Donor-Derived Cell-Free DNA as a Companion Biomarker for AMR Treatment With Daratumumab: Case Series.

Antibody-mediated rejection (AMR) is among the most frequent causes for graft loss after kidney transplantation. While there are no approved therapies, several case reports with daratumumab and the very recent phase 2 trial of felzartamab in AMR have indicated the potential efficacy of therapeutic interventions targeting CD38. Donor-derived cell-free DNA (dd-cfDNA) is an emerging biomarker with injury-specific release and a short half-life, which could facilitate early diagnosis of AMR and monitoring of treatment response. We describe two cases of patients with chronic active AMR, who were treated with monthly daratumumab infusions, and in whom donor-derived cell-free DNA (dd-cfDNA) was measured longitudinally to monitor treatment response. In both patients, daratumumab treatment led to stabilization of kidney function parameters, a strong decline of dd-cfDNA below the previously established threshold for rejection, and partial or complete histologic resolution of AMR activity. Our case series suggests that dd-cfDNA may be a useful companion biomarker for longitudinal monitoring of anti-CD38 treatment in patients with AMR.

A Short History of B-Cell HLA Epitopes.

Background: HLA epitopes are currently in the focus of transplantation immunogenetics. The main reason is the complexity of the HLA system with >38,000 alleles, the number of which increases steadily. These alleles are determined by the current state-of-the art typing methods like second- and third-generation sequencing. Screening for HLA antibodies is hampered by the lack of specific target beads with all possible alleles described. Summary: A way to circumvent the problem is to define HLA epitopes. The number of antibody-confirmed epitopes, on the other hand, was found to be 72 for HLA class I and 74 for HLA class II. Here, we elaborate on the current knowledge on these HLA epitopes. Absolute definitions of these structures are not yet available. Key Messages: Making use of eplets is a comparable way allowing statistical analyses. However, one should keep in mind that the results obtained are approximative or perhaps better associative. Continuous collaboration is needed for the full understanding of the HLA epitopes. The reactivity toward epitopes remains patient-specific.

Sensitive and specific serological ELISA for the detection of SARS-CoV-2 infections.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered the worldwide coronavirus disease 2019 (COVID-19) pandemic. Serological assays for the detection of SARS-CoV-2 infections are important to understand the immune response in patients and to obtain epidemiological data about the number of infected people, especially to identify asymptomatic persons not aware of a past infection. METHODS: We recombinantly produced SARS-CoV-2 nucleocapsid (N)-protein in Escherichia coli. We used the purified protein to develop an indirect enzyme-linked immunosorbent assay (ELISA) for the detection of SARS-CoV-2 specific antibodies. This ELISA method was optimized and validated with serum samples collected from 113 patients with RT-PCR-confirmed SARS-CoV-2 infections including hospitalized COVID-19 patients and 1500 control sera mostly collected before 2015 with different clinical background. RESULTS: The optimized N-protein-ELISA provided a sensitivity of 89.7% (n = 68) for samples collected from patients with confirmed SARS-CoV-2 infections and mild to severe symptoms more than 14 days after symptom onset or a positive PCR test. The antibody levels remained low for serum samples collected in the first six days (n = 23) and increased in the second week (n = 22) post symptom onset or PCR confirmation. At this early phase, the ELISA provided a sensitivity of 39.1% and 86.4%, respectively, reflecting the time of an IgG immune response against pathogens. The assay specificity was 99.3% (n = 1500; 95% CI 0.995-0.999). Serum samples from persons with confirmed antibody titers against human immunodeficiency viruses 1/2, parvovirus B19, hepatitis A/B virus, cytomegalovirus, Epstein Barr virus, and herpes simplex virus were tested negative. CONCLUSIONS: We conclude that the N-protein-based ELISA developed here is well suited for the sensitive and specific serological detection of SARS-CoV-2 specific IgG antibodies in human serum for symptomatic infections. It may also prove useful to identify previous SARS-CoV-2 infections in vaccinated people, as all currently approved vaccines rely on the SARS-CoV-2 spike (S-) protein.

Homozygosity in any HLA locus is a risk factor for specific antibody production: the taboo concept 2.0.

Objective: In a cooperative study of the University Hospital Leipzig, University of Leipzig, and the Charité Berlin on kidney transplant patients, we analysed the occurrence of HLA-specific antibodies with respect to the HLA setup of the patients. We aimed at the definition of specific HLA antigens towards which the patients produced these antibodies. Methods: Patients were typed for the relevant HLA determinants using mainly the next-generation technology. Antibody screening was performed by the state-of-the-art multiplex-based technology using microspheres coupled with the respective HLA alleles of HLA class I and II determinants. Results: Patients homozygous for HLA-A*02, HLA-A*03, HLA-A*24, HLA-B*07, HLA-B*18, HLA-B*35, HLA-B*44, HLA-C*03, HLA-C*04, and HLA-C*07 in the class I group and HLA-DRB1*01, HLA-DRB1*03, HLA-DRB1*07, HLA-DRB1*15, HLA-DQA1*01, HLA-DQA1*05, HLA-DQB1*02, HLA-DQB1*03(7), HLA-DQB1*06, HLA-DPA1*01, and HLA-DPB1*04 in the class II group were found to have a significant higher antibody production compared to the heterozygous ones. In general, all HLA determinants are affected. Remarkably, HLA-A*24 homozygous patients can produce antibodies towards all HLA-A determinants, while HLA-B*18 homozygous ones make antibodies towards all HLA-B and selected HLA-A and C antigens, and are associated with an elevation of HLA-DRB1, parts of DQB1 and DPB1 alleles. Homozygosity for the HLA class II HLA-DRB1*01, and HLA-DRB1*15 seems to increase the risk for antibody responses against most of the HLA class I antigens (HLA-A, HLA-B, and HLA-C) in contrast to HLA-DQB1*03(7) where a lower risk towards few HLA-A and HLA-B alleles is found. The widely observed differential antibody response is therefore to be accounted to the patient's HLA type. Conclusion: Homozygous patients are at risk of producing HLA-specific antibodies hampering the outcome of transplantation. Including this information on the allocation procedure might reduce antibody-mediated immune reactivity and prevent graft loss in a patient at risk, increasing the life span of the transplanted organ.

epiArt: a graphical HLA eplet amino acid repertoire translation reveals the need for an epitope driven revision of allele group nomenclature.

Introduction: The immune response after transplantation depends on recipient/donor HLA allele mismatches. To enhance our understanding of the relations of HLA alleles in terms of amino-acid polymorphisms and shared epitopes, we assessed pairwise sequence difference between HLA-alleles. Methods: We translated amino-acid sequences of confirmed eplets into an atlas of HLA class I and II antigens, followed by visualization of the pairwise allele distances by means of antigen-specific disparity graphs in differential amino-acid space. We obtained an overview of relationships of all alleles of an antigen, corresponding similarity/dissimilarity structures, outliers, alleles with similarity to different antigen groups. Additionally, we calculated prevalence of the amino-acids for each polymorphic sequence position and visualized them in amino-acid motif plots of all alleles belonging to an antigen. Results: Our visualizations show strongly varying intra-group heterogeneity of HLA class I and II alleles, as well as shared inter-group and inter-locus eplets and epitopes, indicating a benefit of epitope-based transplant matching: Single allele recipient/donor mismatches potentially refer to identical eplets, or to a set of multiple mismatched eplets. Discussion: This data reveals inconsistencies in the HLA group nomenclature and consequently adds a new level of quality to allocation, motivating the definition of tolerable or taboo mismatches.

Potential of a Bead-Based Multiplex Assay for SARS-CoV-2 Antibody Detection.

Serological assays for SARS-CoV-2 play a pivotal role in the definition of whether patients are infected, the understanding of viral epidemiology, the screening of convalescent sera for therapeutic and prophylactic purposes, and in obtaining a better understanding of the immune response towards the virus. The aim of this study was to investigate the performance of a bead-based multiplex assay. This assay allowed for the simultaneous testing of IgG antibodies against SARS-CoV-2 spike, S1, S2, RBD, and nucleocapsid moieties and S1 of seasonal coronaviruses hCoV-22E, hCoV-HKU1, hCoV-NL63, and hCoV-OC43, as well as MERS and SARS-CoV. We compared the bead-based multiplex assay with commercial ELISA tests. We tested the sera of 27 SARS-CoV-2 PCR-positive individuals who were previously tested with different ELISA assays. Additionally, we investigated the reproducibility of the results by means of multiple testing of the same sera. Finally, the results were correlated with neutralising assays. In summary, the concordance of the qualitative results ranged between 78% and 96% depending on the ELISA assay and the specific antigen. Repeated freezing-thawing cycles resulted in reduced mean fluorescence intensity, while the storage period had no influence in this respect. In our test cohort, we detected up to 36% of sera positive for the development of neutralising antibodies, which is in concordance with the bead-based multiplex and IgG ELISA.

Prognostic Role of Human Leukocyte Antigen Alleles and Cytokine Single-Nucleotide Polymorphisms in Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitor Drugs.

Tyrosine kinase inhibitor (TKI) drugs have significantly improved chronic myeloid leukemia (CML) outcomes. Neopeptides from CML cells may induce specific immune responses, which are crucial for deep molecular (DMR) and treatment-free remission (TFR). In this study of Ethiopian patients with CML (n = 162), the HLA alleles and single-nucleotide polymorphisms of five cytokines revealed significant associations with clinical outcomes. Clinically unfavorable outcomes correlated with HLA alleles A*03:01/02, A*23:17:01, B*57:01/02/03, and HLA-DRB4*01:01 (p-value = 0.0347, p-value = 0.0285, p-value = 0.037, and p-value = 0.0127, respectively), while HLA-DRB4*01:03:01 was associated with favorable outcomes (p-value = 0.0058). After assigning values for the 'low', 'intermediate', and 'high' gene expression of the SNPs' respective cytokine genes, Kaplan-Meier estimates for relapse-free survival, adjusted for age, treatment duration, and relapse risk among patients after the administration of TKIs, indicated that a gene expression ratio above the overall median of TNF-α, IL-6, and the combination of TGF-ß1/IL-10, IFNγ, and IL-6/IL-10 TGF-ß1 was correlated with a higher likelihood of treatment failure ((RR: 3.01; 95% CI: 1.1-8.3; p-value = 0.0261) and (RR: 2.4; 95% CI: 1.1-5.2; p-value = 0.022), respectively). Multi-SNPs, surpassing single-SNPs, and HLA allele polymorphisms showed promise in predicting outcomes of patients with CML during TKI treatment, prompting further exploration into their potential utility.

High resolution HLA genotyping with third generation sequencing technology-A multicentre study.

Molecular HLA typing techniques are currently undergoing a rapid evolution. While real-time PCR is established as the standard method in tissue typing laboratories regarding allocation of solid organs, next generation sequencing (NGS) for high-resolution HLA typing is becoming indispensable but is not yet suitable for deceased donors. By contrast, high-resolution typing is essential for stem cell transplantation and is increasingly required for questions relating to various disease associations. In this multicentre clinical study, the TGS technique using nanopore sequencing is investigated applying NanoTYPE™ kit and NanoTYPER™ software (Omixon Biocomputing Ltd., Budapest, Hungary) regarding the concordance of the results with NGS and its practicability in diagnostic laboratories. The results of 381 samples show a concordance of 99.58% for 11 HLA loci, HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1 and -DPB1. The quality control (QC) data shows a very high quality of the sequencing performed in each laboratory, 34,926 (97.15%) QC values were returned as 'passed', 862 (2.4%) as 'inspect' and 162 (0.45%) as 'failed'. We show that an 'inspect' or 'failed' QC warning does not automatically lead to incorrect HLA typing. The advantages of nanopore sequencing are speed, flexibility, reusability of the flow cells and easy implementation in the laboratory. There are challenges, such as exon coverage and the handling of large amounts of data. Finally, nanopore sequencing presents potential for applications in basic research within the field of epigenetics and genomics and holds significance for clinical concerns.

Leadership's long arm: The positive influence of digital leadership on managing technology-driven change over a strengthened service innovation capacity.

Introduction: In this qualitative study, we examine digital leadership (DL) capabilities and their positive influence on the management of technology-driven change by leveraging service innovations. The context of digital transformation (DT) has triggered a new leadership paradigm, among others referred to as digital leadership (DL). However, despite its practical relevance, leadership research has yet paid little attention to conceptualise DL as an approach to digitally transform organisations. Methods: Drawing on mid- and top-level mangers' experiences with service innovation projects, and based on Grounded Theory, we develop a taxonomy of DL-related capabilities and a conceptual framework which exemplifies their influences on dynamic service innovation capabilities (DSICs). DSICs build on the dynamic capabilities view (DCV) and represent the "organisational muscle" to repeatedly deliver service innovations indicating an effective management of technology-driven change. Results and Discussion: Taxonomy results show that aggregated dimensions in terms of a digital leader's personal, social, and organisational capital serve as underpinnings (DL-related capabilities) to drive strategic change in DT contexts. The conceptual framework further reveals that especially the personal and organisational capital of a digital leader owns several strong and moderate influences on DSICs which demonstrates DL's "long arm" on the management of technology-driven change. Our findings contribute to leadership research by advancing the conceptualisation of DL and by adding a novel micro-foundational perspective towards the DCV discourse. As organisations struggle to realise the full benefits of DT initiatives, our results also provide a valuable contribution for practitioners by supporting them to strategically prepare for the human-related challenges of DT.

Individual Immune Response to SARS-CoV-2 Infection-The Role of Seasonal Coronaviruses and Human Leukocyte Antigen.

During the coronavirus pandemic, evidence is growing that the severity, susceptibility and host immune response to SARS-CoV-2 infection can be highly variable. Several influencing factors have been discussed. Here, we investigated the humoral immune response against SARS-CoV-2 spike, S1, S2, the RBD, nucleocapsid moieties and S1 of seasonal coronaviruses: hCoV-229E, hCoV-HKU1, hCoV-NL63 and hCoV-OC43, as well as MERS-CoV and SARS-CoV, in a cohort of 512 individuals. A bead-based multiplex assay allowed simultaneous testing for all the above antigens and the identification of different antibody patterns. Then, we correlated these patterns with 11 HLA loci. Regarding the seasonal coronaviruses, we found a moderate negative correlation between antibody levels against hCoV-229E, hCoV-HKU1 and hCoV-NL63 and the SARS-CoV-2 antigens. This could be an indication of the original immunological imprinting. High and low antibody response patterns were distinguishable, demonstrating the individuality of the humoral response towards the virus. An immunogenetical factor associated with a high antibody response (formation of ≥4 different antibodies) was the presence of HLA A*26:01, C*02:02 and DPB1*04:01 alleles, whereas the HLA alleles DRB3*01:01, DPB1*03:01 and DB1*10:01 were enriched in low responders. A better understanding of this variable immune response could enable more individualized protective measures.

Genetic Predisposition to SARS-CoV-2 Infection: Cytokine Polymorphism and Disease Transmission within Households.

We addressed the question of the influence of the molecular polymorphism of cytokines from different T helper subsets on the susceptibility to SARS-CoV-2 infection. From a cohort of 527 samples (collected from 26 May 2020 to 31 March 2022), we focused on individuals living in the same household (n = 58) with the SARS-CoV-2-infected person. We divided them into households with all individuals SARS-CoV-2 PCR positive (n = 29, households, 61 individuals), households with mixed PCR pattern (n = 24, 62) and negative households (n = 5, 15), respectively. TGF-ß1 and IL-6 were the only cytokines tested with a significant difference between the cohorts. We observed a shift toward Th2 and the regulatory Th17 and Treg subset regulation for households with all members infected compared to those without infection. These data indicate that the genetically determined balance between the cytokines acting on different T helper cell subsets may play a pivotal role in transmission of and susceptibility to SARS-CoV-2 infection. Contacts infected by their index persons were more likely to highly express TGF-ß1, indicating a reduced inflammatory response. Those not infected after contact had a polymorphism leading to a higher IL-6 expression. IL-6 acts in innate immunity, allergy and on the T helper cell differentiation, explaining the reduced susceptibility to SARS-CoV-2.

Outcome differences in HPV-driven head and neck squamous cell carcinoma attributable to altered human leukocyte antigen frequencies.

Background: Effective immune surveillance requires a functioning immune system and natural killer (NK) and T cells for adequate innate and antigen-specific immune responses critically depending on human leukocyte antigens (HLAs) and haplotypes representing advantageous combinations of HLA antigens. Recently, we reported a link between altered frequencies of HLA alleles and haplotypes and developing head and neck squamous cell carcinoma (HNSCC). Whereas the majority of HNSCCs seem to be related to classical risk factors alcohol and tobacco, a subset of HNSCC and especially oropharyngeal squamous cell carcinoma (OPSCC) were etiologically linked to human papillomavirus (HPV) recently. Here, we demonstrate in HPV-driven (p16-positive high risk-HPV DNA-positive) HNSCC a deviating distribution of HLA antigens and haplotypes and their relevance to outcome. Methods: Leukocyte DNA of n = 94 HPV-driven HNSCC patients (n = 57 OPSCC, n = 37 outside oropharynx) underwent HLA SSO typing, allowing allele, antigen (allele group), and haplo-typing. Besides comparing these frequencies with those of German blood donors, we analyzed their impact on outcome using Kaplan-Meier plots and Cox proportional hazard regression. Results: Antigen and haplotype frequencies demonstrate enrichment of rare antigens and haplotypes. The HLA score for unselected HNSCC patients was not predictive for outcome here. However, together with alcohol consumption, tobacco smoking, T category, and extranodal extension of locoregional metastases and treatment applied, eight HLA traits allow for predicting progression-free and tumor-specific survival. Conclusion: Patients can be categorized into low, intermediate-low, intermediate-high, and high risk groups. Using a new PFS risk score for HPV-driven HNSCC may allow to improve prognostication.

Extended genomic HLA typing identifies previously unrecognized mismatches in living kidney transplantation.

Introduction: Antibody mediated rejection (ABMR) is the most common cause of long-term allograft loss in kidney transplantation (KT). Therefore, a low human leukocyte antigen (HLA) mismatch (MM) load is favorable for KT outcomes. Hitherto, serological or low-resolution molecular HLA typing have been adapted in parallel. Here, we aimed to identify previously missed HLA mismatches and corresponding antibodies by high resolution HLA genotyping in a living-donor KT cohort. Methods: 103 donor/recipient pairs transplanted at the University of Leipzig Medical Center between 1998 and 2018 were re-typed using next generation sequencing (NGS) of the HLA loci -A, -B, -C, -DRB1, -DRB345, -DQA1, -DQB1, -DPA1, and -DPB1. Based on these data, we compiled HLA MM counts for each pair and comparatively evaluated genomic HLA-typing with pre-transplant obtained serological/low-resolution HLA (=one-field) typing results. NGS HLA typing (=two-field) data was further used for reclassification of de novo HLA antibodies as "donor-specific". Results: By two-field HLA re-typing, we were able to identify additional MM in 64.1% (n=66) of cases for HLA loci -A, -B, -C, -DRB1 and -DQB1 that were not observed by one-field HLA typing. In patients with biopsy proven ABMR, two-field calculated MM count was significantly higher than by one-field HLA typing. For additional typed HLA loci -DRB345, -DQA1, -DPA1, and -DPB1 we observed 2, 26, 3, and 23 MM, respectively. In total, 37.3% (69/185) of de novo donor specific antibodies (DSA) formation was directed against these loci (DRB345 ➔ n=33, DQA1 ➔ n=33, DPA1 ➔ n=1, DPB1 ➔ n=10). Conclusion: Our results indicate that two-field HLA typing is feasible and provides significantly more sensitive HLA MM recognition in living-donor KT. Furthermore, accurate HLA typing plays an important role in graft management as it can improve discrimination between donor and non-donor HLA directed cellular and humoral alloreactivity in the long range. The inclusion of additional HLA loci against which antibodies can be readily detected, HLA-DRB345, -DQA1, -DQB1, -DPA1, and -DPB1, will allow a more precise virtual crossmatch and better prediction of potential DSA. Furthermore, in living KT, two-field HLA typing could contribute to the selection of the immunologically most suitable donors.

A novel cross-talk between endothelin and ErbB receptors controlling glutamate transporter expression in astrocytes.

The endothelin and epidermal growth factor (EGF) systems are central to the control of reactive brain processes and are thought to partly exert these tasks by endothelin-induced transactivation of the epidermal growth factor receptor (EGFR) Here we show that beyond EGFR transactivation, endothelins prevent the ligand-induced internalization of the EGFR. We unravel that endothelins abrogate internalization of the EGFR by either promoting the formation of "internalization-deficient" EGFR/ErB2-heterodimers or by activating c-Abl kinase, a negative regulator of EGFR internalization. We further provide evidence that this cross-talk is operational in the control of astrocytic glutamate transport. Specifically, we establish that the inhibitory effects exerted by endothelins on basal as well as EGF-induced expression of the major astroglial glutamate transporter subtype, glutamate transporter 1, are a direct consequence of the endothelin-dependent retention of the EGFR at the cell surface. Together our findings unravel a previously unknown cross-talk between endothelin and epidermal growth factor receptors, which may have implications for a variety of pathological conditions.

Is advanced cancer associated with demoralization and lower global meaning? The role of tumor stage and physical problems in explaining existential distress in cancer patients.

OBJECTIVE: This longitudinal study examines the extent to which global meaning, existential distress in terms of demoralization, and depression are predicted by tumor stage (UICC stages 0-II vs III/IV), palliative treatment, and physical problems in cancer patients. METHODS: N = 270 cancer patients were studied at baseline (T1, response rate: 41%) and after 3 months (T2) (N = 178, 72%). The following standardized self-report measures were used: Demoralization Scale, Life Attitude Profile--Revised, Hospital Anxiety and Depression Scale, NCCN DT (physical problems list). RESULTS: Multivariate regression analyses controlling for sociodemographic variables showed the number of physical problems significantly predicting higher demoralization (ß = 0.42, p<0.001) and depression (ß = 0.34, p<0.001), but not global meaning. While palliative treatment intention was related to higher depression (ß = 0.21, p = 0.03) and higher demoralization (ns), there was no effect of tumor stage on dependent variables. The hypothesized moderating effect of global meaning on the relation between physical problems and depression or demoralization, respectively, was not found. CONCLUSIONS: Results indicate a risk of existential distress in cancer patients across all disease stages, possibly due to confrontation with, albeit different, existential stressors throughout the illness. The general protective effect of global meaning against distress, independent of the number of physical problems, underscores the notion of existential concerns being relevant to cancer patients more generally, rather than just to a subgroup. However, physical problems might play a central role in the process of becoming demoralized through impairing the sense of mastery and competence. Findings finally strengthen the difference between the concepts of demoralization and global meaning.

Psychometric properties of the German version of the Short-Form Supportive Care Needs Survey Questionnaire (SCNS-SF34-G).

PURPOSE: The recommendation to screen for distress and supportive care needs among cancer patients focuses on improving the quality, effectiveness, and efficiency of comprehensive cancer care. The purpose of this study was to test the psychometric properties of the German version of the Short-Form Supportive Care Needs Survey (SCNS-SF34-G). METHODS: One thousand forty-seven participants with heterogeneous tumor entities were recruited in inpatient and outpatient cancer care facilities (female, 51%; median age, 57 years; breast cancer, 26%; prostate cancer, 22%). Concurrent and divergent validity of the SCNS-SF34-G was analyzed through associations with measures of distress, depression, anxiety, and social support. RESULTS: Principal component analyses revealed five dimensions replicating the factorial structure of the original SCNS-SF34 (health system and information, psychological, physical and daily living, patient care and support, sexuality needs) explaining 68% of variance. Cronbach's alpha values ranged from 0.82 to 0.94. Convergent validity was supported by significant correlations between all SCNS-SF34-G subscales and psychosocial burden. Divergent validity was indicated by marginal correlations with social support. The SCNS-SF34-G was able to discriminate patient groups with respect to sex and age but not regarding tumor stage. CONCLUSIONS: The SCNS-SF34-G is an instrument with excellent psychometric properties for assessing supportive care needs among patients with various cancer entities. It seems to be useful to integrate the questionnaire into diagnostic assessment to tailor interventions according to patient needs. Further research is needed to gain knowledge of the development of unmet needs during the illness trajectory as well as of associations with offer and utilization of healthcare services.

Immunogenetic Predisposition to SARS-CoV-2 Infection.

Herein, we included 527 individuals from two Hospitals, Chemnitz and University-Hospital Leipzig. In total, 199 were negative for PCR and 328 were positive upon first admission. We used next generation sequencing for HLA-A, B, C, DRB1, DRB345, DQA1, DQB1, DPA1, and DPB1, and in some cases, HLA-E, F, G, and H. Furthermore, we molecularly defined 22 blood group systems comprising 26 genes and 5 platelet antigen genes. We observed a significant enrichment of homozygosity for DQA/DQB in the positive group. Within the negative subjects, HLA-B*57:01, HLA-B*55:01, DRB1*13:01, and DRB1*01:01 were enriched, and in the positive group, homozygosity for DQA/DQB, DRB1*09:01, and DRB1*15:01 was observed. DQA1*01:01, DQA1*02:01, and DQA1*01:03 were enriched in the negative group. HLA-DQB1*06:02 was enriched in the positive group, and HLA-DQB1*05:01 and HLA-DQB1*06:03 were enriched in the negative group. For the blood group systems MNS, RH, LE, FY, JK, YT, DO, and KN, enrichment was seen in both groups, depending on the antigen under observation. Homozygosity for D-positive RHD alleles, as well as the phenotypes M-N+ of the MNS blood group system and Yk(a-) of the KN system, were enriched in the positive group. All of these significances disappeared upon correction. Subjects who carried homozygous HPA-1a were more frequent in the negative group, contrasting with the finding that HPA-1ab was enriched in the positive group.

Evaluation of S- and M-Proteins Expressed in Escherichia coli and HEK Cells for Serological Detection of Antibodies in Response to SARS-CoV-2 Infections and mRNA-Based Vaccinations.

This study investigated the IgG and IgA antibody response against recombinant S1 and receptor binding domains (RBD) of the spike (S-) protein and the membrane (M-) protein using a set of 115 serum samples collected from patients infected with SARS-CoV-2 in Germany before April 2021 using protein and peptide ELISA. As S1- and RBD-proteins expressed in Escherichia coli provided poor sensitivities in ELISA, they were replaced by proteins expressed in HEK cells. The RBD-ELISA provided a sensitivity of 90.6% (N = 85) for samples collected from patients with confirmed SARS-CoV-2 infections more than 14 days after symptom onset or a positive PCR test. In population-based controls, the specificity was 97.9% (N = 94). In contrast, the sensitivities were only 41.2% and 72.6% for M- and N-proteins, respectively, while the specificities were 88.5% and 100%, respectively. Considering also 20 samples collected during the first two weeks of symptom onset or PCR confirmation, the sensitivity of RBD- and N-protein ELISA decreased to 82.6% and 72.6%, respectively. The combination of two data sets, i.e., N- and RBD-, N- and M-, or RBD- and M-proteins increased the sensitivity to 85.8%, 77.9%, and 87.8%, respectively. Peptide mapping mostly confirmed epitopes previously reported for S1- and M-proteins, but they were only recognized by a few samples already tested positive in the corresponding protein ELISA indicating that peptide-based assays will not improve the diagnostic sensitivity.

Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms.

Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient's tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients.

Unmet supportive care needs: a cross-cultural comparison between Hong Kong Chinese and German Caucasian women with breast cancer.

The comparison of psychosocial needs across different cultural settings can identify cultural and service impacts on psychosocial outcomes. We compare psychosocial needs in Hong Kong Chinese and German Caucasian women with breast cancer. Completed questionnaires were collected from 348 Chinese and 292 German women with breast cancer for assessing unmet psychosocial needs (Supportive Care Needs Survey Short Form), psychological distress (the Hospital Anxiety and Depression scale), and listed physical and psychological symptoms. Only 11% of the participants reported not needing help for any of the 34 items. More German (14%) than Chinese women (8%) reported no unmet needs (χ(2) = 6.16, P = .013). With both samples combined, the Health System and Information domain unmet needs were the most prevalent, apart from one Psychological need domain item, "Fear about the cancer spreading." Chinese and German samples differed significantly in prevalence and patterns of unmet psychosocial needs. Multivariate adjustment for demographic, clinical, and sample characteristics, psychological distress, and symptoms showed that significantly greater unmet Health system and Information, and Patient care and support domain needs, associated with the presence of symptoms (ß = .232, P < .001), high HADS Anxiety (ß = .187, P < .001), higher education attainment (ß = .120, P = .002), and Chinese sample membership (ß = .280, P < .001). Greater unmet Psychological, Physical and Daily Living, and Sexuality domain needs were associated with the presence of symptoms, psychological distress, and German group membership, among others. German women reported more anxiety (t = 10.45, P < .001) and depression (t = 3.71, P < .001). In post hoc analyses, German, but not Chinese women reporting greater anxiety and depression had greater unmet Psychological and Sexuality domain needs (P < .001). It can be concluded that culture-specific differences in supportive care needs exist. Hong Kong Chinese women prioritize needs for information about their disease and treatment, whereas German Caucasian women prioritize physical and psychological support. Planning for cancer supportive care services or interventions to reduce unmet needs must consider cultural and/or health service contexts.