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4D structural biology: quantitative dynamics in the eukaryotic RNA exosome complex
No full textMolecular machines play pivotal roles in all biological processes. Most structural methods, however, are unable to directly probe molecular motions. Here, we demonstrate that dedicated NMR experiments can provide quantitative insights into functionally important dynamic regions in very large asymmetric protein complexes. We establish this for the 410 kDa eukaryotic RNA exosome complex that contains ten distinct protein chains. Methyl-group and fluorine NMR experiments reveal site-specific interactions among subunits and with an RNA substrate. Furthermore, we extract quantitative insights into conformational changes within the complex in response to substrate and subunit binding for regions that are invisible in static cryo-EM and crystal structures. In particular, we identify a flexible plug region that can block an aberrant route for RNA towards the active site. Based on molecular dynamics simulations and NMR data, we provide a model that shows how the flexible plug is structured in the open and closed conformations. Our work thus demonstrates that a combination of state-of-the-art structural biology methods can provide quantitative insights into large molecular machines that go significantly beyond the well-resolved and static images of biomolecular complexes, thereby adding the time domain to structural biology
pH-Sensitive TRPC5 Is Differentially Expressed in Various Common Skin Tumors
No full textTransient receptor potential classical or cation channels (TRPCs) are integral to tumor biology, particularly in maintaining Ca2+ homeostasis within cancer cells. TRPC5, a pH-sensitive member of this family, may act as a signaling molecule in the altered microenvironment of solid tumors, which are characterized by an inverted pH-gradient—with decreased extracellular and increased intracellular pH—that promotes tumor progression. This study addresses a gap in the field, as there is currently limited research on TRPC5, particularly regarding its potential role as a tumor marker. While TRPCs are known to be involved in cancer biology, the specific role of TRPC5 in solid tumors, including its potential role as a diagnostic marker, remains largely unexplored. This study is the first to examine TRPC5 expression profiles in common skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), and nevus cell nevi (NCN). Our findings reveal that the frequency of TRPC5 expression in BCC is significantly lower compared to SCC and epidermal portions of NCN and MM. These results suggest that TRPC5 could serve as an immunohistochemical marker to distinguish SCC from BCC. Additionally, this study lays the groundwork for future research into the role of TRPC5 in tumor progression and metastasis, especially since BCCs, which rarely metastasize, are predominantly negative for TRPC5
Correlation of surgical volume in gynecological cancer centers with the quality of ovarian cancer care
No full textPurpose:
Surgical volume in ovarian cancer treatment has been discussed to influence survival. Completeness of staging in early and macroscopic complete resection in advanced ovarian cancer are indicators of treatment quality and surrogate parameters for outcome. This study examines their association with case volume in certified gynecological cancer centers.
Methods:
Certification audit data from ovarian cancer cases treated in 193 gynecological cancer centers certified by the German Cancer Society between 2020 and 2022 were analyzed. In our study 3,881 patients with FIGO stage I-IIIA and 7,219 patients with FIGO stage IIB-IV ovarian cancer were included. Case volume thresholds of 10, 15, 20 and 25 annual cases per hospital were explored for both quality indicators.
Results:
Higher-volume centers consistently performed complete surgical staging in FIGO stage I-IIIA ovarian cancer patients more frequently. For example, centers treating < 15 cases annually had a lower likelihood of complete staging (OR 0.82; 95% CI 0.69–0.98; p = 0.031). Macroscopic complete resection was achieved in 72.32–75.64% of FIGO stage IIB-IV ovarian cancer cases across all four thresholds. High-volume centers performed macroscopic complete resection about 2 percentage points more often.
Conclusion:
These data indicate that case volume of cancer centers is not necessarily an indicator for quality of treatment. Since certification audit data does not account for primary surgery or neoadjuvant chemotherapy, the inherent bias caused by differences in resection rates between these two treatment strategies must be acknowledged
Robo-Advice – Entwicklung und Evaluation eines Prozessmodells zur automatisierten Anlageberatung und Finanzportfolioverwaltung
No full textRobo-Advice bezeichnet voll- oder teilautomatisierte Systeme, die Anleger bei Investitionsentscheidungen unterstützen, indem sie auf Basis von Kundendaten sowie vordefinierten, diversifizierten Anlagestrategien Empfehlungen zur Kapitalanlage bereitstellen. Die persönliche Interaktion mit einem menschlichen Berater entfällt dabei vollständig. Diese Dissertation untersucht systematisch die Potenziale und Grenzen der Automatisierbarkeit von Anlageberatung und Finanzportfolioverwaltung. Ausgangspunkt ist eine Analyse der Anforderungen an die Kapitalanlageberatung, aus der ein idealtypischer Beratungsprozess abgeleitet wird. Die Automatisierbarkeit der einzelnen Prozessschritte wird kritisch bewertet, worauf aufbauend ein konfigurierbares Prozessmodell entwickelt und evaluiert wird. Damit leistet die Arbeit sowohl einen Beitrag zur wissenschaftlichen Fundierung als auch zur praxisnahen Gestaltung von Robo-Advice
Interpreting Venous and Arterial Ulcer Images Through the Grad-CAM Lens: Insights and Implications in CNN-Based Wound Image Classification
No full textBackground/Objectives: Chronic wounds of the lower extremities, particularly arterial and venous ulcers, represent a significant and costly challenge in medical care. To assist in differential diagnosis, we aim to evaluate various advanced deep-learning models for classifying arterial and venous ulcers and visualize their decision-making processes. Methods: A retrospective dataset of 607 images (198 arterial and 409 venous ulcers) was used to train five convolutional neural networks: ResNet50, ResNeXt50, ConvNeXt, EfficientNetB2, and EfficientNetV2. Model performance was assessed using accuracy, precision, recall, F1-score, and ROC-AUC. Grad-CAM was applied to visualize image regions contributing to classification decisions. Results: The models demonstrated high classification performance, with accuracy ranging from 72% (ConvNeXt) to 98% (ResNeXt50). Precision and recall values indicated strong discrimination between arterial and venous ulcers, with EfficientNetV2 achieving the highest precision. Conclusions: AI-assisted classification of venous and arterial ulcers offers a valuable method for enhancing diagnostic efficiency
Germanium-Functionalized Tri- and Tetraphosphido Cobalt Complexes
No full textWe report the synthesis of germanium-containing polyphosphorus ligands in transition metal complexes through the insertion of an Ar′GeCl unit into a P–P bond of polyphosphorus ligands (Ar′ = 2,6-(2,6-iPr2C6H3)2-C6H3). Germatetraphosphido complexes [(L)Co(η4-P4GeAr′)] (1a: L = PHDI; 1b: L = Ar*BIAN; PHDI = bis(2,6-diisopropylphenyl)phenanthrene-9,10-diimine, Ar*BIAN = 1,2-bis(arylimino)acenaphthene, aryl = 2,6-dibenzhydryl-4-isopropylphenyl) were obtained by treatment of the anionic cyclo-P4 complexes [K(18c-6)][(L)Co(η4-P4)] with [Ar′GeCl]2 . Similar reactions of the cyclo-P3 complexes [cat][(L)Co(CN)(η3-P3)] ([cat]+ = [nBu4N]+ or [K(18c-6)]+) afforded [cat][(L)Co(η3-P3GeAr′Cl)(CN)] (2a: L = PHDI, [cat]+ = [nBu4N]+; 2b: L = Ar*BIAN, [cat]+ = [K(18c-6)]+). The reactivity of 2a was studied toward group 14 electrophiles, yielding neutral germatriphosphido analogues [(PHDI)Co(η3-P3GeAr′Cl)(CNER3)] (3-ER3, ER3 = CPh3, Si(iPr)3). Furthermore, treatment of 2a with the group 13 Lewis acid GaCl3 gave [nBu4N][(PHDI)Co(η3-P3GeAr′Cl)(CNGaCl3)] (4-Ga) and [(PHDI)Co(η3-P2Ge(PAr′))(CNGaCl3)] (5-Ga), which features a remarkable P3GeAr′ ligand. Compounds 1–5 were isolated as crystalline materials and characterized by single-crystal X-ray diffraction and multinuclear NMR spectroscopy supported by DFT calculations
Vergleich von leichten B-Lite® Implantaten mit konventionellen Implantaten bei Patientinnen mit Mammarekonstruktion
No full textDie Anwendung der leichten B-Lite® Implantate stellt eine Neuerung im Bereich der Brustimplantate dar. Die Vorteile der 30% leichteren Implantate könnten besonders für Patientinnen mit heterologer Brustrekonstruktion nach Mastektomie hilfreich sein, da dabei meist große Volumina ersetzt werden müssen.
Diese Studie untersuchte den Effekt von B-Lite® Implantaten bei Patientinnen nach Mastektomie im Vergleich zu einer Kontrollgruppe mit konventionellen Implantaten. Der Therapieverlauf beider Gruppen und die Ergebnisse aus einer Follow-up Untersuchung wurden im Hinblick auf Komplikationen, Sensibilitätsstörungen und Narbenreifung verglichen. Die Patientinnen beantworteten sowohl einen, speziell für die Fragestellung der gewichtsreduzierten Implantate entwickelten, Fragebogen, als auch den standardisierten Breast-Q® Fragebogen zur postinterventionellen Lebensqualität nach Mastektomie und Brustrekonstruktion.
Die Studie wies einige Limitationen wie das retrospektive Studiendesign, einen relativ kurzen Nachbeobachtungszeitraum (durchschnittlich 18 und 23 Monate) und eine eher kleine Probandenzahl auf (48 Patientinnen, 78 Implantate); trotzdem konnten bereits erste Hinweise auf Unterschiede zwischen den Studiengruppen gefunden werden.
Die B-Lite® Implantate wiesen trotz ihres höheren Volumens und kürzeren Nachuntersuchungszeitraumes ein signifikant besseres Sensibilitätsempfinden und auch eine vorteilhaftere Narbenreifung auf. Sie hatten allerdings auch eine signifikant höhere Komplikationsrate und die Patientinnen waren signifikant unzufriedener mit der Haptik der B-Lite® Implantate als die Kontrollgruppe. Die höhere Komplikationsrate könnte allerdings durch das im Mittel größere Volumen der B-Lite® Implantate verursacht worden sein. Die Lebensqualität der Patientinnen und generelle Zufriedenheit mit beiden Implantaten war sehr hoch und unterschied sich kaum zwischen den Gruppen.
Die Ergebnisse sollten in prospektiven Längsschnittstudien mit einer längeren Follow-up Zeit überprüft werden, da die Alltagsbelastung und die Wirkung der Gravitationskraft auf die der Brustimplantate mit der Zeit zunehmen können. Somit könnten die Effekte der gewichtsreduzierten B-Lite® Implantate auch noch nach Jahren zu messbaren Unterschieden führen
Preference-oriented quality of life monitoring and linkage with clinical registry data: study protocol of a randomised clinical trial in patients with lung cancer (LePaLuMo Study)
Get PDFBackground
In routine oncological care, the implementation of disease-related quality of life (QoL) is still an open matter. In a complex intervention, a QoL monitoring system including tailored therapeutic options has been designed, implemented, and its effectiveness has been demonstrated in two randomised trials in patients with breast and colorectal cancer. The next step is to extend the usability of the QoL monitoring system for patients with other cancer diagnoses and in other regions. Necessary adaptations include an electronic measurement of QoL and consideration of patient and physician preferences. The present randomised trial investigates the effectiveness of this adapted QoL monitoring system in patients with lung cancer in two regions in Bavaria, Germany.
Methods
In this 2-arm randomised, prospective, pragmatic, multicentre clinical trial with one intervention and one control group, QoL of primary lung cancer patients is assessed with an electronic patient- and physician-oriented QoL monitoring system using the EORTC QLQ-C30 and QLQ-LC29 questionnaires at study entry and at 1, 2, 3, 4, 5, and 6 months during follow-up care. The QoL data of each patient are linked with clinical data from the Bavarian Cancer Registry for the purpose of data analysis. In the intervention group, the results of QoL monitoring are automatically transferred to a QoL profile including 8 dimensions on scales of 0–100 (cut-off “need for QoL therapy” < 50 points). QoL results are obtained in real-time by patients and their treating physicians. To treat QoL deficits, a multi-professional network of healthcare providers is established. In the control group, QoL is also measured, but neither patients nor treating physicians have access to the results. The investigators expect that the proportion of patients in both groups with a need for QoL therapy (< 50 points in at least one dimension of the QoL profile) will be lower in the intervention group than in the control group at the primary endpoint 6 months after study entry.
Discussion
This is the first study investigating the effectiveness of a QoL monitoring system based on patient- and physician-oriented preferences with a high degree of generalisability by including inpatient and outpatient care as well as different study regions
