• SLC22A17
• 5-Azacytidine
• Bioinformatics
• Cancer biomarkers
• Cutaneous melanoma
• DNA methylation
• Epigenetics
• Tumor microenvironment

• DNA Methylation/genetics
• Humans
• Melanoma/genetics
• Melanoma/pathology
• Melanoma/metabolism
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Skin Neoplasms/genetics
• Skin Neoplasms/pathology
• Skin Neoplasms/metabolism
• Gene Expression Regulation, Neoplastic
• Cell Line, Tumor
• Promoter Regions, Genetic/genetics
• Melanoma, Cutaneous Malignant
• Male
• Organic Cation Transport Proteins/genetics
• Organic Cation Transport Proteins/metabolism
• Female
• Azacitidine/pharmacology
• Middle Aged

• European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR M4C2-Action 1.4-Call "Potenziamento strutture di ricerca e creazione di "campioni nazionali di R&S"-Project "National Center for Gene Therapy and Drugs bas European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR M4C2-Action 1.4-Call "Potenziamento strutture di ricerca e creazione di "campioni nazionali di R&S"-Project "National Center for Gene Therapy and Drugs bas
• Italian Ministry of Health (IT-MOH) through 'Ricerca Corrente', grant numbers M2/2 and L2-1 Italian Ministry of Health (IT-MOH) through 'Ricerca Corrente', grant numbers M2/2 and L2-1
• 2017POCSICILIA1/5/5.4/9.2.3/AVV6.22/0001 (CUP: G61I0002200095) 2017POCSICILIA1/5/5.4/9.2.3/AVV6.22/0001 (CUP: G61I0002200095)
• European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR M4C2—Action 1.4—Call “Potenziamento strutture di ricerca e creazione di “campioni nazionali di R&S”—Project “National Center for Gene Therapy and Drugs bas
• Italian Ministry of Health (IT-MOH) through ‘Ricerca Corrente’, grant numbers M2/2 and L2-1

• MMP-9
• clinical progression
• endometrial cancer
• meta-analysis
• prognosis

• chemokine receptors
• chemokines
• coronavirus
• neuroinflammation
• neutrophils

• DNA methylation
• LCN2
• MMP9
• SLC22A17
• bioinformatic
• cancer
• ferroptosis
• gene expression

• MMP
• TIMP
• cancer
• endometrial cancer
• metalloproteinases

• Endometrial Neoplasms/genetics
• Endometrial Neoplasms/pathology
• Endometrium/metabolism
• Endometrium/pathology
• Extracellular Matrix/genetics
• Extracellular Matrix/metabolism
• Female
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Metalloproteases/classification
• Metalloproteases/genetics

• NGAL
• SASP
• iron
• siderophores
• tumor stroma

• Animals
• Antibodies, Monoclonal/therapeutic use
• CRISPR-Cas Systems
• Gene Editing/methods
• Humans
• Lipocalin-2/antagonists & inhibitors
• Lipocalin-2/genetics
• Lipocalin-2/immunology
• Lipocalin-2/metabolism
• Neoplasms/metabolism
• Neoplasms/therapy
• RNA, Small Interfering/genetics
• RNAi Therapeutics/methods
• Secretome/metabolism
• Senescence-Associated Secretory Phenotype
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Stromal Cells/metabolism
• Tumor Microenvironment

The signaling network between cancer and stromal cells plays a crucial role in tumor microenvironment. The fate of tumor progression mainly depends on the huge amount of information that these cell populations exchange from the onset of neoplastic transformation. Interfering with such signaling has been producing exciting results in cancer therapy: just think of anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies that, acting as immune checkpoint inhibitors, interrupt the inhibitory signaling exerted by cancer cells on immune cells or the CAR-T technology that fosters the reactivation of anti-tumoral immunity in a restricted group of leukemias and lymphomas. Nevertheless, many types of cancers, in particular solid tumors, are still refractory to these treatments, so the identification of novel molecular targets in tumor secretome would benefit from implementation of current anti-cancer therapeutical strategies. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a secreted protein abundantly expressed in the secretome of various human tumors. It represents a promising target for the multiple roles that are played inside cancer and stromal cells, and also overall in their cross-talk. The review focuses on the different roles of NGAL in tumor microenvironment and in cancer senescence-associated secretory phenotype (SASP), highlighting the most crucial functions that could be eventually targetable in cancer therapy.

• NGAL
• SASP
• iron
• siderophores
• tumor stroma

Tubular adenocarcinoma of the colon, which originates from the epithelium of the glands, is a major health concern worldwide. However, it is difficult to detect at an early stage. The lack of biomarkers is a main barrier to the diagnosis and treatment of tubular adenocarcinoma. Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted protein that induces the expression of matrix metalloproteinase-9 (MMP-9) and is involved in various tumors. NGAL and MMP-9 have been reported to be associated with tumorigenesis and development. They may have potential as biomarkers for diagnosis of tubular adenocarcinoma of the colon.

To determine whether NGAL and MMP-9 can be used as potential biomarkers to indicate the progression of tubular adenocarcinoma of the colon.

Samples were collected from surgically excised tissue from various patients. The content of pro-gastrin-releasing peptide (pro-GRP) in the serum was measured by an electrochemiluminescence immunoassay. The expression patterns of NGAL and MMP-9 and the relationship between NGAL and MMP-9 were examined by quantitative real-time PCR, Western blotting and immunohistochemical analysis.

In this study, we found that NGAL and MMP-9 can be used as biomarkers for the detection of tubular adenocarcinoma of the colon and that their combination improved diagnostic accuracy. By analyzing the expression of NGAL in tubular adenocarcinoma at different levels, we found that NGAL expression was significantly upregulated in primary tubular adenocarcinoma tissues compared with normal tissues. The upregulation of NGAL expression was strongly correlated with both the degree of differentiation and the disease stage (I–III), indicating that NGAL could serve as a diagnostic biomarker for tubular adenocarcinoma. When using NGAL as a biomarker for diagnosis, the accuracy was similar to that achieved with the widely used biomarker pro-GRP, suggesting that NGAL is reliable. Moreover, the expression of MMP-9 was also strongly correlated with the differentiation stage, demonstrating that MMP-9 could be used as a biomarker to indicate the progression of tubular adenocarcinoma of the colon. More importantly, the combination of NGAL and MMP-9 produced a more accurate diagnosis of tubular adenocarcinoma, and these results were further confirmed by immunohistochemical analysis of tissue sections.

Our study demonstrated that both NGAL and MMP-9 can be used as biomarkers for the diagnosis of colon tubular adenocarcinoma and that the results could be further improved by combining them.

• Tubular adenocarcinoma
• Colon
• Neutrophil gelatinase-associated lipocalin
• Matrix metalloproteinase-9
• Biomarker

Matrix metalloproteinases-9 (MMP-9) can regulate extracellular matrix deposition in diabetic glomerular injury. However, it remains unknown whether MMP-9 is involved in the renal tubular injury. Meanwhile, neutrophil gelatinase-associated lipocalin (NGAL), defined as a biomarker of proximal tubular injury, may influence MMP-9 by forming the MMP-9/NGAL complex. The aim of this study was to investigate MMP-9 expression in proximal renal tubules and the relationship of MMP-9 and NGAL in diabetic rat model treated with Valsartan.

Sprague Dawley rats were randomly divided into three groups: Diabetic group, Control group, and Treated group. The diabetic rat model was established by injection of streptozotocin. Related indexes were measured at the end of the 2nd, 4th, 8th and 12th week post-modeling.

In diabetic groups, the concentrations of MMP-9 markedly increased in the serum and urine of rats in the early stage, even before the appearance of pathological albuminuria. Markedly elevated MMP-9/NGAL complex concentrations were also tested in diabetic groups. Western blot and qPCR tests confirmed that MMP-9 expression levels in the proximal renal tubular epithelial cells of diabetic rats were significantly higher than in control groups (P < 0.05). Correlation analysis showed that MMP-9 was positively correlated with NGAL at both protein and gene expression levels. In addition, Valsartan observably reduced tubular injury as well as MMP-9 expression in diabetic rats.

In diabetic kidney injury, the expression of MMP-9 in the proximal renal tubular epithelial cells was significantly increased. Besides, a positive correlation was found between MMP-9 and NGAL expression, along with high levels of MMP-9/NGAL complex, which indicated that NGAL might participate in the regulation of MMP-9 expression. The administration of Valsartan may reduce this effect.

• Diabetic rats
• Matrix Metalloproteinases-9
• Neutrophil Gelatinase-associated Lipocalin

Amyotrophic lateral sclerosis (ALS) remains a fatal, neurodegenerative disease frequently leading to dysarthria and impaired swallowing. Better understanding of ALS pathophysiology is prompting the use of humoral cell therapies. Hence, a repeated cellular therapy was applied to ALS patients as an attempt to prevent speech deterioration. Autologous bone marrow-derived lineage-negative (Lin⁻) cells were intrathecally administered three times at six-week intervals to 42 sporadic ALS patients. Patients were examined for articulatory functions using subjective (VHI) and objective (FDA) scales. Selected trophic, proinflammatory factors and expression profiles of miRNA were measured in cerebrospinal fluid (CSF) and plasma by multiplex Luminex and q-PCR in different timepoints. Of the 42 patients who received the Lin⁻ cells, 6 showed improvement in articulatory functions, 27 remained stable, and 9 deteriorated after 18 weeks of therapy according to FDA scale. Clinical improvement was particularly evident by the 7^th day of each cell application and concerned better cough and swallow reflex, soft palate, laryngeal time, pitch, and volume. These results correlated with significant changes in the concentration of various trophic and proinflammatory factors and miRNA expression profiles. A multiple application of Lin⁻ cells proved to be safe and feasible. The repeated procedure can potentate a humoral effect and prevent speech deterioration. A short-lasting trophic effect of each Lin⁻ cells administration was observed on local and systemic level. However, further in-depth studies are necessary to sustain the beneficial effect.

• copper
• gynecological cancer
• metallothionein
• micronutrients
• zinc

• Antioxidants/metabolism
• Carcinogenesis
• Copper/administration & dosage
• Copper/metabolism
• Dietary Supplements
• Female
• Genital Neoplasms, Female/metabolism
• Homeostasis
• Humans
• Matrix Metalloproteinases
• Metallothionein/metabolism
• Oxidative Stress
• Trace Elements
• Zinc/administration & dosage
• Zinc/metabolism
• Zinc Fingers

Amyotrophic lateral sclerosis (ALS) remains a fatal disease with limited therapeutic options. Signaling via neurotrophins (NTs), neuroinflammation, and certain micro-RNAs are believed to play essential role in ALS pathogenesis. Lineage-negative stem/progenitor cells (Lin⁻) were obtained from bone marrow of 18 ALS patients and administered intrathecally. Clinical assessment was performed using ALS Functional Rating Scale (FRSr) and Norris scale. Protein concentrations were measured in plasma and cerebrospinal fluid (CSF) by multiplex fluorescent bead-based immunoassay. Gene expression in nucleated blood cells was assessed using gene microarray technique. Finally, miRNA expression was analyzed using qPCR in CSF and plasma samples. We observed a significant decrease of C-reactive protein (CRP) concentration in plasma on the seventh day from the application of cells. Gene array results revealed decreased expression of gene sets responsible for neutrophil activation. Further analysis revealed moderate negative correlation between CRP level in CSF and clinical outcome. Brain-derived neurotrophic factor (BDNF) concentrations in both plasma and CSF significantly correlated with the favorable clinical outcome. On a micro-RNA level, we observed significant increase of miR-16-5p expression one week after transplantation in both body fluids and significant increase of miR-206 expression in plasma. Administration of Lin⁻ cells may decrease inflammatory response and prevent neurodegeneration. However, these issues require further investigations.

• amyotrophic lateral sclerosis (ALS)
• gene microarrays
• inflammatory response
• lineage-negative cells
• neurotrophins

• Chemoresistance
• LCN2/NGAL
• Metastasis
• Neoplasms
• Targeting therapy

The safety and effectiveness of robotic surgery are evaluated by comparing perioperative outcomes with laparoscopy and laparotomy in endometrial cancer.

PubMed, MEDLINE, Embase, Cochrane, and other databases were searched for eligible studies up to April 2019. Studies that compared robotic surgery with laparoscopy or laparotomy in surgical staging of endometrial cancer were included. The pooled odds ratio and weighted mean difference were calculated using a random-effects or a fixed-effects model to summarize the results.

Twenty-seven articles were ultimately included, with one randomized controlled trial and 26 observational studies. A total of 6568 patients were included. Meta-analysis showed that robotic surgery had less estimated blood loss (P < 0.001), blood transfusion (P = 0.04), intraoperative complications (P = 0.001), and conversion to open surgery (P = 0.001), and a shorter hospital stay (P = 0.001), but had a longer operation time (P = 0.04) in surgical staging of endometrial cancer compared with laparoscopy. There were no significant differences in postoperative complications, the total number of lymph nodes harvested, the number of pelvic lymph nodes harvested, and the number of para-aortic lymph nodes harvested between techniques. Robotic surgery had a longer operation time (P = 0.008), less estimated blood loss (P < 0.001), blood transfusion (P < 0.001), and postoperative complications (P < 0.001), and a shorter hospital stay (P < 0.001) compared with laparotomy. There were no significant differences in other variables between techniques.

Robotic surgery is a safer surgical approach than laparoscopy and laparotomy in surgical staging of endometrial cancer, with less estimated blood loss, blood transfusion, and conversion, and the same number of lymph nodes harvested.

• complement system proteins
• gene expression
• immunity
• premature birth

• LIN- stem/progenitor cells
• amyotrophic lateral sclerosis
• dysarthria
• neurotrophins
• speech disorders

• MMP-9
• NGAL
• endometriosis
• stage

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease, leading to loss of muscle strength and motor control. Impaired speech and swallowing lower the quality of life and consequently may induce acute respiratory failure. Bone marrow-derived stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed whether adjuvant cellular therapy could affect the levels of selected neurotrophins and proinflammatory factors in the cerebrospinal fluid (CSF) and subsequently prevent the deterioration of articulation.

The study group consisted of 32 patients with sporadic ALS who underwent autologous lineage-negative (Lin⁻) stem cell intrathecal administration to the spinal canal. Lin⁻ cells were aspirated from the bone marrow and isolated using immunomagnetic beads and a lineage cell depletion kit. Patients were examined for articulatory functions by means of the Voice Handicap Index (VHI) questionnaire and Frenchay Dysarthria Assessment (FDA). In parallel, we carried out the analysis of selected trophic and proinflammatory factors in CSF utilizing multiplex fluorescent bead-based immunoassays.

Of the 32 patients who received the Lin⁻ progenitor cell therapy, 6 (group I) showed improvement in articulatory functions, 23 remained stable (group II), and 3 deteriorated (group III) on the 28^th day. The improvement was particularly noticeable in a better cough reflex, laryngeal time, and dribble reflex. A statistically significant lower level of brain-derived neurotrophic factor (BDNF) was observed on day 0 in group I compared to group II. The CSF concentrations of C-reactive protein (CRP) in group I significantly decreased 7 days after Lin⁻ SPC transplantation. On the contrary, a significant increase in the tumor necrosis factor receptor (TNF-R) level was confirmed among patients from group I with improvement of dribble and coughing reflex, tongue movements, and respiration on the 7^th day, as well as on day 28 including dribble reflex solely.

An application of Lin⁻ stem cells could potentate the beneficial humoral effect. The prevention of deterioration of articulatory functions in ALS patients after applying adjuvant Lin⁻ stem cell therapy seems to be promising. Although the procedure is safe and feasible, it requires further in-depth studies.

• GPP
• OLFM4
• autoimmune
• neutrophils
• vesicles

Human neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein present in a wide variety of tissues and cell types. NGAL exists as a 25 kDa monomer, a 46 kDa homodimer (the most abundant form in healthy subjects) and a 130 kDa disulfide-linked heterodimer bound to latent matrix metalloproteinase-9. Dysregulated expression of NGAL in human malignancies suggests its value as a clinical marker. A growing body of evidence is highlighting NGAL’s paradoxical (i.e., both beneficial and detrimental) effects on cellular processes associated with tumor development (proliferation, survival, migration, invasion, and multidrug resistance). At least two distinct cell surface receptors are identified for NGAL. This review (i) summarizes our current knowledge of NGAL’s expression profiles in solid tumors and leukemias, and (ii) critically evaluates the beneficial and detrimental activities of NGAL having been documented in a diverse range of cancer-derived cell lines. A better understanding of the causal relationships between NGAL dysregulation and tumor development will require a fine analysis of the molecular aspects and biological role(s) of NGAL both in primary tumors and at different stages of disease. Having an accurate picture of NGAL’s contribution to tumor progression is a prerequisite for attempting to modulate this protein as a putative therapeutic target.

• cancer
• drug resistance
• invasion
• matrix metalloproteinase-9
• migration
• neutrophil gelatinase-associated lipocalin
• signaling
• survival

Therapeutic options for amyotrophic lateral sclerosis (ALS) are still limited. Great hopes, however, are placed in growth factors that show neuroprotective abilities (e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF)) and in the immune modulating features, in particular, the anti-inflammatory effects. In our study we aimed to investigate whether a bone marrow-derived lineage-negative (Lin-) cells population, after autologous application into cerebrospinal fluid (CSF), is able to produce noticeable concentrations of trophic factors and inflammatory-related proteins and thus influence the clinical course of ALS. To our knowledge, the evaluation of Lin- cells transplantation for ALS treatment has not been previously reported. Early hematopoietic Lin- cells were isolated from twelve ALS patients’ bone marrow, and later, the suspension of cells was administered into the subarachnoid space by lumbar puncture. Concentrations of selected proteins in the CSF and plasma were quantified by multiplex fluorescent bead-based immunoassays at different timepoints post-transplantation. We also chose microRNAs (miRNAs) related to muscle biology (miRNA-1, miRNA-133a, and miRNA-206) and angiogenesis and inflammation (miRNA-155 and miRNA-378) and tested, for the first time, their expression profiles in the CSF and plasma of ALS patients after Lin- cells transplantation. The injection of bone marrow cells resulted in decreased concentration of selected inflammatory proteins (C3) after Lin- cells injection, particularly in patients who had a better clinical outcome. Moreover, several analyzed miRNAs have changed expression levels in the CSF and plasma of ALS patients subsequent to Lin- cells administration. Interestingly, the expression of miR-206 increased in ALS patients, while miR-378 decreased both in the CSF and plasma one month after the cells’ injection. We propose that autologous lineage-negative early hematopoietic cells injected intrathecally may be a safe and feasible source of material for transplantations to the central nervous system (CNS) environment aimed at anti-inflammatory support provision for ALS adjuvant treatment strategies. Further research is needed to evaluate whether the observed effects could significantly influence the ALS progression.

• Lin- cells
• amyotrophic lateral sclerosis (ALS)
• complement
• microRNA
• neurotrophins
• trophic effects of stem cell-based therapy