Changes and predictors of social support in adolescent and young adult cancer survivors-Results of a 7-year longitudinal study.

OBJECTIVE: As social support has been shown to have beneficial effects on coping with cancer, our study aims to close the research gap on perceived social support in adolescent and young adult (AYA) cancer survivors. METHODS: AYAs evaluated their perceived positive social support (PS) and detrimental interactions (DI) by completing the Illness-Specific Social Support Scale (ISSS-8) upon completion of acute treatment (t1) as well as 1 year (t2) and 7 years (t6) later. Temporal changes of social support were examined. Sociodemographic, psychological and medical factors were investigated as predictors for PS and DI by using mixed effects models. RESULTS: We analyzed data from 319 cancer survivors (74.9% women). At baseline, survivors reported an average score of 13.73 (SD = 2.52) for PS and 3.92 (SD = 2.85) for DI. Average perceived PS changed over time, while DI remained stable. Males, AYAs without a partner and AYAs with clinically meaningful anxiety or depression levels reported fewer PS. Higher effort to cope with the disease and clinically significant anxiety and depression levels were associated with more perceived DI. CONCLUSIONS: Existing social networks and perceived social support should be evaluated regularly in AYA-cancer survivorship. The identification and discussion of mental health of AYAs should also be a standard component in survivor consultations both during treatment and follow-up care, as elevated depression and anxiety levels were associated with fewer PS and more perceived DI.

Sleep quality in cancer patients: a common metric for several instruments measuring sleep quality.

PURPOSE: Sleep problems are frequently observed in cancer patients. Multiple questionnaires for assessing sleep quality have been developed. The aim of this study was to present transfer rules that allow the conversion of the patients' scores from one questionnaire to another. In addition, we anchored this common metric to the general population. METHODS: A sample of 1,733 cancer patients completed the following questionnaires: Pittsburgh Sleep Quality Index, Insomnia Sleep Index, Jenkins Sleep Scale, EORTC QLQ-C30, and the sleep scale of the EORTC QLQ-SURV100. The methods for establishing a common metric were based on Item Response Theory. RESULTS: The main result of the study is a figure that allows the conversion from one of the above-mentioned sleep scales into another. Furthermore, the scores of the questionnaires can be transferred to theta scores that indicate the position within the group of cancer patients and also to T scores that indicate the position in relation to the general population. The correlations between the sleep scales ranged between 0.70 and 0.85. CONCLUSIONS: The conversion rules presented in the study enable researchers and clinicians to directly compare single scores or mean scores across studies using different sleep scales, to assess the degree of sleep problems with regard to the general population, and to relate cutoff scores from one questionnaire to another.

Digital Therapeutic (Mika) Targeting Distress in Patients With Cancer: Results From a Nationwide Waitlist Randomized Controlled Trial.

BACKGROUND: Distress is highly prevalent among patients with cancer, but supportive care needs often go unmet. Digital therapeutics hold the potential to overcome barriers in cancer care and improve health outcomes. OBJECTIVE: This study conducted a randomized controlled trial to investigate the efficacy of Mika, an app-based digital therapeutic designed to reduce distress across the cancer trajectory. METHODS: This nationwide waitlist randomized controlled trial in Germany enrolled patients with cancer across all tumor entities diagnosed within the last 5 years. Participants were randomized into the intervention (Mika plus usual care) and control (usual care alone) groups. The participants completed web-based assessments at baseline and at 2, 6, and 12 weeks. The primary outcome was the change in distress from baseline to week 12, as measured by the National Comprehensive Cancer Network Distress Thermometer. Secondary outcomes included depression, anxiety (Hospital Anxiety and Depression Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), and quality of life (Clinical Global Impression-Improvement Scale). Intention-to-treat and per-protocol analyses were performed. Analyses of covariance were used to test for outcome changes over time between the groups, controlling for baseline. RESULTS: A total of 218 patients (intervention: n=99 and control: n=119) were included in the intention-to-treat analysis. Compared with the control group, the intervention group reported greater reductions in distress (P=.03; ηp²=0.02), depression (P<.001; ηp²=0.07), anxiety (P=.03; ηp²=0.02), and fatigue (P=.04; ηp²=0.02). Per-protocol analyses revealed more pronounced treatment effects, with the exception of fatigue. No group difference was found for quality of life. CONCLUSIONS: Mika effectively diminished distress in patients with cancer. As a digital therapeutic solution, Mika offers accessible, tailored psychosocial and self-management support to address the unmet needs in cancer care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00026038; https://drks.de/search/en/trial/DRKS00026038.

New progress in an old debate? Applying the DSM-5 criteria to assess traumatic events and stressor-related disorders in cancer survivors.

OBJECTIVE: The rather broad definition of medical trauma within DSM-IV has contributed to long-lasting debates on the applicability of Posttraumatic Stress Disorder (PTSD) in oncological patients and its differentiation from Adjustment Disorder (AjD) which results from non-traumatic critical life events. The DSM-5 criteria have introduced a narrower definition of medical traumatization. However, studies on updated prevalence rates in cancer patients are missing. METHODS: Within a cross-sectional study, we assessed hematological cancer survivors using the Structured Clinical Interview for DSM-5. We investigated (i) the frequency and type of cancer-related stressors, (ii) the proportion of stressors qualifying as traumatic according to DSM-5 (i.e., an event of sudden and catastrophic character) and (iii) the prevalence of PTSD, AjD and cancer-related PTSD according to DSM-5. RESULTS: 291 patients participated (response rate: 58%). Mean age was 54 years, 60% were male. 168 patients (59%) reported cancer-related stressors, with the most frequent being cancer diagnosis disclosure (n = 58, 27%). Eight percent of reported stressors qualified as traumatic events according to DSM-5. Five (1.8%), 15 (5.3%) and 20 (7.0%) cancer survivors met DSM-5 criteria for current PTSD, lifetime PTSD and AjD, respectively. Among all PTSD cases, three were cancer-related (1.1%). In addition, seven patients (2.5%) met all symptoms for cancer-related PTSD, but not the DSM-5 criterion for medical trauma. Considering receiving the cancer diagnosis as traumatic event, which is debatable according to DSM-5, 38% of stressors qualified as traumatic and six patients (2.1%) met criteria for cancer-related PTSD. CONCLUSIONS: DSM-5 criteria enable a clear identification of traumatic events in the context of cancer. This change may inform discussions on the appropriateness of PTSD in cancer patients and facilitates its differentiation from AjD. Larger studies need to validate our findings.

Symptoms of posttraumatic stress disorder and adjustment disorder in hematological cancer patients with different treatment regimes.

BACKGROUND: Symptoms of posttraumatic stress disorder (PTSD) and adjustment disorder (AjD) are common in hematological cancer patients as they face severe stressors during their serious disease and often intensive treatment, such as stem cell transplantation (SCT). Aims of the present study were to provide frequency and risk factors for PTSD and AjD based on updated diagnostic criteria that are lacking to date. MATERIAL AND METHODS: In a cross-sectional study, hematological cancer patients were assessed for stressor-related symptoms via validated self-report questionnaires based on updated criteria for PTSD (PCL-5) and AjD (ADMN-20). Frequency and symptom severity were estimated among the total sample and SCT subgroups (allogeneic, autologous, no SCT). SCT subgroups were compared using Chi-squared-tests and ANOVAs. Linear regression models investigated sociodemographic and medical factors associated with symptomatology. RESULTS: In total, 291 patients were included (response rate: 58%). 26 (9.3%), 66 (23.7%) and 40 (14.2%) patients met criteria for cancer-related PTSD, subthreshold PTSD and AjD, respectively. Symptom severity and frequency of criteria-based PTSD and AjD did not differ between SCT subgroups (all p > 0.05). Factors associated with elevated symptomatology were younger age (PTSD: p < 0.001; AjD: p = 0.02), physical comorbidity (PTSD: p < 0.001; AjD: p < 0.001) and active disease (PTSD: p = 0.12; AjD: p = 0.03). CONCLUSION: Based on new criteria, a considerable part of hematological cancer patients reports PTSD and AjD symptoms. Younger patients and patients with physical symptom burden might be particularly at risk and need to be monitored closely to enable effective treatment at an early stage.

Effect of depression, anxiety, and distress screeners on the need, intention, and utilization of psychosocial support services among cancer patients.

PURPOSE: In clinical cancer care, distress screening is recommended to identify highly burdened patients in objective need for psychosocial support to improve psychological distress and quality of life and to enhance patient empowerment. It is however unclear whether distress screeners are suitable for psychosocial care planning and thus whether they can predict the willingness that is need, intention, and utilization, to seek psychosocial support. METHODS: In a secondary analysis of a cluster intervention study, we assessed cancer patients with three distress screeners (DT, PHQ-9, GAD-7) at baseline. The willingness to seek psychosocial support services was assessed binary for psychosocial services at 3 and 6 months. Logistic regression models were applied to examine the predictive effect of the screeners on need, intention, and utilization. We corrected all models for multiple testing. RESULTS: The 660 patients included in the study were on average 60 years, 54% were male. At the 3- and 6-month follow-up, 353 and 259 patients participated, respectively. The screeners were best in predicting the need for support (OR reaching up to 1.15, 1.20, and 1.22 for the PHQ-9, GAD-7, and DT respectively). The intention was predicted by the PHQ-9 and GAD-7, whereas utilization of psychosocial support services was not predicted by the screeners. CONCLUSION: The three distress screeners might be useful in psychosocial care planning, as they are able to predict the need and to some degree the intention to seek psychosocial support. Future research needs to examine potential barriers and supporting factors that may explain utilization of psychosocial support. TRIAL REGISTRATION: The study was retrospectively registered (2/2021) at ClinicalTrials.gov (number: NCT04749056).

Spontaneous protein-protein crosslinking at glutamine and glutamic acid residues in long-lived proteins.

Long-lived proteins (LLPs) are susceptible to the accumulation of both enzymatic and spontaneous post-translational modifications (PTMs). A prominent PTM observed in LLPs is covalent protein-protein crosslinking. In this study, we examined aged human lenses and found several proteins to be crosslinked at Glu and Gln residues. This new covalent bond involves the amino group of Lys or an α-amino group. A number of these crosslinks were found in intermediate filament proteins. Such crosslinks could be reproduced experimentally by incubation of Glu- or Gln-containing peptides and their formation was consistent with an amino group attacking a glutarimide intermediate. These findings show that both Gln and Glu residues can act as sites for spontaneous covalent crosslinking in LLPs and they provide a mechanistic explanation for an otherwise puzzling observation, that a major fraction of Aß in the human brain is crosslinked via Glu 22 and the N-terminal amino group.

New insights into the mechanisms of age-related protein-protein crosslinking in the human lens.

Although protein crosslinking is often linked with aging as well as some age-related diseases, very few molecular details are available on the nature of the amino acids involved, or mechanisms that are responsible for crosslinking. Recent research has shown that several amino acids are able to generate reactive intermediates that ultimately lead to covalent crosslinking through multiple non-enzymatic mechanisms. This information has been derived from proteomic investigations on aged human lenses and the mechanisms of crosslinking, in each case, have been elucidated using model peptides. Residues involved in spontaneous protein-protein crosslinking include aspartic acid, asparagine, cysteine, lysine, phosphoserine, phosphothreonine, glutamic acid and glutamine. It has become clear, therefore, that several amino acids can act as potential sites for crosslinking in the long-lived proteins that are present in aged individuals. Moreover, the lens has been an invaluable model tissue and source of crosslinked proteins from which to determine crosslinking mechanisms that may lead to crosslinking in other human tissues.

Psychosocial aftercare of adolescent and young adult cancer survivors in Germany: Awareness, utilisation, satisfaction and associated factors.

AIM: This study systematically assesses the awareness of, utilisation of and satisfaction with psychosocial care for adolescents and young adult (AYA) cancer survivors in aftercare. METHODS: Survivors between 18 and 39 years were surveyed in aftercare. Awareness of, utilisation of and satisfaction with psychological counselling (PC), social-legal counselling (SLC) and other psychosocial care (OPC) were measured using self-developed questionnaires. Multivariate analyses were conducted to determine factors correlated with awareness and use of psychosocial care. RESULTS: Five hundred and fourteen survivors participated; the mean age at diagnosis was 29.6 years (SD = 6.14). 54% of cancer survivors were aware of PC, 45% of SLC and 24% of OPC. Those who possessed knowledge about these services used it to a considerable extent (63%-74%), and the majority (66%-75%) was highly satisfied. No common factors could be found that increase the likelihood of being aware of these three services (R2  = 0.028-0.138). Female gender (OR = 2.08-2.18) and high anxiety (OR = 1.19-1.38) were identified as common factors that increase the likelihood of utilising psychosocial services (R2  = 0.160-0.395). CONCLUSION: AYA who are aware of psychosocial services in aftercare are motivated to use them and express high satisfaction with use. For the utilisation of psychosocial services, anxiety and female gender can be identified as common factors. The visibility of psychosocial services for aftercare should be increased given the high number of unaware AYA survivors. The active and repeated addressing of psychosocial issues and regular provision of information (e.g., written guides on survivorship) by caregivers should be made a standard of care for AYA cancer survivors.

Development and preliminary psychometric investigation of the German Satisfaction with Comprehensive Cancer Care (SCCC) Questionnaire.

PURPOSE: The assessment of patient satisfaction during treatment is essential to provide patient-centered high-quality cancer care. Nevertheless, no German instrument assesses patient satisfaction with comprehensive cancer care, which not only includes oncological treatment, but also interpersonal quality of care as well as psychosocial support services. Based on the French REPERES-60, we developed the German Patient Satisfaction with Comprehensive Cancer Care (SCCC) questionnaire. METHODS: The REPERES-60 was translated and the items were adapted to make it applicable to the German healthcare system and across different tumor entities. Scales of the resulting instrument were extracted via principal axis factoring (PAF). Subsequently, we investigated the reliability (Cronbach's Alpha, CA), discriminatory power (corrected item-scale correlations) and convergent validity (pre-specified correlations of the SCCC with different outcomes). RESULTS: The SCCC consisted of 32 items which were subsequently tested among a sample of 333 patients across different tumor entities (response rate: 47%). Average age was 59 years (standard deviation: 14), 63% were male. PAF revealed four multi-item scales named Competence, Information, Access and Support accounting for 71% of the variance. Two single-items scales assess global satisfaction with medical and psychosocial care, respectively. CA across the multi-item scales ranged from .84 to .96. Discriminatory power was sufficiently high, with all r ≥ .5. Convergent validity was largely verified by negative associations of the four multi-item scales with depressive/anxious symptomatology (r ≥ - .18, p < .01) and fatigue/overall symptom burden (r ≥ - .14, p < .01). CONCLUSION: We developed a tool to assess patient satisfaction with comprehensive cancer care in Germany. The SCCC showed satisfactory psychometric properties. Further studies are needed to verify these preliminary findings.

What turns CREB on? And off? And why does it matter?

Altered expression and function of the transcription factor cyclic AMP response-binding protein (CREB) has been identified to play an important role in cancer and is associated with the overall survival and therapy response of tumor patients. This review focuses on the expression and activation of CREB under physiologic conditions and in tumors of distinct origin as well as the underlying mechanisms of CREB regulation by diverse stimuli and inhibitors. In addition, the clinical relevance of CREB is summarized, including its use as a prognostic and/or predictive marker as well as a therapeutic target.

Rapid screener for the assessment of fear of progression in cancer survivors: The Fear of progression-Questionnaire Rapid Screener.

OBJECTIVES: Fear of progression (FoP) among cancer survivors can adversely affect all areas of life. Existing instruments are too long for implementation in routine care. Therefore, we developed and tested a rapid screener for FoP (FoP-Q-RS). METHODS: Data were derived from a register-based study among cancer survivors. The 12-item short form of the Fear-of-Progression Questionnaire (FoP-Q-SF) served as item-pool. Confirmatory factor analysis (CFA) was applied to determine (a) fit indices including comparative fit index (CFI) and standardised root mean square residual (SRMR) and (b) measures of reliability including composite reliability (CR). Fit indices were compared to the FoP-Q-SF. Sensitivity and specificity were calculated to recommend a cut-off (criterion: GAD-7 score ≥10). RESULTS: One thousand two cancer survivors participated (response rate: 53%). We selected five items for the FoP-Q-RS. CFA indicated acceptable fit (CFI = 0.936; SRMR = 0.048) and reliability (CR = 0.793). Fit indices were better than for the FoP-Q-SF. The cut-off ≥12 showed optimal balance between sensitivity (72%) and specificity (70%), the cut-off ≥10 revealed higher sensitivity (86%) with still tolerable specificity (52%). CONCLUSION: The FoP-Q-RS shows good psychometric properties and may be applied in routine care. Further studies on preferable cut-offs and other populations are needed.

Tau Is Truncated in Five Regions of the Normal Adult Human Brain.

The truncation of Tau is thought to be important in promoting aggregation, with this feature characterising the pathology of dementias such as Alzheimer disease. Antibodies to the C-terminal and N-terminal regions of Tau were employed to examine Tau cleavage in five human brain regions: the entorhinal cortex, prefrontal cortex, motor cortex, hippocampus, and cerebellum. These were obtained from normal subjects ranging in age from 18 to 104 years. Tau fragments of approximately 40 kDa and 45 kDa with an intact N-terminus retained were found in soluble and insoluble brain fractions. In addition, smaller C-terminal Tau fragments ranging in mass from 17 kDa to 25 kDa were also detected. These findings are consistent with significant Tau cleavage taking place in brain regions from 18 years onwards. It appears that site-specific cleavage of Tau is widespread in the normal human brain, and that large Tau fragments that contain the N-terminus, as well as shorter C-terminal Tau fragments, are present in brain cells across the age range.

Old Proteins in Man: A Field in its Infancy.

It has only recently been appreciated that the human body contains many long-lived proteins (LLPs). Their gradual degradation over time contributes to human aging and probably also to a range of age-related disorders. Indeed, the role of progressive damage of proteins in aging may be indicated by the fact that many neurological diseases do not appear until after middle age. A major factor responsible for the deterioration of old proteins is the spontaneous breakdown of susceptible amino acid residues resulting in racemization, truncation, deamidation, and crosslinking. When proteins decompose in this way, their structures and functions may be altered and novel epitopes can be formed that can induce an autoimmune response.

Characterization of the expression and immunological impact of the transcriptional activator CREB in renal cell carcinoma.

BACKGROUND: The non-classical human leukocyte antigen (HLA)-G is a strong immunomodulatory molecule. Under physiological conditions, HLA-G induces immunological tolerance in immune privileged tissues, while under pathophysiological situations it contributes to immune escape mechanisms. Therefore, HLA-G could act as a potential immune checkpoint for future anti-cancer immunotherapies. Recent data suggest an aberrant expression of the cAMP response element binding protein (CREB) in clear cell renal cell carcinoma (ccRCC), which is correlated with tumor grade and stage. Furthermore, preliminary reports demonstrated a connection of CREB as a control variable of HLA-G transcription due to CREB binding sites in the HLA-G promoter region. This study investigates the interaction between CREB and HLA-G in different renal cell carcinoma (RCC) subtypes and its correlation to clinical parameters. METHODS: The direct interaction of CREB with the HLA-G promoter was investigated by chromatin immunoprecipitation in RCC cell systems. Furthermore, the expression of CREB and HLA-G was determined by immunohistochemistry using a tissue microarray (TMA) consisting of 453 RCC samples of distinct subtypes. Staining results were assessed for correlations to clinical parameters as well as to the composition of the immune cell infiltrate. RESULTS: There exists a distinct expression pattern of HLA-G and CREB in the three main RCC subtypes. HLA-G and CREB expression were the lowest in chromophobe RCC lesions. However, the clinical relevance of CREB and HLA-G expression differed. Unlike HLA-G, high levels of CREB expression were positively associated to the overall survival of RCC patients. A slightly, but significantly elevated number of tumor infiltrating regulatory T cells was observed in tumors of high CREB expression. Whether this small increase is of clinical relevance has to be further investigated. CONCLUSIONS: An interaction of CREB with the HLA-G promoter could be validated in RCC cell lines. Thus, for the first time the expression of CREB and its interaction with the HLA-G in human RCCs has been shown, which might be of clinical relevance.

Creating novel specificities in a fungal nonself recognition system by single step homologous recombination events.

In many organisms, two component systems have evolved to discriminate self from nonself. While the molecular function of the two components has been elucidated in several systems, the evolutionary events leading to the large number of different specificities for self-nonself recognition found in most systems remain obscure. We have investigated the variation within a multiallelic nonself recognition system in the phytopathogenic basidiomycete Ustilago maydis by means of sequence analysis and functional studies. The multiallelic b mating type locus of U. maydis ensures outbreeding during sexual development. Nonself recognition is specified by the two homeodomain proteins, bE and bW, encoded by the b locus. While bE-bW combinations from the same allele do not dimerize, bE and bW proteins originating from different alleles form a heterodimeric complex that functions as master regulator for sexual and pathogenic development. We show that novel specificities of the b mating type locus have arisen by single homologous recombination events between distinct b alleles that lead to a simultaneous exchange of subdomains involved in dimerization in both bE and bW, altering the specificity of both proteins in a single step.

Risk and associated factors of depression and anxiety in men with prostate cancer: Results from a German multicenter study.

OBJECTIVE: In order to optimize psycho-oncological care, studies that quantify the extent of distress and identify certain risk groups are needed. Among patients with prostate cancer (PCa), findings on depression and anxiety are limited. METHODS: We analyzed data of PCa patients selected from a German multi-center study. Depression and anxiety were assessed with the PHQ-9 and the GAD-7 (cut-off ≥7). We provided physical symptom burden, calculated absolute and relative risk (AR and RR) of depression and anxiety across patient subsets and between patients and the general population (GP) and tested age as a moderator within the relationship of disease-specific symptoms with depression and anxiety. RESULTS: Among 636 participants, the majority reported disease-specific problems (sexuality: 60%; urination: 52%). AR for depression and anxiety was 23% and 22%, respectively. Significant RR were small, with higher risks of distress in patients who are younger (eg, RRdepression = 1.15; 95%-CI: 1.06-1.26), treated with chemotherapy (RRdepression = 1.46; 95%-CI: 1.09-1.96) or having metastases (RRdepression = 1.30; 95%-CI: 1.02-1.65). Risk of distress was slightly elevated compared to GP (eg, RRdepression = 1.13; 95%-CI: 1.07-1.19). Age moderated the relationship between symptoms and anxiety (Burination = -0.10, P = .02; Bsexuality = -0.11, P = .01). CONCLUSIONS: Younger patients, those with metastases or treatment with chemotherapy seem to be at elevated risk for distress and should be closely monitored. Many patients suffer from disease-specific symptom burden, by which younger patients seem to be particularly distressed. Support of coping mechanisms associated with disease-specific symptom burden seems warranted.

Depression and anxiety in long-term survivors 5 and 10 years after cancer diagnosis.

PURPOSE: Our study provides data on depression and anxiety in long-term cancer survivors, in men, women and various age groups, as well as identifies associated factors and coping-related resources. METHODS: We present data obtained from 1002 cancer survivors across a large variety of tumour entities 5 years (cohort 1) and 10 years (cohort 2) after diagnosis, in a cross-sectional study. We analysed depression (PHQ-9) and anxiety (GAD-7) symptomatology in comparison with two large age- and sex-matched samples randomly selected from the general population. RESULTS: Moderate to severe depression and anxiety were reported in 17% and 9% of cancer survivors, respectively. There were no significant differences between the 5 years and 10 years after diagnosis cohorts (p = 0.232). In both cohorts, we found higher depression and anxiety in women than in men (p < 0.001), and lower depression and anxiety in elderly patients (p < 0.001). Cancer survivors younger than 60 years of age were more depressed and anxious than the general population (p < 0.001). The variables, financial problems (Beta = 0.16, p < 0.001), global quality of life (Beta = - 0.21, p < 0.001) and cognitive function (Beta = - 0.30, p < 0.001), had the strongest association with depression and anxiety. CONCLUSIONS: For the prevention of depression and anxiety in long-term cancer survivors, individual treatment of physical and psychological symptoms is as important as social support and professional counselling. Post-treatment, cognitive limitations should be carefully assessed in long-term cancer survivorship to distinguish them from symptoms of a mental disorder, especially since younger cancer survivors of working age and female survivors seem to be more affected by depression and anxiety.

Mechanism of protein cleavage at asparagine leading to protein-protein cross-links.

Long-lived proteins (LLPs) are present in numerous tissues within the human body. With age, they deteriorate, often leading to the formation of irreversible modifications such as peptide bond cleavage and covalent cross-linking. Currently understanding of the mechanism of formation of these cross-links is limited. As part of an ongoing study, proteomics was used to characterise sites of novel covalent cross-linking in the human lens. In this process, Lys residues were found cross-linked to C-terminal aspartates that had been present in the original protein as Asn residues. Cross-links were identified in major lens proteins such as αA-crystallin, αB-crystallin and aquaporin 0. Quantification of the level of an AQP0/AQP0 cross-linked peptide showed increased cross-linking with age and in cataract lenses. Using model peptides, a mechanism of cross-link formation was elucidated that involves spontaneous peptide bond cleavage on the C-terminal side of Asn residues resulting in the formation of a C-terminal succinimide. This succinimide does not form cross-links, but can hydrolyse to a mixture of C-terminal Asn and C-terminal Asp amide peptides. The C-terminal Asp amide is unstable at neutral pH and decomposes to a succinic anhydride. If the side chain of Lys attacks the anhydride, a covalent cross-link will be formed. This multi-step mechanism represents a link between two spontaneous events: peptide bond cleavage at Asn and covalent cross-linking. Since Asn deamidation and cleavage are abundant age-related modifications in LLPs, this finding suggests that such susceptible Asn residues should also be considered as potential sites for spontaneous covalent cross-linking.

Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy.

Immunotherapy aims to activate the immune system to fight cancer in a very specific and targeted manner. Despite the success of different immunotherapeutic strategies, in particular antibodies directed against checkpoints as well as adoptive T-cell therapy, the response of patients is limited in different types of cancers. This attributes to escape of the tumor from immune surveillance and development of acquired resistances during therapy. In this review, the different evasion and resistance mechanisms that limit the efficacy of immunotherapies targeting tumor-associated antigens presented by major histocompatibility complex molecules on the surface of the malignant cells are summarized. Overcoming these escape mechanisms is a great challenge, but might lead to a better clinical outcome of patients and is therefore currently a major focus of research.