Miracle-dz/UniFAR-FTUs huggingface dataset:
The Role of Tumor-Associated Macrophages in Hematologic Malignancies

Simple Summary Tumor-associated macrophages (TAM) represent a leading component of the tumor microenvironment in hematologic malignancies. TAM could display antitumor activity or, conversely, could contribute to tumor growth and survival, depending on their polarization. TAM are polarized towards form M1, with a pro-inflammatory phenotype and an antineoplastic activity, or M2, with an alternately activated phenotype, associated with a poor outcome in patients presenting with leukemia, lymphoma or multiple myeloma. The molecular mechanisms of TAM in different types of hematologic malignancies are different due to the peculiar microenvironment of each disease. TAM could contribute to tumor progression, reduced apoptosis and angiogenesis; a different TAM polarization could explain a reduced treatment response in patients with a similar disease subtype. The aim of our review is to better define the role of TAM in patients with leukemia, lymphoma or multiple myeloma. Finally, we would like to focus on TAM as a possible target for antineoplastic therapy. Abstract The tumor microenvironment includes dendritic cells, T-cytotoxic, T-helper, reactive B-lymphoid cells and macrophages; these reactive cells could interplay with malignant cells and promote tumor growth and survival. Among its cellular components, tumor-associated macrophages (TAM) represent a component of the innate immune system and play an important role, especially in hematologic malignancies. Depending on the stimuli that trigger their activation, TAM are polarized towards form M1, contributing to antitumor responses, or M2, associated with tumor progression. Many studies demonstrated a correlation between TAM, disease progression and the patient’s outcome in lymphoproliferative neoplasms, such as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), even if with conflicting results. A critical hurdle to overcome is surely represented by the heterogeneity in the choice of the optimal markers and methods used for TAM analysis (gene-expression profile vs. immunohistochemistry, CD163vs. CD68vs. CD163/CD68 double-positive cells). TAM have been recently linked to the development and progression of multiple myeloma and leukemia, with a critical role in the homing of malignant cells, drug resistance, immune suppression and angiogenesis. As such, this review will summarize the role of TAM in different hematologic malignancies, focusing on the complex interplay between TAM and tumor cells, the prognostic value of TAM and the possible TAM-targeted therapeutic strategies.
Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

Significance The chromosome 10q26 locus is the genetic region most strongly associated with elevated risk of age-related macular degeneration (AMD), but the underlying genetic defects initiating disease are unresolved. Using human-derived eye tissues, we demonstrate that mRNA encoding the serine protease, HTRA1, is reduced in the retinal pigment epithelium (RPE) of donors with risk-associated variants that disrupt a cis-regulatory element within the 10q26 locus. Consequentially, there is diminished HtrA1 protein within the RPE–Bruch’s membrane interface, the primary site of AMD initiation, with age. This indicates that HtrA1 functions to maintain the integrity of this interface during the aging process and that HtrA1 levels are impaired by chromosome 10q26 risk-associated variants. HtrA1 augmentation may be a viable therapeutic option for AMD. Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151–171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389–407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227–3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE–Bruch’s membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE–BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD.
Magnetic Reversal in Wiegand Wires Evaluated by First-Order Reversal Curves

The magnetic structure of Wiegand wires cannot be evaluated using conventional magnetization hysteresis curves. We analyzed the magnetization reversal of a Wiegand wire by measuring the first-order reversal curves (FORCs). A FeCoV Wiegand wire with a magnetically soft outer layer and a hard magnetic core was used in this study. The magnetization reversal of the soft and hard regions in the wire was identified in the FORC diagrams. The magnetization reversal of the dominantly irreversible process of the soft layer and the magnetic intermediate region between the soft and hard regions was clarified.
Assessing the Role of Lipids in the Molecular Mechanism of Membrane Proteins

Membrane proteins have evolved to work optimally within the complex environment of the biological membrane. Consequently, interactions with surrounding lipids are part of their molecular mechanism. Yet, the identification of lipid–protein interactions and the assessment of their molecular role is an experimental challenge. Recently, biophysical approaches have emerged that are compatible with the study of membrane proteins in an environment closer to the biological membrane. These novel approaches revealed specific mechanisms of regulation of membrane protein function. Lipids have been shown to play a role in oligomerization, conformational transitions or allosteric coupling. In this review, we summarize the recent biophysical approaches, or combination thereof, that allow to decipher the role of lipid–protein interactions in the mechanism of membrane proteins.
Qualitative Analysis of Remineralization Capabilities of Bioactive Glass (NovaMin) and Fluoride on Hydroxyapatite (HA) Discs: An In Vitro Study

Tooth decay is a prevalent disease that initiates when the oral pH becomes acidic. Fluoride and/or bioactive glass (NovaMin) were used to regenerate/repair teeth that had been decalcified. In this present study, we investigated the effect of fluoride and/or bioactive glass (NovaMin) on remineralization of hydroxyapatite (HA) discs, which mimic the enamel surface of natural teeth. HA discs were etched with phosphoric acid and treated with one of the following toothpastes: (1) Sensodyne toothpaste with fluoride; (2) Sensodyne toothpaste with fluoride and bioactive glass (NovaMin); (3) Tom’s toothpaste without fluoride or bioactive glass (NovaMin); and (4) Tom’s toothpaste with bioactive glass (NovaMin). The toothpastes were applied on the etched discs for two minutes, once a day for 15 days. Scanning electron microscopy (SEM) was used to analyze surface morphologies and X-ray photoelectron spectroscopy (XPS) was used to analyze surface compositions. Tom’s toothpaste with only NovaMin demonstrated the most remineralization potential compared with the other groups. In conclusion, incorporating bioactive glass (NovaMin) into toothpastes could benefit the repair and remineralization of teeth.
Increased Beta-Hydroxybutyrate Level Is Not Sufficient for the Neuroprotective Effect of Long-Term Ketogenic Diet in an Animal Model of Early Parkinson’s Disease. Exploration of Brain and Liver Energy Metabolism Markers

The benefits of a ketogenic diet in childhood epilepsy steered up hope for neuroprotective effects of hyperketonemia in Parkinson’s disease (PD). There are multiple theoretical reasons but very little actual experimental proof or clinical trials. We examined the long-term effects of the ketogenic diet in an animal model of early PD. A progressive, selective dopaminergic medium size lesion was induced by 6-OHDA injection into the medial forebrain bundle. Animals were kept on the stringent ketogenic diet (1% carbohydrates, 8% protein, 70% fat) for 3 weeks prior and 4 weeks after the brain operation. Locomotor activity, neuron count, dopaminergic terminal density, dopamine level, and turnover were analyzed at three time-points post-lesion, up to 4 weeks after the operation. Energy metabolism parameters (glycogen, mitochondrial complex I and IV, lactate, beta-hydroxybutyrate, glucose) were analyzed in the brain and liver or plasma. Protein expression of enzymes essential for gluconeogenesis (PEPCK, G6PC) and glucose utilization (GCK) was analyzed in the liver. Despite long-term hyperketonemia pre- and post-lesion, the ketogenic diet did not protect against 6-OHDA-induced dopaminergic neuron lesions. The ketogenic diet only tended to improve locomotor activity and normalize DA turnover in the striatum. Rats fed 7 weeks in total with a restrictive ketogenic diet maintained normoglycemia, and neither gluconeogenesis nor glycogenolysis in the liver was responsible for this effect. Therefore, potentially, the ketogenic diet could be therapeutically helpful to support the late compensatory mechanisms active via glial cells but does not necessarily act against the oxidative stress-induced parkinsonian neurodegeneration itself. A word of caution is required as the stringent ketogenic diet itself also carries the risk of unwanted side effects, so it is important to study the long-term effects of such treatments. More detailed metabolic long-term studies using unified diet parameters are required, and human vs. animal differences should be taken under consideration.
Comparing the impact of an icon array versus a bar graph on preference and understanding of risk information: Results from an online, randomized study

Background Few studies have examined the best way to convey the probability of serious events occurring in the future (i.e., risk of stroke or death) to persons with low numeracy or graph literacy proficiency. To address this gap, we developed and user-tested a bar graph and compared it to icon arrays to assess its impact on understanding and preference for viewing risk information. Objectives To determine the: (i) formats’ impact on participants’ understanding of risk information; (ii) formats’ impact on understanding and format preference across numeracy and graph literacy subgroups; (iii) rationale supporting participants’ preference for each graphical display format. Methods An online sample (evenly made up of participants with high and low objective numeracy and graph literacy) was randomized to view either the icon array or the bar graph. Each format conveyed the risk of major stroke and death five years after choosing surgery, a stent, or medication to treat carotid artery stenosis. Participants answered questions to assess their understanding of the risk information. Lastly, both formats were presented in parallel, and participants were asked to identify their preferred format to view risk information and explain their preference. Results Of the 407 participants, 197 were assigned the icon array and 210 the bar graph. Understanding of risk information and format preference did not differ significantly between the two trial arms, irrespective of numeracy and graph literacy proficiency. High numeracy and graph literacy proficiency was associated with high understanding (p<0.01) and a preference for the bar graph (p = 0.01). Conclusion We found no evidence to demonstrate the superiority of one format over another on understanding. The majority of participants preferred viewing the risk information using the bar graph format.
A Cu(II)-MOF Based on a Propargyl Carbamate-Functionalized Isophthalate Ligand as Nitrite Electrochemical Sensor

This paper investigates the electrochemical properties of a new Cu(II)-based metal-organic framework (MOF). Noted as Cu-YBDC, it is built upon a linker containing the propargyl carbamate functionality and immobilized on a glassy carbon electrode by drop-casting (GC/Cu-YBDC). Afterward, GC/Cu-YBDC was treated with HAuCl4 and the direct electro-deposition of Au nanoparticles was carried at 0.05 V for 600 s (GC/Au/Cu-YBDC). The performance of both electrodes towards nitrite oxidation was tested and it was found that GC/Au/Cu-YBDC exhibited a better electrocatalytic behavior toward the oxidation of nitrite than GC/Cu-YBDC with enhanced catalytic currents and a reduced nitrite overpotential from 1.20 to 0.90 V. Additionally GC/Au/Cu-YBDC showed a low limit of detection (5.0 μM), an ultrafast response time (<2 s), and a wide linear range of up to 8 mM in neutral pH.
Epithelial Mesenchymal Transition and Immune Response in Metaplastic Breast Carcinoma

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial–mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.
Expression of RUNX1-JAK2 in Human Induced Pluripotent Stem Cell-Derived Hematopoietic Cells Activates the JAK-STAT and MYC Pathways

A heterogeneous genetic subtype of B-cell precursor acute lymphoblastic leukemia is driven by constitutive kinase-activation, including patients with JAK2 fusions. In our study, we model the impact of a novel JAK2 fusion protein on hematopoietic development in human induced pluripotent stem cells (hiPSCs). We insert the RUNX1-JAK2 fusion into one endogenous RUNX1 allele through employing in trans paired nicking genome editing. Tagging of the fusion with a degron facilitates protein depletion using the heterobifunctional compound dTAG-13. Throughout in vitro hematopoietic differentiation, the expression of RUNX1-JAK2 is driven by endogenous RUNX1 regulatory elements at physiological levels. Functional analysis reveals that RUNX1-JAK2 knock-in cell lines yield fewer hematopoietic progenitors, due to RUNX1 haploinsufficiency. Nevertheless, these progenitors further differentiate toward myeloid lineages to a similar extent as wild-type cells. The expression of the RUNX1-JAK2 fusion protein only elicits subtle effects on myeloid differentiation, and is unable to transform early hematopoietic progenitors. However, phosphoprotein and transcriptome analyses reveal that RUNX1-JAK2 constitutively activates JAK-STAT signaling in differentiating hiPSCs and at the same time upregulates MYC targets—confirming the interaction between these pathways. This proof-of-principle study indicates that conditional expression of oncogenic fusion proteins in combination with hematopoietic differentiation of hiPSCs may be applicable to leukemia-relevant disease modeling.
NPM1 Mutational Status Underlines Different Biological Features in Pediatric AML

Simple Summary Nucleophosmin (NPM1) protein regulates several cellular processes and is predominantly located in the nucleolus, owing to the localization signal provided by two tryptophan residues. In acute myeloid leukemia (AML), NPM1 gene is frequently mutated, leading to the aberrant translocation of the protein into cytoplasm. In the present work, we classified NPM1 mutations according to the loss of either one or both tryptophan residues as non-A-like and A-like mutations, respectively, and evaluated their biological features. We found that non-A-like mutations partially delocalize NPM1 protein into the cytoplasm, with a proportion of remaining nucleolar protein preserving p53 protein expression and downstream activity. Different HOXA and HOXB gene expression and cell death pathway activation between A-like and non-A-like NPM1-mutated cells were shown, with an enhanced sensitivity to chemotherapy for AML cells with non-A-like mutations. This study suggests the need for a sub-classification of NPM1-mutated AML, with subsequent implications in the therapeutic management. Abstract Nucleophosmin (NPM1) is a nucleocytoplasmic shuttling protein, predominantly located in the nucleolus, that regulates a multiplicity of different biological processes. NPM1 localization in the cell is finely tuned by specific signal motifs, with two tryptophan residues (Trp) being essential for the nucleolar localization. In acute myeloid leukemia (AML), several NPM1 mutations have been reported, all resulting in cytoplasmic delocalization, but the putative biological and clinical significance of different variants are still debated. We explored HOXA and HOXB gene expression profile in AML patients and found a differential expression between NPM1 mutations inducing the loss of two (A-like) Trp residues and those determining the loss of one Trp residue (non-A-like). We thus expressed NPM1 A-like- or non-A-like-mutated vectors in AML cell lines finding that NPM1 partially remained in the nucleolus in the non-A-like NPM1-mutated cells. As a result, only in A-like-mutated cells we detected HOXA5, HOXA10, and HOXB5 hyper-expression and p14ARF/p21/p53 pathway deregulation, leading to reduced sensitivity to the treatment with either chemotherapy or Venetoclax, as compared to non-A-like cells. Overall, we identified that the NPM1 mutational status mediates crucial biological characteristics of AML cells, providing the basis for further sub-classification and, potentially, management of this subgroup of patients.
Atypia and Follicular Lesions of Undetermined Significance in Subsequent Biopsy Result: What Clinicians Need to Know

Atypia and follicular lesions of undetermined significance (AUS/FLUS) is the most controversial category of The Bethesda System. The risk of malignancy (ROM) in this group is estimated as 5–15%, however, the occurrence of two or more subsequent biopsy results with AUS/FLUS diagnosis makes these clinical situations more complex. We evaluated the ROM and prognostic value of aggressive ultrasound (US) features in 342 patients with thyroid nodules (TNs) with subsequent biopsy results of AUS/FLUS. We assessed US features and compared them with the final histopathological diagnosis. Overall, 121 (35.4%) individuals after first AUS/FLUS diagnosis underwent surgery and 221 (64.6%) patients had repeated biopsies. The ROM after first, second, and third biopsies with subsequent AUS/FLUS diagnosis were 7.4%, 18.5%, and 38.4% respectively. We demonstrated significantly higher rates of occurrence of aggressive US features in patients with malignancy (p < 0.0001). The age <55 years old was also a significant risk factor for TC (p = 0.044). Significant associations were found between aggressive US features and malignancy in patients after first diagnosis of AUS/FLUS (p < 0.05). The juxtaposition of US features with the number of biopsy repetitions of TN with consecutive AUS/FLUS diagnoses may simplify the decision-making process in surgical management. Two or three consecutive biopsy results with AUS/FLUS diagnosis increases the ROM.
Expression of Connexin43 Stimulates Endothelial Angiogenesis Independently of Gap Junctional Communication In Vitro

Connexins (Cx) form gap junctions (GJ) and allow for intercellular communication. However, these proteins also modulate gene expression, growth, and cell migration. The downregulation of Cx43 impairs endothelial cell migration and angiogenetic potential. Conversely, endothelial Cx43 expression is upregulated in an in vivo angiogenesis model relying on hemodynamic forces. We studied the effects of Cx43 expression on tube formation and proliferation in HUVECs and examined its dependency on GJ communication. Expectedly, intercellular communication assessed by dye transfer was linked to Cx43 expression levels in HUVECs and was sensitive to a GJ blockade by the Cx43 mimetic peptide Gap27. The proliferation of HUVECs was not affected by Cx43 overexpression using Cx43 cDNA transfection, siRNA-mediated knockdown of Cx43, or the inhibition of GJ compared to the controls (transfection of an empty vector, scrambled siRNA, and the solvent). In contrast, endothelial tube and sprout formation in HUVECs was minimized after Cx43 knockdown and significantly enhanced after Cx43 overexpression. This was not affected by a GJ blockade (Gap27). We conclude that Cx43 expression positively modulates the angiogenic potential of endothelial cells independent of GJ communication. Since proliferation remained unaffected, we suggest that Cx43 protein may modulate endothelial cell migration, thereby supporting angiogenesis. The modulation of Cx43 expression may represent an exploitable principle for angiogenesis induction in clinical therapy.
Influence of Genotype on High Glucosinolate Synthesis Lines of Brassica rapa

This study was conducted to investigate doubled haploid (DH) lines produced between high GSL (HGSL) Brassica rapa ssp. trilocularis (yellow sarson) and low GSL (LGSL) B. rapa ssp. chinensis (pak choi) parents. In total, 161 DH lines were generated. GSL content of HGSL DH lines ranged from 44.12 to 57.04 μmol·g−1·dry weight (dw), which is within the level of high GSL B. rapa ssp. trilocularis (47.46 to 59.56 μmol g−1 dw). We resequenced five of the HGSL DH lines and three of the LGSL DH lines. Recombination blocks were formed between the parental and DH lines with 108,328 single-nucleotide polymorphisms in all chromosomes. In the measured GSL, gluconapin occurred as the major substrate in HGSL DH lines. Among the HGSL DH lines, BrYSP_DH005 had glucoraphanin levels approximately 12-fold higher than those of the HGSL mother plant. The hydrolysis capacity of GSL was analyzed in HGSL DH lines with a Korean pak choi cultivar as a control. Bioactive compounds, such as 3-butenyl isothiocyanate, 4-pentenyl isothiocyanate, 2-phenethyl isothiocyanate, and sulforaphane, were present in the HGSL DH lines at 3-fold to 6.3-fold higher levels compared to the commercial cultivar. The selected HGSL DH lines, resequencing data, and SNP identification were utilized for genome-assisted selection to develop elite GSL-enriched cultivars and the industrial production of potential anti-cancerous metabolites such as gluconapin and glucoraphanin.