Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance.

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.

Effect of acute intravenous beta-blocker administration on myocardial blood flow during same-day hybrid CCTA/PET imaging.

This study aimed to evaluate the impact of acute intravenous beta-blocker administration on myocardial blood flow (MBF) during same-day hybrid coronary computed tomography angiography (CCTA) and 13N-ammonia positron emission tomography (PET) myocardial perfusion imaging (MPI). Previous research on the discontinuation of oral beta-blockers before MPI has shown mixed results, with no studies yet exploring the acute intravenous administration in the context of same-day hybrid imaging. This retrospective study included patients with suspected chronic coronary syndromes undergoing same-day hybrid CCTA/13N-ammonia PET MPI. Exclusion criteria comprised coronary artery stenosis ≥ 50% or regional perfusion abnormalities on PET, and baseline oral beta-blocker medication. Intravenous metoprolol (up to 30 mg) was administered as needed for heart rate control before CCTA. MBF measurements were obtained at rest (rMBF) and during stress (sMBF), and myocardial flow reserve (MFR) was calculated. After excluding 281 patients, 154 were eligible for propensity-score matching, resulting in 108 patients divided into two equal groups based on beta-blocker administration. The groups showed no significant differences in baseline characteristics. Among those who received beta-blockers, there was a significant decrease in sMBF (2.21 [IQR 1.72-2.78] versus 2.46 [2.08-2.99] ml∙min-1∙g-1, p = 0.027) and MFR (3.46 [2.70-4.05] versus 3.79 [3.22-4.46], p = 0.030), respectively, compared to those who did not receive beta-blockers. In contrast, rMBF remained unaffected (0.65 [0.54-0.78] versus 0.64 [0.55-0.76] ml∙min-1∙g-1, p = 0.931). Acute intravenous beta-blocker administration significantly impacts MBF, leading to a slight reduction in sMBF and MFR. In contrast, rMBF appears unaffected, suggesting that beta-blockers primarily affect the coronary capacity to respond to vasodilators.

Chronic hepatitis E virus-induced spinal cord atrophy in a patient with chronic lymphatic leukemia: a case report and interdisciplinary management proposal.

Background: The hepatitis E virus (HEV) can cause acute viral hepatitis with or without neurological manifestations, and occasionally progresses to chronic infection in immunocompromised individuals. The management of chronic HEV infection in cancer patients may be challenging due to the complex immunological constellation. Furthermore, the diagnostic workflow and the impact on quality of life of neurological HEV manifestations in immunocompromised patients have not been sufficiently delineated previously. Case description: A 61-year-old male with systemically treated chronic lymphocytic leukemia (CLL) experienced a slowly progressive atrophy of the spinal cord due to a chronic HEV infection. Despite continuous antiviral treatment with ribavirin, the patient's neurological condition continued to deteriorate, particularly following subsequent attempts to treat CLL. Treatment with obinutuzumab resulted in acute bowel and urinary retention and a further deterioration of motor skills, prompting the discontinuation of obinutuzumab. The patient's neurological status improved after the administration of intravenous immunoglobulins. Conclusion: This case study provides a comprehensive long-term follow-up of a cancer patient with chronic HEV infection and associated CNS involvement, which resulted in progressive neurological disability over several years. The challenges faced in diagnosing new neurological symptoms in patients undergoing immunosuppressive cancer treatment underscore the need for an interdisciplinary diagnostic approach that includes HEV testing. We propose a diagnostic pathway for future validation in immunocompromised cohorts presenting with neurological symptoms, emphasizing its potential to enhance clinical outcomes.

Energy expenditure estimation during activities of daily living in middle-aged and older adults using an accelerometer integrated into a hearing aid.

Background: Accelerometers were traditionally worn on the hip to estimate energy expenditure (EE) during physical activity but are increasingly replaced by products worn on the wrist to enhance wear compliance, despite potential compromises in EE estimation accuracy. In the older population, where the prevalence of hearing loss is higher, a new, integrated option may arise. Thus, this study aimed to investigate the accuracy and precision of EE estimates using an accelerometer integrated into a hearing aid and compare its performance with sensors simultaneously worn on the wrist and hip. Methods: Sixty middle-aged to older adults (average age 64.0 ± 8.0 years, 48% female) participated. They performed a 20-min resting energy expenditure measurement (after overnight fast) followed by a standardized breakfast and 13 different activities of daily living, 12 of them were individually selected from a set of 35 activities, ranging from sedentary and low intensity to more dynamic and physically demanding activities. Using indirect calorimetry as a reference for the metabolic equivalent of task (MET), we compared the EE estimations made using a hearing aid integrated device (Audéo) against those of a research device worn on the hip (ZurichMove) and consumer devices positioned on the wrist (Garmin and Fitbit). Class-estimated and class-known models were used to evaluate the accuracy and precision of EE estimates via Bland-Altman analyses. Results: The findings reveal a mean bias and 95% limit of agreement for Audéo (class-estimated model) of -0.23 ± 3.33 METs, indicating a slight advantage over wrist-worn consumer devices (Garmin: -0.64 ± 3.53 METs and Fitbit: -0.67 ± 3.40 METs). Class-know models reveal a comparable performance between Audéo (-0.21 ± 2.51 METs) and ZurichMove (-0.13 ± 2.49 METs). Sub-analyses show substantial variability in accuracy for different activities and good accuracy when activities are averaged over a typical day's usage of 10 h (+61 ± 302 kcal). Discussion: This study shows the potential of hearing aid-integrated accelerometers in accurately estimating EE across a wide range of activities in the target demographic, while also highlighting the necessity for ongoing optimization efforts considering precision limitations observed across both consumer and research devices.

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.

Antibodies targeting the glycan cap of Ebola virus glycoprotein are potent inducers of the complement system

Antibodies to Ebola virus glycoprotein (EBOV GP) represent an important correlate of the vaccine efficiency and infection survival. Both neutralization and some of the Fc-mediated effects are known to contribute the protection conferred by antibodies of various epitope specificities. At the same time, the role of the complement system remains unclear. Here, we compare complement activation by two groups of representative monoclonal antibodies (mAbs) interacting with the glycan cap (GC) or the membrane-proximal external region (MPER) of GP. Binding of GC-specific mAbs to GP induces complement-dependent cytotoxicity (CDC) in the GP-expressing cell line via C3 deposition on GP in contrast to MPER-specific mAbs. In the mouse model of EBOV infection, depletion of the complement system leads to an impairment of protection exerted by one of the GC-specific, but not MPER-specific mAbs. Our data suggest that activation of the complement system represents an important mechanism of antiviral protection by GC antibodies.

Exhausted Lag-3+ CD4+ T cells are increased in pediatric Inflammatory Bowel Disease.

T cells are one of the main drivers of inflammatory bowel diseases (IBD). Infliximab (IFX) is used in the treatment of IBD as an anti-inflammatory drug to induce remission by neutralizing TNFα. We determined the individual chemokine/homing receptor and cytokine profile in pediatric IBD patients before and during IFX therapy to identify predictive biomarkers for therapy success. Peripheral blood CD4+ cells from pediatric patients with IBD were immunomagnetically isolated and either directly analyzed by FACS for cell distribution and chemokine/homing receptor expression or evaluated for cytokine production after in-vitro-stimulation. 21 responders (RS) and 21 non-responders (NRS) were recruited. Before IFX therapy, flow cytometry revealed decreased percentages of naïve conventional T cells in pediatric IBD patients. The proportions of CD62-L+ T cells were decreased in both CD and UC therapy responders. The cytokine profile of T cells was highly altered in IBD patients compared to healthy controls (HC). During IFX therapy, the frequencies of conventional memory and regulatory memory T cells expanded in both cohorts. IFX response was marked by a decrease of α4ß7+ and IFNγ+ memory T cells in both CD and UC. In contrast, frequencies of Lag-3+ T cells proved to be significantly increased in NRS. These observations were irrespective of the underlying disease. T cells of pediatric IBD patients display an activated and rather Th1/Th17 shifted phenotype The increased expression of the checkpoint molecule Lag-3 on T cells of NRS resembles a more exhausted phenotype than in RS and HC which appeared to be a relevant predictive marker for therapy failure.

Chasing Red Herrings: Palladium Metal Salt Impurities Feigning KRAS Activity in Biochemical Assays.

Identifying promising chemical starting points for small molecule inhibitors of active, GTP-loaded KRAS "on" remains of great importance to clinical oncology and represents a significant challenge in medicinal chemistry. Here, we describe broadly applicable learnings from a KRAS hit finding campaign: While we initially identified KRAS inhibitors in a biochemical high-throughput screen, we later discovered that compound potencies were all but assay artifacts linked to metal salts interfering with KRAS AlphaScreen assay technology. The source of the apparent biochemical KRAS inhibition was ultimately traced to unavoidable palladium impurities from chemical synthesis. This discovery led to the development of a Metal Ion Interference Set (MIIS) for up-front assay development and testing. Profiling of the MIIS across 74 assays revealed a reduced interference liability of label-free biophysical assays and, as a result, provided general estimates for luminescence- and fluorescence-based assay susceptibility to metal salt interference.

Type-I interferon shapes peritoneal immunity in cirrhosis and drives caspase-5-mediated progranulin release upon infection.

BACKGROUND & AIMS: Gut bacterial translocation contributes to immune dysfunction and spontaneous bacterial peritonitis (SBP) in cirrhosis. We hypothesized that exposure of peritoneal macrophages (PMs) to bacterial DNA results in type-I interferon (IFN) production, shaping subsequent immune responses, inflammasome activation, and the release of damage-associated molecular patterns (DAMPs). METHODS: PMs from patients with cirrhosis were stimulated with E. coli single-stranded DNA (ssDNA), lipopolysaccharide and IFN, or infected with E. coli, S. aureus, and Group B streptococcus in vitro. Cytokine release, inflammasome activation, and DAMP release were quantified by quantitative-PCR, ELISA, western blots, and reporter cells employing primary PMs, monocytes, and caspase-deficient THP-1 macrophages. Serum progranulin concentration was correlated with transplant-free survival in 77 patients with SBP. RESULTS: E. coli ssDNA induced strong type-I IFN activity in PMs and monocytes, priming them for enhanced lipopolysaccharide-mediated tumor necrosis factor production without inducing toll-like receptor 4 tolerance. During in vitro macrophage bacterial infection, type-I IFN release aligned with upregulated expression of IFN-regulatory factors (IRF)1/2 and guanylate binding proteins (GBP)2/5. PMs upregulated inflammasome-associated proteins and type-I IFN upon E. coli ssDNA exposure and released interleukin-1ß upon bacterial infection. Proteomic screening in mouse macrophages revealed progranulin release as being caspase-11-dependent during E. coli infection. PMs and THP-1 macrophages released significant amounts of progranulin when infected with S. aureus or E. coli via gasdermin D in a type-I IFN- and caspase-5-dependent manner. During SBP, PMs upregulated IRF1, GBP2/5 and caspase-5 and higher serum progranulin concentrations were indicative of lower 90-day transplant-free survival after SBP. CONCLUSIONS: Type-I IFN shapes peritoneal immune responses and regulates caspase-5-mediated progranulin release during SBP. IMPACT AND IMPLICATIONS: Patients with cirrhosis exhibit impaired immune responses and increased susceptibility to bacterial infections. This study reveals that type-I interferon responses, triggered by pathogen-associated molecular patterns, are crucial in regulating macrophage activation and priming them for inflammatory responses. Additionally, we elucidate the mechanisms by which type-I interferons promote the release of progranulin from macrophages during spontaneous bacterial peritonitis. Our findings enhance understanding of how bacterial translocation affects immune responses, identify novel biomarkers for inflammasome activation during infections, and point to potential therapeutic targets.

Virtual reality assessment of a high-calorie food bias: Replication and food-specificity in healthy participants.

BACKGROUND: Theoretical models and behavioural studies indicate faster approach behaviour for high-calorie food (approach bias) among healthy participants. A previous study with Virtual Reality (VR) and online motion-capture quantified this approach bias towards food and non-food cues in a controlled VR environment with hand movements. The aim of this study was to test the specificity of a manual approach bias for high-calorie food in grasp movements compared to low-calorie food and neutral objects of different complexity, namely, simple balls and geometrically more complex office tools. METHODS: In a VR setting, healthy participants (N = 27) repeatedly grasped or pushed high-calorie food, low-calorie food, balls and office tools in randomized order with 30 item repetitions. All objects were rated for valence and arousal. RESULTS: High-calorie food was less attractive and more arousing in subjective ratings than low-calorie food and neutral objects. Movement onset was faster for high-calorie food in push-trials, but overall push responses were comparable. In contrast, responses to high-calorie food relative to low-calorie food and to control objects were faster in grasp trials for later stages of interaction (grasp and collect). Non-parametric tests confirmed an approach bias for high-calorie food. CONCLUSION: A behavioural bias for food was specific to high-calorie food objects. The results confirm the presence of bottom-up advantages in motor-cognitive behaviour for high-calorie food in a non-clinical population. More systematic variations of object fidelity and in clinical populations are outstanding. The utility of VR in assessing approach behaviour is confirmed in this study by exploring manual interactions in a controlled environment.

Glenoid Concavity Affects Anterior Shoulder Stability in an Active-Assisted Biomechanical Model.

Background: The treatment of bony glenoid defects after anteroinferior shoulder dislocation currently depends on the amount of glenoid bone loss (GBL). Recent studies have described the glenoid concavity as an essential factor for glenohumeral stability. The role of glenoid concavity in the presence of soft tissue and muscle forces is still unknown. Hypothesis: Glenoid concavity would have a major impact on glenohumeral stability in an active-assisted biomechanical model including soft tissue and the rotator cuff's compression forces. Study Design: Controlled laboratory study. Methods: In 8 human shoulder specimens, individual coordinate systems were calculated based on anatomic landmarks. The glenoid concavity was measured biomechanically and based on computed tomography. Static load was applied to the rotator cuff tendons and the deltoid muscle. In a robotic test setup, anteriorly directed force was applied to the humeral head until translation of 5 mm (Nant) was achieved. Nant was used as a parameter indicating shoulder stability. This was performed in the following testing stages: (1) intact joint, (2) labral lesion, (3) 10% GBL, and (4) 20% GBL. The 8 specimens were divided equally into 2 subgroups (low concavity [LC] versus high concavity [HC]), with 4 specimens each, according to the previously measured concavity. Results: Anterior glenohumeral stability was highly correlated with the native glenoid concavity (R 2 = 0.8). In the testing stages 1 to 3, we found a significantly higher mean stability in the HC subgroup compared with the LC subgroup (P≤ .0142). The HC subgroup still showed higher absolute Nant values with 20% GBL; however, there was no significant difference from the LC subgroup. The loss of stability in 20% GBL was correlated with the initial concavity (R 2 = 0.86). Thus, a higher loss of Nant in the HC subgroup was observed (P = .0049). Conclusion: In an active-assisted model with intact soft tissue surrounding and muscular compression forces, the glenoid concavity correlates with shoulder stability. In bony defects, loss of concavity is an essential factor causing instability. Due to their significantly higher native stability, glenoids with HC can tolerate a higher amount of GBL. Clinical Relevance: Glenoid concavity should be considered in an individualized treatment of bony glenoid defects. Further studies are required to establish reference values and develop therapeutic algorithms.

Predictors of short-term anxiety outcome in subthalamic stimulation for Parkinson's disease.

The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson's disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.

Engineering an inducible leukemia-associated fusion protein enables large-scale ex vivo production of functional human phagocytes.

Ex vivo expansion of human CD34+ hematopoietic stem and progenitor cells remains a challenge due to rapid differentiation after detachment from the bone marrow niche. In this study, we assessed the capacity of an inducible fusion protein to enable sustained ex vivo proliferation of hematopoietic precursors and their capacity to differentiate into functional phagocytes. We fused the coding sequences of an FK506-Binding Protein 12 (FKBP12)-derived destabilization domain (DD) to the myeloid/lymphoid lineage leukemia/eleven nineteen leukemia (MLL-ENL) fusion gene to generate the fusion protein DD-MLL-ENL and retrovirally expressed the protein switch in human CD34+ progenitors. Using Shield1, a chemical inhibitor of DD fusion protein degradation, we established large-scale and long-term expansion of late monocytic precursors. Upon Shield1 removal, the cells lost self-renewal capacity and spontaneously differentiated, even after 2.5 y of continuous ex vivo expansion. In the absence of Shield1, stimulation with IFN-γ, LPS, and GM-CSF triggered terminal differentiation. Gene expression analysis of the obtained phagocytes revealed marked similarity with naïve monocytes. In functional assays, the novel phagocytes migrated toward CCL2, attached to VCAM-1 under shear stress, produced reactive oxygen species, and engulfed bacterial particles, cellular particles, and apoptotic cells. Finally, we demonstrated Fcγ receptor recognition and phagocytosis of opsonized lymphoma cells in an antibody-dependent manner. Overall, we have established an engineered protein that, as a single factor, is useful for large-scale ex vivo production of human phagocytes. Such adjustable proteins have the potential to be applied as molecular tools to produce functional immune cells for experimental cell-based approaches.

Inhibition of de novo ceramide synthesis by Sirtuin-1 improves beta-cell function and glucose metabolism in type 2 diabetes.

BACKGROUND: Obesity and type 2 diabetes (T2D) are major risk factors for cardiovascular diseases (CVD). Dysregulated pro-apoptotic ceramide synthesis reduces ß-cell insulin secretion, thereby promoting hyperglycemic states which may manifest as T2D. Pro-apoptotic ceramides modulate insulin sensitivity and glucose tolerance while being linked to poor cardiovascular outcomes. Sirtuin-1 (SIRT1) is a NAD + - dependent deacetylase that protects against pancreatic ß-cell dysfunction; however, systemic levels are decreased in obese T2D mice and may promote pro-apoptotic ceramide synthesis and hyperglycemia. Herein, we aimed to assess the effects of restoring circulating SIRT1 levels to prevent metabolic imbalance in obese and diabetic mice. METHODS AND RESULTS: Circulating SIRT1 levels were reduced in obese diabetic mice (db/db) as compared to age-matched non-diabetic db/+ controls. Restoration of SIRT1 plasma levels with recombinant murine SIRT1 for 4-weeks prevented body weight gain, improved glucose tolerance, insulin sensitivity and vascular function in mice models of obesity and T2D. Untargeted lipidomics revealed that SIRT1 restored insulin-secretory function of ß-cells by reducing synthesis and accumulation of pro-apoptotic ceramides. Molecular mechanisms involved direct binding to and deacetylation of Toll-like receptor 4 (TLR4) by SIRT1 in ß-cells thereby decreasing the rate limiting enzymes of sphingolipid synthesis SPTLC1/2 via AKT/NF-κB. Among T2D patients, those with high baseline plasma levels of SIRT1 prior to metabolic surgery displayed restored ß-cell function (HOMA2- ß) and were more likely to have T2D remission during follow-up. CONCLUSION: Acetylation of TLR4 promotes ß-cell dysfunction via ceramide synthesis in T2D, which is blunted by systemic SIRT1 replenishment. Hence, restoration of systemic SIRT1 may provide a novel therapeutic strategy to counteract toxic ceramide synthesis and mitigate cardiovascular complications of T2D.

Percutaneous transcatheter aspiration of pulmonary embolism leading to diagnosis of hepatocellular carcinoma tumor embolus and change in systemic chemotherapy.

The management of metastatic hepatocellular carcinoma (HCC) is complex, particularly when complicated by pulmonary embolism. In these cases, atezolizumab-bevacizumab therapy is contraindicated due to an elevated risk of thromboembolic events. Differentiating pulmonary tumor embolism from thromboembolic disease is diagnostically challenging. This report outlines the benefit of transcatheter aspiration to obtain pathological evidence of pulmonary artery tumor embolus in an HCC patient. The intervention enabled a significant shift in the management strategy, leading to an escalation of systemic HCC therapy. This case underscores the importance of precise diagnostic techniques such as transcatheter aspiration in guiding treatment decisions, particularly in cases where pulmonary embolism may signify an underlying malignancy-driven process.

Microstructure predicts non-motor outcomes following deep brain stimulation in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) effectively treats motor and non-motor symptoms in advanced Parkinson's disease (PD). As considerable interindividual variability of outcomes exists, neuroimaging-based biomarkers, including microstructural metrics, have been proposed to anticipate treatment response. In this prospective open-label study, we sought to detect microstructural properties of brain areas associated with short-term non-motor outcomes following STN-DBS. Thirty-seven PD patients underwent diffusion MRI and clinical assessments at preoperative baseline and 6-month follow-up. Whole brain voxel-wise analysis assessed associations between microstructural metrics and non-motor outcomes. Intact microstructure within specific areas, including the right insular cortex, right putamen, right cingulum, and bilateral corticospinal tract were associated with greater postoperative improvement of non-motor symptom burden. Furthermore, microstructural properties of distinct brain regions were associated with postoperative changes in sleep, attention/memory, urinary symptoms, and apathy. In conclusion, diffusion MRI could support preoperative patient counselling by identifying patients with above- or below-average non-motor responses.

Immunohistochemistry as a Reliable Tool for the Diagnosis of Cystic Echinococcosis in Patients from Sardinia, Italy-A Confirmatory Study.

Cystic Echinococcosis (CE) is a zoonotic disease caused by the larval stage of the tapeworm Echinococcus granulosus sensu lato (s.l.). This study aims to investigate the use of two monoclonal antibodies (mAbEmG3 and mAbEm2G11) by immunohistochemistry (IHC) to confirm the diagnosis of CE in human patients, in particular in those cases in which other techniques fail to provide a correct or conclusive diagnosis. For this purpose, a survey on 13 patients was performed. These subjects were referred to Sardinian hospitals (Italy) from 2017 to 2022 and were suspected to be affected by CE. Our findings from these 13 patients showed the detection of E. granulosus sensu stricto by IHC in 12 of 13 echinococcal cysts, as one sample was of a non-parasitological origin. The results confirmed that IHC, by means of the mAbEmG3 and mAbEm2G11, is a reliable diagnostic tool that showed a very high performances when tested on strain of E. granulosus s.l. from Sardinia.

Molecular subgroups of T-cell acute lymphoblastic leukemia in adults treated according to pediatric-based GMALL protocols.

In contrast to B-cell precursor acute lymphoblastic leukemia (ALL), molecular subgroups are less well defined in T-lineage ALL. Comprehensive studies on molecular T-ALL subgroups have been predominantly performed in pediatric ALL patients. Currently, molecular characteristics are rarely considered for risk stratification. Herein, we present a homogenously treated cohort of 230 adult T-ALL patients characterized on transcriptome, and partly on DNA methylation and gene mutation level in correlation with clinical outcome. We identified nine molecular subgroups based on aberrant oncogene expression correlating to four distinct DNA methylation patterns. The subgroup distribution differed from reported pediatric T-ALL cohorts with higher frequencies of prognostic unfavorable subgroups like HOXA or LYL1/LMO2. A small subset (3%) of HOXA adult T-ALL patients revealed restricted expression of posterior HOX genes with aberrant activation of lncRNA HOTTIP. With respect to outcome, TLX1 (n = 44) and NKX2-1 (n = 4) had an exceptionally favorable 3-year overall survival (3y-OS) of 94%. Within thymic T-ALL, the non TLX1 patients had an inferior but still good prognosis. To our knowledge this is the largest cohort of adult T-ALL patients characterized by transcriptome sequencing with meaningful clinical follow-up. Risk classification based on molecular subgroups might emerge and contribute to improvements in outcome.

Associations between brain morphology, inflammatory markers and symptoms of fatigue, depression or anxiety in active and remitted Crohn's disease.

BACKGROUND: Fatigue and psychosocial impairments are highly prevalent in IBD, especially during active disease. Disturbed brain-gut-interactions may contribute to these symptoms. This study examined associations between brain structure, faecal calprotectin and symptoms of fatigue, depression and anxiety in persons with Crohn's Disease (CD) in different disease states. METHODS: In this prospective observational study, n=109 participants (n=67 persons with CD, n=42 healthy controls) underwent cranial magnetic resonance imaging, provided stool samples for analysis of faecal calprotectin and completed questionnaires to assess symptoms of fatigue, depression and anxiety. We analysed differences in grey matter volume (GMV) between patients and controls and associations between regional GMV alterations, neuropsychiatric symptoms and faecal calprotectin. RESULTS: Symptoms of fatigue, depression and anxiety were increased in patients with CD compared to controls, with highest scores in active CD. Patients exhibited regionally reduced GMV in cortical and subcortical sensorimotor regions, occipitotemporal and medial frontal areas. Regional GMV differences showed a significant negative association with fatigue, but not with depression or anxiety. Subgroup analyses revealed symptom-GMV-associations for fatigue in remitted, but not in active CD, while fatigue was positively associated with faecal calprotectin in active, but not remitted disease. CONCLUSION: Our findings support disturbed brain-gut-interactions in CD which may be particularly relevant for fatigue during remitted disease. Reduced GMV in the precentral gyrus and other sensorimotor areas could reflect key contributions to fatigue pathophysiology in CD. A sensorimotor model of fatigue in CD could also pave the way for novel treatment approaches.