👤 Michael Drozd

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder that complicates the identification of effective therapeutic targets. The potential of stem cells and neurotrophins as promising candidates has become increasingly evident, owing to their neuroprotective and anti-inflammatory properties. In this study, a preclinical evaluation of the safety and biodistribution of mesenchymal stromal/stem cells (MSCs) combined with neurotrophin-releasing polyelectrolyte nanoparticles (NTs) was conducted in a porcine intrathecal delivery model relevant to ALS therapy development. Four groups of male pigs were administered saline with NTs, adipose-derived stem cells (ASCs) with NTs, Wharton's jelly-derived MSCs (WJ-MSCs) with NTs, or spinal puncture only. The safety of the treatment was assessed using magnetic resonance imaging (MRI), haematological and biochemical analyses, cerebrospinal fluid profiling, and histology. No adverse effects or significant systemic alterations were observed. It is noteworthy that C-reactive protein levels diminished following NT and NT-MSC administration, suggesting a systemic anti-inflammatory effect. The migration of MSCs was facilitated by cerebrospinal fluid, leading to their accumulation around the spinal cord and brain parenchyma. The present findings demonstrate short-term safety and biodistribution patterns following intrathecal administration of MSCs combined with neurotrophin-releasing nanoparticles in a large-animal model. These preliminary observations provide a pilot framework for future efficacy studies in disease-specific ALS models. This work establishes a translational platform for the development of future ALS therapies, with subsequent studies focused on efficacy testing in disease-specific models that more accurately reflect the slow, heterogeneous, multisystem nature of human ALS. Show less

Circulating tumor cells (CTCs) have emerged as a key biomarker in cancer detection and prognosis, and their molecular profiling is gaining importance in precision oncology. Liquid biopsies, which allow the extraction of CTCs, circulating tumor DNA (ctDNA) or cell-free DNA (cfDNA), have measurable advantages over traditional tissue biopsies, especially when molecular material is difficult to obtain. However, this method is not without limitations. Difficulties in differentiating between primary and metastatic lesions, uncertain predictive values and the complexity of the biomarkers used can prove challenging. Recently, high cell heterogeneity has been identified as the main obstacle to achieving high diagnostic accuracy. Because not all cells undergo epithelial-mesenchymal transition (EMT) at the same time, there is a large population of hybrid CTCs that express both epithelial and mesenchymal markers. Since traditional diagnostic tools primarily detect epithelial markers, they are often unable to detect cells with a hybrid phenotype; therefore, additional markers may be required to avoid false negatives. In this review, we summarize recent reports on emerging CTCs markers, with particular emphasis on their use in cancer diagnosis. Most of them, including vimentin, TWIST1, SNAI1, ZEB1, cadherins, CD44, TGM2, PD-L1 and GATA, hold promise for the detection of CTCs, but are also implicated in cancer progression, metastasis, and therapeutic resistance. Therefore, understanding the nature and drivers of epithelial-mesenchymal plasticity (EMP) is critical to advancing our knowledge in this field. Show less

Diabetes mellitus (DM) increases heart failure incidence and worsens prognosis, but its molecular basis is poorly defined in humans. We aimed to define the diabetic myocardial transcriptome and validate hits in their circulating protein form to define disease mechanisms and biomarkers. RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project was used to define differentially expressed genes (DEGs) in right atrial (RA) and left ventricular (LV) myocardium from people with vs. without DM (type 1 or 2). DEGs were validated as plasma proteins in the UK Biobank cohort, searching for directionally concordant differential expression. Validated plasma proteins were characterized in UK Biobank participants, irrespective of diabetes status, using cardiac magnetic resonance imaging, incident heart failure, and cardiovascular mortality. We found 32 and 32 DEGs associated with DM in the RA and LV, respectively, with no overlap between these. Plasma proteomic data were available for 12, with ERBB3, NRXN3, and HSPA2 (all LV hits) exhibiting directional concordance. Irrespective of DM status, lower circulating ERBB3 and higher HSPA2 were associated with impaired LV contractility and higher LV mass. Participants in the lowest quartile of circulating ERBB3 or highest quartile of circulating HSPA2 had increased incident heart failure and cardiovascular death vs. all other quartiles. DM is characterized by lower Erbb3 and higher Hspa2 expression in the myocardium, with directionally concordant differences in their plasma protein concentration. These are associated with LV dysfunction, incident heart failure, and cardiovascular mortality. Show less

Vanadium compounds are promising antidiabetic agents. In addition to regulating glucose metabolism, they also alter lipid metabolism. Due to the clear association between diabetes and atherosclerosis, the purpose of the present study was to assess the effect of sodium orthovanadate on the amount of individual fatty acids and the expression of stearoyl-coenzyme A desaturase (SCD or Δ Show less