Specific Profile Research Articles

Early Communicative Development in Williams Syndrome: A Longitudinal Case Study.

Individuals with Williams Syndrome (WS) have a specific and atypical neuropsychological profile, where language is above what is expected for their mental age, although it shows a late onset. There exists only one longitudinal study in infants younger than 20 months old with WS about early language precursors (joint attention, referential and instrumental behaviors, pointing gesture, verbal tags). The aim of this investigation is to evaluate these precursors in a baby with WS (8 to 18 months). Seven sessions of systematic observation were performed (six at baby's home, one at the Early Childhood Assistance center). The Battelle Developmental Inventory was used to evaluate the baby's development in two occasions (12 and 18 months). The results show an atypical development, and he is 5-6 months under what is expected for his chronological age. Attention towards objects prevails over preference for faces, but this one tends to increase. The pointing gesture does not emerge at the end of the observation period and therefore follows the first words that appear. The implications for the comprehension of the early linguistic profile in WS are discussed, as well as the implications for specific intervention strategies in the context of early childhood care.

Prediction of effective size of a propagated laser beam with a known phase profile and its experimental validation

In this paper we demonstrate that the size of a laser beam, which increases with propagation due to diffraction induced divergence, carrying a given phase profile, can be predicted and the same can be validated experimentally. Since an arbitrary phase profile is also a linear combination of a set of Zernike polynomials hence the divergence corresponding to each Zernike mode can be utilized to estimate the effective size of the beam carrying the arbitrary phase profile. Numerical simulation using the scalar diffraction theory shows how a laser beam with a certain Zernike mode describing its phase profile diverges. Observations from numerical simulations lead to construction of a functional form that can predict the effective size of a laser beam carrying a specific Zernike mode in its phase profile, at different propagation distances. In this paper we develop an experimental arrangement to holographically incorporate a specific phase profile into an incident laser beam. We utilize the programmable control of the beam size for a given propagation distance to achieve different Fresnel numbers. We further develop a detector assembly which can be used to measure the effective size of the beam in the observation plane. We then show experimentally that the effective size of a laser beam propagating distances corresponding to different Fresnel numbers and carrying a known phase profile, described either by a single Zernike mode or a random combination of several Zernike modes, can be very well predicted by the functional form even in a realistic scenario.

Effect of recycled powder and gear profile into the functionality of additive manufacturing polymer gears

PurposePolymer laser powder bed fusion (PBF-LB/P) is an additive manufacturing technology that is sustainable due to the possibility of recycling the powder multiple times and allowing the fabrication of gears without the aid of support structures and subsequent assembly. However, there are constraints in the process that negatively affect its adoption compared to other additive technologies such as material extrusion to produce gears. This study aims to demonstrate that it is possible to overcome the problems due to the physics of the process to produce accurate mechanism.Design/methodology/approachTechnological aspects such as orientation, wheel-shaft thicknesses and degree of powder recycling were examined. Furthermore, the evolving tooth profile was considered as a design parameter to provide a manufacturability map of gear-based mechanisms.FindingsResults show that there are some differences in the functioning of the gear depending on the type of powder used, 100% virgin or 50% virgin and 50% recycled for five cycles. The application of a groove on a gear produced with 100% virgin powder allows the mechanism to be easily unlocked regardless of the orientation and wheel-shaft thicknesses. The application of a specific evolutionary profile independent of the diameter of the reference circle on vertically oriented gears guarantees rotation continuity while preserving the functionality of the assembled mechanism.Originality/valueIn the literature, there are various studies on material aging and reuse in the PBF-LB/P process, mainly focused on the powder deterioration mechanism, powder fluidity, microstructure and mechanical properties of the parts and process parameters. This study, instead, was focused on the functioning of gears, which represent one of the applications in which this technology can have great success, by analyzing the two main effects that can compromise it: recycled powder and vertical orientation during construction.

An Examination of the Intersectional Experience of Incarcerated Parents

ABSTRACTData from the 2004 Survey of Inmates in State and Federal Correctional Facilities, consisting of 9,262 incarcerated parents, were used to explore patterns of anger, with a particular focus on understanding the interplay between emotional distress and other predictors of anger among incarcerated parents through the lens of General Strain Theory. Through a conjunctive analysis of case configurations (CACC), results from the current study show that 1) reports of anger cluster moderately among specific situational profiles, which are defined by the unique combination of variable attributes; 2) incarcerated parents most likely to report anger have consistently reported emotional distress, but incarcerated parents least likely to report anger rarely described emotional distress; and 3) incarcerated parents who report emotional distress can increase their chances of reported anger by as much as 12% in some situational contexts, but can have almost no influence on feelings of anger in others. Current findings are discussed considering existing scholarship on the well-being of incarcerated parents and recommendations for policy and future areas of research are offered.

Waldenström Macroglobulinemia: Targeted Agents Taking Center Stage.

With the worldwide approval of the oral covalent Bruton tyrosine kinase (BTK) inhibitors ibrutinib and zanubrutinib for treating patients with Waldenström macroglobulinemia (WM), targeted agents have certainly taken center stage in the therapeutic landscape of WM. This review discusses the biological and clinical data supporting current and up-and-coming targeted agents in WM. Bruton tyrosine kinase inhibitors induce fast, deep, and durable responses in patients with WM, comparable to chemoimmunotherapy; however, there is a glaring absence of comparative studies between these regimens. The high response and progression-free survival rate and the ease of administration of BTK inhibitors must be balanced against their specific adverse-event profile with unique toxicity (e.g., bleeding and cardiac arrhythmia) and the indefinite duration of the therapy. Novel targeted agents of interest include BCL2 antagonists (e.g., venetoclax and sonrotoclax) and non-covalent BTK inhibitors (e.g., pirtobrutinib and nemtabrutinib), among others. The therapeutic landscape of patients with WM will benefit from the robust participation of patients in clinical trials.

UAV Atmosphere Sounding for Rocket Launch Support.

One of the crucial branches of activity at the Łukasiewicz Research Network-Institute of Aviation is developing a suborbital rocket vehicle capable of launching small payloads beyond the Earth's atmosphere, reaching over 100 km in altitude. Ensuring safety is a primary concern, particularly given the finite flight zone and impact area. Crucial to safety analysis is the wind profile, especially in the very first seconds of a flight, when rocket velocity is of the same order as the wind speed. Traditional near-ground wind data sources, ranging from wind towers to numerical models of the atmosphere, have limitations. Wind towers are costly and unfeasible at many test ranges used for launches, while numerical modeling may not reflect the specific ground profile near the launcher due to their large cell size (2 to +10 km). Meteorological balloons are not favorable for such measurements as they aim to provide the launch operator with a wind profile at high altitudes, and are launched only 1-2 times per flight attempt. Our study sought to prototype a wind measurement system designed to acquire near-ground wind profile data. It focuses on measuring wind direction and speed at near-ground altitudes with higher flight frequency, offering data on demand shortly before launch to help ensure safety. This atmosphere sounding system consists of an Unmanned Aerial Vehicle (UAV) equipped with an onboard ultrasonic wind sensor. Some reports in the literature have discussed the possibility of using UAV-borne anemometers, but the topic of measurement errors introduced by placing the anemometer onboard an UAV remains under studied. Limited research in this area underlines the need for experimental validation of design choices-for specific types of UAVs, anemometers, and mounting. This paper presents a literature review, a detailed overview of the prototyped system, and flight test results in both natural (outdoor) and controlled (indoor, no wind) conditions. Data from the UAV system's anemometer was benchmarked against a stationary reference weather station, in order to examine the influence of the UAV's rotor on the anemometer readings. Our findings show a wind speed Root Mean Square Error (RMSE) of 5 m/s and a directional RMSE of below 5.3° (both averaged for 1 min). The results were also compared with similar UAV-based wind measurements. The prototyped system was successfully used in a suborbital rocket launch campaign, thus demonstrating the feasibility of integrating UAVs with dedicated sensors for performing regular meteorological measurements in automatic mode.

Immunophenotypic profile defines cytogenetic stability and unveils distinct prognoses in patients with newly-diagnosed multiple myeloma (NDMM).

Prognostic significance of multiple immune antigens in multiple myeloma has been well established. However, a level of uncertainty remains regarding the intrinsic relationship between immunophenotypes and cytogenetic stability and precise risk stratification. To address these unresolved issues, we conducted a study involving 1389 patients enrolled in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Our results revealed that the correlation between antigen expression and cytogenetics is more prominent than cytopenia or organ dysfunction. Most immune antigens, apart from CD38, CD138, and CD81, exhibit significant associations with the incidence of at least one cytogenetic abnormality. In turn, we identified CD138-low/CD27-neg as specific adverse immunophenotypic profile, which remaining independent impact on progression-free survival (HR, 1.49; P = 0.007) and overall survival (HR, 1.77; P < 0.001) even in the context of cytogenetics. Importantly, CD138-low/CD27-neg profile was also associated with inferior survival after first relapse (P < 0.001). Moreover, the antigen expression profiles were not strictly similar when comparing diagnosis and relapse; in particular, the CD138-low/CD27-neg pattern was notably increased after disease progression (19.1 to 29.1%; P = 0.005). Overall, our study demonstrates that diverse immune profiles are strongly associated with cytogenetic stability, and a specific immunophenotype (CD138-low/CD27-neg) could effectively predict prognoses across different disease stages.

A single atom cobalt anchored MXene bifunctional platform for rapid, label-free and high-throughput biomarker analysis and tissue imaging

Few of single-atom materials have been served as platform to analyze small molecules for surface assisted laser desorption/ionization mass spectrometry (SALDI-MS). Herein, a novel single Co atom-anchored MXene (Co–N–Ti3C2) is prepared to achieve enhanced SALDI-MS and mass spectrometry imaging (MSI) performance for the first time. The Co–N–Ti3C2 films were prepared by a simple in situ self-assembly strategy to generate an efficient SALDI-MS platform. Compared to typical inorganic/organic matrices, Co–N–Ti3C2 films exhibit superior performance in small molecules detection with ultra-high sensitivity (LOD at amol level), excellent repeatability (CV <4%), clean background and wide analyte coverage, enabling accurate quantitative analysis of various low-concentration metabolites from 1 μL biofluid in seconds. Its usage efficiently enhanced SALDI-MS detection of various small-molecule biomarkers such as amino acids, succinic acid, itaconic acid, arachidonic acid, citrulline, prostaglandin E2, creatinine, uric acid, glutamine, D-mannose, cholesterol and inositol in positive ion mode. The blood glucose level in humans was successfully determined from a linearity concentration range (0.25–10 mM). Notably, the Co–N–Ti3C2 assisted SALDI-MSI enables study the spatial distribution of small molecules covering the range central to metabolomics at a high resolution on a tissue section. Furthermore, Co–N–Ti3C2 platform revealed a specific peak profile that distinguishes osteoarthritis (OA) from rheumatoid arthritis (RA) tissue. Density functional theory theoretical investigation revealed that single Co atoms anchored on Ti3C2 could highly enhanced the ionization ability of metabolites, resulting in high-sensitivity and heterogeneous metabolome coverage.

Sex‐specific metabolomics‐derived blood biomarkers of Alzheimer’s disease.

AbstractBackgroundReadily accessible diagnostic tools are crucial for early detection of Alzheimer’s disease (AD). Here, we sought to identify peripheral metabolism biomarkers predicting the presence of AD pathology.MethodUntargeted liquid chromatography‐mass spectrometry was used to quantify 2286 serum metabolites in participants on a longitudinal memory clinic study. Unbiased between‐group analysis using Orthogonal Partial Least Squares Discriminant Analysis, Linear Discriminant analysis and Principal Component Analysis were performed to build a classifier for AD as indicated by CSF biomarkers. MetaboAnalyst was subsequently used for selection of the most relevant metabolites. Pathway enrichment was used to determine biological pathway alterations related to AD.ResultNo biomarker signature of AD was found in the whole cohort. Stratification according to sex allowed building a classifier for AD using 14 serum metabolites in males and 9 in females. Thirteen enriched pathways were identified, including arachidonic acid and tryptophan metabolism (Figure 1). The selected metabolites significantly improved the prediction of cognitive decline in females compared to a reference model (Figure 2, AUC 0.874 vs. 0.719).ConclusionSex specific peripheral metabolism biomarker profiles are useful to predict cerebral AD pathology and cognitive decline, and detect related metabolic alterations. This highlights the need for personalised diagnostic and therapeutic approaches in AD.

Dispersed Relativistic Electron Precipitation Patterns Between the Ion and Electron Isotropy Boundaries

AbstractRelativistic electron precipitation to the Earth's atmosphere is an important loss mechanism of inner magnetosphere electrons, contributing significantly to the dynamics of the radiation belts. Such precipitation may be driven by electron resonant scattering by middle‐latitude whistler‐mode waves at dawn to noon; by electromagnetic ion cyclotron (EMIC) waves at dusk; or by curvature scattering at the isotropy boundary (at the inner edge of the electron plasma sheet anywhere on the nightside, from dusk to dawn). Using low‐altitude ELFIN and near‐equatorial THEMIS measurements, we report on a new type of relativistic electron precipitation that shares some properties with the traditional curvature scattering mechanism (occurring on the nightside and often having a clear energy/L‐shell dispersion). However, it is less common than the typical electron isotropy boundary and it is observed most often during substorms. It is seen equatorward of (and well separated from) the electron isotropy boundary and around or poleward of the ion isotropy boundary (the inner edge of the ion plasma sheet). It may be due to one or more of the following mechanisms: EMIC waves in the presence of a specific radial profile of the cold plasma density; a regional suppression of the magnetic field enhancing curvature scattering locally; and/or electron resonant scattering by kinetic Alfvén waves.

Discriminative power of multi‐PET tracer approach targeting reactive astrogliosis, tau pathology, and dopaminergic impairment in 4R primary tauopathies

AbstractBackgroundThe 4R tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are described as dementias with parkinsonian syndrome. Even if they are proven to represent clinically different entities, their complex neuropathology and common hallmarks often make the differential clinical diagnosis of CBD and PSP challenging. The highly entangled astrocytic and tau pathologies observed in these diseases are however displaying unique disparities which might unravel specific neuropathological profiles for each disease. The multi‐PET tracer approach applied in the present study in postmortem brain tissue might provide new mechanistic insights. We recently demonstrated that the second‐generation tau PET tracer, 3H‐PI2620 had a discriminative potential in CBD, PSP, and Alzheimer’s disease (AD) brains (Malarte et al. Mol. Psychiatry. 2022). To further understand the interaction between tau spatial distribution and its potential effects on astrocytic reactivity, we conducted a comparative multi‐tracer investigation in CBD, PSP, AD, and control brains using novel tau and astrocytic tracers. To gain a deeper insight into the relationship between tau, astrogliosis, and concomitant motor impairments, we also studied the interaction with the dopaminergic system.MethodWe performed autoradiography studies on large frozen hemispherical brain tissue of CBD, PSP, AD, and control cases using the tau PET tracer 3H‐PI2620, in comparison to astrocytic tracers (3H‐BU99008 and 3H‐Deprenyl) and dopaminergic tracers (3H‐Raclopride and 3H‐FE‐PE2I). We also analyzed the regional distribution of these tracers in small adjacent frozen brain sections of pathologically specific brain regions (globus pallidus, putamen, caudate, frontal cortex, medulla oblongata). We also performed saturation studies with 3H‐BU99008 and 3H‐Deprenyl on CBD and PSP brain homogenatesResultOur preliminary results are promising and suggest high astrogliosis measured by 3H‐BU99008 and 3H‐Deprenyl in large frozen autoradiography in CBD and PSP brains, and with different binding intensities in different brain regions comparable with regional 3H‐PI2620 binding. 3H‐BU99008 and 3H‐Deprenyl both highlighted two binding sites in the putamen of CBD cases, but only one site in PSP.ConclusionOngoing multi‐PET tracer studies targeting different pathological hallmarks of CBD and PSP tauopathies will improve differentiation and provide new knowledge regarding the spatial distribution of tau and its correlation with astrogliosis and the dopaminergic system in primary tauopathies.

“Mirror, Mirror, Am I as My Coach Sees Me?”: Discrepancy Between Athlete Self-Appraisals and Reflected Appraisals of Their Coach, and Relations With Athlete Burnout

Using a person-centered approach, this study was conducted to identify (a) specific athlete profiles in terms of degree of discrepancy between their self-appraisals and the reflected appraisals of their coach and (b) the relations between these profiles and athlete burnout. Athletes (N = 369; Mage = 21.15 years) fulfilled measures of self-appraisals, reflected appraisals of their coach, and burnout. Latent profile analysis allowed the identification of three profiles: concordance (84%), positive discrepancy (11%), and negative discrepancy (5%). Analyses revealed relationships between athletes’ profile membership and the three dimensions of burnout: emotional and physical exhaustion, sport devaluation, and reduced sense of accomplishment. More specifically, results indicated that athletes with a positive discrepancy profile (i.e., who rated themselves more positively than they think their coaches see them) were more at risk of burnout. This study contributes to existing research on psychosocial determinants of athlete burnout in the context of the coach–athlete relationship.

Debate 6: Microbiome Testing is Indicated for Implantation Failure in 2023

Motion: For Uninvestigated Recurrent Implantation Failure (RIF) has a significant cost, can waste embryos with the potential for life and leads to empirical therapies such as the use of steroids. Chronic Endometritis (CE) is a known cause of RIF is diagnosed by presence of plasma cells and worsens if steroids suppress the protective immune system response. Identifying plasma cells in endometrial tissue samples requires histological expertise, special staining and there is variation in numbers between tissue sections and microscope fields. Furthermore, culturing bacteria from low biomass environments like the endometrium is difficult and will not identify anaerobes and other fastidious organisms. The molecular technique of sequencing the 16S ribosome enables the identification of microbes that can create a hostile environment for embryos. There is clear evidence that some microbes and microbiome signatures are associated with RIF and that changing the microbiome is associated with higher implantation rates. There are established and emerging treatments for an aberrant microbiome that include antibiotic therapy, probiotics, faecal transplantation, and curettage. The more diagnostic information we can obtain to determine the cause of our patients RIF and then design specific, targeted treatments that are effective, the better their pregnancy outcomes will be. It is useful to test the microbiome and will only become more useful as this technology improves. Motion: Against The microbiome is closely related to women’s reproductive health, and therefore microbiome testing is becoming increasingly important in the field of reproductive medicine, especially in guiding assisted reproduction treatments such as infertility. The human microbiome is a collection of all microorganisms that exist on or within human tissues and fluids, as well as the corresponding anatomical sites where they are located, including the female reproductive tract, gastrointestinal tract, skin, semen, saliva, oral mucous membranes, etc., of which the ones that are most relevant to the study of female infertility mainly include the female reproductive tract flora and gastrointestinal tract flora. Several studies have shown that the composition of the microbiota in the female reproductive tract may affect embryo implantation and pregnancy success. An imbalanced or dysbiased microbiome of the female reproductive tract flora may lead to inflammation, altered immune responses, and hinder the optimal conditions needed for successful embryo implantation. Microbiome Testing can be accomplished through a variety of technologies, such as next-generation sequencing, which allows for a comprehensive analysis of microbial composition. Thus, microbiome testing that involves analyzing the microbial community in the female reproductive tract for imbalance or dysbiosis is a breakthrough point with great potential to aid in the treatment of recurrent implantation failure. For recurrent implantation failures, microbiome testing can help fertility specialists tailor a personalized treatment plan. By understanding an individual’s specific microbial profile, physicians can make informed decisions about potential interventions such as antibiotic therapy, probiotics, or other microbial modulation therapies. Of course, the use of microbiome testing should be carefully considered on a case-by-case basis and should be used in conjunction with other diagnostic tools and assessments to provide optimal treatment for patients with implantation failure.

Discriminative power of multi‐PET tracer approach targeting reactive astrogliosis, tau pathology, and dopaminergic impairment in 4R primary tauopathies

AbstractBackgroundThe 4R tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are described as dementias with parkinsonian syndrome. Even if they are proven to represent clinically different entities, their complex neuropathology and common hallmarks often make the differential clinical diagnosis of CBD and PSP challenging. The highly entangled astrocytic and tau pathologies observed in these diseases are however displaying unique disparities which might unravel specific neuropathological profiles for each disease. The multi‐PET tracer approach applied in the present study in postmortem brain tissue might provide new mechanistic insights. We recently demonstrated that the second‐generation tau PET tracer, 3H‐PI2620 had a discriminative potential in CBD, PSP, and Alzheimer’s disease (AD) brains (Malarte et al. Mol. Psychiatry. 2022). To further understand the interaction between tau spatial distribution and its potential effects on astrocytic reactivity, we conducted a comparative multi‐tracer investigation in CBD, PSP, AD, and control brains using novel tau and astrocytic tracers. To gain a deeper insight into the relationship between tau, astrogliosis, and concomitant motor impairments, we also studied the interaction with the dopaminergic system.MethodWe performed autoradiography studies on large frozen hemispherical brain tissue of CBD, PSP, AD, and control cases using the tau PET tracer 3H‐PI2620, in comparison to astrocytic tracers (3H‐BU99008 and 3H‐Deprenyl) and dopaminergic tracers (3H‐Raclopride and 3H‐FE‐PE2I). We also analyzed the regional distribution of these tracers in small adjacent frozen brain sections of pathologically specific brain regions (globus pallidus, putamen, caudate, frontal cortex, medulla oblongata). We also performed saturation studies with 3H‐BU99008 and 3H‐Deprenyl on CBD and PSP brain homogenatesResultOur preliminary results are promising and suggest high astrogliosis measured by 3H‐BU99008 and 3H‐Deprenyl in large frozen autoradiography in CBD and PSP brains, and with different binding intensities in different brain regions comparable with regional 3H‐PI2620 binding. 3H‐BU99008 and 3H‐Deprenyl both highlighted two binding sites in the putamen of CBD cases, but only one site in PSP.ConclusionOngoing multi‐PET tracer studies targeting different pathological hallmarks of CBD and PSP tauopathies will improve differentiation and provide new knowledge regarding the spatial distribution of tau and its correlation with astrogliosis and the dopaminergic system in primary tauopathies.

Amazonian mixed‐species flocks demonstrate flexible preferences for vertical forest structure

AbstractHow species interact with human‐disturbed environments is a central focus of conservation biology. Within disturbed landscapes, regenerating forests have potential to provide habitat for forest species, especially as increasing amounts of primary forest are lost. As secondary forest regenerates beside primary forest, it increases habitat heterogeneity. However, relatively little is known about the influence of habitat heterogeneity on space use. In this study, we analyzed the topography and vertical vegetation structure of regenerating forest, small forest fragments, and undisturbed rainforest in the central Amazon to determine (1) how these structural characteristics influence understory mixed‐species flock space use and (2) how the vegetative preferences of flocks varied across a disturbance gradient. We first used behavioral observations to quantify the vertical foraging niche of flocks and then associated variation in horizontal space use with the three‐dimensional features of forest structure. Surprisingly, we found that flock space use was not consistently associated with any variable, even though available habitat differed both within and across forest types. Overall, the best predictors were elevation and leaf area density within the subcanopy (16–25 m), yet most flock foraging occurred in the midstory (6–15 m). Together, these results indicate that while flocks may have certain habitat preferences, these preferences are flexible or idiosyncratic and do not correspond to a specific vertical profile. For example, flocks spent a disproportionate amount of time in low elevations when available, but not all flocks had access to low‐lying areas within their home ranges. Although other studies show flock size and diversity can be highly sensitive to habitat disturbance, mixed‐species flocks demonstrate remarkable plasticity as a unit, virtually saturating undisturbed and disturbed forest at our site, as long as regeneration has passed a certain threshold.

Abstract B035: The contribution of inflammasomes and cGAS-STING in RT-induced cell fate

Abstract Radiotherapy (RT) is a curative treatment modality for many solid cancers. Our group has previously demonstrated that activation of the cGAS-STING pathway by RT induces inflammatory cytokine production and subsequent stimulation of anti-tumour immunity in concert with immune checkpoint blockade treatment. We have identified three other proteins that contribute to inflammatory signalling after RT: AIM2 (Absent in Melanoma 2), NLRP3 (NOD-Like Receptor Pyrin Domain-Containing 3), and IFI16 (Interferon Gamma Inducible Protein 16). Each of these proteins contribute to form distinct protein complexes called inflammasomes that, like cGAS-STING, sense cytoplasmic DNA. Little is known about how inflammasome signalling may change after RT, or how inflammasomes may influence RT-ICB induced anti-tumour immunity. We hypothesize that RT induces inflammasome signalling to influence specific gene expression and cytokine profiles, in tandem with alterations in cellular fate with implications for systemic anti-tumour immunity triggered by radiotherapy. We will present ongoing work in which we show that pharmacological or genetic disruption of inflammasomes alters cytokine production post-RT. We also demonstrate that manipulation of cell fate through senolytic therapy or manipulation of caspase activity alters the balance of cytokine production post-RT. Together our data strongly implicates the role of several inflammasome complexes in the response of epithelial cells to RT. Our work will also highlight the possible crosstalk between the cGAS-STING pathway and inflammasome complex pathway, both triggered by RT. Understanding and subsequent manipulation of cell fate, in part through inflammasome and cGAS-STING mediated activity, may be a therapeutic strategy to influence treatment responses, such as anti-tumour immunity, in cancer. Citation Format: Cindy T Ha, Shirony Nicholson-Puthenveedu, Shane M Harding. The contribution of inflammasomes and cGAS-STING in RT-induced cell fate [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B035.

Abstract B029: Targeting phosphodiesterase: A potential strategy to treat LKB1-mutant cancers

Abstract Cancer heterogeneity poses numerous challenges to treatment, underscoring the need for personalized/targeted therapies that align with each patient's specific genetic and molecular disease profile. Metabolic deregulation, often correlating with oncogenic alterations, is commonly observed in cancers. Such deregulation frequently presents metabolic vulnerabilities within the cancer, which could potentially be exploited for targeted therapy. Liver Kinase B1 (LKB1), a protein known for its diverse roles in cellular metabolism and its critical function as a tumor suppressor, ranks as the third most frequently mutated gene in non-small cell lung cancer (NSCLC). LKB1 mutations are linked to accelerated tumor progression and invasion, resulting in adverse clinical outcomes. Our research uncovers a novel role for LKB1 in cyclic nucleotide metabolism, wherein it suppresses a set of phosphodiesterase (PDE) expressions. Specifically, LKB1 represses PDE3 via the activation of the downstream salt-inducible kinase. Our data demonstrate that PDE3 modulators can selectively eliminate LKB1-deficient tumor cells while leaving LKB1-wildtype cells unharmed. However, some LKB1-deficient cells develop resistance due to the loss of SLFN12, whose expression is required for PDE3 modulator-induced cell death. Interestingly, this resistance can be overcome by inducing SLFN12 expression, through either epigenetic inhibitors or cAMP inducers. These findings not only broaden our understanding of the role of LKB1 in metabolic regulation but also suggest a promising strategy for targeted therapy against LKB1-mutant cancers. Citation Format: Catherine Rono, Xiaohu (Mark) Tang. Targeting phosphodiesterase: A potential strategy to treat LKB1-mutant cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B029.

Abstract C004: Liquid biopsy based on the lipid profiles in plasma-derived extracellular vesicles which can be utilized for breast cancer diagnosis

Abstract Lipids are a major component of cells that can influence multiple cellular functions. Our group previously found that the breast cancer cells could dramatically change their lipid profile during their progression. Thus, we hypothesized that the lipid profile of extracellular vesicles (EVs) could be used as a biomarker for breast cancer (BC) since the lipid profiles of breast cancer cells can be reflected in that of EVs secreted from cancer cells. In the present study, we optimized a method to isolate EVs from human plasma samples that could be used for the comprehensive lipid analysis. We then explored specific lipid profiles in plasma-derived EVs that could discriminate BC and healthy individuals, tumor subtypes and stages. Plasma-derived EVs from breast cancer (n = 105), benign (n = 11), and healthy individuals (n = 43) were used for lipid analysis. The results showed that the change in proportion of the lipids in the EVs could well discriminate stages and subtypes of BC. The proportion of major phospholipids, phosphatidylethanolamines, phosphatidylserines, phosphatidylcholines (PCs) and phosphatidylinositols (PIs) showed different patterns at different stages. Importantly, PI (18:0/20:3), which we previously identified as a lipid biomarker of disease progression expressed in the primary breast cancer tissue, showed a similar trend in the plasma-derived EVs. This finding supports our initial hypothesis. Besides the phospholipids, sphingomyelins were found to be higher in stage IV. With regard to tumor subtypes, PCs and ceramides were enriched in HER2-positive subtype, while lysoPCs and polyunsaturated triglycerides were enriched in triple negative subtype. Furthermore, a BC diagnostic model consisting of three lipids was successfully established and the model showed good performance in discriminating between healthy individuals and BC in the two independent data sets (the area under the ROC curve was estimated around 0.759 to 0.804). In conclusion, profiling of lipids in plasma-derived EVs has the potential to be used as a liquid biopsy that can diagnose BC, and its stages and subtypes. Further validation and improvement in EV isolation technique would be needed to achieve sufficient performance sufficient for clinical application. Citation Format: Masahiro Kawashima. Liquid biopsy based on the lipid profiles in plasma-derived extracellular vesicles which can be utilized for breast cancer diagnosis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C004.

What is the Optimum Endometrium Needed for Implantation?

Implantation most critical step in reproduction. A complex process where blastocyst becomes intimately connected with maternal endometrium/decidua and requires; Competent embryo at blastocyst stage Receptive endometrium Synchronized dialogue between maternal and embryonic tissues Endometrial Changes for Implantation include architectural, morphological, cytochemical, molecular and genetic. These Changes Induce Endometrial receptivity, which is endometrial lining in a state of readiness for blastocyst implantation. It involves acquisition of adhesion ligands and loss of inhibitory components that may act as a barrier to an attaching embryo. Receptive endometrium is capable of selecting good quality embryos and reject the incompetent embryos. Endometrial Evaluation includes 1. Non-Invasive Assessment of Endometrial Receptivity by USG 2. Detection of abnormal Uterine cavity by 3D USG/SIS, HSG and Hysteroscopy 3. Diagnose Chronic Endometritis by hysteroscopy and Molecular tests? 4. Endometrial Microbiome by molecular tests 5. Endometrial asynchrony - Proteomics and transcriptomics 2D and 3D Ultrasound can Identify patients with poor implantation prognosis but has low predictive value in determining endometrial receptivity and IVF outcome. Ideal endometrial thickness for optimal outcome is between 7-14 mm. No Association was seen between clinical pregnancy rates (CPR) and endometrial pattern for women undergoing in IVF with fresh ET and FET. Minimum Endometrial Volume associated with pregnancy is 1.59 mL – 3D. But most pregnancies occur in volumes of 2-13 mL. Evaluation of endometrial volume is particularly useful in synechiae, adenomyosis and uterine anomalies. Vascularity demonstrated within Zone 3 or within Zones 3 and 4 prior to transfer is associated with good implantation rate. Presence of &gt;3 peristaltic contractions of the sub endometrial myometrium/2 minutes interval on Day of hCG administration associated with poor implantation. Diagnosis of chronic endometritis is based on hysteroscopy, endometrial biopsy with plasma cells being identified histologically and specific treatment is determined based on microbial culture. Existence of non-Lactobacillus bacteria in the endometrium is correlated with negative impacts on reproductive function and should be considered as an emerging cause of implantation failure and pregnancy loss. Endometrial Receptivity Array (ERA) is validated for analysing the expression of 238 genes that are intimately related to endometrial receptivity. Abnormality in endometrial receptivity is displayed a specific gene expression profile. Intrauterine secretory profile directly linked to successful implantation and evaluation of endometrial fluid for cytokine, interleukin and growth factor secretions can be used to assess the endometrium. Conclusion: Identification of one or more of endometrial parameters that definitely indicate receptivity for implantation remains an elusive goal. None of the endometrial receptivity markers have sufficient discriminatory value to act as a diagnostic test for endometrial receptivity based on their ability to predict clinical pregnancy. Due to the dynamic, cyclic nature of the endometrium it may be difficult, to reliably assess endometrial function on the basis of a single test.

Intermediate actors and their significance for the historical formation of specific professional profiles and labor markets in public adult education

ZusammenfassungDie Erwachsenenbildung ist durch vielfältige Berufsbilder und Beschäftigungsverhältnisse geprägt, aus denen sich zugleich die Existenz heterogener Teilarbeitsmärkte für diesen Sektor erklärt. Am Beispiel des öffentlich verantworteten Erwachsenenbildungsbereichs der Volkshochschulen behandelt der Beitrag die historische Genese von spezifischen Berufsbildern und dazugehörigen (Teil‑)Arbeitsmärkten. Der Schwerpunkt liegt auf dem Berufsbild für hauptberufliche pädagogische Mitarbeitende (HPM) und Leitungskräfte, das als Referenzmodell in der Reformära der 1960er und 1970er-Jahre vor dem Hintergrund neuer Förderungsstrukturen für hauptberufliche Stellen konzipiert wurde. Es wird untersucht, welche Akteure und rechtlichen Normierungen die Formierung dieses spezifischen Berufsbilds beeinflusst und zu seiner Verbreitung und Durchsetzungsfähigkeit geführt haben. Dazu werden Ergebnisse aus einer historischen Stellenanzeigen- und Dokumentenanalyse vorgestellt, die sich u. a. auf Verbände, bildungspolitische Akteure und gesetzliche Grundlagen beziehen. Für die Analyse der empirischen Befunde wird theoretisch an die Konzepte Situation, Intermediäre und Forminvestition aus der konventionensoziologischen Forschung zur Genese von Berufskategorien und Arbeitsmärkten angeknüpft. Die Ergebnisse beleuchten nicht nur die Bedeutung von Intermediären für die Etablierung von Berufsbildern und Arbeitsmärkten, sondern zeigen auch die Auswirkungen auf die Organisationsebene und die impliziten Handlungsspielräume für die einzelnen Volkshochschulen im Untersuchungszeitraum.