Physische und psychische sowie sozial-emotionale Effekte konventioneller Krebstherapien auf Brustkrebspatientinnen

Im Mittelpunkt dieser kumulativ angefertigten Forschungsarbeit stehen vier prospektive Beobachtungsstudien, die die physischen und psychischen sowie sozial-emotionalen Effekte konventioneller Krebstherapien (Operation, Chemotherapie, Radiotherapie und Hormontherapie) auf Brustkrebspatientinnen in frühen Krebsstadien von der Diagnose über die Behandlung hinweg untersuchen. In der ersten Studie wird die feinmotorische Geschicklichkeit inklusive der Hand- und Fingerfunktion überprüft. Die zweite Studie beschäftigt sich mit individuellen Veränderungen physischer Leistungsfähigkeit und Aktivität, bioelektrischem Phasenwinkel, Symptomen krebsbedingter Fatigue, Angst und Depressivität sowie dem Auftreten von Risikoparametern. Im Fokus der dritten Studie stehen patientenberichtete Endpunkte der gesundheitsbezogenen Lebensqualität und der wahrgenommenen kognitiven Funktion. Ein biopsychosoziales Profil einschließlich klinischer Charakteristika, physischer Leistungsfähigkeit, Phasenwinkel, Angst, Depressivität, Fatigue-Symptomatik sowie gesundheitsbezogener Lebensqualität wird in einer vierten Studie erstellt.:In Kapitel 1 der vorliegenden kumulativen Dissertationsschrift erfolgt die Herleitung der dieser Arbeit zugrunde liegenden wissenschaftlichen Untersuchungen. In Kapitel 2 werden theoretische Grundlagen zur Brustkrebserkrankung erläutert, um dem Leser einen besseren Einblick in die Thematik zu bieten und das Verständnis der eigenen Beiträge zu fördern. Die Publikationen selbst können dem Anhang entnommen werden und stehen als Veröffentlichungen nach Peer-Review-Verfahren in internationalen Fachzeitschriften zur Verfügung. In Kapitel 3 wird das methodische Vorgehen zum Ablauf, Umsetzung und Analyse der Studien beschrieben. In Kapitel 4 werden die einzelnen Studien zur Übersicht zusammengefasst und die wichtigsten Ergebnisse präsentiert. Anschließend erfolgt die Diskussion der gewonnenen Erkenntnisse zu physischen und psychischen sowie sozial-emotionalen Effekten konventioneller Krebstherapien auf Brustkrebspatientinnen (Kapitel 5). Den Abschluss bildet eine kurze Zusammenfassung der Untersuchungen (Kapitel 6)

Impact of airport operations and road traffic on the particle number concentration in the vicinity of a suburban airport

The impact of airports on ambient air pollution is a major concern due to its impact on public health. This study analyzes the sub-micron total particle number concentration (PNC) as a proxy for ultrafine particles in the immediate vicinity of Berlin-Tegel Airport (TXL) based on a mobile measurement campaign in summer 2019. With predominantly westerly winds, 45 measurement runs took place along a 20–30 km route to the east of the airport. The highlights of the study are as follows: 1. Berlin-Tegel Airport had a distinct but a spatially limited impact on the residential areas to the east of the airport. 2. Particle number concentrations in the lee of the airport are significantly higher than the mean of the entire area. 3. Locations along the eastward extension of the runways are significantly more affected than those outside the approach corridor. 4. The impact of airport operations on PNC in the adjacent neighborhood is comparable to the combined impact of busy roads in the area. The closure of Berlin-Tegel Airport at the end of 2020 should have considerably improved the air quality in the residential areas in the close vicinity of the airport.Peer Reviewe

Neuronale Reaktivität auf Gesichtsausdrücke bei Sozialer Angststörung: Eine ALE-Metaanalyse.

Ziel Bei Sozialer Angststörung (SAD) liegen Ängste in sozialen Situationen vor. Bildgebende Studien dazu verglichen die Hirnaktivierungsunterschiede beim Betrachten emotionaler Gesichtsausdrücke zwischen SAD-Patienten und gesunden Kontrollen (HC). Bisher liegen heterogene Ergebnisse vor, die mithilfe einer ALE-Metaanalyse auf Konvergenzen überprüft werden sollen, um potenziell generalisierbare Aktivierungsunterschiede festzustellen. Methode Aus selektierter Literatur wurden die Aktivierungsunterschiede extrahiert, daraus in einer ALE-Metaanalyse jeweils dreidimensionale Wahrscheinlichkeitsverteilungen erstellt und auf signifikante Überschneidungen geprüft. Ergebnisse Basierend auf 96 Foci aus acht inkludierten Studien mit insgesamt 137 Probanden wurden keine signifikanten Konvergenzen gefunden. Somit bestanden keine konsistenten Aktivierungsunterschiede zwischen SAD-Patienten und HC bei der neuralen Prozessierung emotionaler Gesichtsausdrücke. Schlussfolgerungen Der Nullbefund könnte auf Unterschiede im Design der Experimente und Paradigmen sowie auf Stichprobenunterschiede zurückzuführen sein, sowie auf liberale statistische Schwellen in der Analyse der Ganzhirndaten

IRF4 and BATF are critical for CD8(+) T-cell function following infection with LCMV.

CD8(+) T-cell functions are critical for preventing chronic viral infections by eliminating infected cells. For healthy immune responses, beneficial destruction of infected cells must be balanced against immunopathology resulting from collateral damage to tissues. These processes are regulated by factors controlling CD8(+) T-cell function, which are still incompletely understood. Here, we show that the interferon regulatory factor 4 (IRF4) and its cooperating binding partner B-cell-activating transcription factor (BATF) are necessary for sustained CD8(+) T-cell effector function. Although Irf4(-/-) CD8(+) T cells were initially capable of proliferation, IRF4 deficiency resulted in limited CD8(+) T-cell responses after infection with the lymphocytic choriomeningitis virus. Consequently, Irf4(-/-) mice established chronic infections, but were protected from fatal immunopathology. Absence of BATF also resulted in reduced CD8(+) T-cell function, limited immunopathology, and promotion of viral persistence. These data identify the transcription factors IRF4 and BATF as major regulators of antiviral cytotoxic T-cell immunity

B-Cell Metabolic Remodeling and Cancer.

peer reviewedCells of the immune system display varying metabolic profiles to fulfill their functions. B lymphocytes overcome fluctuating energy challenges as they transition from the resting state and recirculation to activation, rapid proliferation, and massive antibody production. Only through a controlled interplay between metabolism, extracellular stimuli, and intracellular signaling can successful humoral responses be mounted. Alterations to this balance can promote malignant transformation of B cells. The metabolic control of B-cell fate is only partially understood. Here, we provide a compelling overview of the current state of the art and describe the main metabolic features of B cells during normal development and oncogenesis, with emphasis on the major B-cell transcriptional and metabolic regulators, including myelocytomatosis virus oncogene cellular homolog (Myc) and hypoxia-inducible factor 1-α (HIF-1α)

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

peer reviewedPyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity

Prospective observational pilot study of young women undergoing initial breast cancer treatment and their biopsychosocial profile

Background: Breast cancer in young women can be a major challenge for those affected. To offer support, the establishment of a biopsychosocial profile may be beneficial. Methods: For this prospective observational pilot study, we collected data of 19 women with a mean age of 42.8 ± 5.4 years (30.0-49.0 year) before (T0) and after (T1) initial breast cancer treatment. The handgrip strength (HGS), 6-minute walk test (6MWT), and bioimpedance analysis for the detection of phase angle (PhA) and bioimpedance vector analysis (BIVA) were used. Assessments included the Hospital Anxiety and Depression Scale (HADS), Functional Assessment of Cancer Therapy-Breast (FACT-B), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Results: Women (age <50 years) with breast cancer showed impaired functional status (HGS, 6MWT, and PhA), abnormal physiologic findings (BIVA), decreased health-related quality of life (HRQoL), and cancer-related fatigue (CRF) after breast cancer diagnosis prior to the onset of cancer treatment with significant deterioration following cancer treatment. This was accompanied by a potentially higher risk of mortality and impaired function due to the prevalence of values below a critical threshold (PhA: T0 = 11%, T1 = 42%; HGS: T0 = 21%, T1 = 32%). In addition, there was evidence of anxiety (47%) and depression (32%) at T0. Conclusion: Routine assessment of biomarkers of physical function, mental health, HRQoL, and CRF may lead to individual risk stratification and multidisciplinary intervention in young patients with breast cancer, which could help to personalize and optimize survivorship care plans

Routine cancer treatments and their impact on physical function, symptoms of cancer-related fatigue, anxiety, and depression

Background and purpose. Breast cancer can be a major challenge for affected women. Knowledge of the physical function, symptoms of cancer-related fatigue, anxiety, and depression based on the cancer treatment may help to guide adequate support. Methods. For this prospective observational study, we collected data from seventy-nine women with a mean age 54.6 ± 9.5 years prior to the onset of breast cancer treatment (T0) and after (T1/T2). Handgrip strength test (HGS), six-minute walk test (6MWT), the phase angle (PhA), the hospital anxiety and depression scale (HADS), and functional assessment of chronic illness therapy-fatigue (FACIT-F) were used to collect data from four treatment subgroups SC, surgery + chemotherapy; SCR, surgery + chemotherapy + radiation therapy; SR, surgery + radiation therapy; and S, surgery. Results. A mixed ANOVA revealed a significant interaction between time and group for PhA, F = 8.55, p < 0.01; HGS, F = 3.59, p < 0.01; 6MWT, F = 4.47, p < 0.01; and FACIT-F, F = 2.77, p < 0.05 with most pronounced deterioration seen in group SCR (PhA 4.8°; HGS 27.5 kg, 6MWT 453.4 m, FACIT-F 33.8 points). HADS data displayed moderate anxiety and depression predominantly after treatment. Conclusion. Our study showed that the extent of change in physical function, symptoms of fatigue, anxiety, and depression depends on the treatment conditions. The potentially higher risk of impaired function due to the prevalence of values below a critical threshold requires early initiated multidisciplinary support

Cancer treatment regimens and their impact on the patient-reported outcome measures health-related quality of life and perceived cognitive function

Background and purpose. Breast cancer can be a significant challenge for those affected. Knowledge of physical function, social-emotional challenges, and perceived cognitive function based on the cancer treatment regimens may help to inform adequate support. Methods. For this prospective observational pilot study, we collected data of seventy-nine women (mean age 54.6 ± 9.5 years) before (T0) and after (T1) initial breast cancer treatment. Functional Assessment of Cancer Therapy-Breast (FACT-B) and Functional Assessment of Cancer Therapy–Cognitive-Function (FACT-Cog) were used to collect data of four treatment subgroups: SCR = Surgery + Chemotherapy + Radiation Therapy; SC = Surgery + Chemotherapy; SR = Surgery + Radiation Therapy; S = Surgery. A mixed ANOVA and posthoc analysis (Tukey, Games-Howell) were used to detect interactions (group by time) and the main effect. A repeated-measures ANOVA displayed individual group differences (time). Results. Significant interaction showed more deterioration was experienced with SC and SCR than SR and S for FACT-B (p < 0.01) and FACT-Cog (p < 0.001). The longitudinal comparison between T0 and T1 indicated a significant group main effect on all subscales (p < 0.001) except for Emotional Well-Being. Significant reductions (p < 0.05) in FACT-B, (− 19%); FACT-Cog, (− 21%) with most pronounced effect in Physical Well-Being (− 30%), Functional Well-Being (− 20%), Breast Cancer Subscale (− 20%), Perceived Cognitive Impairments (− 18%) and Impact of Cognitive Impairments on Quality of Life (− 39%) were detected for SCR. Conclusion. Our study showed that the extent of change in health-related quality of life (HRQoL) and perceived cognitive function (PCF) depends on the treatment regimen. Multidisciplinary support initiated early in breast cancer therapy is needed, especially for women undergoing combined cancer treatment. Routine assessment of patient-reported outcomes (PROs) in oncology practice may increase the transparency of patients’ perceived circumstances, leading to personalized and optimized acute and survivorship care

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections