived NK cells probably recognize recipient leukemic blasts by engagement of NKG2C with HLA-E and/or by the lack of donor (self) HLA molecules. Vδ2
T cells probably recognize as yet unidentified antigens on leukemic blasts via their TCR. Second, immunological imprints of CMV infection, such as expanded numbers of Vδ2
T cells and terminally differentiated TCRαβ
T cells, as well as enhanced NKG2C gene expression in peripheral blood of operationally tolerant liver transplant patients, suggest that CMV infection or reactivation may be associated with liver graft acceptance. Mechanistically, poor alloreactivity of CMV-induced terminally differentiated TCRαβ
T cells and CMV-induced IFN-driven adaptive immune resistance mechanisms in liver grafts may be involved. In conclusion, direct associations indicate that CMV reactivation may protect against AML relapse after allogeneic HSCT, and indirect associations suggest that CMV infection may promote allograft acceptance after liver transplantation. The causative mechanisms need further investigations, but are probably related to the profound and sustained imprint of CMV infection on the immune system.
End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation ...predicts the risk for early acute allograft rejection (EAR).
222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31+ naive T cells were determined as T-cell ageing parameters.
Of the 222 patients analyzed, 30 (14%) developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively) and the number of related donor kidney transplantation was significantly lower (p = 0.018) in the EAR group. EAR-patients showed lower CD4+CD28null T-cell numbers (p<0.01) and the same trend was observed for CD8+CD28null T-cell numbers (p = 0.08). No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4+CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028). In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001).
Immunological ageing-related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. ...Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM
PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed "ATAC-array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.
End-stage renal disease is associated with premature ageing of the T cell immune system but inter-individual variation is substantial. The hypothesis was tested that advanced immunological T cell ...ageing assessed by peripheral T cell differentiation increases the long-term mortality risk after renal transplantation.
Circulating T cells of 211 recipients of a kidney from a living donor were analyzed before and in the first year after transplantation. The number of CD31-positive naive T cells (as a marker for recent thymic emigrants) and the differentiation status of the memory T cells was assessed. Thirty recipients died during follow-up of at least 5 years. Absolute numbers of naive CD4
(living:258 cells/μl vs. deceased:101 cells/μl,
< 0.001) and naive CD8
T cells (living:97 cells/μl vs. deceased:37 cells/μl, p < 0.001) were significantly lower in the deceased group prior to transplantation. In a multivariate proportional hazard analysis the number of naive CD4
T cells remained associated with all-cause mortality (HR 0.98, CI 0.98-0.99,
< 0.001). The low number of naive T cells in the deceased patient group was primarily caused by a decrease in recent thymic emigrants (i.e. less CD31
naive T cells) indicating a lowered thymus function. In addition, the physiological age-related compensatory increase in CD31
naïve T cells was not observed. Within the first year after transplantation, the number and characteristics of naive T cells remained stable.
A severe reduction in circulating naïve T cells because of a decrease in recent thymic emigrants is highly associated with all-cause mortality after renal transplantation.
Development of T-cell hyporesponsiveness to donor antigen may explain the substantial decreased risk for acute rejection in the years following kidney transplantation. The underlying mechanisms of ...donor-specific hyporesponsiveness (DSH) are largely unknown but may allow for lowering of immunosuppressive medication. Due to the onset of DSH being more rapid and pronounced in older recipients (+55 years), we hypothesized that immunosenescence/exhaustion of T lymphocytes would be a contributing factor. This study tested whether donor-reactive recipient T cells become hyporesponsive due to exhaustion from continuous stimulation by donor antigen. Circulating donor-reactive T cells of both young and elderly stable kidney transplant recipients (N=17) before and 3-5 years after transplantation were analyzed at the single cell level for expression of exhaustion markers by multi-parameter flow cytometry followed by unsupervised and unbiased clustering. Clusters containing cells of a particular expression profile with significant differential abundance after transplantation were identified and further analyzed. Unexpectedly, our results do not demonstrate an increase in exhausted donor antigen-reactive T cells post transplantation. Instead, we demonstrate a significant decrease in donor antigen-reactive CD4+ T cells expressing T cell immunoglobulin and ITIM domain (TIGIT) long after transplantation. Further analysis at earlier timepoints indicated that this decrease is already present at six months post transplantation. Characterization of these CD4+ T donor-reactive cells expressing TIGIT revealed them to have a predominantly central and effector memory T cell phenotype and a highly poly-functional cytokine expression profile. This study has therefore identified TIGIT as a marker for a previously undescribed polyfunctional donor-reactive CD4+ T cell population whose decline following kidney transplantation may explain development of DSH.
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