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.

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.

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.

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.

Development of a Human Leukocyte Antigen Score to Predict Progression-Free Survival in Head and Neck Squamous Cell Carcinoma Patients.

BACKGROUND: In personalized medicine and treatment stratification of head and neck squamous cell carcinoma (HNSCC), the heterogeneous genetic background of patients is not considered. Human leukocyte antigen (HLA) alleles and HLA haplotypes (HLA traits) are linked to development of HNSCC and affect progression-free survival (PFS) of HNSCC patients but most head and neck oncologists are not familiar with HLA typing. Hence, we developed an HLA-score abstracting from complexity of HLA-typing results to facilitate potential use of HLA-associated hazard ratios (HR) for prognostic stratification. METHODS: The HR for PFS of 8 HLA traits shown to be independent predictors (Pi) of PFS in a test cohort (TC) of 90 HNSCC patients were used to build the HLA-score based on the natural logarithm (ln) of the Pi-associated HR. Crude ln-transformed HR of the eight Pi, alleles B*13 (2), B*35 (1), B*51 (2), DQB1*06 (1), homozygous Cw (1), homozygous DRB4 (2), and haplotypes A*01/B*08 (-6) and B*08/C*07 (4), were summed up to yield the individual patient's HLA-score. Receiver operating characteristic (ROC) and Kaplan-Meier curves were used to proof the suitability of the HLA-score as prognostic marker for PFS. An independent validation cohort (iVC) of 32 patients treated in the larynx-organ preservation trial DeLOS-II was utilized for validation. RESULTS: The individual HLA-scores (range -2 to 6) in TC classified HNSCC patients regarding PFS. ROC analysis (area under the curve = 0.750, 95% CI 0.665-0.836; P = 0.0000034) demonstrated an optimum cutoff for the HLA-score at 0.5 (97.9% sensitivity, 34.7% specificity), and 70/90 patients in TC with HLA-score > 0 had significant reduced PFS (P = 0.001). Applying the same classifier (HLA-score > 0) confirmed these findings in the iVC revealing reduced PFS of 25/32 patients (P = 0.040). CONCLUSION: HLA traits constitute critical Pi. Considering the HLA-score may potentially facilitate the use of genetic information from HLA typing for prognostic stratification, e.g., within clinical trials.

Communication Preferences in Young, Middle-Aged, and Elderly Cancer Patients.

BACKGROUND: While psychosocial distress and supportive care needs of young adult cancer patients have been increasingly studied, little knowledge exists about preferences for communicating bad news. We aimed to analyze patients' communication preferences against their actual experiences with regard to doctor-patient interactions. PATIENTS AND METHODS: We surveyed a total of 270 cancer patients with different tumor entities. 3 age groups (young, middle-aged, and elderly) were compared concerning their communication preferences (MPP; Measure of Patients' Preferences questionnaire) and the impact on distress (National Comprehensive Cancer Network Distress Thermometer). RESULTS: We found no age differences of communication preferences and the content of bad news. A significant difference was found in the dimension 'professional expertise/patient orientation (p < 0.01) which was rated as more important by younger patients. Binary logistic regression showed an impact of 'children' (odds ratio (OR) 0.296; 95% confidence interval (CI) 0.155, 0.563), tumor staging (OR 1.737, 95% CI 1.028, 2.936), and insufficient 'privacy' (OR 0.987; 95% CI 0.978, 0.997) and 'clarity' (OR 1.013; 95% CI 1.002, 1.025) on distress. CONCLUSION: Communication preferences related to breaking bad news depend less on age differences than on other variables. Future studies should investigate the long-term impact of ineffective patient-physician communication, taking into account unmet patient preferences in different age groups.

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.

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.

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.

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.

Demoralization and depression in patients with advanced cancer: validation of the German version of the demoralization scale.

CONTEXT: The concept of demoralization has been widely used to describe states of existential distress and a self-perceived incapacity to deal effectively with a specific stressful situation. OBJECTIVES: To evaluate the psychometric properties of the German adaptation of the Demoralization Scale (DS) in patients with advanced cancer. METHODS: Participants with heterogeneous tumor sites were recruited in several treatment and rehabilitation facilities. Concurrent and divergent validity of the DS was analyzed through associations with and group differences between measures of distress, depression, anxiety, and meaning-related life attitudes. RESULTS: From a total sample of 1102 patients, 516 individuals (45%) with advanced cancer were enrolled (male 53%, median age 58 years [range 18-88], breast cancer 21%, prostate cancer 17%). The total mean score of the DS was 29.8 (SD=10.41). Four factors were extracted by exploratory factor analysis, which accounted for 59% of the variation (Cronbach α=0.84): loss of meaning and purpose (α=0.88), disheartenment (α=0.88), dysphoria (α=0.80), and sense of failure (α=0.76). DS dimensions shared between 12% and 62% of the variance. Demoralization was significantly associated with anxiety (r=0.71), depression (r=0.61), and distress (r=0.42). Fifty-seven percent of patients had high distress, 24% depression, and 11% high anxiety. According to different cutoff values, between 16% and 39% were seriously demoralized and 73% had moderate levels of demoralization. Between 5% and 20% of patients were seriously demoralized but not clinically depressed; 60% of patients with moderate levels of demoralization had no depression. CONCLUSION: Results provide further evidence that the DS is a valid and reliable instrument of high clinical relevance in patients with advanced cancer.

Global meaning and meaning-related life attitudes: exploring their role in predicting depression, anxiety, and demoralization in cancer patients.

GOAL OF WORK: While significance of the concept of meaning in understanding adaptation to cancer is widely accepted, it has been little studied, especially in longitudinal data. This study aims to clarify the role of global meaning and meaning-related life attitudes (death acceptance and goal seeking) in predicting different aspects of psychological and existential distress by reference to a specified research model. PATIENTS AND METHODS: At baseline (T1), a sample of 270 cancer patients was recruited. Data from 178 patients could be obtained after 3 months at T2. Patients completed the Life-Attitude-Profile-Revised assessing global meaning and meaning-related life attitudes, the Hospital Anxiety and Depression Scale, and the Demoralization Scale. Hierarchical regression analyses were carried out in two steps. Sociodemographic and physical factors were controlled. RESULTS: Global meaning emerged as a significant negative predictor of depression (ß = -0.27) (p ≤ 0.001) and demoralization (ß = -0.27) (p ≤ 0.001). Death acceptance was a predictor of anxiety only (ß = -0.21) (p ≤ 0.003), whereas goal seeking was a positive predictor of depression (ß = 0.29) (p ≤ 0.001), anxiety (ß = 0.36) (p ≤ 0.001), and demoralization (ß = 0.35) (p ≤ 0.001). DISCUSSION: Findings confirm a global sense of meaning as an important protecting factor regarding the development of distress symptoms. Results suggest that different dimensions of meaning contribute to different dimensions of psychological well-being, as they refer to different existential problems. The need for and relevance of meaning-focused interventions in cancer patients is strengthened.

[Course of psychosocial distress and health-related quality of life in patients at different age groups during cancer rehabilitation]. / Verlauf der psychosozialen Belastung und gesundheitsbezogenen Lebensqualitat bei Patienten verschiedener Altersgruppen in der onkologischen Rehabilitation.

OBJECTIVES: This study investigates psychosocial distress and health-related quality of life in younger (up to 40 years), middle-aged (up to 50 years), and elderly cancer patients (up to 60 years). METHODS: 637 patients (94%women, 75% breast-cancer patients) completed validated questionnaires measuring distress, anxiety, depression, fear of progression, and quality of life at the beginning (T0) and the end (T1) of a cancer rehabilitation program (T0/T1 response rate: 72 %) as well as at 1-year follow-up (T2) (n = 485, T2 response rate: 76 %). RESULTS: Patients in the different age groups did not differ significantly in psychosocial distress at T0 except for fear of progression, which is lower among the younger age group. Elderly patients have a significantly lower physical quality of life. At the beginning of the rehabilitation program, patients in all age groups were significantly more anxious compared to population-based normative values, whereas higher depression was found only in younger and middle-aged patients. Patients in all age groups have a significantly lower quality of life compared to population-based normative values. In particular, large effect sizes were found for physical functioning domains. Patients in all age groups improve significantly in psychosocial distress and quality of life over time; however, significant interaction effects between age group and time were not observed in psychosocial distress and quality of life. CONCLUSIONS: Age differences are predominantly observed in physical quality-of-life dimensions rather than in psychosocial distress. This finding should be considered for the development of rehabilitation services.

[Impact of the doctor-patient-communication on distress and utilization of psychosocial services among cancer patients. A review of the current literature]. / Die Bedeutung der Arzt-Patient-Kommunikation für die psychische Belastung und die Inanspruchnahme von Unterstützungsangeboten bei Krebspatienten. Ein Literaturüberblick über den gegenwärtigen Forschungsstand unter besonderer Berücksichtigung patientenseitiger Präferenzen.

A poor doctor-patient-communication in cancer care has negative effects on psychological well being and causes high economic costs. This review analyses the current literature on the impact of communication on distress, satisfaction and utilization of psychosocial services among cancer patients with regard to patients' communication preferences. Crucial to a successful communication seems to be the match of patients' preferences and actual physician's behaviour. However, preferences depend on various factors and can change during the illness trajectory. As preferences often remain unconsidered in everyday practice, they should be assessed repeatedly. For the lack of theoretical foundation, future research should be designed according to theoretical assumptions. In this respect we developed and suggest a model on the impact of patients' preferences on physician-patient-communication, knowledge and use of psychosocial treatment offers that particularly considers psychosocial distress of cancer patients.

Role of endothelins as mediators of injury-induced alterations of glial glutamate turnover.

Astroglia terminate glutamatergic neurotransmission and prevent excitotoxic extracellular glutamate concentration by clearing synaptically released glutamate through the high-affinity, sodium-dependent glutamate transporters GLT-1 and GLAST. Many brain injures are associated with the disturbed expression of glial glutamate transporters and a subsequent increase of extracellular glutamate to neurotoxic levels. We have now followed up initial hints pointing to endothelins, a family of injury-regulated peptides, as mediators of this injury-induced loss of glial glutamate transporter expression. We observed that, in line with such a role, endothelins not only act as potent inhibitors of basal and exogenously (dbcAMP)-induced expression of GLT-1 in cortical astrocytes as shown before, but likewise inhibit expression of GLT-1 or GLAST in astrocytes cultured from the diencephalon, mesencephalon, cerebellum, and spinal cord. We further demonstrate that endothelins equally inhibit GLT-1 expression in cortical slice cultures, a culture system closely resembling the in vivo situation. Although brain injuries are usually associated with an increase in the expression of the glutamate-converting enzyme glutamine synthetase, cultured cortical astrocytes maintained with endothelins showed an almost complete loss of glutamine synthetase. Interestingly, the inhibitory effects of endothelins on the expression of glutamine synthetase, but not of glutamate transporters, was overridden by high extracellular glutamate, indicating that the primarily inhibitory action of endothelins on the various components of glial glutamate turnover dissociates in the injured brain.

Presence of symptom distress and prostate cancer-related anxiety in patients at the beginning of cancer rehabilitation.

BACKGROUND: A growing body of research points towards a substantial number of prostate cancer patients experiencing distress and anxiety. This study examines the frequency and character of cancer- and treatment-related problems and its association with symptom distress and prostate cancer-related anxiety in patients at the beginning of an oncological rehabilitation program. PATIENTS AND METHODS: 197 prostate cancer patients who had undergone prostatectomy (92.5% participation rate) completed the Memorial Anxiety Scale for Prostate Cancer (MAX-PC), the NCCN Distress Thermometer and EORTC QLQ-C30 subscales emotional function and global quality of life. RESULTS: 88% of patients report cancer- or treatment-related problems with a mean of 5 problems, and 104 patients (53%) experience distress and/or prostate cancer-related anxiety. The most prevalent symptoms are changes in urination, sexual problems, difficulties getting around, pain, fatigue and sleep problems. Emotional problems such as nervousness, worries, fears and sadness are prevalent in at least 53% of patients. Patients with distress and anxiety are confronted with a higher number and a wider range of problems and experience significantly lower levels of quality of life. CONCLUSION: Findings emphasize the role of cancer rehabilitation and underline the importance of psychosocial screening measures and the provision of psychosocial support in prostate cancer patients.

Gap junctional control of glial glutamate transporter expression.

The uptake of glutamate into astroglia is the predominant mechanism to terminate glutamatergic neurotransmission and to prevent neurotoxic extracellular glutamate concentrations. Here, we show that uncoupling cultured cortical astrocytes with the gap junction blocker, propofol, or the Cx43 mimetic peptide, Gap27, inhibits the expression of GLT-1, the major glutamate transporter subtype in the cortex. The dependence of GLT-1 expression on gap junctions was further confirmed by the use of astrocytes in which either the expression of Cx43, the major astrocytic gap junction protein, was inhibited by RNA interference or which were derived from animals carrying an astrocyte-specific deletion of the Cx43 gene. In both cases, reduced astrocytic coupling was associated with a pronounced decline in GLT-1 expression. Finally, a luciferase reporter gene assay demonstrated that blockade of gap junctions/connexins suppressed transcriptional activity of GLT-1 promoter. These observations unravel a previously unrecognized role of gap junctions in the control of glial glutamate transport.

[Assessment of psychosocial distress and resources in oncology--a literature review about screening measures and current developments]. / Die Erfassung psychosozialer Belastungen und Ressourcen in der Onkologie--Ein Literaturüberblick zu Screeningmethoden und Entwicklungstrends.

A substantial percentage of cancer patients suffers from psychosocial distress to severe mental disorders and psychosocial crisis during the course of the illness and cancer treatment. However, only a small percentage of patients with severe psychosocial distress and mental disorders in the present oncological practice is accurately identified, diagnosed, and appropriately treated. Therefore, sufficient knowledge about psychosocial distress and mental disorders as well as screening procedures are urgent concerns to improve psychosocial care for cancer patients. First, the article provides an overview of psychosocial distress and the epidemiology of mental disorders in cancer patients. Then a few of the most important objectives and problems of psychosocial assessment in cancer patients will be explained. The following part will offer an overview of questionnaires and screening procedures that are frequently used to assess psychosocial distress, mental disorders, personal and social resources, and health related quality of life in cancer patients.

Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines.

BACKGROUND & AIMS: Wilson's disease, a hereditary disorder caused by mutations in the Wilson's disease gene (ATP7B), leads to hepatic and/or neurological pathology resulting from cellular copper overload. In vitro studies showed that ATP7B, located in the trans-Golgi network, traffics to a cytoplasmic vesicular compartment in response to increased copper concentration. Mislocalization and failed intracellular trafficking of ATP7B mutants are suggested to be among disease-causing mechanisms; however, the effect of mutations on ATP7B localization in human tissues has not been directly shown. Therefore, we characterized the subcellular localization of normal and mutant ATP7B in human livers and in hepatoma cell lines. METHODS: Subcellular distribution of ATP7B in liver tissue from 3 control individuals and 3 Wilson's disease patients harboring a homozygous H1069Q-ATP7B mutation was analyzed by using immunogold electron microscopy. In addition, 14 ATP7B mutants tagged to green fluorescent protein were generated and expressed in HuH-7 and HepG2 cells; intracellular localization of these mutants was characterized by confocal microscopy. RESULTS: In hepatocytes, ATP7B was localized in trans-Golgi vesicles, whereas H1069Q-ATP7B was trapped in the endoplasmic reticulum. Similar results were observed for wild-type ATP7B and H1069Q-ATP7B expressed in hepatoma cells. Most ATP7B proteins harboring missense mutations were distributed similarly to wild-type ATP7B. In contrast, truncated ATP7B mutants showed a diffuse, clustered, cytoplasmic pattern, distinct from the trans-Golgi network or endoplasmic reticulum. CONCLUSIONS: These results provide a detailed demonstration of the ATP7B distribution in control and diseased human livers and indicate that several Wilson's disease mutations lead to incorrect localization of ATP7B to distinct cell compartments.