Systematic Exposure Research Articles

Occupational and Hobby Exposures Associated with Myositis Phenotypes in a National Myositis Patient Registry.

To investigate occupational and hobby exposures to silica, solvents, and heavy metals and odds of idiopathic inflammatory myositis (IIM) phenotypes, dermatomyositis (DM) and polymyositis (PM) versus inclusion body myositis (IBM), lung disease plus fever or arthritis (LD+), and systemic autoimmune rheumatic disease-overlap myositis (OM). The sample included 1390 patients (598 DM, 409 PM, and 383 IBM) ages ≥18 years from a national registry. Of these, 218 (16%) were identified with LD+, i.e., self-reported lung disease with fever and/or arthritis, and 166 (12%) with OM. Questionnaire data on jobs, hobbies, and exposures before diagnosis were evaluated using a rules-based protocol and expert assessment of silica dust, solvents, and heavy metals exposure. We calculated adjusted odds ratios (OR) and 95% confidence intervals (CI) and explored joint effects with smoking. High silica exposure was associated with an increased odds of having DM (OR=2.02; 95%CI 1.18-3.46, compared to no exposure; p-trend=0.004), LD+ (1.75; 1.10-2.78; p-trend=0.005, versus no LD), and OM (2.07; 1.19-3.61; p-trend=0.020). Moderate to high heavy metals exposure was associated with greater odds of having LD+ (1.49; 1.00-2.14; p-trend=0.026) and OM (1.59; 0.99-2.55, p-trend=0.051). Greater odds of LD+ were seen among smokers with moderate to high silica exposure versus non-smokers with low or no exposure (high-certainty assessment, 2.53; 1.31-4.90; p-interaction=0.061). These findings, based on a systematic exposure assessment, suggest that occupational and hobby exposures to silica and heavy metals contribute to adult IIM phenotypes, including DM, OM, and LD+, a possible marker for anti-synthetase or other autoantibody-associated lung disease.

Diagnostic models for differentiating fatty liver disease of alcohol and non-alcoholic genesis

Introduction. Fatty liver disease is the largest contributor to the burden of chronic liver disease worldwide. Current approaches do not allow sufficient differentiation between alcoholic and non-alcoholic etiology of the process.Aim. Create diagnostic panels including electrical and viscoelastic parameters of erythrocytes to differentiate fatty liver disease of alcoholic and non-alcoholic genesis.Materials and methods. The study included 38 men (47.5 ± 2.9 years) with NAFLD; 31 men with alcoholic fatty liver disease (AFLD) (45.1 ± 3.1 years) according to ultrasound of the abdominal organs, the degree of fibrosis did not exceed F1 (FibroScan® 502). Electrical and viscoelastic parameters of erythrocytes were studied by dielectrophoresis using an electro-optical cell detection system. To determine the parameters of erythrocytes – biomarkers for distinguishing between AFLD and NAFLD, a system of machine learning methods – Random Forest was used.Results. Electrical, viscoelastic parameters of erythrocytes, which are biomarkers for distinguishing between AFLD and NAFLD, were established: cell membrane capacity (p = 1.21E-11), the degree of change in the deformation amplitude at a frequency of 5 x 105 Hz (p = 2.38E-08), cell polarizability at a frequency of 106 Hz (p = 9.38E-08), the speed of erythrocyte movement to the electrodes (p = 4.32E-06), the magnitude of the dipole moment (p = 1.66E-05), relative polarizability (p = 2.35E-05), the index of erythrocyte destruction at a frequency of 5 x 105 Hz (p = 0.016), the position of the crossover frequency (p = 2.13E- 06). The diagnostic model, including five parameters – the position of the crossover frequency, cell polarizability at a frequency of 106 Hz, cell electrical conductivity, membrane capacity, the degree of change in the deformation amplitude at a frequency of 5 x 105 Hz, provided the highest diagnostic accuracy with an AUC of 0.975, a sensitivity of 96.3%, and a specificity of 91.8% in differentiating between AFLD and NAFLD.Conclusion. Thus, systematic exposure to alcohol modifies the structure of erythrocyte membranes, leading to a decrease in the surface charge, the barrier function of membranes, reducing the resistance of cells, their ability to deform, which determines the key role of the identified electrical, viscoelastic parameters of erythrocytes in differentiating between AFLD and NAFLD.

Impact of air pollution on mortality: Geo-epidemiological study in French-speaking Africa

According to the World Health Organization, air pollution is responsible for 90 % of deaths in Africa. However, limited data on exposure to air pollution is available, and studies are rare, particularly in French-speaking Africa. This study aims to investigate the impact of air pollution on mortality in 12 French-speaking African countries (Algeria, Burkina Faso, Burundi, Cameroon, Guinea, Ivory Coast, Madagascar, Mali, Morocco, Democratic Republic of Congo, Senegal, Tunisia). Using data from the Institute for Health Metrics and Evaluation (IHME), annual concentrations of the PM2.5 pollutant from different cities were integrated into a spatial interpolation model (IDW) at the scale of each country. The interpolation was validated using cross-validation models. For each of the considered cardiorespiratory diseases (LRI, stroke, COPD, IHD), the attributable mortality fraction was estimated using literature data and population exposure calculated using demographic data from each country. Large variations in ambient PM2.5 concentration between the 12 countries are observed, with concentrations ranging from 1.76 μg/m3 in Morocco to 64.99 μg/m3 in Cameroon. Concentrations are higher in West Africa than in Central or North Africa. In 2019, 136 457 deaths attributable to air pollution were recorded in the 12 countries: 40.8 % from ischemic heart disease, 38.5 % from stroke, 13.2 % from lower respiratory infections and 7.5 % from chronic obstructive pulmonary disease. Our model allowed us to obtain a spatial distribution and the number of deaths related to air pollution. However, the estimation of the health impact from air pollution could be improved by more systematic and comprehensive local exposure assessments from a robust air quality monitoring system.

Integrating the Gap Between Faith Education and Christian Learning in the Indonesian Context with a Christian Worldview

In Indonesia, there is a striking contrast between faith education and Christian learning, which raises major questions regarding integration. Faith education is often associated with worship and character formation in the church, while schools are expected to strengthen Christian values. Understanding Christianity in the concept of worldview is very important, stressing the Christian's responsibility to live in the world, not of the world. This research used qualitative methods, including surveys and thematic analysis, which produced three main findings. First, faith education is usually carried out in religious schools, in line with specific religious doctrines, whereas Christian learning involves systematic exposure to Christian teachings. Second, religious education in Indonesia aims to overcome inter-religious disorders, while Christian education seeks to understand God's will. Research puts forward the concept of a universal worldview as a means of bridging this gap. Three proposed approaches are Teaching for commitment, Teaching for commitment Teaching about commitment, and Teaching from commitment.

Dual-Responsive Microsphere Based on Natural Sunflower Pollen for Hemostasis and Repair in Inflammatory Bowel Disease.

Noninvasive treatment of inflammatory bowel disease with lower gastrointestinal bleeding is a major clinical challenge. In this study, we designed an orally targeted microsphere based on sunflower pollen microcapsules to localize the site of inflammatory injury and promote hemostasis and tissue repair. Due to the Eudragit and ascorbate palmitate coatings, EL/AP@PS(t+Dex) demonstrates pH- and enzyme-responsive release of loaded drugs and helps to resist the harsh environment of the gastrointestinal tract. Both in vitro and in vivo experiments show the characteristics of inflammation targeting and mucosal adhesion, which reduce the systematic exposure and increase the local drug concentration. In the DSS model, orally administered EL/AP@PS(t+Dex) significantly alleviates hematochezia, inhabits intestinal inflammation, and remarkably promotes the recovery of the intestinal epithelial barrier to reduce the exposure of intestinal microvessels. Furthermore, EL/AP@PS(t+Dex) optimized the composition of intestinal microbiota, which benefits intestinal homeostasis. This finding provides a fundamental solution for the treatment of intestinal bleeding caused by inflammatory bowel disease (IBD).

How can urban green space be planned for a ‘happy city’? Evidence from overhead- to eye-level green exposure metrics

The benefits of urban green spaces (UGSs) for human health have been extensively documented. Nevertheless, few studies have incorporated multidimensional UGS exposure indicators, and little is known about the effectiveness of different metrics that should be prioritized as nature-based solutions for improving mental well-being. This study aimed to investigate the associations between various UGS exposure metrics and residents’ expressed happiness (EH) as well as to determine the prioritization of metrics in Nanjing, China, a megacity with 9.5 million inhabitants. The study region was divided into 500 m × 500 m grids, and 330,000 geotagged posts from social media (Sina Weibo) were retrieved for sentiment analysis using the Natural Language Processing (NLP). We developed a systematic UGS exposure framework using satellite, land-cover, and street view-derived data, encompassing 17 indicators of composition and configuration at overhead level as well as street green space visibility and perceived quality at eye level. A regression model and Likelihood Ratio Test were used to examine the associations between various UGS indicators and EH and determine the prioritization of indicators. The results indicated that UGS size had the greatest potential for promoting residents’ EH, followed by overall greenness in the surrounding area, aggregated UGS, perceived quality, and visibility of street green spaces. This study also found that overhead-level metrics may be more effective than eye-level metrics in enhancing residents’ EH, although both perspectives showed significant associations with EH. These findings provide valuable insights into health-oriented landscapes and urban planning to promote the development of a “happy city,” particularly in low-green resource settings in low- and middle-income countries.

Phase 1 study of ZV0203, a first in class pertuzumab ADC, in patients with HER2 positive advanced solid tumors.

e15004 Background: ZV0203, a first in class (FIC) pertuzumab antibody-drug conjugate (ADC), targets HER2 positive tumor cells with tubulin inhibitor DUO5 as its payload via a stable and protease-cleavable valine-citrulline linker. In preclinical studies, ZV0203 demonstrated superior antitumor activity compared to Kadcyla in multiple tumor cell line xenograft models with no noticeable toxicity. GLP toxicity studies indicated that ZV0203 was well tolerated with an estimated therapeutic index of 35. Methods: This was an open-label, multicenter, phase 1, dose-escalation study in patients (pts) with HER2+ advanced solid tumors. Primary objectives were safety, tolerability and RP2D. Secondary objectives included PK, immunogenicity and preliminary clinical efficacy. ZV0203 was administered intravenously Q3W on a 21-day cycle. An accelerated titration design was used for the 0.3 and 0.6 mg/kg doses, followed by a 3+3 design for 1.2, 1.8, 2.7 and 3.6 mg/kg dose levels. Results: As of January 18, 2024, 15 pts with solid tumors (breast [11], colorectal [2], gastric [1], lung [1]) were enrolled across doses of 0.3-3.6 mg/kg with a median age of 52 years old (range 35-65), of which 9 pts received prior HER2-targeted therapy (trastuzumab ± pertuzumab) and 14 pts completed 21-day DLT assessment (0.3 mg/kg and 0.6 mg/kg [1 each], 1.2 mg/kg, 1.8 mg/kg, 2.7 mg/kg and 3.6mg/kg [3 each]) with no DLT incidence. Treatment-related adverse events (TRAE) occurred in 14 (93.3%) pts. The most frequent TRAEs were corneal epitheliopathy [9], elevated liver enzymes [6], dry eyes [6], neutropenia [4], anemia [4], leukopenia [3], and proteinuria [3], and most were grade 1-2 in severity. 5 pts experienced grade 3 TRAEs: lymphocytopenia (1.8mg/kg [1]) , corneal epitheliopathy (3.6 mg/kg [1]) and blurred vision (2.7 mg/kg [2], 3.6 mg/kg [1]), which were manageable during treatment. No unexpected safety signals were reported. TRAEs led to 13.3% (2/15) treatment discontinuation. Among 14 pts evaluated, 5 pts achieved a best tumor response of PR; 4 pts had SD; 1 pt had Non-CR/Non-PD per RECIST v1.1. Thus, disease control rate was 71.4% (10/14). PK results demonstrated that the PK profile of total antibody was similar to that of ZV0203 ADC, whose systematic exposure increased in a dose-dependent manner and remained stable after repeated administration. Concentration of DUO5 remained scarce, suggesting good stability of ZV0203. Conclusions: ZV0203 was well tolerated and showed clinically encouraging anti-tumor activity in heavily pretreated pts with HER2 positive cancer. Clinical trial information: NCT05423977 .

Frequency of comedication of proton pump inhibitors with crystalline dasatinib in chronic myeloid leukemia and effects on TKI-bioavailability.

6561 Background: Tyrosine kinase inhibitors (TKI), including dasatinib, have profoundly improved clinical outcome in chronic myeloid leukemia (CML). However, solubility, bioavailability and systematic exposure of the crystalline formulation of dasatinib (Sprycel) is reduced at higher gastric pH levels. This is problematic for comedication with acid reducing agents as lower bioavailability may reduce clinical response. Methods: We investigated proton pump inhibitor (PPI) and TKI comedication, including dasatinib, in a large real world CML cohort. Furthermore, we assessed the influence of timing of PPI comedication on the absorption and bioavailability of dasatinib. Results: Using the Swedish CML- and Prescribed Drug-Registries, we identified 1,328 chronic phase CML patients, diagnosed 2002-2018. 1,261 (95%) had received specified/known TKI treatment and 685 of those (54%) were prescribed a PPI (ATC-code: “A02BC”) at some point after CML diagnosis. TKIs and PPIs prescribed within 12 months of CML diagnosis were prescribed by different HCPs in 66% of cases (284/432). Of the 388 patients treated with dasatinib, 91 (23.5%) received a concomitant PPI. The PPI prescription rate increased to 53% (204/388) in the dasatinib cohort after dasatinib treatment had ended. Further, we assessed the drug-drug interaction (DDI) in 18 healthy volunteers given crystalline dasatinib (100mg) alone or together with omeprazole (40mg, at steady state) administered 9 hours apart; a time point when a high effect on bioavailability is expected. Compared to dosing with crystalline dasatinib alone, Cmax and AUC0-24 were reduced by 96% and 88% by omeprazole comedication (Table). Conclusions: Despite warnings, comedication with PPI is common among dasatinib treated CML patients. Further, an even larger proportion of patients need PPI co-treatment, which however, cannot fully be administered due to its negative impact on dasatinib pharmacokinetics. Moreover, with an optimized study design, we observed a higher than previously reported negative interaction of PPI comedication on crystalline dasatinib bioavailability. This may compromise clinical efficacy and risk CML disease progression. For patients in need of PPI, selection of a non-crystalline, less pH-sensitive formulation of dasatinib therefore appears more appropriate. Clinical trial information: NCT06145217 . [Table: see text]

Improving Anorexia Nervosa Treatment with Virtual Reality Body Exposure and Attentional Bias Modification: A Single Case Study

This case study explores the potential of integrating attentional bias modification training (ABMT) with mirror exposure therapy (MET), utilizing virtual reality and eye-tracking, for a 14-year-old girl diagnosed with anorexia nervosa (AN). The ABMT-MET intervention was used alongside a standard treatment program called Home Treatment (HoT), which combines cognitive behavioral therapy with family-based therapy. Though the patient began HoT with a 3-week inpatient phase, the ABMT-MET intervention specifically took place during the subsequent Home Treatment sessions. The experimental treatment, comprising five consecutive weekly sessions, was bookended by pre- and post-assessment sessions and included a six-month follow-up. During the sessions, the patient engaged in systematic and hierarchical exposure to a virtual representation of her silhouette, with gradual adjustments made to the avatar’s body mass index (BMI) toward a healthier range. ABMT sessions, conducted before each MET session, aimed to redistribute the patient’s focus evenly across her body, successfully neutralizing her initial attentional bias toward non-weight-related body parts. The patient demonstrated consistent decreases in anxiety and fear of weight gain, effectively progressing through the BMI hierarchy in the virtual setting. Post-treatment assessments indicated significant enhancements in body dissatisfaction, drive for thinness, body-checking behaviors, and body appreciation, with these gains preserved at the six-month follow-up, although the attentional bias returned to pre-treatment levels. Though the single-case design limits definitive conclusions, these findings suggest ABMT-MET may be a promising adjunct therapy for AN, requiring further research for confirmation.

Null cross-modal effects of olfactory training on visual, auditory or olfactory working memory in 6- to 9-year-old children.

Systematic exposure to odours (olfactory training, OT) is a method of smell loss treatment. Due to olfactory system projections to prefrontal brain areas, OT has been hypothesized to enhance cognitive functions, but its effects have been studied predominantly in adults. This study tested OT effects on working memory (WM), i.e., the ability to store and manipulate information for a short time, in healthy children aged 6-9 years. We expected OT to improve olfactory WM and establish cross-modal transfer to visual and auditory WM. Participants performed 12 weeks of bi-daily OT with either 4 odours (lemon, eucalyptus, rose, cloves; OT group) or odourless propylene glycol (placebo group). Pre- and post-training, participants' WM was measured utilizing odours (olfactory WM) or pictures (visual WM) and a word-span task (auditory WM). 84 children (40 girls) completed the study. The analyses revealed no changes in the WM performance following OT. The olfactory WM task was the most difficult for children, highlighting the need to include olfactory-related tasks in educational programmes to improve children's odour knowledge and memory, just as they learn about sounds and pictures. Further neuroimaging research is needed to fully understand the impact of OT on cognitive functions in children.

Dynamic changes in somatosensory and cerebellar activity mediate temporal recalibration of self-touch

An organism’s ability to accurately anticipate the sensations caused by its own actions is crucial for a wide range of behavioral, perceptual, and cognitive functions. Notably, the sensorimotor expectations produced when touching one’s own body attenuate such sensations, making them feel weaker and less ticklish and rendering them easily distinguishable from potentially harmful touches of external origin. How the brain learns and keeps these action-related sensory expectations updated is unclear. Here we employ psychophysics and functional magnetic resonance imaging to pinpoint the behavioral and neural substrates of dynamic recalibration of expected temporal delays in self-touch. Our psychophysical results reveal that self-touches are less attenuated after systematic exposure to delayed self-generated touches, while responses in the contralateral somatosensory cortex that normally distinguish between delayed and nondelayed self-generated touches become indistinguishable. During the exposure, the ipsilateral anterior cerebellum shows increased activity, supporting its proposed role in recalibrating sensorimotor predictions. Moreover, responses in the cingulate areas gradually increase, suggesting that as delay adaptation progresses, the nondelayed self-touches trigger activity related to cognitive conflict. Together, our results show that sensorimotor predictions in the simplest act of touching one’s own body are upheld by a sophisticated and flexible neural mechanism that maintains them accurate in time.

Inhibition of p38α MAPK-MK2 axis alleviate inflammatory response in various inflammation-related disease models

Abstract Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated by p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. Preclinical studies indicate that targeting MK2 may be a much safer approach than blocking p38a MAPK activation because that dissect the pathway downstream of p38α MAPK without affecting additional cellular functions. 141-A was identified as a highly potent and selective p38α MAPK-MK2 allosteric inhibitor that exhibited nanomolar-level inhibition on p38α MAPK activation of MK2 while sparing the p38α MAPK activation of ATF2 and PRAK. 141-A potently reduced various cytokine production (TNFα, IL-1β, IL-6, IL-8 and IL-17) in human peripheral blood mononuclear cells (PBMC) and displayed excellent efficacy in adjuvant-induced arthritis (AIA), psoriasis and MSU-induced air pouch rat models with 1/6 of the systematic exposure of CDD450. The compound exhibits favorable physicochemical and pharmacokinetic properties, along with an excellent preclinical toxicity profile, which may enhance therapeutic efficacy without causing side effects. 141-A is currently under IND-enabling studies and P1 trial is planned in early 2025.

Methylation of PLK-1 Potentially Drives Bendamustine Resistance in Leukemia Cells.

Drug resistance remains a significant impediment in leukemia treatment. While Bendamustine hydrochloride (BH) stands out as a promising therapeutic agent for non-Hodgkin's lymphoma and mantle cell lymphoma, the mechanisms of resistance to BH are not yet fully understood. Our study focuses on elucidating the mechanisms behind bendamustine resistance in leukemia cells, with a specific emphasis on epigenetics. Bendamustine-resistant cells were cultivated from human B cell lymphoblastic leukemia cell lines through systematic and sustained exposure to bendamustine, using the limiting dilution method. Gene expression was assessed via real-time polymerase chain reaction, while the expression of the multidrug resistance protein 1 (MDR1) was evaluated using flow cytometry. Bendamustine-resistant leukemia cells exhibited a decreased RNA expression level for Polo-like kinase-1 (PLK-1). Notably, after treatment with the demethylating agent 5-aza-2'-deoxycytidine, PLK-1 gene expression surged significantly, enhancing bendamustine's cytotoxicity in the resistant leukemia cells. However, MDR1 expression, as determined by flow cytometry, remained consistent between parental and bendamustine-resistant leukemia cells. Our findings indicate that the methylation of the PLK-1 gene plays a pivotal role in modulating PLK-1 expression and is central to the development of bendamustine resistance in leukemia cells.

First comprehensive assessment of dietary chlorinated paraffins intake and exposure risk for the rural population of the Tibetan Plateau, China

Knowledge regarding the occurrence of short-chain and medium-chain chlorinated paraffins (SCCPs and MCCPs) in foodstuffs and their dietary exposure risks for rural Tibetan residents remains largely unknown. Herein, we collected main foodstuffs (including highland barley, vegetables, Tibetan butter, mutton, and yak beef) across the rural Tibetan Plateau and characterized the CP profiles and concentrations. The highest SCCPs concentrations were detected in Tibetan butter (geometric mean (GM): 240.6 ng/g wet weight (ww)), followed by vegetables (59.4 ng/g ww), mutton (51.4 ng/g ww), highland barley (46.3 ng/g ww), and yak beef (31.7 ng/g ww). For MCCPs, the highest concentrations were also detected in Tibetan butter (319.5 ng/g ww), followed by mutton (181.9 ng/g ww), vegetables (127.0 ng/g ww), yak beef (71.2 ng/g ww), and highland barley (30.3 ng/g ww). The predominant congener profiles of SCCPs were C13Cl7–8 in mutton and yak beef, C10Cl7–8 in Tibetan butter, and C10–11Cl6–7 in highland barley and vegetables. The predominant congener profiles of MCCPs were C14Cl7–9 in all sample types. Combined with our previous results of free-range chicken eggs, the median estimated daily intakes (EDIs) of SCCPs and MCCPs via diet for Tibetan rural adults and children was estimated to be 728.8 and 1853.9 ng/kg bw/day and 2565.6 and 5952.8 ng/kg bw/day, respectively. In the worst scenario, MCCPs might induce potential health risks for rural Tibetan population. To our knowledge, this is the first systematic dietary exposure research of SCCPs and MCCPs in the remote rural areas.

Evaluation of sub-chronic toxicity of melamine via systematic or oral delivery in adult zebrafish based on behavioral endpoints

Melamine-tainted products have been found in the market and raised issues about food safety. Recent studies done in rodents and humans demonstrated the toxicities of melamine, especially in causing kidney damage and bladder stone formation. However, very few studies assessed its behavior toxicity in organisms, including fish. Therefore, in this study, the researchers aim to determine whether sub-chronic exposure to melamine via oral and systematic administration could induce behavioral abnormality in zebrafish. After 14 days of systematic exposure to melamine at doses of 0.1 and 10 ppm levels, zebrafish were subjected to multiple behavioral assays. Results from both exposure routes showed that melamine indeed slightly increased fish locomotion and altered their exploratory behaviors in the novel tank assay. Furthermore, tightened shoaling formation was also displayed by the treated fish in the waterborne exposure group. However, melamine exposure did not cause any obvious alterations in fish behaviors during other behavioral tests. In addition, in comparison with previously published data on the behavior toxicities of several solvents in zebrafish, our phenomic analysis suggests the relatively low behavior toxicities of melamine via either systematic exposure or oral administration to zebrafish compared to those solvents. Nevertheless, our data indicate that the potential neurotoxicity of chronic low-dose melamine should not be ignored.

Pathological characteristic of the eye changes within dogs ophthalmopathy associated with paraneoplastic syndrome

Ophthalmopathy associated with parneoplastic syndrome is a poorly studied pathology of the dogs eye. They occur as a result of the malignant neoplasm’s systematic exposure on the animal's body. They appear in the form of non-specific clinical signs. Main objective of the study – to study the pathomorphological changes in the dog’s eyes with malignant neo-plasms. The material for the study were 30 eyeballs enucleated in dogs in the terminal stage of cancer. Autopsy material obtained from animals was subjected to standard histological processing. As a result of histological studies, pathomorphological changes in eyeball structures associated with Patnaik G2 and G3 mastocytomas (28.6% of cases), liver and kidney carcinomas (28.6%), lymphoma (28.6%) and spleen hemangiosarcoma (14.2%) were revealed in 46.7% of cases. The main histopathological changes were thickening of the iris due to inflammatory cellular infiltration (57.1%) and vasodilation of blood vessels (42.9%), the presence of fibrinous hemorrhagic exudate in the anterior chamber of the eye (28.6%), edema and inflammatory infiltration of the vascular membrane proper (42.9%), thinning, loss of layering and weak retinal atrophy (42.9%). The revealed histological changes indicate the predominant involvement in the pathological process of the vascular membrane of the eye with a violation of the hematophthalmic barrier, as the main pathogenetic mechanism for the development of endogenous uveitis against the background of malignant neoplasm in the animal body.

Abstract 7275: GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation

Abstract As a tumor suppressor, p53 can prevent tumor development through multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumor cell death and rapid tumor progression. The oncogenic Y220C mutation is the ninth most frequent p53 missense mutation in cancer. Y220C mutation creates a narrow, hydrophobic pocket on the surface of the p53 DBD that reduces its thermal stability. As a result, the Y220C mutation causes a rapidly unfold of the p53 protein under physiological conditions, abrogates p53 signaling and drives tumorigenesis. There are approximately 100,000 new Y220C mutation cancer cases per year worldwide with limited treatment choices. The initial clinical evaluation of PC14586 that can restore missense-mutant p53 protein has seen efficacy in patients harboring p53 Y220C mutation even though there is still room for improvement. Here we report a brain-penetrable, highly potent p53 Y220C reactivator which has great in vitro activity as well as induce tumor shrinkage in multiple tumor models at a much lower systematic exposure comparing to PC14586. In vitro, GS-P-328 could bind to p53 Y220C protein with a single nM potency and potently induce cell death in a wide range of p53 Y220C tumor cells while have no anti-proliferative effects with p53 WT cells. GS-P-328 is also active in patient-derived cell (PDC) models in various tumor background including SCLC, gastric, ovarian and colon. In vivo, GS-P-328, at approximately 1/3 of systematic exposure comparing to a leading clinical reactivator, causes tumor shrinkage in multiple CDX models. GS-P-328 could induce MDM2/p21 upregulation in cell systems. In vivo, GS-P-328 could induce 2 fold and more increase in MDM2/p21 protein levels in tumor tissues at approximately 1/3 of plasma concentrations comparing to PC14586. More importantly, in a NUGC3-luc intracranial model, GS-P-328 could strongly inhibit growth of cancer cells in the mouse brain. GS-P-328 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GS-P-328 is now under IND-enabling study and P1 study is planned in early 2025. Citation Format: Meng Liu, Kaijun Geng, Biao Lu, Yuanfeng Xia, Fanglong Yang. GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7275.

Abstract 664: GSC000190, a highly potent inhibitor of KIF18A, for tumors with chromosome instability

Abstract Chromosome instability (CIN) and Genetic instability is a common feature of malignant tumor cells, which may contribute to tumor progression and lead to drug resistance and tumor metastasis. KIF18A, a member of the kinesin-8 family, is an ATP dependent plus end microtubule motor protein. Studies have found that genetic depletion of KIF18A greatly impacts the chromosome alignment, elongation of mitotic spindles, activation spindle assembly checkpoint of CIN+ tumor cell and leads to cell death, while have little impact towards the survival of normal cells, making KIF18A an attractive therapeutic target for targeting the vulnerability of CIN related tumors. Here we report the pharmacology characterization of a “best in class” potential KIF18A inhibitor for CIN+ tumors. In vitro, GSC000190 inhibited KIF18A ATPase activity with a single nM potency and has great potency inhibiting growth of a wide range of TP53 mutant/CIN+ tumor cells. In vivo, GSC000190, at approximately one tenth of systematic exposure comparing to that of AMG650, the leading clinical KIF18A inhibitor, causes tumor shrinkage in multiple CDX models including ovarian, colon and lung cancers. In an HGSOC PDX model which is resistant to platinum and olaparib, GSC000190 induced strong tumor regression both as single agent and through combination without significant body weight reduction. PD study confirms a more elevated mitotic phosphorylated histone 3 (PH3) staining in GSC000190 treated tumor tissues, correlating with a better in vivo efficacy than that of AMG650. GSC000190 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GSC000190 is now under IND-enabling study and P1 study is planned in the second quarter of 2024. Legal entity responsible for the study: The authors. Disclosure: All authors have declared no conflicts of interest. Citation Format: Peng Tu, Chen Zhang, Biao Lu, Yuanfeng Xia, Fanglong Yang. GSC000190, a highly potent inhibitor of KIF18A, for tumors with chromosome instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 664.

Systematic light exposure to prevent fatigue and sleep disturbances in prostate cancer patients (PC-LIGHT Study)

Systematic light exposure to prevent fatigue and sleep disturbances in prostate cancer patients (PC-LIGHT Study)

Sectoral Asset Concentrations and Insurance Solvency Regulation

Historical evidence, like the global financial crisis from 2007–2009, highlights that sectoral asset concentrations can play an important role in the solvency of insurers. Yet, current regulatory frameworks, such as the U.S. risk-based capital (RBC) framework, neglect sectoral asset concentrations in the determination of capital requirements, potentially underestimating the asset portfolio’s systematic loss exposure and reducing incentives for corresponding risk mitigation. By creating a detailed data sample of U.S. insurers’ asset holdings from 2009 to 2018 by means of their statutory filings, we find that insurers concentrate their assets particularly toward the financial, public, and real estate sector and that sectoral asset concentrations toward the public sector are associated with improved solvency, while concentrations toward the real estate sector weaken solvency. Our findings can serve as a starting point to revise current regulatory practices, particularly in terms of creating proactive incentives for insurers to mitigate the accumulation of systematic risk exposures associated with sectoral asset concentrations.