Antifungal Synergy: Mechanistic Insights into the R-1-R Peptide and Bidens pilosa Extract as Potent Therapeutics against Candida spp. through Proteomics.

Previous reports have demonstrated that the peptide derived from LfcinB, R-1-R, exhibits anti-Candida activity, which is enhanced when combined with an extract from the Bidens pilosa plant. However, the mechanism of action remains unexplored. In this research, a proteomic study was carried out, followed by a bioinformatic analysis and biological assays in both the SC5314 strain and a fluconazole-resistant isolate of Candida albicans after incubation with R-1-R. The proteomic data revealed that treatment with R-1-R led to the up-regulation of most differentially expressed proteins compared to the controls in both strains. These proteins are primarily involved in membrane and cell wall biosynthesis, membrane transport, oxidative stress response, the mitochondrial respiratory chain, and DNA damage response. Additionally, proteomic analysis of the C. albicans parental strain SC5314 treated with R-1-R combined with an ethanolic extract of B. pilosa was performed. The differentially expressed proteins following this combined treatment were involved in similar functional processes as those treated with the R-1-R peptide alone but were mostly down-regulated (data are available through ProteomeXchange with identifier PXD053558). Biological assays validated the proteomic results, evidencing cell surface damage, reactive oxygen species generation, and decreased mitochondrial membrane potential. These findings provide insights into the complex antifungal mechanisms of the R-1-R peptide and its combination with the B. pilosa extract, potentially informing future studies on natural product derivatives.

Effect on Feeding Behaviour and Growing of Being a Dominant or Subordinate Growing Pig and Its Relationship with the Faecal Microbiota.

Pigs are a social species, and they establish hierarchies for better use of resources and to reduce conflicts. However, in pig production, the opportunities for growth can differ between dominant and subordinate animals. In the present study, a system was tested to perform a dominant versus subordinate test in growing pigs to investigate how the hierarchy affects feeding behaviour, growth, and gut microbiota assessed in faeces. Sixty-four animals housed in eight different pens were used, with four castrated males and four females in each one, weighing 18 kg at arrival and maintained during the whole growing period, until 140 kg. Three stool samples were obtained from the animals directly from the anus to avoid contamination of the faeces 58, 100, and 133 days after the start of the study to investigate the microbiota composition. The dominant animals had higher gains during the growing period than the subordinates. In addition, they were performing more visits to the feeder throughout the day. Differential abundance patterns were observed in five bacterial genera, with Oliverpabstia, Peptococcus, and Faecalbacterium being more abundant in dominant animals and Holdemanella and Acetitomaculum being overrepresented in subordinate ones. This microbial biomarker accurately classified dominant versus subordinate groups of samples with an AUC of 0.92.

Insights into the pathophysiology and response of persistent spinal pain syndrome type 2 to spinal cord stimulation: a human genome-wide association study.

BACKGROUND: Spinal cord stimulation (SCS) provides pain relief for some patients with persistent spinal pain syndrome type 2 (PSPS 2), but the precise mechanisms of action and prognostic factors for a favorable pain response remain obscure. This in vivo human genome-wide association study provides some pathophysiological clues. METHODS: We performed a high-density oligonucleotide microarray analysis of serum obtained from both PSPS 2 cases and pain-free controls who had undergone lower back spinal surgery at the study site. Using multivariate discriminant analysis, we tried to identify different expressions between mRNA transcripts from PSPS 2 patients relative to controls, SCS responders to non-responders, or SCS responders to themselves before starting SCS. Gene ontology enrichment analysis was used to identify the biological processes that best discriminate between the groups of clinical interest. RESULTS: Thirty PSPS 2 patients, of whom 23 responded to SCS, were evaluated together with 15 pain-free controls. We identified 11 significantly downregulated genes in serum of PSPS 2 patients compared with pain-free controls and two significantly downregulated genes once the SCS response became apparent. All were suggestive of enhanced inflammation, tissue repair mechanisms and proliferative responses among the former. We could not identify any gene differentiating patients who responded to SCS from those who did not respond. CONCLUSIONS: This study points out various biological processes that may underlie PSPS 2 pain and SCS therapeutic effects, including the modulation of neuroimmune response, inflammation and restorative processes.

Clinical value of liquid biopsy in FGFR2 fusion-positive cholangiocarcinoma patients during targeted therapy.

PURPOSE: FGFR2 fusions occur in 10%-15% of intrahepatic cholangiocarcinoma (iCCA) patients, potentially benefiting from FGFR inhibitors (FGFRi). We aimed to assess the feasibility of detecting FGFR2 fusions in plasma and explore plasma biomarkers for managing FGFRi treatment. EXPERIMENTAL DESIGN: We conducted a retrospective study on 18 patients with iCCA and known FGFR2 fusions previously identified in tissue samples from prior FGFRi treatment. Both tissue and synchronous plasma samples were analyzed using a custom hybrid capture gene panel with next-generation sequencing (VHIO-iCCA panel) and validated against commercial vendor results. Longitudinal plasma analysis during FGFRi was performed. Subsequently, we explored the correlation between plasma biomarkers, liver enzymes, tumor volume, and clinical outcomes. RESULTS: Sixteen patients (88.9%) were positive for FGFR2 fusion events in plasma. Remarkably, the analysis of plasma suggests that lower levels of circulating tumor DNA (ctDNA) are linked to clinical benefits from targeted therapy and result in improved progression-free survival and (PFS) overall survival (OS). Higher concentrations of cell-free DNA (cfDNA) before FGFRi treatment were linked to worse OS, correlating with impaired liver function, and indicating compromised cfDNA removal by the liver. Additionally, increased ctDNA or the emergence of resistance mutations allowed earlier detection of disease progression compared to standard radiological imaging methods. CONCLUSIONS: VHIO-iCCA demonstrated accurate detection of FGFR2 fusions in plasma. The integration of information from various plasma biomarkers holds the potential to predict clinical outcomes and identify treatment failure prior to radiological progression, offering valuable guidance for the clinical management of patients with iCCA.

Cell Therapy in the Treatment of Female Stress Urinary Incontinence: Current Status and Future Proposals.

BACKGROUND: Stress urinary incontinence (SUI) is a common condition with a significant impact on the quality of life of female patients. The limitations of current treatment strategies have prompted the exploration of new effective and minimally invasive alternative approaches, including cell therapy. METHODS: A literature search was conducted to update the current clinical status of stem cell therapy in the management of female stress urinary incontinence. RESULTS: Over thirty clinical studies have been designed to assess the feasibility, safety and efficacy of cell therapy for female SUI. Despite differences in cell types and protocols, the overall treatment procedures were similar. Standard subjective and objective assessment tools, and follow-up periods ranged from 6 weeks to 6 years have been used. Cell injection has shown to be a safe therapy in the treatment of female SUI. However, the results from more recent randomized trials have shown less promising results than expected in restoring continence. Heterogeneous research methodologies using different cell types and doses make it difficult to draw conclusions about effectiveness. Several key points remain that need to be further explored in future clinical trials. CONCLUSION: To advance in the development of cell therapy, it is essential to know the mechanisms involved to be able to direct it properly, its efficacy and the durability of the injected cells. Rigorous and homogenized preclinical and clinical studies that demonstrate its scope and improve its application are necessary for validation in the treatment of female SUI.

Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally.

Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.

Impacts of early deprivation on behavioral and neural measures of executive function in early adolescence.

Children reared in institutional settings experience early deprivation that has lasting implications for multiple aspects of neurocognitive functioning, including executive function (EF). Changes in brain development are thought to contribute to these persistent EF challenges, but little research has used fMRI to investigate EF-related brain activity in children with a history of early deprivation. This study examined behavioral and neural data from a response conflict task in 12-14-year-olds who spent varying lengths of time in institutional care prior to adoption (N = 84; age at adoption - mean: 15.85 months, median: 12 months, range: 4-60 months). In initial analyses, earlier- and later-adopted (EA, LA) youth were compared to a group of children raised in their biological families (non-adopted, NA). NA youth performed significantly more accurately than LA youth, with EA youth falling in between. Imaging data suggested that previously institutionalized (PI) youth activated additional frontoparietal regions, including dorsolateral prefrontal cortex, as compared to NA youth. In addition, EA youth uniquely activated medial prefrontal regions, and LA uniquely activated parietal regions during this task. A separate analysis in a larger group of PI youth examined whether behavioral or brain measures of EF varied with the duration of deprivation experienced. Duration of deprivation was negatively associated with activation of default mode network (DMN) regions. Overall, results suggest that there are lasting effects of deprivation on EF, but that those who are removed from institutional care earlier may be able to recruit additional neural resources as a compensatory mechanism.

Pericytes Are Immunoregulatory Cells in Glioma Genesis and Progression.

Vascular co-option is a consequence of the direct interaction between perivascular cells, known as pericytes (PCs), and glioblastoma multiforme (GBM) cells (GBMcs). This process is essential for inducing changes in the pericytes' anti-tumoral and immunoreactive phenotypes. Starting from the initial stages of carcinogenesis in GBM, PCs conditioned by GBMcs undergo proliferation, acquire a pro-tumoral and immunosuppressive phenotype by expressing and secreting immunosuppressive molecules, and significantly hinder the activation of T cells, thereby facilitating tumor growth. Inhibiting the pericyte (PC) conditioning mechanisms in the GBM tumor microenvironment (TME) results in immunological activation and tumor disappearance. This underscores the pivotal role of PCs as a key cell in the TME, responsible for tumor-induced immunosuppression and enabling GBM cells to evade the immune system. Other cells within the TME, such as tumor-associated macrophages (TAMs) and microglia, have also been identified as contributors to this immunomodulation. In this paper, we will review the role of these three cell types in the immunosuppressive properties of the TME. Our conclusion is that the cellular heterogeneity of immunocompetent cells within the TME may lead to the misinterpretation of cellular lineage identification due to different reactive stages and the identification of PCs as TAMs. Consequently, novel therapies could be developed to disrupt GBM-PC interactions and/or PC conditioning through vascular co-option, thereby exposing GBMcs to the immune system.

A guide to artificial intelligence for cancer researchers.

Artificial intelligence (AI) has been commoditized. It has evolved from a specialty resource to a readily accessible tool for cancer researchers. AI-based tools can boost research productivity in daily workflows, but can also extract hidden information from existing data, thereby enabling new scientific discoveries. Building a basic literacy in these tools is useful for every cancer researcher. Researchers with a traditional biological science focus can use AI-based tools through off-the-shelf software, whereas those who are more computationally inclined can develop their own AI-based software pipelines. In this article, we provide a practical guide for non-computational cancer researchers to understand how AI-based tools can benefit them. We convey general principles of AI for applications in image analysis, natural language processing and drug discovery. In addition, we give examples of how non-computational researchers can get started on the journey to productively use AI in their own work.

Tumor Size Is Not Everything: Advancing Radiomics as a Precision Medicine Biomarker in Oncology Drug Development and Clinical Care. A Report of a Multidisciplinary Workshop Coordinated by the RECIST Working Group.

Radiomics, the science of extracting quantifiable data from routine medical images, is a powerful tool that has many potential applications in oncology. The Response Evaluation Criteria in Solid Tumors Working Group (RWG) held a workshop in May 2022, which brought together various stakeholders to discuss the potential role of radiomics in oncology drug development and clinical trials, particularly with respect to response assessment. This article summarizes the results of that workshop, reviewing radiomics for the practicing oncologist and highlighting the work that needs to be done to move forward the incorporation of radiomics into clinical trials.

Let it glow: genetically encoded fluorescent reporters in Plasmodium.

The use of fluorescent proteins (FPs) in Plasmodium parasites has been key to understand the biology of this obligate intracellular protozoon. FPs like the green fluorescent protein (GFP) enabled to explore protein localization, promoter activity as well as dynamic processes like protein export and endocytosis. Furthermore, FP biosensors have provided detailed information on physiological parameters at the subcellular level, and fluorescent reporter lines greatly extended the malariology toolbox. Still, in order to achieve optimal results, it is crucial to know exactly the properties of the FP of choice and the genetic scenario in which it will be used. This review highlights advantages and disadvantages of available landing sites and promoters that have been successfully applied for the ectopic expression of FPs in Plasmodium berghei and Plasmodium falciparum. Furthermore, the properties of newly developed FPs beyond DsRed and EGFP, in the visualization of cells and cellular structures as well as in the sensing of small molecules are discussed.