Activation of lysosomal iron triggers ferroptosis in cancer.

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death referred to as ferroptosis1-3. Identifying where this chemistry takes place in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Whereas genetic approaches have revealed underlying mechanisms of lipid peroxide detoxification1,4,5, small molecules can provide unparalleled spatiotemporal control of the chemistry at work6. Here, we show that the ferroptosis inhibitor liproxstatin-1 (Lip-1) exerts a protective activity by inactivating iron in lysosomes. Based on this, we designed the bifunctional compound fentomycin that targets phospholipids at the plasma membrane and activates iron in lysosomes upon endocytosis, promoting oxidative degradation of phospholipids and ferroptosis. Fentomycin effectively kills primary sarcoma and pancreatic ductal adenocarcinoma cells. It acts as a lipolysis-targeting chimera (LIPTAC), preferentially targeting iron-rich CD44high cell-subpopulations7,8 associated with the metastatic disease and drug resistance9,10. Furthermore, we demonstrate that fentomycin also depletes CD44high cells in vivo and reduces intranodal tumour growth in an immunocompetent murine model of breast cancer metastasis. These data demonstrate that lysosomal iron triggers ferroptosis and that lysosomal iron redox chemistry can be exploited for therapeutic benefits.

Ether lipids influence cancer cell fate by modulating iron uptake.

Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with a high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, leading directly to significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.

ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress.

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

PSL Chemical Biology Symposia: Recent Progress in Ferroptosis.

This symposium is the 5th PSL (Paris Sciences & Lettres) Chemical Biology meeting (2015, 2016, 2019, 2023, 2024) held at Institut Curie. This initiative originally started at Institut de Chimie des Substances Naturelles (ICSN) in Gif-sur-Yvette, with a strong focus on chemistry. It was then continued at the Institut Curie (2015) covering a larger scope, before becoming the official PSL Chemical Biology meeting. This latest edition hosted around 150 participants and was focused on the burgeoning field of ferroptosis, its mechanism and implications in health and disease. While not initially planned, it was felt that the next large Ferroptosis venue (CSHA, China) would not happen before late 2024. A discussion involving Conrad, Birsoy, Ubellacker, Brabletz and Rodriguez next to lake Como in Italy sponsored by the DKFZ, prompted us to fill in this gap and to organize a Ferroptosis meeting in Paris beforehand.

Functional and Radiologic Outcomes of Degenerative Versus Traumatic Full-Thickness Rotator Cuff Tears Involving the Supraspinatus Tendon.

BACKGROUND: Arthroscopic rotator cuff repair (ARCR) is among the most commonly performed orthopaedic procedures. Several factors-including age, sex, and tear severity-have been identified as predictors for outcome after repair. The influence of the tear etiology on functional and structural outcome remains controversial. PURPOSE: To investigate the influence of tear etiology (degenerative vs traumatic) on functional and structural outcomes in patients with supraspinatus tendon tears. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Patients undergoing ARCR from 19 centers were prospectively enrolled between June 2020 and November 2021. Full-thickness, nonmassive tears involving the supraspinatus tendon were included. Tears were classified as degenerative (chronic shoulder pain, no history of trauma) or traumatic (acute, traumatic onset, no previous shoulder pain). Range of motion, strength, the Subjective Shoulder Value, the Oxford Shoulder Score (OSS), and the Constant-Murley Score (CMS) were assessed before (baseline) and 6 and 12 months after ARCR. The Subjective Shoulder Value and the OSS were also determined at the 24-month follow-up. Repair integrity after 12 months was documented, as well as additional surgeries up to the 24-month follow-up. Tear groups were compared using mixed models adjusted for potential confounding effects. RESULTS: From a cohort of 973 consecutive patients, 421 patients (degenerative tear, n = 230; traumatic tear, n = 191) met the inclusion criteria. The traumatic tear group had lower mean baseline OSS and CMS scores but significantly greater score changes 12 months after ARCR (OSS, 18 [SD, 8]; CMS, 34 [SD,18] vs degenerative: OSS, 15 [SD, 8]; CMS, 22 [SD, 15]) (P < .001) and significantly higher 12-month overall scores (OSS, 44 [SD, 5]; CMS, 79 [SD, 9] vs degenerative: OSS, 42 [SD, 7]; CMS, 76 [SD, 12]) (P≤ .006). At the 24-month follow-up, neither the OSS (degenerative, 44 [SD, 6]; traumatic, 45 [SD, 6]; P = .346) nor the rates of repair failure (degenerative, 14 [6.1%]; traumatic 12 [6.3%]; P = .934) and additional surgeries (7 [3%]; 7 [3.7%]; P = .723) differed between groups. CONCLUSION: Patients with degenerative and traumatic full-thickness supraspinatus tendon tears who had ARCR show satisfactory short-term functional results. Although patients with traumatic tears have lower baseline functional scores, they rehabilitate over time and show comparable clinical results 1 year after ARCR. Similarly, degenerative and traumatic rotator cuff tears show comparable structural outcomes, which suggests that degenerated tendons retain healing potential.

MRI Treatment Response Assessment Maps (TRAMs) for differentiating recurrent glioblastoma from radiation necrosis.

BACKGROUND: MRI treatment response assessment maps (TRAMs) were introduced to distinguish recurrent malignant glioma from therapy related changes. TRAMs are calculated with two contrast-enhanced T1-weighted sequences and reflect the "late" wash-out (or contrast clearance) and wash-in of gadolinium. Vital tumor cells are assumed to produce a wash-out because of their high turnover rate and the associated hypervascularization, whereas contrast medium slowly accumulates in scar tissue. To examine the real value of this method, we compared TRAMs with the pathology findings obtained after a second biopsy or surgery when recurrence was suspected. METHODS: We retrospectively evaluated TRAMs in adult patients with histologically demonstrated glioblastoma, contrast-enhancing tissue and a pre-operative MRI between January 1, 2017, and December 31, 2022. Only patients with a second biopsy or surgery were evaluated. Volumes of the residual tumor, contrast clearance and contrast accumulation before the second surgery were analyzed. RESULTS: Among 339 patients with mGBM who underwent MRI, we identified 29 repeated surgeries/biopsies in 27 patients 59 ± 12 (mean ± standard deviation) years of age. Twenty-eight biopsies were from patients with recurrent glioblastoma histology, and only one was from a patient with radiation necrosis. We volumetrically evaluated the 29 pre-surgery TRAMs. In recurrent glioblastoma, the ratio of wash-out volume to tumor volume was 36 ± 17% (range 1-73%), and the ratio of the wash-out volume to the sum of wash-out and wash-in volumes was 48 ± 21% (range 22-92%). For the one biopsy with radiation necrosis, the ratios were 42% and 54%, respectively. CONCLUSIONS: Typical recurrent glioblastoma shows a > 20%ratio of the wash-out volume to the sum of wash-out and wash-in volumes. The one biopsy with radiation necrosis indicated that such necrosis can also produce high wash-out in individual cases. Nevertheless, the additional information provided by TRAMs increases the reliability of diagnosis.

Differentiation of multiple brain metastases and glioblastoma with multiple foci using MRI criteria.

OBJECTIVE: Glioblastoma with multiple foci (mGBM) and multiple brain metastases share several common features on magnetic resonance imaging (MRI). A reliable preoperative diagnosis would be of clinical relevance. The aim of this study was to explore the differences and similarities between mGBM and multiple brain metastases on MRI. METHODS: We performed a retrospective analysis of 50 patients with mGBM and compared them with a cohort of 50 patients with multiple brain metastases (2-10 lesions) histologically confirmed and treated at our department between 2015 and 2020. The following imaging characteristics were analyzed: lesion location, distribution, morphology, (T2-/FLAIR-weighted) connections between the lesions, patterns of contrast agent uptake, apparent diffusion coefficient (ADC)-values within the lesion, the surrounding T2-hyperintensity, and edema distribution. RESULTS: A total of 210 brain metastases and 181 mGBM lesions were analyzed. An infratentorial localization was found significantly more often in patients with multiple brain metastases compared to mGBM patients (28 vs. 1.5%, p < 0.001). A T2-connection between the lesions was detected in 63% of mGBM lesions compared to 1% of brain metastases. Cortical edema was only present in mGBM. Perifocal edema with larger areas of diffusion restriction was detected in 31% of mGBM patients, but not in patients with metastases. CONCLUSION: We identified a set of imaging features which improve preoperative diagnosis. The presence of T2-weighted imaging hyperintensity connection between the lesions and cortical edema with varying ADC-values was typical for mGBM.

A 19-color single-tube full spectrum flow cytometry assay for the detection of measurable residual disease in acute myeloid leukemia.

Multiparameter flow cytometry (MFC) has emerged as a standard method for quantifying measurable residual disease (MRD) in acute myeloid leukemia. However, the limited number of available channels on conventional flow cytometers requires the division of a diagnostic sample into several tubes, restricting the number of cells and the complexity of immunophenotypes that can be analyzed. Full spectrum flow cytometers overcome this limitation by enabling the simultaneous use of up to 40 fluorescent markers. Here, we used this approach to develop a good laboratory practice-conform single-tube 19-color MRD detection assay that complies with recommendations of the European LeukemiaNet Flow-MRD Working Party. We based our assay on clinically-validated antibody clones and evaluated its performance on an IVD-certified full spectrum flow cytometer. We measured MRD and normal bone marrow samples and compared the MRD data to a widely used reference MRD-MFC panel generating highly concordant results. Using our newly developed single-tube panel, we established reference values in healthy bone marrow for 28 consensus leukemia-associated immunophenotypes and introduced a semi-automated dimensionality-reduction, clustering and cell type identification approach that aids the unbiased detection of aberrant cells. In summary, we provide a comprehensive full spectrum MRD-MFC workflow with the potential for rapid implementation for routine diagnostics due to reduced cell requirements and ease of data analysis with increased reproducibility in comparison to conventional FlowMRD routines.

Necrosectomy Versus Stand-Alone Suboccipital Decompressive Craniectomy for the Management of Space-Occupying Cerebellar Infarctions-A Retrospective Multicenter Study.

BACKGROUND AND OBJECTIVES: Space-occupying cerebellar stroke (SOCS) when coupled with neurological deterioration represents a neurosurgical emergency. Although current evidence supports surgical intervention in such patients with SOCS and rapid neurological deterioration, the optimal surgical methods/techniques to be applied remain a matter of debate. METHODS: We conducted a retrospective, multicenter study of patients undergoing surgery for SOCS. Patients were stratified according to the type of surgery as (1) suboccipital decompressive craniectomy (SDC) or (2) suboccipital craniotomy with concurrent necrosectomy. The primary end point examined was functional outcome using the modified Rankin Scale (mRS) at discharge and at 3 months (mRS 0-3 defined as favorable and mRS 4-6 as unfavorable outcome). Secondary end points included the analysis of in-house postoperative complications, mortality, and length of hospitalization. RESULTS: Ninety-two patients were included in the final analysis: 49 underwent necrosectomy and 43 underwent SDC. Those with necrosectomy displayed significantly higher rate of favorable outcome at discharge as compared with those who underwent SDC alone: 65.3% vs 27.9%, respectively ( P < .001, odds ratios 4.9, 95% CI 2.0-11.8). This difference was also observed at 3 months: 65.3% vs 41.7% ( P = .030, odds ratios 2.7, 95% CI 1.1-6.7). No significant differences were observed in mortality and/or postoperative complications, such as hemorrhagic transformation, infection, and/or the development of cerebrospinal fluid leaks/fistulas. CONCLUSION: In the setting of SOCS, patients treated with necrosectomy displayed better functional outcomes than those patients who underwent SDC alone. Ultimately, prospective, randomized studies will be needed to confirm this finding.

K-Wire Osteosynthesis for Arthrodesis of the Paediatric Foot Is a Good and Valid Procedure.

BACKGROUND: Foot deformities in children are common, and the majority can be treated conservatively. Nevertheless, there are deformities that require surgical treatment. These include rigid clubfeet, severe forms of pes planovalgus, pes cavus and several more. We retrospectively analysed the pseudarthrosis rate of surgical treatment of foot deformities with transcutaneous K-wire osteosynthesis in neurologically healthy children and adolescents. The aim of the study was to show that the results with K-wires are comparable to those with other osteosynthesis methods in the literature. METHODS: A total of 46 paediatric patients aged 6 to 17 years treated between January 2010 and December 2015 met the inclusion criteria. Depending on the diagnosis, different surgical interventions were necessary. In clubfoot and pes planovalgus, representing n = 81, 70% of the whole collective triple arthrodesis with fusion of the talonavicular, calcaneocuboid and subtalar joints or Evans osteotomy was usually performed. Radiographs were taken at least 6 months post-surgery, and bony consolidation of the subtalar, talonavicular (TN), and calcaneocuboidal (CC) joints and the metatarsal I (MT I) osteotomy were assessed. If there was no evidence of fusion at this time, it was considered non-union. RESULTS: In total, 117 arthrodesis procedures with K-wires were performed. Overall, 110 of the arthrodesis (94%) healed, and only 7 joints (6%) showed non-union (subtalar 0%, TN 7.7%, CC 6.5% and MT I 6.7%). All non-unions occurred in subjects with clubfoot deformities. No significant risk factors were observed. CONCLUSION: This study replicated the good consolidation rates reported in the literature with screws, plates, intramedullary nails or staples in arthrodesis of the adolescent foot in neurologically healthy subjects and confirmed the efficacy of K-wires. The main advantages of transcutaneous K-wire treatment are easy metal removal, lower osteosynthesis material costs and less concomitant damage. Further studies, especially randomised controlled trials, are needed to further investigate this topic.

Ambulatory knee biomechanics and muscle activity 2 years after ACL surgery: InternalBraceTM-augmented ACL repair versus ACL reconstruction versus healthy controls.

BACKGROUND: Little is known about knee mechanics and muscle control after augmented ACL repair. Our aim was to compare knee biomechanics and leg muscle activity during walking between the legs of patients 2 years after InternalBraceTM-augmented anterior cruciate ligament repair (ACL-IB) and between patients after ACL-IB and ACL reconstruction (ACL-R), and controls. METHODS: Twenty-nine ACL-IB, 27 sex- and age-matched ACL-R (hamstring tendon autograft) and 29 matched controls completed an instrumented gait analysis. Knee joint angles, moments, power, and leg muscle activity were compared between the involved and uninvolved leg in ACL-IB (paired t-tests), and between the involved legs in ACL patients and the non-dominant leg in controls (analysis of variance and posthoc Bonferroni tests) using statistical parametric mapping (SPM, P < 0.05). Means and 95% confidence intervals (CI) of differences in discrete parameters (DP; i.e., maximum/minimum) were calculated. RESULTS: Significant differences were observed in ACL-IB only in minimum knee flexion angle (DP: 2.4°, CI [-4.4;-0.5]; involved > uninvolved) and maximum knee flexion moment during stance (-0.07Nm/kg, CI [-0.13;-0.00]; involved < uninvolved), and differences between ACL-IB and ACL-R only in maximum knee flexion during swing (DP: 3.6°, CI [0.5;7.0]; ACL-IB > ACL-R). Compared to controls, ACL-IB (SPM: 0-3%GC, P = 0.015; 98-100%, P = 0.016; DP: -6.3 mm, CI [-11.7;-0.8]) and ACL-R (DP: -6.0 mm, CI [-11.4;-0.2]) had lower (maximum) anterior tibia position around heel strike. ACL-R also had lower maximum knee extension moment (DP: -0.13Nm/kg, CI [-0.23;-0.02]) and internal knee rotation moment (SPM: 34-41%GC, P < 0.001; DP: -0.03Nm/kg, CI [-0.06;-0.00]) during stance, and greater maximum semitendinosus activity before heel strike (DP: 11.2%maximum voluntary contraction, CI [0.1;21.3]) than controls. CONCLUSION: Our results suggest comparable ambulatory knee function 2 years after ACL-IB and ACL-R, with ACL-IB showing only small differences between legs. However, the differences between both ACL groups and controls suggest that function in the involved leg is not fully recovered and that ACL tear is not only a mechanical disruption but also affects the sensorimotor integrity, which may not be restored after surgery. The trend toward fewer abnormalities in knee moments and semitendinosus muscle function during walking after ACL-IB warrants further investigation and may underscore the importance of preserving the hamstring muscles as ACL agonists. LEVEL OF EVIDENCE: Level III, case-control study. TRIAL REGISTRATION: clinicaltrials.gov, NCT04429165 (12/06/2020).

Favorable Patient-Reported, Clinical, and Functional Outcomes 2 Years After ACL Repair and InternalBrace Augmentation Compared With ACL Reconstruction and Healthy Controls.

BACKGROUND: Recently, interest in anterior cruciate ligament (ACL) preservation and repair after proximal ACL tears has been resurrected. Although good clinical outcomes have been reported in the literature with adequate patient selection, to date detailed scientific evidence for the functional benefit of primary ACL repair with ligament augmentation is scarce. PURPOSE: To compare patient-reported, clinical, and functional outcomes in patients 2 years after ACL repair and InternalBrace augmentation (ACL-IB) with age- and sex-matched patients 2 years after ACL reconstruction (ACL-R) and with matched healthy controls. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: In total, 29 patients 2 years after ACL-IB, 27 sex- and age- matched patients 2 years after ACL-R (hamstring autografts), and 29 matched healthy controls were included. Patient-reported outcomes were assessed using the International Knee Documentation Committee score, Knee injury and Osteoarthritis Outcome Score, EQ-5D-5L, Tegner Activity Scale, and Anterior Cruciate Ligament Return to Sports after Injury scale. Surgery time was recorded. For clinical outcomes, range of motion and thigh and shank circumference were measured, and passive anterior translation was determined using the Rolimeter. Isokinetic muscle strength was measured using a Biodex dynamometer. The limb symmetry index (operated/contralateral or nondominant/dominant × 100), side-to-side differences (operated - contralateral, nondominant - dominant), and hamstring-quadriceps ratios were calculated for functional parameters. Failure and reoperation rates were not compared. RESULTS: Two years after surgery, patients treated with ACL-IB showed good to excellent patient-reported outcomes comparable with those of patients after ACL-R. Surgery time, including concomitant surgeries, was significantly shorter in the ACL-IB group (mean, 81 minutes) compared with the ACL-R group (mean, 97 minutes) (P = .024). Isokinetic muscle strength was comparable between patient groups without significant differences in extensor and flexor strength or in hamstring-quadriceps ratios. CONCLUSION: These results suggest that ACL-IB achieves comparable patient-reported, clinical, and functional outcomes with ACL-R at 2 years postoperatively and, after careful patient selection, should be considered as a valuable early treatment alternative for proximal ACL tears. REGISTRATION: NCT04429165 (ClinicalTrials.gov identifier).

Functional leg performance 2 years after ACL surgery: a comparison between InternalBrace™-augmented repair versus reconstruction versus healthy controls.

BACKGROUND: While clinical and patient-reported outcomes have been investigated in patients after InternalBrace™-augmented anterior cruciate ligament repair (ACL-IB), less is known regarding restoration of functional performance. We aimed to determine differences in functional performance within and between patients 2 years after ACL-IB, patients 2 years after ACL reconstruction (ACL-R), and healthy controls. MATERIALS AND METHODS: A total of 29 ACL-IB, 27 ACL-R (hamstring autograft), and 29 controls performed single-leg hop (maximum forward distance hop, SLH; side hop > 40 cm in 30 s, SH), proprioception (knee joint position sense at 30° and 60° flexion), and dynamic postural balance (Y Balance) tests. Differences were calculated within groups (side-to-side difference) and between the involved leg of patients and the non-dominant leg of controls, and were evaluated to predefined statistical (P < 0.05), clinically relevant, and methodological (smallest detectable change) thresholds. The number of exceeded thresholds represented no (0), small (1), moderate (2), or strong (3) differences. In addition, the relative number of participants achieving leg symmetry (≥ 90%) and normal performance (≥ 90% of the average performance of the non-dominant leg of controls) were compared between groups (chi-squared tests, P < 0.05). RESULTS: We observed no-to-moderate leg differences within ACL-IB (moderate difference in hops) and within ACL-R (moderate difference in knee proprioception), no leg differences between patient groups, no-to-small leg differences between ACL-IB and controls, and no leg differences between ACL-R and controls in functional performance. However, two patients in ACL-IB and ACL-R, respectively, passed the hop pretest only with their uninvolved leg, and fewer patients after ACL-IB and ACL-R than controls reached a leg symmetry and normal leg performance of controls in SLH (P < 0.001). CONCLUSIONS: Functional performance seems to be comparable 2 years postoperatively between ACL-IB and ACL-R for a specific subgroup of patients (i.e., proximal ACL tears, moderate activity level). However, the presumed advantage of comparable functional outcome with preserved knee structures after augmented ACL repair compared with ACL-R, and the tendency of both patient groups toward leg asymmetry and compromised single-leg hop performance in the involved legs, warrants further investigation. Level of Evidence Level III, case-control study. Trial registration clinicaltrials.gov, NCT04429165 (12/09/2020). Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT04429165 .

A druggable copper-signalling pathway that drives inflammation.

Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

Comparison of EPI DWI and STEAM DWI in Early Postoperative MRI Controls After Resection of Tumors of the Central Nervous System.

PURPOSE: Diffusion-weighted imaging (DWI) is important for differentiating residual tumor and subacute infarctions in early postoperative magnetic resonance imaging (MRI) of central nervous system (CNS) tumors. In cases of pneumocephalus and especially in the presence of intraventricular trapped air, conventional echo-planar imaging (EPI) DWI is distorted by susceptibility artifacts. The performance and robustness of a newly developed DWI sequence using the stimulated echo acquisition mode (STEAM) was evaluated in patients after neurosurgical operations with early postoperative MRI. METHODS: We compared EPI and STEAM DWI of 43 patients who received 3­Tesla MRI within 72 h after a neurosurgical operation between 1 October 2019 and 30 September 2021. We analyzed susceptibility artifacts originating from air and blood and whether these artifacts compromised the detection of ischemic changes after surgery. The DWI sequences were (i) visually rated and (ii) volumetrically analyzed. RESULTS: In 28 of 43 patients, we found severe and diagnostically relevant artifacts in EPI DWI, but none in STEAM DWI. In these cases, in which artifacts were caused by intracranial air, they led to a worse detection of ischemic lesions and thus to a possible failed diagnosis or lack of judgment using EPI DWI. Additionally, volumetric analysis demonstrated a 14% smaller infarct volume detected with EPI DWI. No significant differences in visual rating and volumetric analysis were detected among the patients without severe artifacts. CONCLUSION: The newly developed version of STEAM DWI with highly undersampled radial encodings is superior to EPI DWI in patients with postoperative pneumocephalus.

The Rosetta Stone Hypothesis-Based Interaction of the Tumor Suppressor Proteins Nit1 and Fhit.

In previous studies, we have identified the tumor suppressor proteins Fhit (fragile histidine triad) and Nit1 (Nitrilase1) as interaction partners of ß-catenin both acting as repressors of the canonical Wnt pathway. Interestingly, in D. melanogaster and C. elegans these proteins are expressed as NitFhit fusion proteins. According to the Rosetta Stone hypothesis, if proteins are expressed as fusion proteins in one organism and as single proteins in others, the latter should interact physically and show common signaling function. Here, we tested this hypothesis and provide the first biochemical evidence for a direct association between Nit1 and Fhit. In addition, size exclusion chromatography of purified recombinant human Nit1 showed a tetrameric structure as also previously observed for the NitFhit Rosetta Stone fusion protein Nft-1 in C. elegans. Finally, in line with the Rosetta Stone hypothesis we identified Hsp60 and Ubc9 as other common interaction partners of Nit1 and Fhit. The interaction of Nit1 and Fhit may affect their enzymatic activities as well as interaction with other binding partners.

Biplanar high tibial osteotomy for the combined correction of varus and posterior tibial slope malalignment.

Varus malalignment combined with an increased posterior tibial slope (PTS) in the ACL deficient knee is a frequent pathology; yet, treatment for this condition remains challenging. The presented biplanar osteotomy technique allows to simultaneously address both components of malalignment in a single step. A detailed preoperative planning is best achieved by means of a digital planning software and constant intraoperative imaging is performed to verify the correction angle. A bony wedge is resected along with the extension osteotomy according to the preoperative planning and the medial-opening tibial osteotomy site is filled with bone allograft. Two bicortical lag screws are placed in anterior-posterior direction to secure the extension osteotomy, whereas a plate fixation is used for the medial-open osteotomy.

Arthrofibrosis is a common but poorly defined complication in multiligament knee injuries: a systematic review.

PURPOSE: The purpose of this study is to systematically review multiligament knee injury (MLKI) outcome studies to determine definitions of arthrofibrosis (AF) and provide information about incidence, management as well as potential risk factors. METHODS: A systematic literature search was performed (PubMed and Cochrane library) following the PRISMA guidelines of operatively treated MLKI (Schenck II-IV) studies reporting the incidence of AF. Twenty-five studies met the inclusion criteria. Injury pattern, timing of surgery, surgical technique, treatment of AF, rehabilitation programs and PROMS were inquired. Risk of bias and quality of evidence were assessed using the Coleman methodological score. RESULTS: Twenty-five studies with a total of 709 patients with a mean age of 33.6 ± 4.8 years were included and followed 47.2 ± 32.0 months. The majority of studies (22/25) used imprecise and subjective definitions of AF. A total of 86 patients were treated for AF, resulting in an overall prevalence of 12.1% (range 2.8-57.1). Higher-grade injuries (Schenck III-IV), acute treatment and ROM (range of motion) limiting rehabilitation programs were potential risk factors for AF. The time from index surgery to manipulation anesthesia (MUA) and arthroscopic lysis of adhesions (LOA) averaged at 14.3 ± 8.8 and 27.7 ± 12.8 weeks. Prior to MUA and LOA, the ROM was 51.7° ± 23.5 and 80.2° ± 17.0, resulting in a total ROM gain after intervention of 65.0° ± 19.7 and 48.0° ± 10.6, respectively; with no reports of any complication within the follow-up. The overall methodological quality of the studies was poor as measured by the Coleman score with average 56.3 ± 12.5 (range 31-84) points. CONCLUSIONS: AF is a common but poorly defined complication particularly in high-grade MLKI. Early postoperative and intensified physiotherapy is important to reduce the risk of AF. MUA and LOA are very effective treatment options and result in good clinical outcome. Prospective studies with bigger study population are needed to optimize treatment algorithms of further patients after MLKI. The protocol of this systematic review has been prospectively registered with PROSPERO (CRD42021229187, January 4th, 2021).

Expedited gene delivery for osteochondral defect repair in a rabbit knee model: A one-year investigation.

Objective: To evaluate a single-step, gene-based procedure for repairing osteochondral lesions. Design: Osteochondral lesions were created in the patellar groove of skeletally mature rabbits. Autologous bone marrow aspirates were mixed with adenovirus vectors carrying cDNA encoding green fluorescent protein (Ad.GFP) or transforming growth factor-ß1 (Ad.TGF-ß1) and allowed to clot. The clotted marrow was press-fit into the defects. Animals receiving Ad.GFP were euthanized at 2 weeks and intra-articular expression of GFP examined by fluorescence microscopy. Animals receiving Ad.TGF-ß1 were euthanized at 3 months and 12 months; repair was compared to empty defects using histology and immunohistochemistry. Complementary in vitro experiments assessed transgene expression and chondrogenesis in marrow clots and fibrin gels. In a subsequent pilot study, repair at 3 months using a fibrin gel to encapsulate Ad.TGF-ß1 was evaluated. Results: At 2 weeks, GFP expression was seen at variable levels within the cartilaginous lesion. At 3 months, there was no statistically significant improvement (p > 0.05) in healing of lesions receiving Ad.TGF-ß1 and variability was high. At 12 months, there were still no significant difference (p > 0.05) between the empty defects and those receiving Ad.TGF-ß1 in the overall, cartilage, and bone scores. Variability was still high. In vitro experiments suggested that variability reflected variable transduction efficiency and chondrogenic activity of the marrow clots; using fibrin gels instead of marrow may address this issue but more research is needed. Conclusions: This approach to improving the repair of osteochondral lesions needs further refinement to reduce variability and provide a more robust outcome.

Advantages of CT Versus MRI for Preoperative Assessment of Osteochondritis Dissecans of the Capitellum.

BACKGROUND: Magnetic resonance imaging (MRI) is considered to be the gold standard for imaging of osteochondritis dissecans (OCD). PURPOSE/HYPOTHESIS: The purpose was to determine the additional value of a preoperative computed tomography (CT) scan in adolescent patients with capitellar OCD of the elbow. Consistent with the fact that OCD is a lesion involving the subchondral bone, the hypothesis was that CT would be superior to MRI for imaging OCD of the capitellum. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: All patients being treated surgically for an OCD of the capitellum between 2006 and 2016 at one institution were reviewed for preoperative imaging. A total of 28 patients met the inclusion criteria. Corresponding MRI and CT scans were compared retrospectively. Multiple parameters were recorded, with special emphasis on OCD lesion size, fragmentation, and tilt as well as joint surface integrity, loose bodies, and osteophytes. RESULTS: The OCD lesions were best seen on CT scans, whereas MRI T1-weighted images overestimated and T2-weighted images underestimated the size of defects. A subchondral fracture nonunion was found on CT scans in 18 patients, whereas this was seen on MRI T1-weighted images in only 2 patients (P < .001) and MRI T2-weighted images in 4 patients (P < .001). Fragmentation of the OCD fragment was found on CT scans in 17 patients but on MRI scans in only 9 patients (P = .05). Osteophytes as a sign of secondary degenerative changes were seen on CT scans in 24 patients and were seen on MRI scans in 15 patients (P = .02). Altogether, only 51 of 89 secondary changes including loose bodies, effects on the radial head and ulnohumeral joint, and osteophytes that were seen on CT scans were also seen on MRI scans (P = .002). CONCLUSION: OCD fragmentation and secondary changes were more often diagnosed on CT. These factors indicate OCD instability or advanced OCD stages, which are indications for surgery. In an adolescent who is considered at risk for OCD (baseball, gymnastics, weightlifting, tennis) and who has lateral elbow joint pain with axial or valgus load bearing, CT is our imaging modality of choice for diagnosing and staging OCD of the capitellum.