Biology subjects

Dominguez, P.

Publications and source records attributed to Dominguez, P..

3 recordsLinked to original sources

bioRxiv2026

Evaluation of ivermectin effectiveness under contrasting anthelmintic resistance scenarios in beef cattle: a comparative study in Italy and Argentina

Beef cattle farming plays a crucial role in the livestock-related economies of both Italy and Argentina. Although both countries have grazing systems of meat production, the heterogeneity of those systems leads to different parasitological scenarios regarding epidemiology and the presence of resistance to commonly used anthelmintic drugs. Considering ivermectin (IVM) is the most widely used anthelmintic for treating gastrointestinal nematode (GIN) infections in cattle, the current studies evaluated the efficacy of ivermectin (IVM) given subcutaneously (SC) to both young calves and adult cows in ten (10) commercial cattle farms from Italy (A to E) and Argentina (F to J). The work was complemented with the assessment of the IVM plasma exposure and disposition kinetics both in young and adult animals. While adult cows and young calves were included in the study performed in Italy (Campania region), only calves aged 8-14 months old were selected to perform the efficacy trials in Argentina (central area of the Buenos Aires province). Fifteen (15) calves/cows naturally infected with GINs were treated with IVM (0.2 mg/kg) in each of the Farms. The therapeutic response (efficacy) was determined at 14 days after treatment by the faecal egg count reduction test. Six (6) adult cows and eight (8) young calves treated with IVM were randomly selected to perform the pharmacokinetic (PK) study with blood samples being taken 2 h and 21 days post-treatment. Drug concentrations were measured by HPLC. Similar IVM PK trends were obtained for both adult and young cattle. The IVM systemic exposure (expressed as AUC) obtained for adult cattle (380{+/-}158 ng.d/mL) was similar to that observed in calves group (313{+/-}85.5 ng.d/mL). No statistical differences between animals from both ages were observed for the most representative PK parameters (P>0.05). Surprisingly, while in Argentina IVM resistance was present in all the farms evaluated (90% CI = 0%-95%), in Italy a fully susceptible nematode population was presented in three farms (90% CI = 96%-100%) and only a very low level of IVM resistance was detected in the rest of the farms (90% CI = 92%-98%). Whereas Cooperia spp. and Haemonchus spp. were identified as the principal genera exhibiting resistance to IVM in Argentina, Cooperia spp., Ostertagia spp., and Oesophagostomum spp. were reported to display low levels of resistance under the Italian field scenario. In conclusion, IVM can be safely and effectively used in both young and adult cattle with similar disposition kinetic patterns. While its therapeutic response is failing under the conditions investigated in the Argentinian farms, its efficacy remains notably high in the Italian region under study. However, the use of IVM, as well any other active antiparasitic principle, should always be preceded by a diagnostic assessment of the nematode populations resistance status.

pharmacology and toxicology↗

bioRxiv2025

Epigenetic remodeling via HDAC6 inhibition amplifies anti-tumoral immune responses in pediatric AML

Histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic target in cancer due to its immunomodulatory effects. While its prognostic significance remains debated, we demonstrate that HDAC6 loss significantly impairs myeloid leukemia progression in vivo, despite having no functional impact on leukemia cell proliferation in vitro. Global proteome and secretome profiling of HDAC6-knockout (KO) cells revealed upregulation of several immune-related modulators, including RNase T2, a tumor suppressor known to modulate the tumor microenvironment. Notably, RNase T2 upregulation upon HDAC6 loss was restricted to myeloid but not B-ALL cells. Moreover, pharmacological inhibition of HDAC6 recapitulated this phenotype, leading to RNase T2 upregulation in myeloid leukemia cells. ATAC-seq revealed increased chromatin accessibility of RNase T2 following HDAC6 loss, highlighting a functionally epigenetic regulatory contribution. Further functional assays conducted in an immunocompetent setting both ex vivo and in vivo demonstrated that HDAC6 inhibition sensitized murine myeloid leukemia cells to broad CD8+ T cell activation as evidenced by increased TNF and CD107a expression. Consistently, in a syngeneic model, HDAC6 inhibition restricted growth myeloid leukemia cells. Moreover, an extended drug screening analysis identified Cytarabine and Clofarabine as significantly synergizing with HDAC6 inhibitor (Ricolinostat) in myeloid leukemia cell lines and in patient derived xenograft (PDX) cells, while showing limited synergy in lymphoid leukemia cell lines, PDX or healthy control cells. These findings suggest that HDAC6 represents a promising therapeutic target in myeloid lineage derived leukemia cells by simultaneously enhancing immune activation and increasing chemosensitivity.

cell biology↗

bioRxiv2021

Inhibition of pyrimidine biosynthesis targets protein translation in AML.

The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anti-cancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) by down-regulation of the multi-functional transcription factor YY1, has potent activity against AML in vivo and is well tolerated with minimal impact on normal blood development. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.

cancer biology↗