GTx (United States)

Abstract Micvotabart pelidotin (micvo) is an antibody-drug conjugate (ADC) that targets extradomain-B of fibronectin (EDB+FN), a non-cellular structural component within the tumor extracellular matrix that is highly expressed in tumors compared to normal adult tissues. Micvo is designed to kill cancer cells, remodel the tumor microenvironment, and mobilize an anti-tumor immune response. Support for the latter was shown in preclinical studies where a mouse analogue of micvo induced CD3+ T-cell infiltration into tumors from syngeneic mice. The present study aimed to confirm micvo’s ability to mobilize an anti-tumor immune response in tumor samples from clinical trial participants with advanced solid tumors in the dose escalation part of a phase 1 study (NCT05720117) and characterize this pharmacodynamic response. Baseline and matched on-treatment biopsies from participants were collected prior to study enrollment and during Cycle 2 of micvo treatment, respectively. Biopsies were evaluated for pharmacodynamic biomarkers and correlation to drug response. H&E-stained tumor sections were evaluated using AI-powered digital pathology to characterize the tumor-immune interaction. Multiplex-immunofluorescence (mIF) staining, coupled with digital pathology analysis, was deployed using a panel designed to characterize changes in the tumor immune microenvironment. Gene expression analysis with RNA isolated from tumor biopsies was evaluated using the Nanostring IO360 panel. Micvo induced an increase in the proportion of lymphocytes within the cancer epithelium of clinical tumors after treatment as determined by digital pathology. Using an orthogonal technique, micvo increased the density of CD3 staining in tumor nests as determined by mIF assessment. This increased density of CD3 staining within tumor nests was not accompanied by an increase in FoxP3 staining. Notably, the magnitude of T-cell infiltration was greater in participants with a stable disease response compared to those with progressive disease, per RECIST v1.1. Greater T-cell infiltration after treatment correlated with a longer total time on study. Lastly, gene expression profiling revealed an increase in the expression of immune-related signatures (e.g. antigen presentation and leukocyte migration) after treatment supporting the histology-based observations of lymphocyte infiltration and suggesting concurrent myeloid changes. Collectively, these results support micvo’s ability to mobilize an anti-tumor immune response across participants’ solid tumors and the resulting T-cell infiltration provides further rationale for the ongoing clinical trial in combination with a PD-1 inhibitor across cancer types. Micvo’s ability to remodel tumor stroma is also under investigation in these biopsies. These pharmacodynamic responses will be further characterized in tumor-specific expansion cohorts from the ongoing clinical evaluation of micvo as monotherapy (NCT05720117) and in combination with pembrolizumab (NCT06795412). Citation Format: Eugene Lurie, Sara Lewandowski, Justin Trickett, Krystal Watkins, Anthony W. Tolcher, Katherine Clifton, Benedito A. Carneiro, Jason T. Henry, Shiraj Shen, Nuria Kotecki, Sylvie Rottey, Rachel Galot, Hongwei Wang, Marsha Crochiere. Micvotabart pelidotin, an ADC targeting non-cellular EDB+FN, induces an immune response in tumors from participants in a phase 1 dose escalation study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A114.

Corporate sustainability affects emissions and waste policy. To show how internal management affects regulatory inputs' environmental implications. An extensive SLR literature review. PRISMA synthesized 50 high-impact empirical research on productive purposes (2018–2025) from 388 records (280 database, 108 citation chaining).Coded governance, regulation, and environment are discussed. Analysis shows pervasive “institutional decoupling” where governance rarely affects operations and compliance is symbolic. Circular economy and markets may reduce industry emissions. Greenwashing may result from generic regulations neglecting high-emission industry. Epistemological Paradox: Self-reported data conceals greenwashing hazards despite methodological breakthroughs. Stakeholder and Neo-Institutional theories contrast business goals and behavior. To improve performance prediction, future models should include internal governance and external limitations. Policymakers must advise sectors, not horizontally.

Repetitive head impacts due to heading in soccer may bear the potential to induce brain changes. To investigate how brain development is affected by heading, effects of heading exposure on neurocognitive and vestibular performance in adolescent soccer players were prospectively examined. In this longitudinal cohort study, male and female high-level youth soccer players of different ages were enrolled in two seasons. Age-matched athletes of other ball sports were included as controls. Before and after each season, neurocognitive performance (six domain scores), vestibulo-ocular reflex, dynamic visual acuity, and postural control (sway velocity) were objectively assessed in all athletes. Every soccer training and match during the observation period was videotaped to analyze individual heading exposure. Associations between heading frequency (total, in duels, >20-m flight distance) and pre- to post-changes were investigated via the Spearman correlation. A total of 103 soccer and 51 control athletes (9-19 yr) participated. Neurocognitive scores and sway velocity significantly improved in each season in soccer and control athletes. There were no associations between total heading numbers and changes in any parameter. Over the first season, the more headers played in duels ( r = -0.255; 95% confidence interval (CI), -0.474 to -0.006; P = 0.04) and from >20-m distance ( r = -0.299; 95% CI, -0.510 to -0.055; P = 0.02), the less psychomotor speed improvement occurred. In the second season, improvements in reaction time were significantly smaller with higher numbers of headers played in duels ( r = 0.375; 95% CI, 0.043 to 0.632; P = 0.02) and from >20-m distance ( r = 0.359; 95% CI, 0.025 to 0.621; P = 0.03). Potential high-impact headers may have affected neurocognitive improvements, exhibiting small to moderate effects. Therefore, more high-impact headers may be more important to consider than solely the overall heading exposure in discussions about adverse effects in youth soccer.

BackgroundCystoisospora suis (C. suis) infects piglets in their first week of life and can subsequently lead to diarrhoea and production losses. The detection of C. suis oocysts relies mostly on the collection of piglet faeces as sampling material and analysis through flotation and autofluorescence microscopy, which involves repeated sampling. The objective of the present study was to evaluate the use of sponges for environmental sampling for the detection of C. suis via real-time PCR and its suitability for surveillance programs applied on farms.ResultsAll farms included in the study were positive for C. suis according to qPCR, with positivity rates ranging from 20 to 100%. The frequency of positive cases was 68% for faecal samples and 67% for samples collected by sponges. The alignment between the different sampling protocols was 100% achieved at the farm level. In the case of the individual pair samples, a difference in 27 samples was observed (10.8%). Considering the faecal sampling strategy as the gold standard, the sensitivity of the sampling protocol with sponges was 91.2%, and the specificity was 84.8%. Compared with the sponge-collected samples, the faecal samples presented slightly greater DNA masses, with a correlation coefficient of r = 0.51, indicating a moderate positive relationship between the two sampling methods. An influence towards a higher DNA load with samples with a pasty and semiliquid consistency was observed, mainly in the case of the sponge technique.ConclusionsOur results indicate that the collection of faecal samples at the litter or farm level and comparisons with environmental samples yield similar detection rates when sampling is combined with qPCR. From that perspective, the use of sponges for the detection of C. suis in organic material from the farrowing crate environment can be considered a good alternative to the more laborious and time-consuming collection of faecal samples.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40813-025-00454-5.

W ostatnich latach ruch na rzecz Sprawiedliwości podatkowej odgrywa coraz ważniejszą rolę w obszarze międzynarodowego opodatkowania, w tym w projekcie OECD dotyczącym filaru II. Grupy takie jak Tax Justice Network (TJN) były bardzo krytyczne wobec globalnego minimalnego podatku. Skąd się to bierze? Niniejszy artykuł przedstawia dziesięć (technicznych i politycznych) zarzutów wobec filaru II z perspektywy Sprawiedliwości podatkowej. Artykuł omawia również samą koncepcję Sprawiedliwości podatkowej, strukturę ruchu na rzecz Sprawiedliwości podatkowej w odniesieniu do filaru II, powiązania z prawami człowieka oraz relacje z pracami Organizacji Narodów Zjednoczonych w tym obszarze.

Ushbu dissertatsiya Mobile CDSS’ning moslashuvchanligi va foydalanish qulayligini oshirish uchun UML modellarini ishlab chiqadi. Aralash uslubda tadqiqot olib borilib, foydalanuvchi ehtiyojlari va samaradorlik ko‘rsatkichlari tahlil qilinadi. Natijalar tizimni yaxshiroq tushunish, muloqotni soddalashtirish va foydalanuvchanlikni oshirishga yordam beradi, bu esa real vaqt rejimida klinik qaror qabul qilish va sog‘liqni saqlash samaradorligini oshirishga xizmat qiladi.

We examined the effects of a 20-wk exercise intervention on whole blood genome-wide DNA methylation signature and its association with the exercise-induced changes in gene expression profiles in boys and girls with overweight/obesity (OW/OB). Twenty-three children (10.05 ± 1.39 yr, 56% girls) with OW/OB were randomized to either a 20-wk exercise intervention [exercise group (EG); n = 10; 4 boys/6 girls] or to usual lifestyle [control group (CG); n = 13; 6 boys/7 girls]. Whole blood genome-wide methylome (CpG sites) analysis using Infinium Methylation EPIC array and transcriptome analysis using RNA-seq (STRT2 protocol) were performed. Exercise-induced modifications in DNA methylation at 485 and 386 CpGs sites in boys and girls, respectively. These CpG sites are mapped to loci enriched in distinct gene pathways related to metabolic diseases, fatty acid metabolism, and immune function. In boys, changes in the DNA methylation of 87 CpG sites (18% of the 485 CpGs sites altered by exercise) were associated with changes in the gene expression levels of 51 genes also regulated by exercise. Among girls, changes in DNA methylation at 46 CpG sites (12% of the initial 386 significant CpGs) were associated with changes in the expression levels of 30 exercise-affected genes. Genes affected by exercise that were associated with DNA methylation are related to obesity, metabolic syndrome, and inflammation. Multiomics analysis of whole blood samples from children with OW/OB suggests that gene expression response to exercise may be modulated by DNA methylation and involve gene pathways related to metabolism and immune functions.NEW & NOTEWORTHY This study pioneers the exploration into the effects of exercise on whole blood genome-wide DNA methylation patterns and its association with changes in transcriptome profiles in children with overweight/obesity. Exercise potentially impacts molecular pathways involved in metabolism and immune functions in children with overweight/obesity (sex-specific responses) through the modification of epigenetic and transcriptomic profiles. Our preliminary results provide initial steps to understand better the molecular mechanisms underlying cardiometabolic benefits of exercise in children with overweight/obesity.