Early Alterations Research Articles

FORCED OSCILLATION TECHNIQUE (FOT) – A NOVEL METHOD FOR THE DETECTION OF EARLY AIRWAY CHANGES

According to the World Health Organization in 2019 chronic obstructive pulmonary disease (COPD) was the third leading cause of death worldwide, causing more than 3 million deaths whereas bronchial asthma affected more than 250 million people and caused 455 000 deaths. Both diseases are chronic obstructive conditions which need to be diagnosed early in order to prevent or slow down the complications. Consequently the world requires new effortless methods for diagnosis of airway obstructions, especially for small children and people who cannot perform the spirometry maneuver. The purpose of this report is to describe the objectives of the forced oscillation technique (FOT) and to establish its applications in the clinical practice. Studies and clinical cases regarding pulmonary function testing are summarized and analyzed. They are found in the following databases - PubMed, Google Scholar and Science Direct. Spirometry is the ‘gold standard’ for the diagnosis of airflow obstruction but it requires effort and can be difficult for patients to perform. Forced oscillation technique (FOT) on the other hand is a relatively new method that may hold the key to identifying smoking-related respiratory early alterations and childhood asthma. FOT requires tidal breathing while applying external, small amplitude oscillations in order to determine the response of the respiratory system. Therefore, it is easy for pre-school children to perform. The benefit of FOT should be taken into account for patients who cannot perform spirometry or other pulmonary function ttests. The minimal cooperation of the patient and the easy tidal breathing maneuvers make this method a great option for every pulmonologist. Compared to spirometry this technique may be more sensitive in the detection of disturbances of the peripheral airways and may be effective for the control of therapy at a long term. The Forced oscillation technique has been successfully applied in many pediatric respiratory disorders, such as asthma, cystic fibrosis, and chronic lung disease. Considering these qualities FOT may be used as an alternative of spirometry in heterogenous ventilatory disturbances of the small airways.

Modulation of early osteoarthritis by tibiofemoral re-alignment in sheep

ObjectiveTo investigate whether tibiofemoral alignment influences early knee osteoarthritis (OA). We hypothesized that varus overload exacerbates early degenerative osteochondral changes, and that valgus underload diminishes early OA. MethodNormal, over- and underload were induced by altering alignment via high tibial osteotomy in adult sheep (n = 8 each). Simultaneously, OA was induced by partial medial anterior meniscectomy. At 6 weeks postoperatively, OA was examined in five individual subregions of the medial tibial plateau using Kellgren-Lawrence grading, quantification of macroscopic OA, semiquantitative histopathological OA and immunohistochemical type-II collagen, ADAMTS-5, and MMP-13 scoring, biochemical determination of DNA and proteoglycan contents, and micro-computed tomographic evaluation of the subchondral bone. ResultsMultivariate analyses revealed that OA cartilaginous changes had a temporal priority over subchondral bone changes. Underload inhibited early cartilage degeneration in a characteristic topographic pattern (P ≥ 0.0983 vs. normal), in particular below the meniscal damage, avoided alterations of the subarticular spongiosa (P ≥ 0.162 vs. normal), and prevented the disturbance of otherwise normal osteochondral correlations. Overload induced early alterations of the subchondral bone plate microstructure towards osteopenia, including significantly decreased percent bone volume and increased bone surface–to–volume ratio (all P ≤ 0.0359 vs. normal). ConclusionThe data provide high-resolution evidence that tibiofemoral alignment modulates early OA induced by a medial meniscus injury in adult sheep. Since underload inhibits early OA, these data also support the clinical value of strategies to reduce the load in an affected knee compartment to possibly decelerate structural OA progression.

Glucose tolerance and insulin resistance/sensitivity associate with retinal layer characteristics: the LIFE-Adult-Study

Aims/hypothesisAs the prevalence of insulin resistance and glucose intolerance is increasing throughout the world, diabetes-induced eye diseases are a global health burden. We aim to identify distinct optical bands which are closely related to insulin and glucose metabolism, using non-invasive, high-resolution spectral domain optical coherence tomography (SD-OCT) in a large, population-based dataset.MethodsThe LIFE-Adult-Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. Cross-sectional, standardised phenotyping included the assessment of various metabolic risk markers and ocular imaging, such as SD-OCT-derived thicknesses of ten optical bands of the retina. Global and Early Treatment Diabetic Retinopathy Study (ETDRS) subfield-specific optical retinal layer thicknesses were investigated in 7384 healthy eyes of 7384 participants from the LIFE-Adult-Study stratified by normal glucose tolerance, prediabetes (impaired fasting glucose and/or impaired glucose tolerance and/or HbA1c 5.7–6.4% [39–47 mmol/mol]) and diabetes. The association of optical retinal band characteristics with different indices of glucose tolerance (e.g. fasting glucose, area under the glucose curve), insulin resistance (e.g. HOMA2-IR, triglyceride glucose index), or insulin sensitivity (e.g. estimated glucose disposal rate [eGDR], Stumvoll metabolic clearance rate) was determined using multivariable linear regression analyses for the individual markers adjusted for age, sex and refraction. Various sensitivity analyses were performed to validate the observed findings.ResultsIn the study cohort, nine out of ten optical bands of the retina showed significant sex- and glucose tolerance-dependent differences in band thicknesses. Multivariable linear regression analyses revealed a significant, independent, and inverse association between markers of glucose intolerance and insulin resistance (e.g. HOMA2-IR) with the thickness of the optical bands representing the anatomical retinal outer nuclear layer (ONL, standardised β=−0.096; p<0.001 for HOMA2-IR) and myoid zone (MZ; β=−0.096; p<0.001 for HOMA2-IR) of the photoreceptors. Conversely, markers of insulin sensitivity (e.g. eGDR) positively and independently associated with ONL (β=0.090; p<0.001 for eGDR) and MZ (β=0.133; p<0.001 for eGDR) band thicknesses. These global associations were confirmed in ETDRS subfield-specific analyses. Sensitivity analyses further validated our findings when physical activity, neuroanatomical cell/tissue types and ETDRS subfield categories were investigated after stratifying the cohort by glucose homeostasis.Conclusions/interpretationAn impaired glucose homeostasis associates with a thinning of the optical bands of retinal ONL and photoreceptor MZ. Changes in ONL and MZ thicknesses might predict early metabolic retinal alterations in diabetes.Graphical

Early Impairment of Paracrine and Phenotypic Features in Resident Cardiac Mesenchymal Stromal Cells after Thoracic Radiotherapy.

Radiotherapy-induced cardiac toxicity and consequent diseases still represent potential severe late complications for many cancer survivors who undergo therapeutic thoracic irradiation. We aimed to assess the phenotypic and paracrine features of resident cardiac mesenchymal stromal cells (CMSCs) at early follow-up after the end of thoracic irradiation of the heart as an early sign and/or mechanism of cardiac toxicity anticipating late organ dysfunction. Resident CMSCs were isolated from a rat model of fractionated thoracic irradiation with accurate and clinically relevant heart dosimetry that developed delayed dose-dependent cardiac dysfunction after 1 year. Cells were isolated 6 and 12 weeks after the end of radiotherapy and fully characterized at the transcriptional, paracrine, and functional levels. CMSCs displayed several altered features in a dose- and time-dependent trend, with the most impaired characteristics observed in those exposed in situ to the highest radiation dose with time. In particular, altered features included impaired cell migration and 3D growth and a and significant association of transcriptomic data with GO terms related to altered cytokine and growth factor signaling. Indeed, the altered paracrine profile of CMSCs derived from the group at the highest dose at the 12-week follow-up gave significantly reduced angiogenic support to endothelial cells and polarized macrophages toward a pro-inflammatory profile. Data collected in a clinically relevant rat model of heart irradiation simulating thoracic radiotherapy suggest that early paracrine and transcriptional alterations of the cardiac stroma may represent a dose- and time-dependent biological substrate for the delayed cardiac dysfunction phenotype observed in vivo.

Extracellular Vesicles and Exosomes in the Control of the Musculoskeletal Health.

The present review will highlight recent reports supporting the relevance of extracellular vesicles to the musculoskeletal system in health and disease. Preserving the health of the musculoskeletal system is important to maintain a good quality of life, and the bone-muscle crosstalk is crucial in this regard. This latter is largely mediated by extracellular vesicles released by the different cell populations residing in muscle and bone, which deliver cargoes, microRNAs, and proteins being the most relevant ones, to target cells. Extracellular vesicles could be exploited as therapeutic tools, in view of their resistance to destruction in the biological fluid and of the possibility to be functionalized according to the need. Extracellular vesicles are recognized as crucial players in the bone-muscle cross-talk. Additional studies however are required to refine their use as biomarkers of early alterations of the musculoskeletal system, and as potential therapeutic tools.

Circulatory levels of lysophosphatidylcholine species in obese adolescents: Findings from cross-sectional and prospective lipidomics analyses

Background and aimsObesity has reached epidemic proportions, emphasizing the importance of reliable biomarkers for detecting early metabolic alterations and enabling early preventative interventions. However, our understanding of the molecular mechanisms and specific lipid species associated with childhood obesity remains limited. Therefore, the aim of this study was to investigate plasma lipidomic signatures as potential biomarkers for adolescent obesity. Methods and resultsA total of 103 individuals comprising overweight/obese (n = 46) and normal weight (n = 57) were randomly chosen from the baseline ORANGE (Obesity Reduction and Noncommunicable Disease Awareness through Group Education) cohort, having been followed up for a median of 7.1 years. Plasma lipidomic profiling was performed using the UHPLC-HRMS method. We used three different models adjusted for clinical covariates to analyze the data. Clustering methods were used to define metabotypes, which allowed for the stratification of subjects into subgroups with similar clinical and metabolic profiles. We observed that lysophosphatidylcholine (LPC) species like LPC.16.0, LPC.18.3, LPC.18.1, and LPC.20.3 were significantly (p < 0.05) associated with baseline and follow-up BMI in adolescent obesity. The association of LPC species with BMI remained consistently significant even after adjusting for potential confounders. Moreover, applying metabotyping using hierarchical clustering provided insights into the metabolic heterogeneity within the normal and obese groups, distinguishing metabolically healthy individuals from those with unhealthy metabolic profiles. ConclusionThe specific LPC levels were found to be altered and increased in childhood obesity, particularly during the follow-up. These findings suggest that LPC species hold promise as potential biomarkers of obesity in adolescents, including healthy and unhealthy metabolic profiles.

Knowns and unknowns about the neurobiology of stuttering.

Stuttering occurs in early childhood during a dynamic phase of brain and behavioral development. The latest studies examining children at ages close to this critical developmental period have identified early brain alterations that are most likely linked to stuttering, while spontaneous recovery appears related to increased inter-area connectivity. By contrast, therapy-driven improvement in adults is associated with a functional reorganization within and beyond the speech network. The etiology of stuttering, however, remains enigmatic. This Unsolved Mystery highlights critical questions and points to neuroimaging findings that could inspire future research to uncover how genetics, interacting neural hierarchies, social context, and reward circuitry contribute to the many facets of stuttering.

Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights.

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous invivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.

Cannabidiol Exposure During Gestation Leads to Adverse Cardiac Outcomes Early in Postnatal Life in Male Rat Offspring.

Introduction: Studies indicate that ∼7% of pregnant individuals in North America consume cannabis in pregnancy. Pre-clinical studies have established that maternal exposure to Δ9-tetrahydrocannabinol (THC; major psychoactive component in cannabis) leads to fetal growth restriction and impaired cardiac function in offspring. However, the effects of maternal exposure to cannabidiol (CBD; major non-euphoric constituent) on cardiac outcomes in offspring remain unknown. Therefore, our objective is to investigate the functional and underlying molecular impacts in the hearts of offspring exposed to CBD in pregnancy. Methods: Pregnant Wistar rats were exposed to either 3 or 30 mg/kg CBD or vehicle control i.p. daily from gestational day 6 to term. Echocardiography was used to assess cardiac function in male and female offspring at postnatal day (PND) 21. Furthermore, quantitative polymerase chain reaction (qPCR), immunoblotting, and bulk RNA-sequencing (RNA-seq) were performed on PND21 offspring hearts. Results: Despite no differences in the heart-to-body weight ratio, both doses of CBD led to reduced cardiac function exclusively in male offspring at 3 weeks of age. Underlying this, significant alterations in the expression of the endocannabinoid system (ECS; e.g., decreased cannabinoid receptor 2) were observed. In addition, bulk RNA-seq data demonstrated transcriptional pathways significantly enriched in mitochondrial function/metabolism as well as development. Conclusion: Collectively, we demonstrated for the first time that gestational exposure to CBD, a constituent perceived as safe, leads to early sex-specific postnatal cardiac deficits and alterations in the cardiac ECS in offspring.

Waveform-based classification of dentate spikes.

Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimer's disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing.

Neural Correlates of Early-Life Urbanization and Their Spatial Relationships with Gene Expression, Neurotransmitter, and Behavioral Domain Atlases.

Previous neuroimaging research has established associations between urban exposure during early life and alterations in brain function and structure. However, the molecular mechanisms and behavioral relevance of these associations remain largely unknown. Here, we aimed to address this question using a combined analysis of multimodal data. Initially, we calculated amplitude of low-frequency fluctuations (ALFF) and gray matter volume (GMV) using resting-state functional and structural MRI to investigate their associations with early-life urbanization in a large sample of 511 healthy young adults. Then, we examined the spatial relationships of the identified neural correlates of early-life urbanization with gene expression, neurotransmitter, and behavioral domain atlases. Results showed that higher early-life urbanization scores were correlated with increased ALFF of the right fusiform gyrus and decreased GMV of the left dorsal medial prefrontal cortex and left precuneus. Remarkably, the identified neural correlates of early-life urbanization were spatially correlated with expression of gene categories primarily involving immune system process, signal transduction, and cellular metabolic process. Concurrently, there were significant associations between the neural correlates and specific neurotransmitter systems including dopamine, acetylcholine, and serotonin. Finally, we found that the ALFF correlates were associated with behavioral terms including "perception," "sensory," "cognitive control," and "reasoning." Apart from expanding existing knowledge of early-life urban environmental risk for mental disorders and health in general, our findings may contribute to an emerging framework for integrating social science, neuroscience, genetics, and public policy to respond to the major health challenge of world urbanization.

Characteristics and control factors of feldspar dissolution in gravity flow sandstone of Chang 7 Member, Triassic Yanchang Formation, Ordos Basin, NW China

To clarify the formation and distribution of feldspar dissolution pores and predict the distribution of high-quality reservoir in gravity flow sandstone of the 7th member of Triassic Yanchang Formation (Chang 7 Member) in the Ordos Basin, thin sections, scanning electron microscopy, energy spectrum analysis, X-ray diffraction whole rock analysis, and dissolution experiments are employed in this study to investigate the characteristics and control factors of feldspar dissolution pores. The results show that: (1) Three types of diagenetic processes are observed in the feldspar of Chang 7 sandstone in the study area: secondary overgrowth of feldspar, replacement by clay and calcite, and dissolution of detrital feldspar. (2) The feldspar dissolution of Chang 7 tight sandstone is caused by organic acid, and is further affected by the type of feldspar, the degree of early feldspar alteration, and the buffering effect of mica debris on organic acid. (3) Feldspars have varying degrees of dissolution. Potassium feldspar is more susceptible to dissolution than plagioclase. Among potassium feldspar, orthoclase is more soluble than microcline, and unaltered feldspar is more soluble than early kaolinized or sericitized feldspar. (4) The dissolution experiment demonstrated that the presence of mica can hinder the dissolution of feldspar. Mica of the same mass has a significantly stronger capacity to consume organic acids than feldspar. (5) Dissolution pores in feldspar of Chang 7 Member are more abundant in areas with low mica content, and they improve the reservoir physical properties, while in areas with high mica content, the number of feldspar dissolution pores decreases significantly.

Immune regulation and blood–brain barrier permeability in cerebral small vessel disease: study protocol of the INflammation and Small Vessel Disease (INSVD) study – a multicentre prospective cohort study

IntroductionThe INflammation and Small Vessel Disease (INSVD) study aims to investigate whether peripheral inflammation, immune (dys)regulation and blood–brain barrier (BBB) permeability relate to disease progression in cerebral small vessel disease...

Predictive value of cerebrovascular time constant for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

Time constant of the cerebral arterial bed (τ) is a transcranial Doppler (TCD) based metric that is expected to quantify the transit time of red blood cells from the insonation point to the arteriole-capillary boundary during a cardiac cycle. This study aims to assess the potential of τ as an early predictor of delayed cerebral ischemia (DCI). Consecutive patients (56 ± 15 years) treated for aneurysmal subarachnoid haemorrhage were included in the study. τ was assessed through a modelling approach that involved simultaneous recordings of arterial blood pressure and cerebral blood flow velocity (CBFV) from TCD's first recordings. 71 patients were included. 17 patients experienced DCI. τ was significantly shorter in patients who later developed DCI: 187 ± 64 ms vs. 249 ± 184 ms; p = 0.040 with moderate effect size (rG = 0.24). Logistic regression showed that there was a significant association between increased CBFV, shortened τ, and the development of DCI (χ2 = 11.54; p = 0.003) with AUC for the model 0.75. Patients who had both shortened τ and increased CBFV were 20 times more likely to develop DCI (OR = 20.4 (2.2–187.7)). Our results suggest that early alterations in τ are associated with DCI after aSAH. The highest performance of the model including both CBFV and τ may suggest the importance of both macrovascular and microvascular changes assessment.

Small noncoding RNAs and sperm nuclear basic proteins reflect the environmental impact on germ cells

BackgroundMolecular techniques can complement conventional spermiogram analyses to provide new information on the fertilizing potential of spermatozoa and to identify early alterations due to environmental pollution.MethodsHere, we present a multilevel molecular profiling by small RNA sequencing and sperm nuclear basic protein analysis of male germ cells from 33 healthy young subjects residing in low and high-polluted areas.ResultsAlthough sperm motility and sperm concentration were comparable between samples from the two sites, those from the high-pollution area had a higher concentration of immature/immune cells, a lower protamine/histone ratio, a reduced ability of sperm nuclear basic proteins to protect DNA from oxidative damage, and an altered copper/zinc ratio in sperm. Sperm levels of 32 microRNAs involved in intraflagellar transport, oxidative stress response, and spermatogenesis were different between the two areas. In parallel, a decrease of Piwi-interacting RNA levels was observed in samples from the high-polluted area.ConclusionsThis comprehensive analysis provides new insights into pollution-driven epigenetic alterations in sperm not detectable by spermiogram.Graphical

Diagnosis and Treatment of Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory condition primarily affecting the axial bone and sacroiliac joints. Its etiology is complicated and involves genetic variables, demographic factors (age of onset, gender, ethnicity, family history), and environmental variables. It typically manifests in males in their third decade. Galen is credited with first recognizing it, according to historical traditions, but it was not until the 19th century that specific diagnostic criteria were developed. The human leukocyte antigen B27 (HLA-B27) variation, around 20% of the genetic risk, is currently the most significant gene associated with AS susceptibility. Over 100 genes have been connected to AS susceptibility. Clinical signs of AS include stiffness and inflammation in the back, eye inflammation, aortitis (inflammation of the aorta), and spinal ankylosis that impacts posture and fatigue. The dagger sign and sacroiliitis on radiographs, in particular, are crucial for diagnosis. Early inflammatory alterations can be found using modern diagnostic tools such as MRI, and the HLA-B27 gene can help confirm the diagnosis. Overall, 80-95% of people with AS have the HLA-B27 marker. Furthermore, although non-specific, elevated inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate, offer supporting evidence. Over time, treatment paradigms have seen significant change. First-line treatments such as non-steroidal anti-inflammatory drugs are no longer the only options, even though disease-modifying anti-rheumatic drugs and biologics, especially tumor necrosis factor blockers, have been developed. Physical therapy, which emphasizes consistent exercise, stretches, and posture maintenance, is extremely helpful in managing AS. Surgical interventions can be required in extreme situations. The significance of the interleukin 23/17 axis in the disease cascade has been demonstrated by recent research. Furthermore, a deeper comprehension of the genetic landscape, mainly the functions of non-HLA-B27 loci, may open the door for more specialized therapies. Early diagnosis and interdisciplinary therapies can improve patient outcomes and quality of life as our understanding of AS grows.

Longitudinal MRI and 1H-MRS study of SCA7 mouse forebrain reveals progressive multiregional atrophy and early brain metabolite changes indicating early neuronal and glial dysfunction.

SpinoCerebellar Ataxia type 7 (SCA7) is an inherited disorder caused by CAG triplet repeats encoding polyglutamine expansion in the ATXN7 protein, which is part of the transcriptional coactivator complex SAGA. The mutation primarily causes neurodegeneration in the cerebellum and retina, as well as several forebrain structures. The SCA7140Q/5Q knock-in mouse model recapitulates key disease features, including loss of vision and motor performance. To characterize the temporal progression of brain degeneration of this model, we performed a longitudinal study spanning from early to late symptomatic stages using high-resolution magnetic resonance imaging (MRI) and in vivo 1H-magnetic resonance spectroscopy (1H-MRS). Compared to wild-type mouse littermates, MRI analysis of SCA7 mice shows progressive atrophy of defined brain structures, with the striatum, thalamus and cortex being the first and most severely affected. The volume loss of these structures coincided with increased motor impairments in SCA7 mice, suggesting an alteration of the sensory-motor network, as observed in SCA7 patients. MRI also reveals atrophy of the hippocampus and anterior commissure at mid-symptomatic stage and the midbrain and brain stem at late stage. 1H-MRS of hippocampus, a brain region previously shown to be dysfunctional in patients, reveals early and progressive metabolic alterations in SCA7 mice. Interestingly, abnormal glutamine accumulation precedes the hippocampal atrophy and the reduction in myo-inositol and total N-acetyl-aspartate concentrations, two markers of glial and neuronal damage, respectively. Together, our results indicate that non-cerebellar alterations and glial and neuronal metabolic impairments may play a crucial role in the development of SCA7 mouse pathology, particularly at early stages of the disease. Degenerative features of forebrain structures in SCA7 mice correspond to current observations made in patients. Our study thus provides potential biomarkers that could be used for the evaluation of future therapeutic trials using the SCA7140Q/5Q model.

Abstract A041: Characterizing antigen presentation associated immune escape mechanisms in pancreatic adenocarcinoma using an integrative computational approach

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal neoplasm of the pancreas characterized by a low survival rate and limited treatment options. Despite the success of immunotherapy in various cancer types, its efficacy in PDAC remains low. The underlying reasons for this discrepancy are not fully understood, despite PDAC exhibiting a moderate mutation burden. One possible determinant could be the loss of heterozygosity (LOH) at the human leukocyte antigen (HLA) loci, resulting in compromised antigen presentation. In this work, we aim to identify and validate HLA LOH events in two independent cohorts to gain insights into both their prevalence and clinical and phenotypic impact on PDAC. Methods: We applied LOHHLA, a specialized pipeline to identify HLA LOH events from paired whole genome sequencing to two independent cohorts comprising over 650 patients. We contextualized these results with the paired transcriptome-wide gene expression data and immunohistochemistry stains. In addition, we developed a machine learning classifier to predict HLA LOH from transcriptomic data. We transfer this classifier to single cell RNA sequencing data to identify the impact of (subclonal) HLA LOH on the tumor microenvironment. Results: HLA LOH events occur in approximately 30% of PDAC patients, with about 50% of these deletions being focal deletions. These events are early genetic alterations and lead to a dosage compensation of the retained HLA genes. We observed a significant association between HLA LOH and the Basal PDAC expression subtype. In addition, we find that HLA expression is the most important determinant of lymphocyte infiltration followed by non-LOH at the HLA locus. Moreover, our transcriptomic classifier allowed us to accurately identify HLA LOH events from RNA sequencing data, which we successfully validated in an independent cohort. Finally, we applied this classifier to single cell sequencing data and identified phenotypic differences in multiple compartments of the tumor microenvironment between samples with intact HLA and HLA LOH. Conclusions: In conclusion, our study provides the most in depth characterization of the consequences of altered antigen presentation in PDAC to date. We have demonstrated that HLA LOH occurs in a substantial proportion of patients. Overall, these findings contribute to a better understanding of the immune landscape in PDAC and may have implications for the development of immunotherapeutic strategies tailored to this challenging cancer type. Citation Format: Michael J. Geuenich, Barbara Gruenwald, Amy Zhang, Oumaima Hamza, Gun Ho Jang, Grainne O’Kane, Faiyaz Notta, Steven Gallinger, Kieran R. Campbell. Characterizing antigen presentation associated immune escape mechanisms in pancreatic adenocarcinoma using an integrative computational approach [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A041.

Early remodeling and loss of light-induced dilation of retinal small arteries in CADASIL

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1–2 μm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity.

Anthracycline-induced cardiotoxicity on regional myocardial work and left ventricular mechanical dispersion in adolescents and young adults in post-lymphoma remission.

Myocardial work (MW) is a new echocardiographic tool with a high sensitivity to detect early and subtle alterations of myocardial function. We aimed to evaluate the late effects of anthracyclines by assessing the global and segmental MW and intraventricular mechanical dispersion from speckle tracking echocardiography in childhood lymphoma survivors (CLS). Thirty-one young adults including CLS and age-matched healthy controls were enrolled. All underwent echocardiography including an evaluation of left ventricular (LV) morphology and regional function. We assessed LV longitudinal (differentiating sub-endocardial and sub-epicardial layers), circumferential strains and twist, global and regional MW index (MWI). LV mechanical dispersion was assessed from the time dispersion of LV longitudinal strain, from myocardial wasted work (MWW) and myocardial work efficiency (MWE). The longitudinal strains both at the level of the sub-endocardium and sub-epicardium were reduced in CLS compared to controls. The global MWI was also decreased (1668 ± 266 vs 1870 ± 264%.mmHg in CLS patients and controls, respectively, p < 0.05), especially on the apical segments. An increase of LV intraventricular mechanical dispersion was observed in CLS. MWW and MWE remained unchanged compared to controls. Our results strongly support that cardiac remodeling is observed in CLS, characterized by a decrease in MW and an increase in LV mechanical dispersion. The apex is specifically altered, but its clinical significance remains uncertain. MW as a complement to strain seems interesting in cancer survivors to detect myocardial dysfunction at early stage and adapt their follow-up.