EGCG Disrupts the LIN28B/Let-7 Interaction and Reduces Neuroblastoma Aggressiveness.

Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology, and the identification of novel potential therapeutic targets and agents is an urgent clinical need. The RNA-binding protein LIN28B has been identified as an oncogene in NB and is associated with a poor prognosis. Given that LIN28B acts by negatively regulating the biogenesis of the tumor suppressor let-7 miRNAs, we reasoned that selective interference with the LIN28B/let-7 miRNA interaction would increase let-7 miRNA levels, ultimately leading to reduced NB aggressiveness. Here, we selected (-)-epigallocatechin 3-gallate (EGCG) out of 4959 molecules screened as the molecule with the best inhibitory activity on LIN28B/let-7 miRNA interaction and showed that treatment with PLC/PLGA-PEG nanoparticles containing EGCG (EGCG-NPs) led to an increase in mature let-7 miRNAs and a consequent inhibition of NB cell growth. In addition, EGCG-NP pretreatment reduced the tumorigenic potential of NB cells in vivo. These experiments suggest that the LIN28B/let-7 miRNA axis is a good therapeutic target in NB and that EGCG, which can interfere with this interaction, deserves further preclinical evaluation.

Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation.

Tissue regeneration and maintenance rely on coordinated stem cell behaviours. This orchestration can be impaired by oncogenic mutations leading to cancer. However, it is largely unclear how oncogenes perturb stem cells' orchestration to disrupt tissue. Here we used intravital imaging to investigate the mechanisms by which oncogenic Kras mutation causes tissue disruption in the hair follicle. Through longitudinally tracking hair follicles in live mice, we found that KrasG12D, a mutation that can lead to squamous cell carcinoma, induces epithelial tissue deformation in a spatiotemporally specific manner, linked with abnormal cell division and migration. Using a reporter mouse capture real-time ERK signal dynamics at the single-cell level, we discovered that KrasG12D, but not a closely related mutation HrasG12V, converts ERK signal in stem cells from pulsatile to sustained. Finally, we demonstrated that interrupting sustained ERK signal reverts KrasG12D-induced tissue deformation through modulating specific features of cell migration and division.

BDNF- and VEGF-Responsive Stimulus to an NGF Mimic Cyclic Peptide with Copper Ionophore Capability and Ctr1/CCS-Driven Signaling.

Neurotrophins are a family of growth factors that play a key role in the development and regulation of the functioning of the central nervous system. Their use as drugs is made difficult by their poor stability, cellular permeability, and side effects. Continuing our effort to use peptides that mimic the neurotrophic growth factor (NGF), the family model protein, and specifically the N-terminus of the protein, here we report on the spectroscopic characterization and resistance to hydrolysis of the 14-membered cyclic peptide reproducing the N-terminus sequence (SSSHPIFHRGEFSV (c-NGF(1-14)). Far-UV CD spectra and a computational study show that this peptide has a rigid conformation and left-handed chirality typical of polyproline II that favors its interaction with the D5 domain of the NGF receptor TrkA. c-NGF(1-14) is able to bind Cu2+ with good affinity; the resulting complexes have been characterized by potentiometric and spectroscopic measurements. Experiments on PC12 cells show that c-NGF(1-14) acts as an ionophore, influencing the degree and the localization of both the membrane transporter (Ctr1) and the copper intracellular transporter (CCS). c-NGF(1-14) induces PC12 differentiation, mimics the protein in TrkA phosphorylation, and activates the kinase cascade, inducing Erk1/2 phosphorylation. c-NGF(1-14) biological activities are enhanced when the peptide interacts with Cu2+ even with the submicromolar quantities present in the culture media as demonstrated by ICP-OES measurements. Finally, c-NGF(1-14) and Cu2+ concur to activate the cAMP response element-binding protein CREB that, in turn, induces the brain-derived neurotrophic factor (BDNF) and the vascular endothelial growth factor (VEGF) release.

Subjective Shoulder Value for Sport Is a Simple, Reliable, and Valid Score to Assess Shoulder Function in Athletes.

PURPOSE: To validate the subjective shoulder value for sport (SSV-Sport) by measuring its correlation with existing patient-reported outcome measures (PROMs) and defining its psychometric properties. METHODS: Between May 2021 and May 2022, we established 2 patient groups. Group 1 included those (1) aged 18 years or older, who were (2) consulting for the first time for any shoulder condition, (3) regularly participated in sports, and were capable of accessing a questionnaire independently. There were asked to rate their SSV and SSV-Sport at admission and 2 weeks later; they also were asked to answer a questionnaire including other PROMS. Group 2 comprised patients who had (1) undergone shoulder stabilization surgery and had (2) a minimum follow-up period of 6 months. RESULTS: For the shoulder disability patients (group 1, n = 62), there was a strong and significant correlation between SSV-Sport and other PROMs: Quick Disabilities of the Arm, Shoulder and Hand Sport (r = 0.84), Walch-Duplay (r = 0.65), Rowe (r = 0.74), Western Ontario Shoulder Instability (r = 0.78), and SSV (r = 0.75) (P = .0001). The SSV-Sport was reliable at baseline and 2 weeks after (0.91, 95% confidence interval 0.85-0.94), and was responsive to change (P < .001). For the anterior instability patients (group 2, n = 83), SSV was on average 50 points greater than SSV-Sport (29.2 vs 79.4, P < .001) for preoperative values. In both groups, the values of SSV were constantly and significantly higher than the values of SSV-Sport (81.9 ± 21.3 vs 54.8 ± 30.9; P < .001). CONCLUSIONS: The SSV-Sport is an easily administered, reliable, responsive, and valid measure of shoulder function in athletes that is highly correlated with other PROMs. SSV-Sport is better adapted than SSV to quantify pre- and postoperative shoulder deficiency in athletes. LEVEL OF EVIDENCE: Level III, cohort study (diagnosis).

A Spatiotemporal Compartmentalization of Glucose Metabolism Guides Mammalian Gastrulation Progression.

Gastrulation is considered the sine qua non of embryogenesis, establishing a multidimensional structure and the spatial coordinates upon which all later developmental events transpire. At this time, the embryo adopts a heavy reliance on glucose metabolism to support rapidly accelerating changes in morphology, proliferation, and differentiation. However, it is currently unknown how this conserved metabolic shift maps onto the three-dimensional landscape of the growing embryo and whether it is spatially linked to the orchestrated cellular and molecular processes necessary for gastrulation. Here we identify that glucose is utilised during mouse gastrulation via distinct metabolic pathways to instruct local and global embryonic morphogenesis, in a cell type and stage-specific manner. Through detailed mechanistic studies and quantitative live imaging of mouse embryos, in parallel with tractable in vitro stem cell differentiation models and embryo-derived tissue explants, we discover that cell fate acquisition and the epithelial-to-mesenchymal transition (EMT) relies on the Hexosamine Biosynthetic Pathway (HBP) branch of glucose metabolism, while newly-formed mesoderm requires glycolysis for correct migration and lateral expansion. This regional and tissue-specific difference in glucose metabolism is coordinated with Fibroblast Growth Factor (FGF) activity, demonstrating that reciprocal crosstalk between metabolism and growth factor signalling is a prerequisite for gastrulation progression. We expect these studies to provide important insights into the function of metabolism in other developmental contexts and may help uncover mechanisms that underpin embryonic lethality, cancer, and congenital disease.

Injury prevents Ras mutant cell expansion in mosaic skin.

Healthy skin is a mosaic of wild-type and mutant clones1,2. Although injury can cooperate with mutated Ras family proteins to promote tumorigenesis3-12, the consequences in genetically mosaic skin are unknown. Here we show that after injury, wild-type cells suppress aberrant growth induced by oncogenic Ras. HrasG12V/+ and KrasG12D/+ cells outcompete wild-type cells in uninjured, mosaic tissue but their expansion is prevented after injury owing to an increase in the fraction of proliferating wild-type cells. Mechanistically, we show that, unlike HrasG12V/+ cells, wild-type cells respond to autocrine and paracrine secretion of EGFR ligands, and this differential activation of the EGFR pathway explains the competitive switch during injury repair. Inhibition of EGFR signalling via drug or genetic approaches diminishes the proportion of dividing wild-type cells after injury, leading to the expansion of HrasG12V/+ cells. Increased proliferation of wild-type cells via constitutive loss of the cell cycle inhibitor p21 counteracts the expansion of HrasG12V/+ cells even in the absence of injury. Thus, injury has a role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin.

Trehalose-Carnosine Prevents the Effects of Spinal Cord Injury Through Regulating Acute Inflammation and Zinc(II) Ion Homeostasis.

Spinal cord injury (SCI) leads to long-term and permanent motor dysfunctions, and nervous system abnormalities. Injury to the spinal cord triggers a signaling cascade that results in activation of the inflammatory cascade, apoptosis, and Zn(II) ion homeostasis. Trehalose (Tre), a nonreducing disaccharide, and L-carnosine (Car), (ß-alanyl-L-histidine), one of the endogenous histidine dipeptides have been recognized to suppress early inflammatory effects, oxidative stress and to possess neuroprotective effects. We report on the effects of the conjugation of Tre with Car (Tre-car) in reducing inflammation in in vitro and in vivo models. The in vitro study was performed using rat pheochromocytoma cells (PC12 cell line). After 24 h, Tre-car, Car, Tre, and Tre + Car mixture treatments, cells were collected and used to investigate Zn2+ homeostasis. The in vivo model of SCI was induced by extradural compression of the spinal cord at the T6-T8 levels. After treatments with Tre, Car and Tre-Car conjugate 1 and 6 h after SCI, spinal cord tissue was collected for analysis. In vitro results demonstrated the ionophore effect and chelating features of L-carnosine and its conjugate. In vivo, the Tre-car conjugate treatment counteracted the activation of the early inflammatory cascade, oxidative stress and apoptosis after SCI. The Tre-car conjugate stimulated neurotrophic factors release, and influenced Zn2+ homeostasis. We demonstrated that Tre-car, Tre and Car treatments improved tissue recovery after SCI. Tre-car decreased proinflammatory, oxidative stress mediators release, upregulated neurotrophic factors and restored Zn2+ homeostasis, suggesting that Tre-car may represent a promising therapeutic agent for counteracting the consequences of SCI.

A Community Study of SARS-CoV-2 Detection by RT-PCR in Saliva: A Reliable and Effective Method.

Efficient, wide-scale testing for SARS-CoV-2 is crucial for monitoring the incidence of the infection in the community. The gold standard for COVID-19 diagnosis is the molecular analysis of epithelial secretions from the upper respiratory system captured by nasopharyngeal (NP) or oropharyngeal swabs. Given the ease of collection, saliva has been proposed as a possible substitute to support testing at the population level. Here, we used a novel saliva collection device designed to favour the safe and correct acquisition of the sample, as well as the processivity of the downstream molecular analysis. We tested 1003 nasopharyngeal swabs and paired saliva samples self-collected by individuals recruited at a public drive-through testing facility. An overall moderate concordance (68%) between the two tests was found, with evidence that neither system can diagnose the infection in 100% of the cases. While the two methods performed equally well in symptomatic individuals, their discordance was mainly restricted to samples from convalescent subjects. The saliva test was at least as effective as NP swabs in asymptomatic individuals recruited for contact tracing. Our study describes a testing strategy of self-collected saliva samples, which is reliable for wide-scale COVID-19 screening in the community and is particularly effective for contact tracing.

Potential prevention and treatment of neurodegenerative disorders by olive polyphenols and hidrox.

Most chronic illnesses are caused by the biological reaction to an injury, rather than the initial injury or the injurious agent itselves as in neurodegeneration. With respect to this, notable attention is emerging on the therapeutic effects of dietary polyphenols for human health, able to counteract and neutralize oxidative stress and inflammatory processes involved in the etiopathogenesis of major neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The acquired concept that cellular stress at low doses induces neuroprotective responses against degenerative processes is a frontier area of the neurobiological research focusing on the development of novel preventive and therapeutic interventions for neurodegenerative disorders. Notably, basal levels of prooxidant species are essential to promote adaptive redox cellular responses including vitagenes, tightly correlated to cell survival against age-related diseases. In this paper we discuss the concept of cellular stress response and hormesis and its applications to the field of neuroprotection and the potential therapeutic support provided by olive polyphenols, in particular hydroxytyrosol (HT)-rich aqueous olive pulp extract (Hidrox), as a pivotal activator of Nrf2 pathway and related vitagenes, and inhibitor of Keap1-Nrf2 interaction.Olive polyphenols are considered potential pharmacological modulators of neuroinflammation by upregulation of the Keap1/Nfr2/ARE pathway thus providing a strong rationale for treating neurodegenerative disorders.

Arthroscopic Distal Clavicular Autograft for Congruent Glenoid Reconstruction.

Arthroscopic distal clavicular autograft (DCA) is effective in shoulder instability with glenoid bone loss. The original technique uses an osteochondral autograft, fixed with screws or suture anchors. We developed a modified procedure called "congruent arc DCA" characterized by (1) use of drilling guides to optimize graft positioning and make the all-arthroscopic procedure safer and reproducible; (2) rotation of the DCA of 90° to reach a congruent arc with its undersurface; (3) fixation of the graft with cortical buttons to simplify its intra-articular passage, avoid hardware problems, and facilitate possible revision surgery; and (4) intraoperative use of a suture tensioner to achieve satisfactory compression of the graft and increase its consolidation.

Ionophore Ability of Carnosine and Its Trehalose Conjugate Assists Copper Signal in Triggering Brain-Derived Neurotrophic Factor and Vascular Endothelial Growth Factor Activation In Vitro.

l-carnosine (ß-alanyl-l-histidine) (Car hereafter) is a natural dipeptide widely distributed in mammalian tissues and reaching high concentrations (0.7-2.0 mM) in the brain. The molecular features of the dipeptide underlie the antioxidant, anti-aggregating and metal chelating ability showed in a large number of physiological effects, while the biological mechanisms involved in the protective role found against several diseases cannot be explained on the basis of the above-mentioned properties alone, requiring further research efforts. It has been reported that l-carnosine increases the secretion and expression of various neurotrophic factors and affects copper homeostasis in nervous cells inducing Cu cellular uptake in keeping with the key metal-sensing system. Having in mind this l-carnosine ability, here we report the copper-binding and ionophore ability of l-carnosine to activate tyrosine kinase cascade pathways in PC12 cells and stimulate the expression of BDNF. Furthermore, the study was extended to verify the ability of the dipeptide to favor copper signaling inducing the expression of VEGF. Being aware that the potential protective action of l-carnosine is drastically hampered by its hydrolysis, we also report on the behavior of a conjugate of l-carnosine with trehalose that blocks the carnosinase degradative activity. Overall, our findings describe a copper tuning effect on the ability of l-carnosine and, particularly its conjugate, to activate tyrosine kinase cascade pathways.

Redox modulation of vitagenes via plant polyphenols and vitamin D: Novel insights for chemoprevention and therapeutic interventions based on organoid technology.

Polyphenols are chemopreventive through the induction of nuclear factor erythroid 2 related factor 2 (Nrf2)-mediated proteins and anti-inflammatory pathways. These pathways, encoding cytoprotective vitagenes, include heat shock proteins, such as heat shock protein 70 (Hsp70) and heme oxygenase-1 (HO-1), as well as glutathione redox system to protect against cancer initiation and progression. Phytochemicals exhibit biphasic dose responses on cancer cells, activating at low dose, signaling pathways resulting in upregulation of vitagenes, as in the case of the Nrf2 pathway upregulated by hydroxytyrosol (HT) or curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Here, the importance of vitagenes in redox stress response and autophagy mechanisms, as well as the potential use of dietary antioxidants in the prevention and treatment of multiple types of cancer are discussed. We also discuss the possible relationship between SARS-CoV-2, inflammation and cancer, exploiting innovative therapeutic approaches with HT-rich aqueous olive pulp extract (Hidrox®), a natural polyphenolic formulation, as well as the rationale of Vitamin D supplementation. Finally, we describe innovative approaches with organoids technology to study human carcinogenesis in preclinical models from basic cancer research to clinical practice, suggesting patient-derived organoids as an innovative tool to test drug toxicity and drive personalized therapy.

Moringa oleifera Protects SH-SY5YCells from DEHP-Induced Endoplasmic Reticulum Stress and Apoptosis.

Moringa oleifera (MO) is a medicinal plant that has been shown to possess antioxidant, anticarcinogenic and antibiotic activities. In a rat model, MO extract (MOe) has been shown to have a protective effect against brain damage and memory decline. As an extending study, here, we have examined the protective effect of MOe against oxidative stress and apoptosis caused in human neuroblastome (SH-SY5Y) cells by di-(2-ethylhexyl) phthalate (DEHP), a plasticizer known to induce neurotoxicity. Our data show that MOe prevents oxidative damage by lowering reactive oxygen species (ROS) formation, restoring mitochondrial respiratory chain complex activities, and, in addition, by modulating the expression of vitagenes, i.e., antioxidant proteins Nrf2 and HO-1. Moreover, MOe prevented neuronal damage by partly inhibiting endoplasmic reticulum (ER) stress response, as indicated by decreased expression of CCAAT-enhancer-binding protein homologous protein (CHOP) and Glucose-regulated protein 78 (GRP78) proteins. MOe also protected SH-SY5Y cells from DEHP-induced apoptosis, preserving mitochondrial membrane permeability and caspase-3 activation. Our findings provide insight into understanding of molecular mechanisms involved in neuroprotective effects by MOe against DEHP damage.

Relationship Between the Lateral Collateral Ligament of the Elbow and the Kocher Approach: A Cadaver Study.

PURPOSE: The lateral ulnar collateral ligament (LUCL) is considered to be the portion of the lateral collateral ligament playing the most important stabilizing role. Iatrogenic forms of posterolateral rotatory instability have been described. The Kocher approach is a popular approach to the lateral side of the elbow. The aim of this study was to describe the relationship between the LUCL and the Kocher interval. METHODS: The Kocher interval was identified and marked in 20 cadavers. The LUCL was identified and the distance between the LUCL insertion on the tubercle of the cresta supinatoris and the Kocher interval was calculated (TK distance). This distance was considered 0 if the Kocher interval was directly above the tubercle, as a positive value if it was anterior to the tubercle, and as a negative value if it was posterior. Finally, the Kocher interval was sharply opened, and elbow stability was tested using the posterolateral rotatory drawer test. RESULTS: A discrete LUCL was identified in 16 specimens. The mean TK distance was -2.3 ± 4.4 mm (range, -11 to +10). The median TK distance was -3 mm. The posterolateral rotatory drawer test was positive for subluxation after the sharp incision of the Kocher interval in 15 specimens. The median TK distance was significantly higher in the stable group (+2 mm) than in the unstable group (-3 mm). CONCLUSIONS: The LUCL often lies beneath the Kocher interval and is at risk during the Kocher approach. CLINICAL RELEVANCE: Iatrogenic forms of posterolateral rotatory instability could result from this approach.

Hydrogen Sulfide and Carnosine: Modulation of Oxidative Stress and Inflammation in Kidney and Brain Axis.

Emerging evidence indicates that the dysregulation of cellular redox homeostasis and chronic inflammatory processes are implicated in the pathogenesis of kidney and brain disorders. In this light, endogenous dipeptide carnosine (ß-alanyl-L-histidine) and hydrogen sulfide (H2S) exert cytoprotective actions through the modulation of redox-dependent resilience pathways during oxidative stress and inflammation. Several recent studies have elucidated a functional crosstalk occurring between kidney and the brain. The pathophysiological link of this crosstalk is represented by oxidative stress and inflammatory processes which contribute to the high prevalence of neuropsychiatric disorders, cognitive impairment, and dementia during the natural history of chronic kidney disease. Herein, we provide an overview of the main pathophysiological mechanisms related to high levels of pro-inflammatory cytokines, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and neurotoxins, which play a critical role in the kidney-brain crosstalk. The present paper also explores the respective role of H2S and carnosine in the modulation of oxidative stress and inflammation in the kidney-brain axis. It suggests that these activities are likely mediated, at least in part, via hormetic processes, involving Nrf2 (Nuclear factor-like 2), Hsp 70 (heat shock protein 70), SIRT-1 (Sirtuin-1), Trx (Thioredoxin), and the glutathione system. Metabolic interactions at the kidney and brain axis level operate in controlling and reducing oxidant-induced inflammatory damage and therefore, can be a promising potential therapeutic target to reduce the severity of renal and brain injuries in humans.

Multiparametric MRI in the management of prostate cancer: an update-a narrative review.

The growing interest in multiparametric MRI is leading to important changes in the diagnostic process of prostate cancer. MRI-targeted biopsy is likely to become a standard for the diagnosis of prostate cancer in the next years. Despite it is well known that MRI has no role as a staging technique, it is clear that multiparametric MRI may be of help in active surveillance protocols. Noteworthy, MRI in active surveillance is not recommended, but a proper understanding of its potential may be of help in achieving the goals of a delayed treatment strategy. Moreover, the development of minimally invasive techniques, like laparoscopic and robotic surgery, has led to greater expectations as regard to the functional outcomes of radical prostatectomy. Multiparametric MRI may play a role in planning surgical strategies, with the aim to provide the highest oncologic outcome with a minimal impact on the quality of life. We maintain that a proper anatomic knowledge of prostate lesions may allow the surgeon to achieve a better result in planning as well as in performing surgery and help the surgeon and the patient engage in a shared decision in planning a more effective strategy for prostate cancer control and treatment. This review highlights the advantages and the limitations of multiparametric MRI in prostate cancer diagnosis, in active surveillance and in planning surgery.

Outcomes of 188 Proximal Humeral Fractures Treated with a Dedicated External Fixator with Follow-up Ranging from 2 to 12 Years.

BACKGROUND: The treatment of a displaced proximal humeral fracture is still a matter of controversy. Minimally invasive techniques are considered promising options. The purpose of this study was to report outcomes at medium to long-term follow-up after surgical treatment with pins stabilized with an external fixator. METHODS: A total of 235 patients (average age, 64 years [95% confidence interval (CI), 62 to 65 years]) were treated with closed or open reduction and fixation with pins stabilized by an external fixator specifically designed for proximal humeral fractures. The pins were inserted using a "pins-crossing-fracture" or a "pins-bridging-fracture" technique. One hundred and eighty-eight patients had a minimum radiographic and clinical follow-up of 2 years. Outcomes were assessed using the Oxford Shoulder Score (OSS), the subjective shoulder value (SSV), a visual analog scale (VAS) for pain, and, for 155 patients, the Constant score. RESULTS: Eighty-one (43%) of the 188 patients had a 2-part fracture, 60 (32%) had a 3-part fracture, and 47 (25%) had a 4-part fracture. The reduction was performed with percutaneous maneuvers in 120 shoulders or a deltopectoral approach, in 68. The external fixator was applied using a "pins-crossing-fracture" technique in 133 shoulders and using a "pins-bridging-fracture" technique in 55. At last follow-up, mean clinical scores were as follows: OSS, 42.6 (95% CI, 42 to 44); SSV, 85.5 (95% CI, 83 to 88); and VAS for pain, 1 (95% CI, 0.7 to 1.2). The complication rate at 3 months was 16% (37 of 235). The most frequent complication was pin-track infection (19 of 235, 8%). A total of 50 patients had ≥1 complication (50 of 188, 27%) and 6 (3%) underwent revision surgery. More complications were observed with the "pins-crossing-fracture" technique. CONCLUSIONS: In our experience, the use of the external fixator has been a valuable option in the treatment of proximal humeral fractures. The complication and revision rates were acceptable. Most of the complications encountered were manageable without revision surgery. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Hair follicle regeneration suppresses Ras-driven oncogenic growth.

Mutations associated with tumor development in certain tissues can be nontumorigenic in others, yet the mechanisms underlying these different outcomes remains poorly understood. To address this, we targeted an activating Hras mutation to hair follicle stem cells and discovered that Hras mutant cells outcompete wild-type neighbors yet are integrated into clinically normal skin hair follicles. In contrast, targeting the Hras mutation to the upper noncycling region of the skin epithelium leads to benign outgrowths. Follicular Hras mutant cells autonomously and nonautonomously enhance regeneration, which directs mutant cells into continuous tissue cycling to promote integration rather than aberrancy. This follicular tolerance is maintained under additional challenges that promote tumorigenesis in the epidermis, including aging, injury, and a secondary mutation. Thus, the hair follicle possesses a unique, enhanced capacity to integrate and contain Hras mutant cells within both homeostatic and perturbed tissue, demonstrating that in the skin, multiple, distinct mechanisms exist to suppress oncogenic growth.

Flexibility sustains epithelial tissue homeostasis.

Epithelia surround our bodies and line most of our organs. Intrinsic homeostatic mechanisms replenish and repair these tissues in the face of wear and tear, wounds, and even the presence of accumulating mutations. Recent advances in cell biology, genetics, and live-imaging techniques have revealed that epithelial homeostasis represents an intrinsically flexible process at the level of individual epithelial cells. This homeostatic flexibility has important implications for how we think about the more dramatic cell plasticity that is frequently thought to be associated with pathological settings. In this review, we will focus on key emerging mechanisms and processes of epithelial homeostasis and elaborate on the known molecular mechanisms of epithelial cell interactions to illuminate how epithelia are maintained throughout an organism's lifetime.

Peptides derived from the histidine-proline rich glycoprotein bind copper ions and exhibit anti-angiogenic properties.

The role of copper in cancer progression has been established since decades. Additionally, copper is able to stimulate angiogenesis through the control of VEGF expression and activity in endothelial cells. In this paper a tetrapeptide, belonging to the histidine-proline-rich glycoprotein (HPRG) and encompassing four repeats of the sequence GHHPH (named TetraHPRG), was synthesized and its copper(ii) complex species were characterized by means of potentiometry, UV-vis, circular dichroism (CD), electron paramagnetic resonance (EPR) and electron spray ionization mass spectrometry (ESI-MS). Moreover, a peptide covalently bound through an amidic bond to trehalose (TH-TetraHPRG) was designed and synthesized as a prodrug system. The activity of both TetraHPRG and TH-TetraHPRG molecules on copper and VEGF induced angiogenic responses in endothelial cells was assessed. The two peptides show a similar and effective anti-angiogenic activity on both molecular and cellular responses. Since the trehalose derivative has a higher resistance to enzymatic degradation, it can be further exploited as a potential drug delivery system with anti-angiogenic activity.