Physiologic MR imaging of the tumor microenvironment revealed switching of metabolic phenotype upon recurrence of glioblastoma in humans

Treating recurrent glioblastoma (GB) is one of the challenges in modern neurooncology. Hypoxia, neovascularization, and energy metabolism are of crucial importance for therapy failure and recurrence. Twenty-one patients with initially untreated GB who developed recurrence were examined with a novel MRI approach for noninvasive visualization of the tumor microenvironment (TME). Imaging biomarker information about oxygen metabolism (mitochondrial oxygen tension) and neovascularization (microvascular density and type) were fused for classification of five different TME compartments: necrosis, hypoxia with/without neovascularization, oxidative phosphorylation, and glycolysis. Volume percentages of these TME compartments were compared between untreated and recurrent GB. At initial diagnosis, all 21 GB showed either the features of a glycolytic dominant phenotype with a high percentage of functional neovasculature (N = 12) or those of a necrotic/hypoxic dominant phenotype with a high percentage of defective tumor neovasculature (N = 9). At recurrence, all 21 GB revealed switching of the initial metabolic phenotype: either from the glycolytic to the necrotic/hypoxic dominant phenotype or vice-versa. A necrotic/hypoxic phenotype at recurrence was associated with a higher rate of multifocality of the recurrent lesions. Our MRI approach may be helpful for a better understanding of treatment-induced metabolic phenotype switching and for future studies developing targeted therapeutic strategies for recurrent GB

Recurrence of glioblastoma is associated with elevated microvascular transit time heterogeneity and increased hypoxia

Dynamic susceptibility contrast (DSC) perfusion MRI provide information about differences in macro- and microvasculature when executed with gradient-echo (GE; sensitive to macrovasculature) and spin-echo (SE; sensitive to microvasculature) contrast. This study investigated whether there are differences between macro- and microvascular transit time heterogeneity (MVTH and µVTH) and tissue oxygen tension (PO2mit) in newly-diagnosed and recurrent glioblastoma. Fifty-seven patients with glioblastoma (25 newly-diagnosed/32 recurrent) were examined with GE- and SE-DSC perfusion sequences, and a quantitative blood-oxygen-level-dependent (qBOLD) approach. Maps of MVTH, µVTH and coefficient of variation (MCOV and µCOV) were calculated from GE- and SE-DSC data, respectively, using an extended flow-diffusion equation. PO2mit maps were calculated from qBOLD data. Newly-diagnosed and recurrent glioblastoma showed significantly lower (P ≤ 0.001) µCOV values compared to both normal brain and macrovasculature (MCOV) of the lesions. Recurrent glioblastoma had significantly higher µVTH (P = 0.014) and µCOV (P = 0.039) as well as significantly lower PO2mit values (P = 0.008) compared to newly-diagnosed glioblastoma. The macrovasculature, however, showed no significant differences. Our findings provide evidence of microvascular adaption in the disorganized tumor vasculature for retaining the metabolic demands in stress response of therapeutically-uncontrolled glioblastomas. Thus, µVTH and PO2mit mapping gives insight into the tumor microenvironment (vascular and hypoxic niches) responsible for therapy resistance

Logical Imputation to Optimize Prognostic Risk Classification in Metastatic Renal Cell Cancer

BACKGROUND: Application of the MSKCC and IMDC models is recommended for prognostication in metastatic renal cell cancer (mRCC). Patient classification in MSKCC and IMDC risk groups in real-world observational studies is often hampered by missing data on required pre-treatment characteristics. OBJECTIVES: To evaluate the effect of application of easy-to-use logical, or deductive, imputation on MSKCC and IMDC risk classification in an observational study setting. PATIENTS AND METHODS: We used data on 713 mRCC patients with first-line sunitinib treatment from our observational European multi-centre study EuroTARGET. Pre-treatment characteristics and follow-up were derived from medical files. Hospital-specific cut-off values for laboratory measurements were requested. The effect of logical imputation of missing data and consensus versus hospital-specific cut-off values on patient classification and the subsequent models' predictive performance for progression-free and overall survival (OS) was evaluated. RESULTS: 45% of the patients had missing data for >= 1 pre-treatment characteristic for either model. Still, 72% of all patients could be unambiguously classified using logical imputation. Use of consensus instead of hospital-specific cut-offs led to a shift in risk group for 12% and 7% of patients for the MSKCC and IMDC model, respectively. Using logical imputation or other cut-offs did not influence the models' predictive performance. These were in line with previous reports (c-statistic similar to 0.64 for OS). CONCLUSIONS: Logical imputation leads to a substantial increase in the proportion of patients that can be correctly classified into poor and intermediate MSKCC and IMDC risk groups in observational studies and its use in the field should be advocated

Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6hi and KRT17hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection

Recurrence of glioblastoma is associated with elevated microvascular transit time heterogeneity and increased hypoxia

Dynamic susceptibility contrast (DSC) perfusion MRI provide information about differences in macro- and microvasculature when executed with gradient-echo (GE; sensitive to macrovasculature) and spin-echo (SE; sensitive to microvasculature) contrast. This study investigated whether there are differences between macro- and microvascular transit time heterogeneity (MVTH and µVTH) and tissue oxygen tension (PO2mit) in newly-diagnosed and recurrent glioblastoma. Fifty-seven patients with glioblastoma (25 newly-diagnosed/32 recurrent) were examined with GE- and SE-DSC perfusion sequences, and a quantitative blood-oxygen-level-dependent (qBOLD) approach. Maps of MVTH, µVTH and coefficient of variation (MCOV and µCOV) were calculated from GE- and SE-DSC data, respectively, using an extended flow-diffusion equation. PO2mit maps were calculated from qBOLD data. Newly-diagnosed and recurrent glioblastoma showed significantly lower (P ≤ 0.001) µCOV values compared to both normal brain and macrovasculature (MCOV) of the lesions. Recurrent glioblastoma had significantly higher µVTH (P = 0.014) and µCOV (P = 0.039) as well as significantly lower PO2mit values (P = 0.008) compared to newly-diagnosed glioblastoma. The macrovasculature, however, showed no significant differences. Our findings provide evidence of microvascular adaption in the disorganized tumor vasculature for retaining the metabolic demands in stress response of therapeutically-uncontrolled glioblastomas. Thus, µVTH and PO2mit mapping gives insight into the tumor microenvironment (vascular and hypoxic niches) responsible for therapy resistance

Nature Communications / UFD-2 is an adaptor-assisted E3 ligase targeting unfolded proteins

Muscle development requires the coordinated activities of specific protein folding and degradation factors. UFD-2, a U-box ubiquitin ligase, has been reported to play a central role in this orchestra regulating the myosin chaperone UNC-45. Here, we apply an integrative in vitro and in vivo approach to delineate the substrate-targeting mechanism of UFD-2 and elucidate its distinct mechanistic features as an E3/E4 enzyme. Using Caenorhabditis elegans as model system, we demonstrate that UFD-2 is not regulating the protein levels of UNC-45 in muscle cells, but rather shows the characteristic properties of a bona fide E3 ligase involved in protein quality control. Our data demonstrate that UFD-2 preferentially targets unfolded protein segments. Moreover, the UNC-45 chaperone can serve as an adaptor protein of UFD-2 to poly-ubiquitinate unfolded myosin, pointing to a possible role of the UFD-2/UNC-45 pair in maintaining proteostasis in muscle cells.(VLID)460221

Femoral defects in revision hip arthroplasty: a therapy-oriented classification

Introduction!#!The complex field of femoral defects in revision hip arthroplasty displays a lack of standardized, intuitive pre- and intraoperative assessment. To address this issue, the femoral defect classification (FDC) is introduced to offer a reliable, reproducible and an intuitive classification system with a clear therapeutic guideline.!##!Materials and methods!#!The FDC is based on the integrity of the main femoral segments which determine function and structural support. It focuses on the femoral neck, the metaphysis consisting of the greater and lesser trochanter, and the femoral diaphysis. The four main categories determine the location of the defect while subcategories a, b and c are being used to classify the extent of damage in each location. In total, 218 preoperative radiographs were retrospectively graded according to FDC and compared to intraoperatively encountered bone defects. To account for inter-rater and intra-rater agreement, 5 different observers evaluated 80 randomized cases at different points in time.!##!Results!#!A Cohens kappa of 0.832 ± 0.028 could be evaluated, accounting for excellent agreement between preoperative radiographs and intraoperative findings. To account for inter-rater reliability, 80 patients have been evaluated by 5 different observers. Testing for inter-rater reliability, a Fleiss Kappa of 0.688 could be evaluated falling into the good agreement range. When testing for intra-rater reliability, Cohens Kappa of each of the 5 raters has been analyzed and the mean was evaluated at 0.856 accounting for excellent agreement.!##!Conclusion!#!The FDC is a reliable and reproducible classification system. It combines intuitive use and structured design and allows for consistent preoperative planning and intraoperative guidance. A therapeutic algorithm has been created according to current literature and expert opinion. Due to the combination of the FDC with the recently introduced Acetabular Defect Classification (ADC) a structured approach to the entire field of hip revision arthroplasty is now available

Social Networks and Cognitive Function: An Evaluation of Social Bridging and Bonding Mechanisms

Background and objectives: Social connectedness has been linked prospectively to cognitive aging, but there is little agreement about the social mechanisms driving this relationship. This study evaluated 9 measures of social connectedness, focusing on 2 forms of social enrichment-access to an expansive and diverse set of loosely connected individuals (i.e., social bridging) and integration in a supportive network of close ties (i.e., social bonding). Research design and methods: This study used egocentric network and cognitive data from 311 older adults in the Social Networks in Alzheimer Disease study. Linear regressions were used to estimate the association between social connectedness and global cognitive function, episodic memory, and executive function. Results: Measures indicative of social bridging (larger network size, lower density, presence of weak ties, and proportion of non-kin) were consistently associated with better cognitive outcomes, while measures of social bonding (close ties, multiplex support, higher frequency of contact, better relationship quality, and being married) largely produced null effects. Discussion and implications: These findings suggest that the protective benefits of social connectedness for cognitive function and memory may operate primarily through a cognitive reserve mechanism that is driven by irregular contact with a larger and more diverse group of peripheral others

Nutzung biologischer Mineralisationsprozesse fuer die Herstellung neuer Werkstoffe und Oberflaechenschichten Abschlussbericht

The formation of bio-compatible hydroxyapatit on titanium, on titanium alloy TiAl6V4 and on a bone replacement material has been studied applying biological mineralization processes. Fibrils of type I collagen were adsorbed on titanium/titania surfaces under conservation of their native structure. In an electrochemically aided mineralization process a collagen-calcium phosphate interface was built up. As the calcium phosphate modification is governed by the process parameters, the material can be adapted to the desired implantation purpose. The obtained materials exhibit viscoelastic properties which can be described by a four-parametric material model. For improved evaluation of service time a new method is described. (WEN)SIGLEAvailable from TIB Hannover: F97B399+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman