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The introduction of the term “Metabolic Steatotic Liver Disease” (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver’s increased production of proteins known as “hepatokines” has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD.

Lipopolysaccharide (LPS) and its binding protein LBP have emerged as potential contributors to the progression from overweight/obesity to overt metabolic diseases and NAFLD. While LPS is known to activate hepatocyte inflammation, thus contributing toward NAFLD development, the role of LBP is more intricate, and recent data have shown that experimental reduction in hepatic LBP promotes NAFLD progression. In this cross-sectional investigation, we evaluated circulating LBP in relation to obesity, NAFLD, visceral adipose tissue (VAT) inflammation, and type 2 diabetes (T2D). We recruited 186 individuals (M/F: 81/105; age: 47 ± 10.4 years; BMI: 35.5 ± 8.6 kg/m2); a subgroup (n = 81) underwent bariatric surgery with intra-operative VAT and liver biopsies. LBP levels were higher in obese individuals than non-obese individuals but were inversely correlated with the parameters of glucose metabolism. Reduced LBP predicted T2D independent of age, sex, and BMI (p < 0.001). LBP levels decreased across more severe stages of hepatosteatosis and lobular inflammation, and were inversely associated with VAT inflammation signatures. In conclusion, LBP levels are increased in obese individuals and are associated with a more favorable metabolic profile and lower NAFLD/NASH prevalence. A possible explanation for these findings is that hepatic LBP production may be triggered by chronic caloric excess and facilitate LPS degradation in the liver, thus protecting these individuals from the metabolic consequences of obesity.

The introduction of the term "Metabolic Steatotic Liver Disease" (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver's increased production of proteins known as "hepatokines" has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD. [ABSTRACT FROM AUTHOR]

Commercial formulations of beneficial microbes have been used to enrich the rhizosphere microbiome of tomato plants grown in pots located in a glasshouse. These plants have been subjected to attacks by soil-borne parasites, such as root-knot nematodes (RKNs), and herbivores, such as the miner insect Tuta absoluta. The development of both parasites and the symptoms of their parasitism were restricted in these plants with respect to plants left untreated. A mixture, named in the text as Myco, containing plant growth-promoting rhizobacteria (PGPR), opportunistic biocontrol fungi (BCF), and arbuscular mycorrhizal fungi (AMF) was more effective in limiting pest damage than a formulation containing the sole AMF (Ozor). Therefore, Myco-treated plants inoculated with RKNs were taken as a model for further studies. The PGPR contained in Myco were not able to reduce nematode infection; rather, they worsened symptoms in plants compared with those observed in untreated plants. Therefore, it was argued that both BCF and AMF were the microorganisms that colonized roots and stimulated the plant immune system against RKNs. Beneficial fungi colonized the roots by lowering the activities of the defense supporting enzymes endochitinases and β-1,3-glucanase. However, as early as three days after nematode inoculation, these enzyme activities and the expression of the encoding pathogenesis-related genes (PR-2, PR-3) were found to be enhanced in roots with respect to non-inoculated plants, thus indicating that plants had been primed against RKNs. The addition of paclobutrazol, which reduces salicylic acid (SA) levels in cells, and diphenyliodonium chloride, which inhibits superoxide generation, completely abolished the repressive effect of Myco on nematode infection. Inhibitors of copper enzymes and the alternative cyanide-resistant respiration did not significantly alter resistance induction by Myco. When Myco-treated plants were subjected to moderate water stress and inoculated with nematodes, they retained numbers of developed individuals in the roots similar to those present in regularly watered plants, in contrast to what occurred in roots of untreated stressed plants that hosted very few individuals because of poor nutrient availability.

Haemophilia A (HA) and haemophilia B (HB) are X-linked inherited bleeding disorders caused by the absence or deficiency of coagulation factors VIII (FVIII) and IX (FIX), respectively. Recent advances in the development of effective treatments for haemophilia have led to a significant increase in life expectancy. As a result, the incidence of some comorbidities, including fragility fractures, has increased in people with haemophilia (PWH). The aim of our research was to perform a review of the literature investigating the pathogenesis and multidisciplinary management of fractures in PWH. The PubMed, Scopus and Cochrane Library databases were searched to identify original research articles, meta-analyses, and scientific reviews on fragility fractures in PWH. The mechanism underlying bone loss in PWH is multifactorial and includes recurrent joint bleeding, reduced physical activity with consequent reduction in mechanical load, nutritional deficiencies (particularly vitamin D), and FVIII and FIX deficiency. Pharmacological treatment of fractures in PWH includes antiresorptive, anabolic and dual action drugs. When conservative management is not possible, surgery is the preferred option, particularly in severe arthropathy, and rehabilitation is a key component in restoring function and maintaining mobility. Appropriate multidisciplinary fracture management and an adapted and tailored rehabilitation pathway are essential to improve the quality of life of PWH and prevent long-term complications. Further clinical trials are needed to improve the management of fractures in PWH.

Genetic resistance in plants against incompatible pests is expressed by the activation of an immune system; however, the molecular mechanisms of pest recognition and expression of immunity, although long the object of investigation, are far from being fully understood. The immune response triggered by the infection of soil-borne parasites, such as root-knot nematodes (RKNs), to incompatible resistant tomato plants was studied and compared to the compatible response that occurred when RKNs attacked susceptible plants. In compatible interactions, the invading nematode juveniles were allowed to fully develop and reproduce, whilst that was impeded in incompatible interactions. In crude root extracts, a first assay of reactive oxygen species (ROS)-scavenging enzymatic activity was carried out at the earliest stages of tomato–RKN incompatible interaction. Membrane-bound and soluble CAT, which is the most active enzyme in hydrogen peroxide (H2O2) scavenging, was found to be specifically inhibited in roots of inoculated resistant plants until 5 days after inoculation, with respect to uninoculated plants. The expression of genes encoding for antioxidant enzymes, such as CAT and glutathione peroxidase (GPX), was not always inhibited in roots of nematode-infected resistant tomato. Therefore, the biochemical mechanisms of CAT inhibition were further investigated. Two CAT isozymes were characterized by size exclusion HPLC as a tetrameric form with a molecular weight of 220,000 dalton and its subunits (55,000 dalton). Fractions containing such isozymes were tested by their sensitivity to both salicylic acid (SA) and H2O2. It was evidenced that elevated concentrations of both chemicals led to a partial inactivation of CAT. Elevated concentrations of H2O2 in incompatible interactions have been suggested to be produced by membrane-bound superoxide anion generating, SOD, and isoperoxidase-enhanced activities. Such partial inactivation of CAT has been depicted as one of the earliest key metabolic events, which is specifically associated with tomato immunity to RKNs. Enhanced ROS production and the inhibition of ROS-scavenging systems have been considered to trigger all the metabolic events leading to cell death and tissue necrosis developed around the head of the invading juveniles by which this special type of plant resistance is exerted.

Multicomponent reactions (MCRs) have emerged as a powerful strategy in synthetic organic chemistry due to their widespread applications in drug discovery and development. MCRs are flexible transformations in which three or more substrates react to form structurally complex products with high atomic efficiency. They are being increasingly appreciated as a highly exploratory and evolutionary tool by the medicinal chemistry community, opening the door to more sustainable, cost-effective and rapid synthesis of biologically active molecules. In recent years, MCR-based synthetic strategies have found extensive application in the field of drug discovery, and several anticancer drugs have been synthesized through MCRs. In this review, we present an overview of representative and recent literature examples documenting different approaches and applications of MCRs in the development of new anticancer drugs.

Arbuscular mycorrhizal fungi (AMF) are generally recognized to induce plant growth and prime plants against soil-borne parasites, such as plant parasitic nematodes. However, the effectiveness of commercial formulates containing AMF has been questioned. Increasing amounts per plant of one commercial AMF-containing formulate, reported in the text as Myco, were used to detect the effects on growth of tomato plants and the resistance induced against root-knot nematodes (RKNs) The doses used per plant (0.5, 1.0, 2.0 g, reported as Myco1, Myco2, Myco3, respectively) were soil-drenched to growing potted plants; the effects of such treatments were analyzed both in plants not inoculated or inoculated by Meloidogyne incognita juveniles. Consistent increases in plant weight were apparent as soon as 7 days only after Myco2 treatments. Moreover, only treatments with Myco2 induced a consistent repression of the nematode infection observed in untreated plants. Conversely, treatments with Myco1 and Myco3 did not produce such an early growth improvement; some plant weight increase was observable only at 28 dpt. Accordingly, such Myco doses did not restrict the level of infestation observed in untreated plants. Control of infection was dependent on the dose of Myco provided to plants five days before nematode inoculation. About one month after all Myco treatments, several areas of roots were found to be colonized by AMF, although in Myco2-treated plants, three genes involved in the AMF colonization process (SlCCaMK, SlLYK9, and SlLYK13) were found to be over-expressed already at 7 dpt; over-expression was generally less consistent at 14 and 21 dpt. The expressions of two key genes of plant defense, the hypersensitive cell death inducer PR4b gene and the glutathione peroxidase-encoding GPX gene, were monitored in roots of Myco2-treated plants 3 and 7 days after nematode inoculation. PR4b was over-expressed and GPX was silenced in treated plants with respect to untreated plants. The repressive effect of Myco2 treatment against RKN infection was completely abolished when Myco2 suspensions were autoclaved to sterilization or treated with the potent anti-fungal agent amphotericin B, thus indicating that the biological control agents contained in the commercial formulate were living fungi.

Self-assembling nanoparticles (SANPs) promise an effective delivery of bisphosphonates or microRNAs in the treatment of glioblastoma (GBM) and are obtained through the sequential mixing of four components immediately before use. The self-assembling approach facilitates technology transfer, but the complexity of the SANP preparation protocol raises significant concerns in the clinical setting due to the high risk of human errors during the procedure. In this work, it was hypothesized that the SANP preparation protocol could be simplified by using freeze-dried formulations. An in-depth thermodynamic study was conducted on solutions of different cryoprotectants, namely sucrose, mannitol and trehalose, to test their ability to stabilize the produced SANPs. In addition, the ability of SANPs to deliver drugs after lyophilization was assessed on selected formulations encapsulating zoledronic acid in vitro in the T98G GBM cell line and in vivo in an orthotopic mouse model. Results showed that, after lyophilization optimization, freeze-dried SANPs encapsulating zoledronic acid could retain their delivery ability, showing a significant inhibition of T98G cell growth both in vitro and in vivo. Overall, these results suggest that freeze-drying may help boost the industrial development of SANPs for the delivery of drugs to the brain.

Type 2 diabetes is characterized by impairment in insulin secretion, with an established genetic contribution. We aimed to evaluate common and low-frequency (1–5%) variants in nine genes strongly associated with insulin secretion by targeted sequencing in subjects selected from the extremes of insulin release measured by the disposition index. Collapsing data by gene and/or function, the association between disposition index and nonsense variants were significant, also after adjustment for confounding factors (OR = 0.25, 95% CI = 0.11–0.59, p = 0.001). Evaluating variants individually, three novel variants in ARAP1, IGF2BP2 and GCK, out of eight reaching significance singularly, remained associated after adjustment. Constructing a genetic risk model combining the effects of the three variants, only carriers of the ARAP1 and IGF2BP2 variants were significantly associated with a reduced probability to be in the lower, worst, extreme of insulin secretion (OR = 0.223, 95% CI = 0.105–0.473, p < 0.001). Observing a high number of normal glucose tolerance between carriers, a regression posthoc analysis was performed. Carriers of genetic risk model variants had higher probability to be normoglycemic, also after adjustment (OR = 2.411, 95% CI = 1.136–5.116, p = 0.022). Thus, in our southern European cohort, nonsense variants in all nine candidate genes showed association with better insulin secretion adjusted for insulin resistance, and we established the role of ARAP1 and IGF2BP2 in modulating insulin secretion.

Biliverdin reductase A (BVR-A) is an enzyme involved in the regulation of insulin signalling. Knockout (KO) mice for hepatic BVR-A, on a high-fat diet, develop more severe glucose impairment and hepato-steatosis than the wild type, whereas loss of adipocyte BVR-A is associated with increased visceral adipose tissue (VAT) inflammation and adipocyte size. However, BVR-A expression in human VAT has not been investigated. We evaluated BVR-A mRNA expression levels by real-time PCR in the intra-operative omental biopsy of 38 obese subjects and investigated the association with metabolic impairment, VAT dysfunction, and biopsy-proven non-alcoholic fatty liver disease (NAFLD). Individuals with lower VAT BVR-A mRNA levels had significantly greater VAT IL-8 and Caspase 3 expression than those with higher BVR-A. Lower VAT BVR-A mRNA levels were associated with an increased adipocytes’ size. An association between lower VAT BVR-A expression and higher plasma gamma-glutamyl transpeptidase was also observed. Reduced VAT BVR-A was associated with NAFLD with an odds ratio of 1.38 (95% confidence interval: 1.02–1.9; χ2 test) and with AUROC = 0.89 (p = 0.002, 95% CI = 0.76–1.0). In conclusion, reduced BVR-A expression in omental adipose tissue is associated with VAT dysfunction and NAFLD, suggesting a possible involvement of BVR-A in the regulation of VAT homeostasis in presence of obesity.

Overactivation of the c-MET/HGF system is a feature of many cancers. We previously reported that type II testicular germ cell tumor (TGCT) cells express the c-MET receptor, forming non-seminomatous lesions that are more positive compared with seminomatous ones. Notably, we also demonstrated that NT2D1 non-seminomatous cells (derived from an embryonal carcinoma lesion) increase their proliferation, migration, and invasion in response to HGF. Herein, we report that HGF immunoreactivity is more evident in the microenvironment of embryonal carcinoma biopsies with respect to seminomatous ones, indicating a tumor-dependent modulation of the testicular niche. PI3K/AKT is one of the signaling pathways triggered by HGF through the c-MET activation cascade. Herein, we demonstrated that phospho-AKT increases in NT2D1 cells after HGF stimulation. Moreover, we found that this pathway is involved in HGF-dependent NT2D1 cell proliferation, migration, and invasion, since the co-administration of the PI3K inhibitor LY294002 together with HGF abrogates these responses. Notably, the inhibition of endogenous PI3K affects collective cell migration but does not influence proliferation or chemotactic activity. Surprisingly, LY294002 administered without the co-administration of HGF increases cell invasion at levels comparable to the HGF-administered samples. This paradoxical result highlights the role of the testicular microenvironment in the modulation of cellular responses and stimulates the study of the testicular secretome in cancer lesions.

Two wild-type field populations of root-knot nematodes (Mi-Vfield, Mj-TunC2field), and two isolates selected for virulence in laboratory on resistant tomato cultivars (SM2V, SM11C2), were used to induce a resistance reaction in tomato to the soil-borne parasites. Epigenetic and metabolic mechanisms of resistance were detected and compared with those occurring in partially or fully successful infections. The activated epigenetic mechanisms in plant resistance, as opposed to those activated in infected plants, were detected by analyzing the methylated status of total DNA, by ELISA methods, and the expression level of key genes involved in the methylation pathway, by qRT-PCR. DNA hypo-methylation and down-regulation of two methyl-transferase genes (CMT2, DRM5), characterized the only true resistant reaction obtained by inoculating the Mi-1.2-carrying resistant tomato cv Rossol with the avirulent field population Mi-Vfield. On the contrary, in the roots into which nematodes were allowed to develop and reproduce, total DNA was generally found to be hyper-methylated and methyl-transferase genes up-loaded. DNA hypo-methylation was considered to be the upstream mechanism that triggers the general gene over-expression observed in plant resistance. Gene silencing induced by nematodes may be obtained through DNA hyper-methylation and methyl-transferase gene activation. Plant resistance is also characterized by an inhibition of the anti-oxidant enzyme system and activation of the defense enzyme chitinase, as opposed to the activation of such a system and inhibition of the defense enzyme glucanase in roots infested by nematodes.

Investigation into the role of methylation of the adenosine base (m6A) of RNA has only recently begun, but it quickly became apparent that m6A is able to control and fine-tune many aspects of mRNA, from splicing to translation. The ability of m6A to regulate translation distally, away from traditional sites near the nucleus, quickly caught the eye of neuroscientists because of implications for selective protein translation at synapses. Work in the brain has demonstrated how m6A is functionally required for many neuronal functions, but two in particular are covered at length here: The role of m6A in 1) neuron development; and 2) memory formation. The purpose of this review is not to cover all data about m6A in the brain. Instead, this review will focus on connecting mechanisms of m6A function in neuron development, with m6A’s known function in memory formation. We will introduce the concept of “translational priming” and discuss how current data fit into this model, then speculate how m6A-mediated translational priming during memory consolidation can regulate learning and memory locally at the synapse.

Angiopoietin-like protein 4 (ANGPTL4) regulates lipid partitioning by inhibiting circulating and tissue lipoprotein lipase (LPL); ANGPTL4 loss-of-function variants improve insulin sensitivity and reduce type 2 diabetes (T2D) risk with mechanisms partially unknown. This study was designed to explore metabolic implications of differential ANGPTL4 and LPL expression in human adipose tissue (AT). We recruited eighty-eight obese individuals, with and without abnormal glucose metabolism (AGM), undergoing bariatric surgery; visceral AT (VAT) fragments were obtained intra-operatively and analyzed by immunohistochemistry and mRNA by rt-PCR. Data on hepatic ANGPTL4 mRNA were available for 40 participants. VAT ANGPTL4 expression was higher in AGM individuals than in those with normal glucose tolerance (NGT) and associated with VAT inflammation, insulin resistance, and presence of adipocyte size heterogeneity. Increased ANGPTL4 was associated with AGM with OR = 5.1 (95% C.I.: 1.2–23; p = 0.02) and AUROC = 0.76 (95% C.I.: 1.2–23; p < 0.001). High LPL was associated with the detection of homogeneous adipocyte size, reduced microvessel density, and higher HIF-1α levels and inversely correlated to blood transaminases. In conclusion, in obese individuals, VAT ANGPTL4 levels are increased in the presence of local inflammation and AGM. Conversely, higher LPL expression describes a condition of increased lipid storage in adipocytes, which may serve as a protective mechanism against ectopic fat accumulation and related metabolic disease in obesity.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with poor outcomes largely due to its unique microenvironment, which is responsible for the low response to drugs and drug-resistance phenomena. This clinical need led us to explore new therapeutic approaches for systemic PDAC treatment by the utilization of two newly synthesized biphenylnicotinamide derivatives, PTA73 and PTA34, with remarkable antitumor activity in an in vitro PDAC model. Given their poor water solubility, inclusion complexes of PTA34 and PTA73 in Hydroxy-Propil-β-Cyclodextrin (HP-β-CD) were prepared in solution and at the solid state. Complexation studies demonstrated that HP-β-CD is able to form stable host–guest inclusion complexes with PTA34 and PTA73, characterized by a 1:1 apparent formation constant of 503.9 M−1 and 369.2 M−1, respectively (also demonstrated by the Job plot), and by an increase in aqueous solubility of about 150 times (from 1.95 µg/mL to 292.5 µg/mL) and 106 times (from 7.16 µg/mL to 762.5 µg/mL), in the presence of 45% w/v of HP-β-CD, respectively. In vitro studies confirmed the high antitumor activity of the complexed PTA34 and PTA73 towards PDAC cells, the strong G2/M phase arrest followed by induction of apoptosis, and thus their eligibility for PDAC therapy.

The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy.

The treatment of cystic fibrosis (CF) patients homozygous for the F508del mutation with Orkambi®, a combination of a corrector (lumacaftor) and a potentiator (ivacaftor) of the mutated CFTR protein, resulted in some amelioration of the respiratory function. However, a great variability in the clinical response was also observed. The aim of this study was to evaluate the response to Orkambi® in a small cohort of F508del/F508del patients (n = 14) in terms of clinical and laboratory parameters, including ex vivo CFTR activity in mononuclear cells (MNCs), during a 12-month treatment. Patients responded with an increase in percent predicted forced expiratory volume in 1 s (FEV1%) and body mass index (BMI) as well as with a decrease in white blood cell (WBC) total counts and serum C-reactive protein (CRP) levels, although not significantly. Sweat chloride and CFTR-dependent chloride efflux were found to decrease and increase, respectively, as compared with pre-therapy values. CFTR and BMI showed a statistically significant correlation during Orkambi® treatment. Clustering analysis showed that CFTR, BMI, sweat chloride, FEV1%, and WBC were strongly associated. These data support the notion that CFTR-dependent chloride efflux in MNCs should be investigated as a sensitive outcome measure of Orkambi® treatment in CF patients.

Some yet unidentified factors released by both oocyte and embryonic microenvironments demonstrated to be non-permissive for tumor development and display the remarkable ability to foster cell/tissue reprogramming, thus ultimately reversing the malignant phenotype. In the present study we observed how molecular factors extracted from Zebrafish embryos during specific developmental phases (20 somites) significantly antagonize proliferation of breast cancer cells, while reversing a number of prominent aspects of malignancy. Embryo extracts reduce cell proliferation, enhance apoptosis, and dramatically inhibit both invasiveness and migrating capabilities of cancer cells. Counteracting the invasive phenotype is a relevant issue in controlling tumor spreading and metastasis. Moreover, such effect is not limited to cancerous cells as embryo extracts were also effective in inhibiting migration and invasiveness displayed by normal breast cells undergoing epithelial−mesenchymal transition upon TGF-β1 stimulation. The reversion program involves the modulation of E-cadherin/β-catenin pathway, cytoskeleton remodeling with dramatic reduction in vinculin, as well as downregulation of TCTP and the concomitant increase in p53 levels. Our findings highlight that—contrary to the prevailing current “dogma”, which posits that neoplastic cells are irreversibly “committed”—the malignant phenotype can ultimately be “reversed”, at least partially, in response to environmental morphogenetic influences.

c-MET pathway over-activation is the signature of malignancy acquisition or chemotherapy resistance of many cancers. We recently demonstrated that type II Testicular Germ Cell Tumours (TGCTs) express c-MET receptor. In particular, we elucidated that the non-seminoma lesions express c-MET protein at higher level, compared with the seminoma ones. In line with this observation, NTERA-2 clone D1 (NT2D1) non-seminoma cells increase their proliferation, migration and invasion in response to Hepatocyte Growth Factor (HGF). One of the well-known adaptor-proteins belonging to c-MET signaling cascade is c-Src. Activation of c-Src is related to the increase of aggressiveness of many cancers. For this reason, we focused on the role of c-Src in c-MET-triggered and HGF-dependent NT2D1 cell activities. In the present paper, we have elucidated that this adaptor-protein is involved in HGF-dependent NT2D1 cell proliferation, migration and invasion, since Src inhibitor-1 administration abrogates these responses. Despite these biological evidences western blot analyses have not revealed the increase of c-Src activation because of HGF administration. However, notably, immunofluorescence analyses revealed that cytoplasmic and membrane-associated localization of c-Src shifted to the nuclear compartment after HGF stimulation. These results shed new light in the modality of HGF-dependent c-Src recruitment, and put the basis for novel investigations on the relationship between c-Src, and TGCT aggressiveness.

Some yet unidentified factors released by both oocyte and embryonic microenvironments demonstrated to be non-permissive for tumor development and display the remarkable ability to foster cell/tissue reprogramming, thus ultimately reversing the malignant phenotype. In the present study we observed how molecular factors extracted from Zebrafish embryos during specific developmental phases (20 somites) significantly antagonize proliferation of breast cancer cells, while reversing a number of prominent aspects of malignancy. Embryo extracts reduce cell proliferation, enhance apoptosis, and dramatically inhibit both invasiveness and migrating capabilities of cancer cells. Counteracting the invasive phenotype is a relevant issue in controlling tumor spreading and metastasis. Moreover, such effect is not limited to cancerous cells as embryo extracts were also effective in inhibiting migration and invasiveness displayed by normal breast cells undergoing epithelial–mesenchymal transition upon TGF-β1 stimulation. The reversion program involves the modulation of E-cadherin/β-catenin pathway, cytoskeleton remodeling with dramatic reduction in vinculin, as well as downregulation of TCTP and the concomitant increase in p53 levels. Our findings highlight that—contrary to the prevailing current "dogma", which posits that neoplastic cells are irreversibly "committed"—the malignant phenotype can ultimately be "reversed", at least partially, in response to environmental morphogenetic influences. [ABSTRACT FROM AUTHOR]