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In a 3-arm presurgical trial, four-six weeks exemestane 25 mg three times/week (TIW) was non-inferior to 25 mg/day (QD) in suppressing circulating estradiol in postmenopausal women with ER-positive breast cancer. Since obesity may decrease exemestane efficacy, we analyzed changes in sex steroids, adipokines, Ki-67, and drug levels in relation to obesity. Postmenopausal women with early-stage ER-positive breast cancer were randomized to either exemestane 25 mg QD (n = 57), 25 mg TIW (n = 57), or 25 mg/week (QW, n = 62) for 4-6 weeks before breast surgery. Serum and tissue pre- and post-treatment biomarkers were stratified by body mass index (BMI)< or ≥30 kg/m2. Post-treatment median exemestane and 17-OH exemestane levels were 5-6 times higher in the QD arm compared to the TIW arm. For obese women, TIW maintained comparable reductions to QD in systemic estradiol levels, although the reduction in estrone was less with the TIW regimen. There was less suppression of SHBG with the TIW versus the QD dose schedule in obese women which should result in less systemic bioavailable estrogens. Metabolically, the effect of the TIW regimen was similar to the QD regimen for obese women in terms of leptin suppression and increase in the adiponectin-leptin ratio. Reduction in tissue Ki-67 was less for obese women on the TIW regimen than QD, although changes were similar for non-obese women. Our findings suggest that TIW exemestane should be explored further for primary cancer prevention in both normal weight and obese cohorts.

BACKGROUND. HER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR). METHODS. To investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing and ERBB2 FISH of 285 pretreatment and posttreatment tumors from 129 patients in this T-DM1+P neoadjuvant trial. A subset of cases was also subject to NanoString spatial digital profiling. RESULTS. Pretreatment tumors from patients with pCR had the highest level of ERBB2 mRNA and ERBB signaling. HER2 heterogeneity was associated with no pCR, basal-like features, and low ERBB2 expression yet high ERBB signaling sustained by activation of downstream pathway components. Residual tumors showed decreased HER2 protein levels and ERBB2 copy number heterogeneity and increased PI3K pathway enrichment and luminal features. HET tumors showed minimal treatment-induced transcriptomic changes compared with non-HET tumors. Immune infiltration correlated with pCR and HER2-HET status. CONCLUSION. Resistance mechanisms in HET and non-HET tumors are distinct. HER2-targeting antibodies have limited efficacy in HET tumors. Our results support the stratification of patients based on HET status and the use of agents that target downstream components of the ERBB signaling pathway in patients with HET tumors. TRIAL REGISTRATION. ClinicalTrials.gov NCT02326974. FUNDING. This study was funded by Roche and the National Cancer Institute., Introduction Breast cancer is one of the most prevalent and life-threatening malignancies in women worldwide (1). Breast cancer is a heterogeneous disease clinically classified on the basis of the expression [...]

BACKGROUND. HER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR). METHODS. To investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing and ERBB2 FISH of 285 pretreatment and posttreatment tumors from 129 patients in this T-DM1+P neoadjuvant trial. A subset of cases was also subject to NanoString spatial digital profiling. RESULTS. Pretreatment tumors from patients with pCR had the highest level of ERBB2 mRNA and ERBB signaling. HER2 heterogeneity was associated with no pCR, basal-like features, and low ERBB2 expression yet high ERBB signaling sustained by activation of downstream pathway components. Residual tumors showed decreased HER2 protein levels and ERBB2 copy number heterogeneity and increased PI3K pathway enrichment and luminal features. HET tumors showed minimal treatment-induced transcriptomic changes compared with non-HET tumors. Immune infiltration correlated with pCR and HER2-HET status. CONCLUSION. Resistance mechanisms in HET and non-HET tumors are distinct. HER2-targeting antibodies have limited efficacy in HET tumors. Our results support the stratification of patients based on HET status and the use of agents that target downstream components of the ERBB signaling pathway in patients with HET tumors. [ABSTRACT FROM AUTHOR]

Bismuth(III) complexes have been reported to act as inhibitors of the enzyme urease, ubiquitously present in soils and implicated in the pathogenesis of several microorganisms. The general insolubility of Bi(III) complexes in water at neutral pH, however, is an obstacle to their utilization. In our quest to improve the solubility of Bi(III) complexes, we selected a compound reported to inhibit urease, namely [Bi(HEDTA)]·2H2O, and co-crystallized it with (i) racemic DL -histidine to obtain the conglomerate [Bi2(HEDTA)2(μ- D -His)2]·6H2O + [Bi2(HEDTA)2(μ- L -His)2]·6H2O, (ii) enantiopure L -histidine to yield [Bi2(HEDTA)2(μ- L -His)2]·6H2O, and (iii) cytosine to obtain [Bi(HEDTA)]·Cyt·2H2O. All compounds, synthesised by mechanochemical methods and by slurry, were characterized in the solid state by calorimetric (DSC and TGA) and spectroscopic (IR) methods, and their structures were determined using powder X-ray diffraction (PXRD) data. All compounds show an appreciable solubility in water, with values ranging from 6.8 mg mL−1 for the starting compound [Bi(HEDTA)]·2H2O to 36 mg mL−1 for [Bi2(HEDTA)2(μ- L -His)2]·6H2O. The three synthesized compounds as well as [Bi(HEDTA)]·2H2O were then tested for inhibition activity against urease. Surprisingly, no enzymatic inhibition was observed during in vitro assays using Canavalia ensiformis urease and in vivo assays using cultures of Helicobacter pylori, raising questions on the efficacy of Bi(III) compounds to counteract the negative effects of urease activity in the agro-environment and in human health. [ABSTRACT FROM AUTHOR]

The conservation of the genetic integrity of Apis mellifera subspecies has emerged as an important objective. In 2019, the Emilia-Romagna region became the first Italian regional authority to issue a law specifically addressing the protection of the native Apis mellifera ligustica subspecies. In this study we analysed a highly informative portion of the mitochondrial DNA (mtDNA), widely used for assessing genetic diversity of honey bee populations. By analysing 1143 honey bees sampled after the introduction of this law, we provided a snapshot of the distribution of mtDNA haplotypes in this region. The two most frequent mtDNA haplotypes were C1 (characteristic of A. m. ligustica) and C2 (characteristic of A. m. carnica), reported in 86.5% and 11.0% of the analysed bees, respectively. About 1.3% and 1.1% of the analysed bees carried mtDNA haplotypes of the A and M lineages (haplotypes A1a, A1e, A4, A26, A65 and two novel ones, A2w and A6a; M3, M3a, M4 and M79). Continued genetic monitoring will be important to assess the impact of this regional law over the coming years. Based on the obtained results, we recommend a more stringent policy to prevent the erosion of the genetic integrity of the native subspecies A. m. ligustica. [ABSTRACT FROM AUTHOR]

Donkeys (Equus asinus) have been used extensively in agriculture and transportations since their domestication, ca. 5000–7000 years ago, but the increased mechanization of the last century has largely spoiled their role as burden animals, particularly in developed countries. Consequently, donkey breeds and population sizes have been declining for decades, and the diversity contributed by autochthonous gene pools has been eroded. Here, we examined coding-region data extracted from 164 complete mitogenomes and 1392 donkey mitochondrial DNA (mtDNA) control-region sequences to (i) assess worldwide diversity, (ii) evaluate geographical patterns of variation, and (iii) provide a new nomenclature of mtDNA haplogroups. The topology of the Maximum Parsimony tree confirmed the two previously identified major clades, i.e. Clades 1 and 2, but also highlighted the occurrence of a deep-diverging lineage within Clade 2 that left a marginal trace in modern donkeys. Thanks to the identification of stable and highly diagnostic coding-region mutational motifs, the two lineages were renamed as haplogroup A and haplogroup B, respectively, to harmonize clade nomenclature with the standard currently adopted for other livestock species. Control-region diversity and population expansion metrics varied considerably between geographical areas but confirmed North-eastern Africa as the likely domestication center. The patterns of geographical distribution of variation analyzed through phylogenetic networks and AMOVA confirmed the co-occurrence of both haplogroups in all sampled populations, while differences at the regional level point to the joint effects of demography, past human migrations and trade following the spread of donkeys out of the domestication center. Despite the strong decline that donkey populations have undergone for decades in many areas of the world, the sizeable mtDNA variability we scored, and the possible identification of a new early radiating lineage further stress the need for an extensive and large-scale characterization of donkey nuclear genome diversity to identify hotspots of variation and aid the conservation of local breeds worldwide. [ABSTRACT FROM AUTHOR]

Simple Summary: Honeybees are vital pollinators, essential for maintaining ecosystems and biodiversity, but there is rising concern about the health of managed honey bee colonies, especially in heavily human-influenced ecosystems. Multiple factors contribute to this decline, including environmental conditions, forage quality, and pesticide use. These elements have a complex effect on the health and nutritional status of honeybee colonies and influence their response to disease and various stressors. In this study, the authors propose a new approach to assess colony health by correlating common measures of colony strength such as honey and pollen reserves, the number of bees, and brood with hemolymph proteins, common bee pathogens (Varroa destructor and Nosema spp.), and essential trace elements (iron, zinc, and copper). Significant correlations were found between hemolymph proteins and colony performance measures, and between V. destructor and hemolymph proteins and iron content. In conclusion, this study confirms the need for a more holistic approach to honeybee health considering all the relevant aspects and critical points that may affect colony survival. Environment, forage quality, management practices, pathogens, and pesticides influence honeybee responses to stressors. This study proposes an innovative approach to assess colony health and performance using molecular diagnostic tools by correlating hemolymph proteins with common measures of colony strength, prevalent honeybee pathogens (Varroa destructor and Nosema spp.), and essential trace elements (iron, zinc and copper). Colonies were selected from four apiaries located in different environmental and foraging conditions in the province of Bologna (Italy). Hemolymph samples were taken from June to October 2019. The Varroa infestation of the colonies was estimated by assessing the natural mortality of the mites, while the bees were tested for Nosema spp. spores using a microscopic method. Hemolymph proteins were quantified and separated using SDS-PAGE, and colony performance was assessed by determining adult bees, total brood, honey, and pollen reserves. The biomarkers measured proved to be useful for monitoring changes in performance and trophic conditions during summer and early autumn. Significant correlations were found between hemolymph proteins and colony performance measures. A positive correlation between pollen reserves, vitellogenin, and hexamerin 70a highlights the importance of these proteins for successful overwintering. In October, Varroa infestation was negatively correlated with total proteins, vitellogenin, apolipophorin II, transferrin, and hexamerin 70a, with negative implications for overwintering; furthermore, Varroa infestation was also negatively correlated with iron content, potentially affecting iron homeostasis. [ABSTRACT FROM AUTHOR]

Scientific and industrial reasons dictate the study of the solid state of imepitoin, a highly safe and tolerable anticonvulsant drug used in the therapy of epileptic dogs that was approved in the Europe Union in 2013. Our investigations allowed us to discover the existence of a new polymorph of imepitoin, which finds itself in a monotropic relationship with the crystalline form (polymorph I) already known and present on the market. This form (polymorph II), obtained by crystallization from xylene, remains metastable under ambient conditions for at least 1 year. Both solid forms were characterized by thermal (DSC and TGA), spectroscopic (FT-IR and Raman), microscopic (SEM and HSM), and diffractometric techniques. The thermodynamic relationship between the two polymorphs (monotropic) is such that it is not possible to study the melting of polymorph II, not even by adopting appropriate experimental strategies. Our measurements highlighted that the melting peak of imepitoin actually also includes an onset of melt decomposition. The ab initio structure solution, obtained from synchrotron X-ray powder diffraction data collected at room temperature, allowed us to determine the crystal structure of the new polymorph (II). It crystallizes in the monoclinic crystal structure, P21/c space group (#14), with a = 14.8687(6) Å, b = 7.2434(2) Å, c = 12.5592(4) Å, β = 107.5586(8)°, V = 1289.61(8) Å3, and Z = 4. [ABSTRACT FROM AUTHOR]

Simple Summary: The ABO gene is the major blood classification system, which, in humans, is present in three main forms: A; B; and O. Under the umbrella of these main forms, other variants modulate the activity of the gene for functions that go beyond the determination of the blood type. However, in other animals, this gene is still poorly studied. The pig is a species of economic relevance, an animal model, and one of the most promising species for the development of xenotransplants. For all these reasons, it is important to investigate the ABO gene in pigs. In this study, we explored the main alleles present in different pig species (A and O) and other variants besides these two major forms to investigate the evolution of ABO and its possible association with several production and blood-related traits. We reported that the ABO gene has multiple variants that helped to define the evolution of the gene across the Suinae species. In an explorative analysis, we also reported that ABO gene polymorphisms were suggestively associated with the level of magnesium in plasma. Further studies are needed to dissect the effect of ABO gene polymorphisms in different pig breeds and populations. Polymorphisms in the human ABO gene determine the major blood classification system based on the three well-known forms: A; B; and O. In pigs that carry only two main alleles in this gene (A and O), we still need to obtain a more comprehensive distribution of variants, which could also impact its function. In this study, we mined more than 500 whole-genome sequencing datasets to obtain information on the ABO gene in different Suidae species, pig breeds, and populations and provide (i) a comprehensive distribution of the A and O alleles, (ii) evolutionary relationships of ABO gene sequences across Suidae species, and (iii) an exploratory evaluation of the effect of the different ABO gene variants on production traits and blood-related parameters in Italian Large White pigs. We confirmed that allele O is likely under balancing selection, present in all Sus species investigated, without being fixed in any of them. We reported a novel structural variant in perfect linkage disequilibrium with allele O that made it possible to estimate the evolutionary time window of occurrence of this functional allele. We also identified two single nucleotide polymorphisms that were suggestively associated with plasma magnesium levels in pigs. Other studies can also be constructed over our results to further evaluate the effect of this gene on economically relevant traits and basic biological functions. [ABSTRACT FROM AUTHOR]