Head and neck cancer (HNC) is one of the most prevalent human malignancies worldwide, with a high morbidity and mortality. Implementation of interdisciplinary treatment modalities has improved the quality of life, but only minor changes in overall survival have been achieved over the past decades. Main causes for treatment failure are an aggressive and invasive tumor growth in combination with a high degree of intrinsic or acquired treatment resistance. A subset of tumor cells gain these properties during malignant progression by reactivating a complex program of epithelia-to-mesenchymal transition (EMT), which is integral in embryonic development, wound healing, and stem cell behavior. EMT is mediated by a core set of key transcription factors, which are under the control of a large range of developmental signals and extracellular cues. Unraveling molecular principles that drive EMT provides new concepts to better understand tumor cell plasticity and response to established as well as new treatment modalities, and has the potential to identify new drug targets for a more effective, less toxic, and individualized therapy of HNC patients. Here, we review the most recent findings on the clinical relevance of a mesenchymal-like phenotype for HNC patients, including more rare cases of mucosal melanoma and adenoid cystic carcinoma. Head and neck cancer (HNC) originates from the mucosal epithelia of the upper aero-digestive tract, and in the majority of cases is diagnosed as head and neck squamous cell carcinoma (HNSCC) of the oral cavity, the naso-, oro- or hypopharynx, the larynx, the paranasal sinuses, or nasal cavity . Apart fDespite the implementation of interdisciplinary treatment modalities and improvements in early detection, surgical techniques, radiation therapy protocols, and chemotherapeutic regimes, the overall survival of advanced HNSCC has only marginally improved over the past decades and appropriate treatment remains a major challenge . This isMucosal melanoma (MM) and adenoid cystic carcinoma (ACC) of salivary glands belong to rare cases of head and neck cancer. MM originates from melanocytes of mucosal epithelia and makes up to 1% of all melanomas . HoweverACC originates from epithelial cells of the major or minor salivary glands of the head and neck, and is the second most common cancer of the salivary glands . ACC is Epithelial-to-mesenchymal transition (EMT) is a complex process in which epithelial cells lose their characteristic features and acquire a mesenchymal-like phenotype . PhenotyA large range of developmental and growth factor signals can drive EMT by triggering genetic and epigenetic programs, which are under the control of or regulate a core set of transcription factors (EMT-TF) belonging to different families, including SNAI1/2, TWIST1, and ZEB1/2, among others  12]. In. In12]. Epithelial plasticity and mesenchymal conversion is often seen in cancer cells as they leave the primary tumor and disseminate to other parts of the body to colonize distant organs and form metastases, which is responsible for the vast majority of cancer-related deaths . HoweverThe expression of well-established markers and key regulators of EMT as well as their potential impact on the pathogenesis and treatment of HNSCC has been reviewed in several recent publications . FurtherThe pluripotency-associated transcription factor SOX2 (sex determining region Y-box 2) is essential during mammalian embryogenesis, adult tissue regeneration, and homeostasis . More reIn a recent study, global gene expression profiling unraveled a pattern of differentially expressed genes after SOX2 silencing in HNSCC cell lines with 3q amplification, which are related to cell motility, regulation of locomotion, and response to wounding . As descIt is also worth noting that for the initiation of somatic reprogramming of fibroblasts into induced pluripotent stem cells, the induction of MET is triggered by SOX2 in a complex with OCT4 . MoreoveIn summary, these data support a model in which high expression of SOX2—as a consequence of copy number variation—but also other so-far less well characterized mechanisms contribute to the pathogenesis of HNSCC by promoting tumor cell proliferation and survival. However, its presence in advanced tumor stages might interfere with tumor cell plasticity and activation of mesenchymal transition by stabilization of the epithelial phenotype, including stemness-like traits C. AlthouThe kallikrein-related peptidase 6 (KLK6) belongs to a family of 15 secreted serine proteases with trypsin or chymotrypsin-like activity, which are encoded by a cluster of genes located on human chromosome 19q13.3–13.4 . AberranIn the context of HNSCC, a recent study provided experimental evidence that silencing of KLK6 activates the EMT program accompanied by a mesenchymal-like cell morphology as well as accelerated tumor cell migration and invasion . In lineConcerning the regulation of KLK6 expression, tumor-specific loss in breast cancer is at least in part mediated by epigenetic silencing due to DNA methylation . It willMelanoma is an aggressive tumor arising from melanocytes, endowed with unique features of cellular plasticity. The high degree of phenotypic and functional diversity—which is also a characteristic trait of melanoma cells—is at least in part due to their capacity to reversibly switch between phenotypes with non-invasive and invasive potentials, and is driven by oncogenic signaling and environmental cues .As melanocytes do not express a classic epithelial phenotype, the term EMT cannot be formally attributed to the progression or metastatic spread of melanoma. However, melanocytes exhibit a stable differentiated state via E-cadherin-mediated communication with keratinocytes, while melanoma cells progressively lose E-cadherin in favor of N-cadherin expression . In addiDue to the small number of cases of mucosal melanoma patients, there is limited information available on the pathogenesis of this aggressive tumor entity that tends to form local recurrences and regional lymph node metastases in 21%, but a significantly lower number of distant metastases than cutaneous melanoma. Furthermore, there is neither a commercially available cell line for mucosal melanoma nor an established in vivo model for further analysis. Apart from the postulation by Hussein et al. and Dupin et al. that mucosal melanomas arise from melanocytes migrating to non-cutaneous organs after neural crest cells undergo EMT, reliable studies on the expression of classical EMT markers or EMT-TFs in mucosal melanoma are still missing .p = 0.013) [p = 0.026).With regard to the newly identified factors related to an EMT-like phenotype in HNSCC, the expression of KLK6 in cutaneous melanoma was analyzed by Krenzer et al. . Althoug= 0.013) . The sam= 0.013) . PD-L1 eCommon carcinomas of the salivary glands are classified as adenocarcinoma, mucoepidermoid carcinoma, and adenoid cystic carcinoma (ACC). ACC represents one of the most common malignancies of the salivary glands, and three distinct growth patterns have been identified, which differ in their clinical behavior. The cribriform and the tubular type are usually associated with a better clinical outcome as compared to the solid type of ACC . It is aTumor cell dissemination as enabled by EMT and followed by MET has been considered as a hallmark of metastasis . HoweverIn summary, we are facing an urgent need to characterize the distinct cellular states associated with EMT plasticity to identify targetable EMT components and create therapeutic strategies to effectively eliminate cells undergoing EMT, since this is ultimately leading to treatment failure. However, by further analyzing the already existing results and investigating the pathogenesis of EMT in different head and neck cancers, the knowledge on cellular and molecular principles of malignant progression can be improved, ultimately aiming to stratify cancer patients at high risk for poor therapy response and to provide applicable therapies targeting EMT processes. By exploring the complex underlying mechanisms which lead from tumor cell dissociation in the primary tumor through EMT towards the formation of metastasis (including MET), our findings might offer promising perspectives for the future.


The scaphoid is the most commonly fractured carpal bone. The presence of a concomitant hook of hamate fracture is of particular relevance given that it is often occult on routine wrist/scaphoid radiographs and that hook of hamate fractures are prone to symptomatic non-union, resulting in chronic ulnar wrist pain. Prompt diagnosis and immobilisation/fixation may minimise such complications. Our study is aimed at assessing the frequency of concomitant hook of hamate fractures in patients with scaphoid fractures.Hook of hamate fracture is often occult on wrist/scaphoid radiographs. Hence, we identified all 2,568 CT and MRI studies performed to investigate scaphoid fracture at our institution from April 2005 to March 2016. Three hundred and twelve out of 2,568 cases were confirmed to have a scaphoid fracture. Images were then retrospectively reviewed by a Consultant Musculoskeletal Radiologist and Musculoskeletal Radiologist Trainee to assess for the presence of concomitant hook of hamate fracture and, if present, whether this was identified on initial reporting.Concomitant hook of hamate fracture was identified in 10.3% of cases ; most were minimally/non-displaced. Sixty percent of fractures identified on CT were missed on the initial review (18 out of 30). Both cases identified on MRI had been initially reported.Scaphoid fracture is associated with higher than expected rates of concomitant hook of hamate fracture. Given the potential morbidity associated with hook of hamate fracture, this should be considered a review area when investigating scaphoid injury. These fractures are often minimally displaced, hence easily overlooked on CT. MRI may therefore be superior when investigating radiographically occult scaphoid fractures. The scaphoid is the most commonly fractured carpal bone, accounting for approximately 60% of all carpal bone fractures , 2. MostPrevious studies assessing rates of concomitant fractures associated with scaphoid injury have been limited in number and scope, but have described a concomitant fracture rate of between 5 and 13%, typically involving the distal radius, and to a lesser extent, the triquetrum, capitate, hamate (non-hook), metacarpals and phalanges . HoweverIn a retrospective analysis, all CT and MRI studies performed to investigate scaphoid injury at a single tertiary centre between April 2005 and March 2016 were analysed for the presence of a scaphoid fracture. Of a total of 2,568 cases, 312 patients were identified to have CT- or MRI-proven scaphoid fracture (265 CT scans and 47 MRI scans). Images were then retrospectively reviewed by both a consultant musculoskeletal radiologist and a musculoskeletal radiologist trainee to identify the presence of a concomitant fracture of the hook of hamate. For each concomitant hook of hamate fracture identified, the degree of fracture displacement was recorded in line with accepted definitions typically applied to scaphoid fracture, such that fractures were categorised as either non-displaced/minimally displaced (up to 1 mm displacement) or displaced (greater than 1 mm displacement) [Of all 312 patients with a scaphoid fracture confirmed on cross-sectional imaging, 32 (10.3%) were identified with concomitant hook of hamate fractures on CT or MRI. Of these 32 patients, 30 were identified from the cohort of 265 CT studies; the remaining 2 were identified from the 47 MRI scans. Of the 30 cases of concomitant hook of hamate identified on CT, only 12 (40%) were identified on initial reporting (Table Most of the concomitant hook of hamate fractures involved the base of the hook (18 out of 32), whereas the remainder involved either the tip or waist in equal proportions (7 out of 32 respectively). None of the hook of hamate fractures were comminuted. The proportion of hook of hamate fractures that were originally reported was greatest for waist fractures (57%), followed by fractures of the base (39%) and tip  –10. ChroInvestigation of scaphoid injury has traditionally been limited to a dedicated four-view plain radiographic “scaphoid series”, often comprising: posterior–anterior (PA) view with ulnar deviation; lateral view; semi-supinated oblique; and semi-pronated oblique views , 13. HowThis frequency of association of hook of hamate fractures with scaphoid fractures is also perhaps a little surprising, as hamate hook fractures are generally thought of as injuries usually sustained through sports such as golf or tennis, by the impact of a racket or club against the hamate. However, the hook of hamate can also be injured by indirect means via a fall on the outstretched hand , and theIn the context of known scaphoid fracture, knowledge of the presence of a concomitant hook of hamate fracture would have implications for the patient’s management. First, in the context of percutaneous scaphoid fracture fixation or open reduction and internal fixation, the patient can be mobilised 2 weeks after fixation. However, knowledge of a concomitant hook of hamate fracture would prolong the length of time the patient is immobilised, given that hook of hamate fractures are typically managed conservatively with immobilisation for 6 weeks . Second,Given that 60% of hook of hamate fractures in our study were not identified at the time of initial CT reporting, this highlights the difficulty in detecting hook of hamate fractures in the routine reporting of CT studies in the absence of the observer being made aware of any clinical suspicion of hamate injury. Indeed, most hook of hamate fractures identified in our study were non-displaced and subtle findings, which on CT, were identified only following dedicated review of the hamate on axial, coronal and sagittal multiplanar reformats as part of the study protocol Figs. , 2. We fConsiderably fewer patients were investigated with MRI compared with CT, in part because of the easier accessibility of prompt CT in our institution. However, in the only two MRI studies, where concomitant hook of hamate fractures were identified, both were also identified on initial reporting. This is perhaps of little surprise, given that on MRI, marrow signal alteration surrounding a recent fracture is easily observed, regardless of the extent of the fracture. The fracture usually manifests as a well-defined low-signal line on a background of surrounding marrow oedema-related signal abnormality Fig. , and is However, owing to constraints of availability and the cost of MRI compared with CT in many centres, CT is frequently performed in the context of suspected/proven scaphoid injury. This is particularly true in two contexts: that of surgical planning, where CT depiction of bony anatomy is often preferred to MRI as a visual aid by orthopaedic surgeons; and in the assessment of scaphoid healing, where CT is the modality of choice. Previous CT studies have fortunately demonstrated the high level of sensitivity of CT for hook of hamate fractures, where the diagnosis is considered .Of the 18 patients in whom the hook of hamate fracture was not identified at initial CT reporting, 1 patient continued to have persistent symptoms at follow-up in the context of a healed scaphoid fracture but persistent hook of hamate fracture at interval CT. Specifically, interval CT 3 months post-injury showed a healed scaphoid tubercle fracture but persistent non-displaced hook of hamate fracture . Clinically, follow-up information was available up to 5 months post-injury, describing persistent volar wrist pain  and reduced grip strength. Although the on-going symptoms in this case cannot with any certainty be attributed to a persistent non-united hook of hamate fracture, in the absence of any other significant CT finding, it is a likely explanation.Scaphoid fractures are associated with a higher than expected rate of concomitant fractures of the hook of hamate (10.3% in our study). These concomitant hook fractures are often either non-displaced or only minimally displaced, and were all occult on conventional radiography. Hook of hamate fractures are associated with a risk of poor healing and non-union, leading to chronic palmar/ulnar-sided wrist pain. In the context of coexistent scaphoid fracture, alerting the clinician to the presence of a concomitant hook of hamate fracture may have implications for optimal management. MRI is the most suitable modality for identifying minimally or non-displaced hook of hamate fractures, whereas on CT the findings are often subtle and easily overlooked. We recommend that the hook of hamate be considered a review area when reporting any cross-sectional studies demonstrating scaphoid fracture.


Early childhood caries discloses a distinct clinical pattern, and the teeth most often involved are the maxillary central incisors, lateral incisors, and the maxillary and man-dibular first molars. The maxillary incisors are most severely affected, with deep carious lesions usually involving the pulp. Teeth that have been endodontically treated often have little coronal tooth tissue remaining and as such require a post to retain the core and restoration .This study evaluated and compared the efficacy of EverStick glass fiber-reinforced composite post with ParaPost Taper Lux in primary maxillary anterior teeth.in vivo study was conducted to evaluate and compare the longevity and failures of two fiber post systems in primary maxillary anterior teeth.An A total of 60 severely mutilated primary maxillary anterior teeth from children aged 3 to 5 years were selected according to the inclusion criteria. These teeth were treated endodontically and were randomly assigned into two groups with 30 samples in each group, group I: EverStick glass fiber-reinforced composite post, group II: ParaPost Taper Lux post. The evaluation of dislodgment of posts, secondary caries, root fracture, and post fracture was carried out clinically and radiographically during every follow-up at 3, 6, 9, and 12 months interval.Statistical tests  suggested that dislodgment of the posts was significant between the two groups at 6, 9, and 12 months follow-ups. But within the group during subsequent follow-up intervals, dislodgment of posts as a mode of failure was not statistically significant. However, clinically failures were seen in both the study groups.Fiber post system has proved to be successful clinically in both primary and permanent teeth due to the mono-block effect with luting agent, post system, core material, and bonding to dentin. Thus, today the EverStick glass fiber post system provides a novel way of fabricating cost-effective and less time-consuming custom-made post in treating mutilated maxillary anteriors.Sawant A, Chunawalla Y, Morawala A, Kanchan NS, Jain K, Talathi R. Evaluation of Novel Glass Fiber-reinforced Composite Technique for Primary Anterior Teeth with Deep Carious Lesions: A 12-month Clinical Study. Int J Clin Pediatr Dent 2017;10(2):126-130. Caries in very young children known as early childhood caries may be defined according to the American Academy of Pediatric Dentistry “as the presence of one or more decayed, missing (due to caries) or filled tooth surfaces in any primary tooth in a child 71 months of age or younger.“2 If left untreated, health as well as esthetics may be compromised.3 The implications of this situation include insufficient growth and development in children who have no other medical problems.4 Decreased dietary intake may develop into nutritional imbalance, which may affect the general status of health as well as dentition.5Early childhood caries discloses a distinct clinical pattern, and the teeth most often involved are the maxillary central incisors, lateral incisors, and the maxillary and mandibular first molars. The maxillary incisors are most severely affected, with deep carious lesions usually involving the pulp. In extreme cases, early childhood caries can even lead to loss of the crown structure.6 Fiber-reinforced composite posts was introduced to dentistry around 15 years ago, and they are composed of glass quartz and carbon fibers embedded in epoxy resin. This study evaluated and compared the efficacy of EverStick glass fiber-reinforced composite post with ParaPost Taper Lux in primary maxillary anterior teeth.Teeth that have been endodontically treated often have little coronal tooth tissue remaining and as such require a post to retain the core and restoration. There are several types of root canal posts available for use in pediatric restorative dentistry, including prefabricated, orthodontic wire in α or Ω forms, metallic posts with macroretention, short posts with composite resin, polyethylene ribbon posts, and biologic posts.in vivo study was carried out in which a total of 60 severely mutilated primary maxillary incisors were selected from children aged 3 to 5 years based on the inclusion criteria such as:A randomized controlled single blind  Children between 3 and 5 years Mentally and physically normal child with no systemic manifestations Pulpally involved maxillary deciduous anterior teeth Teeth with more than two-thirds root length At least 1 mm of supragingival noncarious tooth structure remainingExclusion criteria: Mentally or physically compromised child Presence of deleterious oral habits Presence of trauma from occlusion Teeth with pathologic root resorption Teeth with presence of root caries Teeth with hyoplasiaThese selected teeth were endodontically treated and were further divided into two groups: Group I (EverStick glass fiber-reinforced composite post) and group II (Para-Post Taper Lux post) with 30 samples in each group. The above-mentioned procedure is described in The evaluation of dislodgment of posts, secondary caries, root fracture and post fracture was done during every follow-up at 3, 6, 9, and 12 months interval. Statistical significance of difference of each outcome measure is tested using Chi-square test for independence of attributes if cell frequency is larger than 5; else Fisher’s exact probability test was applied. The results are mentioned in 7In early childhood caries, maxillary anterior teeth are the most affected, mainly because they erupt before molars and are exposed to carious environment for longer duration; they are not protected by tongue, as are the mandibular incisors and they do not have close proximity to salivary gland duct openings. This is in accordance with the progression pattern of early childhood caries stated by Ripa.8 Problems with anterior primary incisor teeth that are grossly decayed are the lack of coronal structure to support and provide adhesion for a composite resin. In such cases, the use of an intracanal post in endodontically treated teeth improves the retention for a longer-lasting restoration. Rifkin described restoring primary anterior teeth with post and crown. But it was not widely accepted because of the potential for interference with physiologic root resorption if the wire extends a long way into the root.9Carious lesions presented in maxillary anterior teeth are associated with problems like reduced vertical dimension, masticatory insufficiency, esthetics, development of parafunctional habits, and psychological problems. Hence, it is necessary to restore and preserve them.10 Glass fiber-reinforced composite posts  are esthetic and easy to use. Flexural strength of silanated E-glass fiber (EverStick) is 1,280 MPa, highest among all fiber-reinforced composite posts. The modulus of elasticity is close to dentin, which helps in even distribution of stress.10 These posts are marketed custom-made posts. These can be manipulated by the operator according to the requirements. The length, width, taper of the post can be manipulated by the operator according to needs. Success of a post also depends on the fit of the post into the canal. Preformed posts may not snugly fit into the canal. Fiber posts (EverStick) can be modified for a snug fit.11 Additional fibers can also be inserted in cases of wide canals.The development of fiber-reinforced composite technology has brought a new material into the realm of metal-free adhesive esthetic dentistry.Occurrence of root fracture was not seen in any of the cases (100% success) during the 12 months follow-up period . Baraju et al in their study found that the modulus of elasticity of the fiber post is close to dentin and hence, there is less stress distribution toward the dentinal walls, making the root less susceptible to fracture.It was noted that most of the restorations adapted closely to tooth along margins. There was no gap between restoration and tooth interface. This is attributed to the absence of secondary caries . None of the 60 cases reported with secondary caries (100% success).12 No additional post space preparation is required for the insertion of the post. ParaPost Taper Lux is a prefabricated post requiring additional post space preparation. Preparation of a post space requires removal of additional radicular dentin beyond the requirements for root canal treatment.15 Thus, the strength of the post is derived from interface between luting agent and the post, resulting in dislodgment of the post.In this study, at the 3-month recall, 1 out of 30 cases in group I and II out of 30 cases in group II showed failure due to dislodgment of the posts. At 6-month recall, 3 out of 30 cases in groups I and 11 out of 30 cases in group II showed failure due to dislodgment of the posts. The difference between the groups was statistically significant. EverStick glass fiber composite is a custom-made post providing ease of manipulation and snug fit in the canal.1112 for rehabilitation of extensively decayed primary incisors, the use of EverStick glass fiber-reinforced composite posts appears to be a cost-effective alternative option, in view of their ability to reinforce composite resin with adequate translucency, durability, improving esthetics, retention, and marginal adaptation.1617In agreement with previous studies noted in the litera-ture,


They associate with proteins involved in DNA damage repair such as PIKK complexes as well as with the core complex of Fanconi anemia pathway. They have also been shown to be important for cell cycle progression, being involved in assembly of telomerase, mitotic spindle, RNA polymerase II, and snoRNPs. When the two ATPases localize to the cytoplasm, they were reported to promote cancer cell invasion and metastasis. Due to their various roles in carcinogenesis, it is not surprising that Pontin and Reptin are proving to be important biomarkers for diagnosis and prognosis of various cancers. They are also current targets for the development of new therapeutic anticancer drugs.Pontin  and Reptin  are highly conserved ATPases of the AAA+ (ATPases Associated with various cellular Activities) superfamily and are involved in various cellular processes that are important for oncogenesis. First identified as being upregulated in hepatocellular carcinoma and colorectal cancer, their overexpression has since been shown in multiple cancer types such as breast, lung, gastric, esophageal, pancreatic, kidney, bladder as well as lymphatic, and leukemic cancers. However, their exact functions are still quite unknown as they interact with many molecular complexes with vastly different downstream effectors. Within the nucleus, Pontin and Reptin participate in the TIP60 and INO80 complexes important for chromatin remodeling. Although not transcription factors themselves, Pontin and Reptin modulate the transcriptional activities of  Pontin  and Reptin  belong to the AAA+ (ATPases Associated with various cellular Activities) superfamily whose proteins are characterized by having the conserved Walker A and Walker B motifs, which are involved in ATP binding and hydrolysis  is well-established  and small cell lung cancer (SCLC) and suggested their potential use as biomarkers for diagnosis and prognosis of lung cancer  as well as node negative early stage breast cancers  assembly of replication machinery, (2) aggresome formation, (3) regulation of cell cycle checkpoint, (4) proper mitotic progression, (5) transcriptional regulation, (6) DNA damage response, and (7) cell invasion/migration.Pontin and Reptin are established critical regulators of cell growth and proliferation. One of the ways they achieve this is through the assembly of multiple molecular complexes belonging to the replication machinery, largely mediated by the HSP90-interacting chaperone-like complex R2TP , the role of R2TP has now expanded to the assembly of RNPs of the L7Ae family members  by the array of biogenesis factors is still under debate. One hypothesis is that the PIH1D1 and RPAP3 of R2TP act as loading factors for Pontin and Reptin onto core snoRNP proteins NOP58 and 15.5K. Subsequently, PIH1D1 and RPAP3 dissociate from this complex  along with all four proteins of the box H/ACA snoRNP family  that cooperatively mediate the splicing of pre-mRNAs for proper gene expression  is a fundamental cellular complex that synthesizes all the mRNAs and capped non-coding RNAs. Its 12 subunits are assembled in the cytoplasm, in part by the R2TP complex, and only fully assembled POL II is imported into the nucleus  signaling family important for DNA repair and cellular metabolism  , and thus can potentially regulate their transcriptional activity for production of cyclins  Figure . ECD is Pontin and Reptin may also play specific and perhaps essential roles in mitosis independent of each other. Whereas, Pontin was largely implicated in the assembly of mitotic spindles, the function of Reptin remains to be uncovered  may be involved in the interactions between Pontin/Reptin and MYC  and androgen receptor (AR), as well as the transcription factor complex interferon stimulated-gene factor 3 (ISGF3) Figure  Kim et .The TIP60 complex, including both Pontin and Reptin subunits, has recently been found to regulate the hypoxia pathway through co-activating the transcription factor HIF1α    Figure  (Xie et ) Figure . p14ARF Nuclear factor-κB (NF-κB) is a family of dimeric transcription factors  activated by cellular stimuli such as oxidative stress, viral/bacterial antigen, and cytokines including TNFα and IL-1β Moynagh, . Their tIn the canonical pathway, NF-κB heterodimers are bound by IκB proteins, which sequester them in the cytoplasm and keep these transcription factors inactivated Figure  Gilmore. A stimuWithin the cytoplasm, RPAP3 of the R2TP complex was found to bind and regulate NEMO of the IKK complex   was found to promote activation of β-catenin-dependent transcription by Pontin   family of transcription factors to activate numerous genes involved in proliferation and survival . For instance, Hint1 (histidine triad nucleotide-binding protein 1) was found to suppress Pontin activation of β-catenin transcription, and APPL1/2  were shown to relieve the repression of transcription by Reptin Figure  Weiske . Hint1 iOct4, one of the main ESC (embryonic stem cell)-specific transcription factors, is essential for regulating embryonic development and the self-renewing property of ESCs , C/EBP (CCAAT/enhancer-binding protein) alpha and beta, which are transcription factors, were found to interact with Pontin and Reptin Figure  Bard-Ch. EVI1 isGenomic instability is a hallmark of cancer. DNA damage response (DDR) and repair pathways are typically induced under these conditions  binds to the damaged site. MRN then recruits TIP60 in complex with checkpoint kinase ATM and facilitates the interaction between TIP60 and methylated H3 Figure  Sun et . This inDepletion of Pontin after DNA damage increased the amount and lifetime of phosphorylated H2AX, which could be mimicked by TIP60 depletion  pathway, responsible for the repair of interstrand crosslinks , where their expression was predominantly cytoplasmic, significantly inhibited cell migration and invasion ability  compared to normal renal tissue (Zhang et al., In addition to the changes in expression profiles of various cell adhesion and cell junction genes, EMT is also helped by changes in the cell matrix and cytoskeleton through reorganization of actin and intermediate filaments. PDAC is the most common type of pancreatic cancer, and one of the most difficult to treat due to its aggressive and highly metastatic nature. Taniuchi et al.  found thThe cellular changes in EMT are controlled by a complex underlying molecular mechanism and crosstalk between many signaling pathways such as TGFβ, WNT, EGF, Notch, and IL-6 Figure  Lamouil. Reptin In a cancer context, stimuli such as hypoxia and mechanical stress from the tumor microenvironment and/or overexpression of pathway components can work cooperatively to induce EMT (Marcucci et al., Transcription factors such as NF-κB, STAT3, H1F1α, and β-catenin are upregulated downstream of the intracellular signaling pathways activated in EMT, which then induces the expression and activation of a pool of EMT-promoting master transcription factors such as TWIST, SNAILs, and ZEBs Figure  Lamouil. These dPontin and Reptin have been found to regulate β-catenin transcription with opposing effects: Pontin enhancing transcription and Reptin repressing it Figure  Bauer e. Nuclearin vivo (Bereshchenko et al., As describe above, Pontin and Reptin are clearly important proteins for the proliferation and survival of cells. Through their diverse cellular functions, they are highly relevant for the progression of cancer, and this makes them novel therapeutic anticancer drug targets. Conditional silencing of Reptin in xenografts of HCC in mice led to arrest of tumor development and even regression of tumors in several mice likely through tumor cell senescence (Menard et al., in silico drug screening for Pontin ATPase inhibitors was able to identify several novel compounds using both molecular docking and in vitro ATPase assays (Elkaim et al., in vitro as well as demonstrated anti-tumor activities in vivo with human xenografts in mice.Preliminary There is accumulating evidence that Pontin and Reptin functions are tightly regulated on multiple levels, including transcription, oligomeric state, subcellular localization, and interacting partners. Recent studies suggested that different post-translation modifications such as methylation, sumoylation, and phosphorylation may partially modulate the specificity of their roles. Thus, developing drugs to target these post-translational modifications and or their specific interactions may be more beneficial and less toxic than inhibiting the overall activities of these proteins.Consistent with the overexpression of Pontin and Reptin in many cancer types, the two AAA+ proteins are found to regulate many fundamental cellular pathways involved in cell proliferation and survival. These include the assembly of macromolecular complexes as part of the R2TP complex, regulation of cell cycle checkpoint and mitosis, regulation of oncogenic transcription factors, regulation of DNA damage response as well as repair, and promotion of epithelial to mesenchymal transition among others. Much is still unknown about the molecular mechanism that Pontin and Reptin use to facilitate these processes or the repertoire of interactors involved. It is, therefore, crucial to shed further light into the roles that Pontin and Reptin perform in the cell to accelerate the discovery of novel therapeutics for various types of cancer.Y-QM and WAH wrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous upper airway disease with multiple etiologies. Clinically, CRSwNP can be classified into either eosinophilic or non-eosinophilic subtypes. The eosinophilic phenotype of CRSwNP is widely thought to be highly associated with recurrence of nasal polyps or surgical failure. Epithelial cells have a crucial role in the development of Th2-biased airway diseases. Recent studies have shown that a wide range of external stimuli such as allergens and microorganisms can elicit the release of epithelial-derived Th2-driving cytokines and chemokines. Protease activity is a feature common to these multiple environmental insults and there is growing evidence for the concept that an imbalance of proteases and protease inhibitors in the epithelial barrier leads to both the initiation and maintenance of chronic eosinophilic airway inflammation. In this review, we analyze recent work on the role of proteases in the development of the sinonasal mucosal type 2 immune response with an emphasis on the molecular pathways promoting adaptive Th2 cell immunity. Chronic rhinosinusitis is a chronic inflammatory upper airway disease characterized by 12 weeks of typical symptoms including nasal discharge, congestion, facial pressure or pain, and olfactory disorder  and non-eosinophilic CRSwNP (NECRSwNP)  can directly degrade tight junctions in the epithelium  DC phenotype which accounts for the induction of Th2 cell response upon protease allergens exposure and fibrinogen-cleavage products can promote the generation of PD-L2+ DC through TLR4 . Cytokine production was, in turn, suppressed by protease inhibitors and anti-TLR4 antibodies  has been reported as a key immunoregulator of eosinophilic inflammation in both CRSwNP and CRSsNP (Bleier et al., In patients with CRSwNP, exogenous allergen and microorganism derived proteases play a crucial role in the development of type 2 immune response at the mucosal surface. Through direct effects on junctional proteins, binding to cell surface PARs, TLR4-dependent epithelial activation, disruption of barrier function, and P-gp activation, proteases both initiate and maintain the inflammation characteristic of Th2 mucosal disease. It has been proposed that drugs targeting protease function (Verma et al., DW drafted the manuscript. Both YW and BB reviewed the manuscript and provided revisions.The senior author has a patent related to P-gp modulation in CRSwNP. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Lymphedema results from lymphatic insufficiency leading to a progressive inflammatory process that ultimately manifests as discomfort, recurrent infections, and, at times, secondary malignancy. Collectively, these morbidities contribute to an overall poor quality of life. Although there have been recent advances in microsurgical interventions, a conservative palliative approach remains the mainstay of treatment for this disabling disease. The absence of a cure is due to an incomplete understanding of the pathophysiological changes that result in lymphedema. A histological hallmark of lymphedema is inflammatory cell infiltration and recent studies with animal models and clinical biopsy specimens have suggested that this response plays a key role in the pathology of the disease. The purpose of this report is to provide an overview of the ongoing research in and the current understanding of the inflammatory manifestations of lymphedema. Lymphedema is a progressive disease resulting from congenital abnormalities, obstruction, injury, or infection of the lymphatic system. Patients with lymphedema have swelling and fibrosis of the affected region resulting in functional problems, decreased quality of life, and recurrent infections . In WestThe primary treatment for lymphedema is a conservative approach known as complete decongestive therapy (CDT), which includes physical therapy, manual lymphatic drainage, and skin care ,6. TheseStudying the mechanisms underlying lymphedema has been complicated by several factors. First, lymphedema develops in a delayed fashion, often years or even decades, after the inciting lymphatic injury ,12. SecoBoth experimental and clinical studies spanning several decades have implicated inflammation as a critical component in the pathophysiology of lymphedema. Nearly forty years ago, Casley-Smith and Gaffney used rats to conclude that lymphedema results in a chronic inflammatory reaction . More reMuch of the recent knowledge in lymphedema is built upon the early work of Olszewski, who utilized a canine lymphedema model in his experimental studies . Since tThe well-described mouse tail surgery model is possibly the most widely utilized means by which to study the cellular and molecular mechanisms of lymphedema . In thisIn contrast to the tail surgery model, the mouse models of axillary and popliteal lymph node dissection  more closely mimic the clinical scenario of lymph node dissection during oncologic surgery. In these models, a popliteal or axillary skin incision is made and respective lymph nodes are dissected out and removed with their corresponding fat pads B. Using + cells results in impaired lymphangiogenesis, collecting fibrosis, and lymphatic smooth muscle cell proliferation associated with lymphedema. The importance of these inflammatory changes will be discussed in greater detail in the following sections. By utilizing these transgenic mice in conjunction with the tail surgery and lymphadenectomy models, it is possible to more accurately study the complex interactions that initiate and propagate the pathology of lymphedema and develop therapies that are effective in both prevention and treatment of this disease.In order to avoid the pitfalls of previous animal models, our laboratory recently reported on a new mouse model in which lymphatic endothelial cells (LECs) are non-surgically ablated with resultant progressive lymphedema C 30]. U. U30]. UFluid flow through the lymphatic vasculature plays a critical role in fluid homeostasis, immunity, and lipid reabsorption ,32. WhenGene expression analysis and protein quantification studies have shown that the expression of pro-inflammatory genes is upregulated in animal models and patients with lymphedema ,37,38,39In addition, Zampell et al. described increased expression of endogenous danger signals high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70) in tissues from both the ALND mouse model and matched human lymphedema biopsy samples and hypothesized that these early responses promote chronic inflammatory changes . The sam+ cells in the pathophysiology [+ cells [+ cells had a positive linear correlation with the severity of disease. Furthermore, using the tail model of lymphedema in nude mice  and CD4 knockout mice (which lack CD4+ cells), Avraham et al. and Zampell et al. found that the absence of T cells in general and CD4+ cells in particular was protective for the development of lymphedema. Knockout mice had significantly decreased swelling, subcutaneous tissue thickness, CD45+ infiltration, and fibrosis, as well as improved lymphatic function. These authors reported similar changes when CD4+ cells were depleted using neutralizing antibodies in wild-type mice. This effect was specific for CD4+ cells since depletion of CD8+ or CD25+ cells using similar methods did not prevent development of lymphedema [+ and CD4+ cells [+ T cells interact with macrophages, leading to vascular endothelial growth factor C (VEGF-C) expression, which then promotes the generation of immature lymphatic vessels that are essential for the development of initial edema [+ cells in lymphedematous tissues of mice and humans. In addition, neutralizing studies and experiments with knockout animals suggest that these cells play a key role in the pathophysiology of lymphedema.Several groups have attempted to characterize the inflammatory response in lymphedema ,44,45,46ysiology ,43,44,47[+ cells ,41. AvraFibrosis is a histological hallmark of lymphedema, as patients with the disease present with fibrosis of the skin and subcutaneous tissues associated with increased collagen deposition . In addi+ IL-4+ IL-13+ Th2 cells  comprise a notable proportion of the inflammatory infiltrate in both mouse models of lymphedema and human biopsy samples [Studies of the CD4 samples . RNA seq samples . In an e samples . However samples . Further samples . Such fi samples .Although Tregs serve an important purpose by attenuating the severity of inflammatory tissue responses in lymphedema, it is likely that these cells also contribute to the local impaired adaptive immune response manifested by the occurrence of recurrent soft tissue infections in lymphedema ,59,60. F+ accumulation and subsequent Th2 differentiation, suggesting that there is an interplay between the inflammatory cell types [Given the known role of macrophages in inflammation and fibrosis, it is not surprising that studies have also noted significant macrophage accumulation in lymphedema ,29,42,61ll types ,51,52. Tll types ,63.Other studies have highlighted the role of macrophages in the regulation of inflammatory lymphangiogenesis by elaborating lymphangiogenic growth factors including VEGF-A and VEGF-C in a variety of settings ,64,65,66Macrophages are also a significant source of IL-6, a cytokine that has been shown to play an important role in the regulation of chronic inflammation and adipose metabolism . Using lFurthermore, macrophages are also known to promote the expression of inducible nitric oxide synthase (iNOS), which attenuates lymphatic vessel contraction in inflammation ,73,74,75DCs comprise a major proportion of lymph fluid and are responsible for the presentation of peripheral antigens to immune effector cells in regional lymph nodes . Followi+ cells from regional lymph nodes and that these cells have increased expression of skin-homing receptors cutaneous lymphocyte antigen (CLA), C–C motif chemokine receptor 4 (CCR4), and CCR10 (unpublished). In addition, the leukocyte adhesion molecules endothelial cell selectin (E-selectin) and platelet selectin (P-selectin), which are ligands for CLA, as well as the chemokines CCL17 and CCL27, which are the ligands for CCR4 and CCR10 respectively, have also been found to be notably increased in lymphedematous skin (unpublished). Additional studies will be necessary to further delineate the importance of these and other molecules promoting the accumulation of CD4+ cells.The molecular pathways leading to the accumulation of the distinct inflammatory infiltrate in lymphedema are not yet fully elucidated. Our ongoing work suggests that lymphatic injury through lymph node dissection leads to activation and release of CD4+ cells such as Th2 cells and Tregs in human lymphadematous tissues, thus putting the findings from the mouse models into context and allowing for appropriate clinical translation [The delayed presentation and natural history of lymphedema make it difficult to study the pathophysiology of this disease without animal models. Transcriptional profiling and histologic analysis of clinical specimens have shed light on specific pathways and the immune cells that participate in them, but time-course studies using readily available and reliably reproducible animal models have been critical in mechanistic studies. Importantly, parallel analysis of clinical biopsy samples by multiple laboratories has shown evidence of increased populations of CD4nslation ,41,56.Secondary lymphedema results when the complex series of molecular interactions with intricately designed regulatory feedback mechanisms following lymphatic injury tips the balance against effective lymphangiogenesis and in favor of chronic inflammation, fibrosis, and immunosuppression. The absence of lymphedema in some patients despite lymphatic injury and the delayed development of the disease in others indicates that secondary events are likely necessary to elicit these important pathologic interactions . Current


PAX6 gene; however, in up to 30% of aniridia patients, disease results from chromosomal rearrangements at the 11p13 region. The aim of this review is to present the clinical and genetic aspects of the disease. Furthermore, we present a molecular diagnostic strategy in the aniridia patients. Recent improvement in the genetic diagnostic approach will precisely diagnosis aniridia patients, which is essential especially for children with aniridia in order to determine the risk of developing a Wilms tumor or neurodevelopmental disorder. Finally, based on the previous studies we describe the current knowledge and latest research findings in the topic of pathogenesis of aniridia and possible future treatment.Aniridia is a rare, panocular disorder characterized by a variable degree of hypoplasia or the absence of iris tissue associated with additional ocular abnormalities. It is inherited in an autosomal dominant manner, with high penetrance and variable expression even within the same family. In most cases the disease is caused by haploinsufficiency truncating mutations in the  Aniridia OMIM 106210) is a congenital panocular disorder characterized by complete or partial iris hypoplasia presenting in early infancy. Clinical expression is highly variable between families and even in the same family. Foveal hypoplasia resulting in reduced visual acuity, as well as cataract, keratopathy, and glaucoma that sometimes develop in the second or third decade, contribute to visual morbidity . It is characterized by Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability. Patients have 50-70% risk to develop Wilms tumor, which is the most common form of kidney cancer in children. Approximately 30% of patients with the sporadic form of aniridia suffer from this syndrome  was the first homeobox gene discovered to play a crucial role in eye development . The insertion, into the NTS subdomain, of 14 additional amino acids encoded by exon 5a abolishes the DNA-binding activity of the NTS and unmasks the DNA-binding ability of the CTS. Thus, exon 5a appears to function as a molecular switch that specifies target genes . Of all intragenic point mutations in the PAX6 gene, 94% result in premature termination codon (PTC), C-terminal extensions (CTE) or amino-acid substitutions (missense mutations)   phenotype demonstrating dosage sensitivity  process, by which mRNA containing premature termination codons are degraded before they produce truncated proteins  in the Single amino acid substitutions (missense mutations) produce a full-length protein that may fold and function abnormally, causing phenotypes ranging from mild iris defects to more severe including optic nerve malformations, Peters anomaly and microphthalmia  or contiguous genes deletions of the PAX6 and other neighboring genes, especially WT1 (WAGR syndrome) , elongation factor protein (ELP4), brain-derived neurotrophic factor (BDNF), beta polypeptide of follicle-stimulating hormone (FSHB), reticulocalbin 1 (RCN1), partial IMP1 inner-mitochondrial membrane (IMMP1L)   such as promoters, enhancers, insulators, and boundary elements play an important role in the regulation of gene expression, they determine the time, place, and the level of the expression of their target genes. Cis-regulatory elements can spread hundreds of kilobases upstream or downstream from the transcription start site of the genes. Human genetic studies using YAC transgenic mouse, DNaseI hypersensitivity mapping and reporter transgenic assays revealed a presence of SIMO enhancer located in the 3′- distal region, 124 kb from the PAX6 polyadenylation site, a retina-specific enhancer located within a fragment containing HS2 and HS3 elements and a lens-specific enhancer. These sequences located within introns of the adjacent Pax6 gene expression in the lens due to the presence of additional enhancers regulating its expression in this tissue  and 31,622,916 (hg18))  at the resolution of single exons . In situations when MLPA, aCGH, and the PAX6 gene sequencing do not identify any cause of the disease, a whole exome (WES) or whole genome sequencing (WGS) could be used for identification of novel  mutations in the PAX6 gene or novel genes involved in pathogenesis of aniridia.Due to clinical and allelic heterogeneity, as well as the great variability of the genetic mechanisms involved in aniridia, molecular analysis of the patients is performed by combining different molecular approaches including Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and an array based comparative genomic hybridization (aCGH). Although the intragenic PAX6 gene mutations, nor genomic rearrangements that involve the PAX6 gene or its regulatory elements. It suggests that mutations in the other genes, yet undiscovered genetic loci or unknown mechanisms disrupting the PAX6 gene function could be the cause of aniridia. We await descriptions of both genocopies and possible recessive mechanisms of aniridia that are already suggested by the pedigree analysis.In our studies, despite using all the above mentioned techniques, there is still a proportion of aniridia patients that remain unsolved. Our patients do not have the


APOBEC cytidine deaminases have been implicated as major contributors to the mutation burden in many cancers on the basis of their mutational signature. A new experimental study sheds light on the inciting factors, linking APOBEC3B expression to oncogene- and drug-induced replication stress.The online version of this article (doi:10.1186/s13059-016-1069-y) contains supplementary material, which is available to authorized users. The Cancer Genome Atlas (TCGA) Project has been an undisputed success in advancing our knowledge of the many and varied subtypes of cancer. The identification of recurrent somatic alterations, patterns of gene expression and relationships between these have provided a crucial resource to inform our understanding of cancer biology and the development of biomarker-driven therapeutic strategies. Moreover, analysis of the types of mutations in these established cancers has revealed mutational signatures that reflect the processes that contributed to their genesis . As expeThe APOBEC enzymes primarily function in innate antiviral immunity and deaminate cytosine to uracil in single-stranded DNA to generate C > T and C > G mutations in a preferential motif. Many solid tumors bear these genomic hallmarks and are believed to reflect the damage caused by one or more APOBECs. First identified in breast cancer datasets , 4, the increased risk of breast cancer [increased burden of APOBEC-pattern mutations [The complexity of this undertaking is significant. The seven human APOBEC3 family members share significant homology, which limits the availability of reagents with high specificity. In addition, mice only have a single APOBEC3, meaning that mouse models have limited experimental application. Furthermore, the biology is complicated by the existence of a common human germline deletion polymorphism in APOBEC3B, which eliminates the entire coding region of this gene but is paradoxically associated with an t cancer  and an iutations , 7. It hKanu and colleagues focused on the association between replication stress and APOBEC3B activity in breast cancer cell lines, starting from the observation that the HER2-enriched subtype of breast cancers exhibits the greatest burden of APOBEC mutations  and the In their study, the authors also showed that the APOBEC3B upregulation following induction of replication stress is dependent on signaling through the ATR–CHK1 (checkpoint kinase 1) pathway, providing a mechanism for the observed phenomena. While not a primary focus of the paper, the authors examined the association between APOBEC3B expression and drug sensitivities. Interestingly, they noted a trend between APOBEC3B expression levels and in vitro sensitivity to the novel oral CHK1 inhibitor CCT244747 and speculated that markers of replication stress, including APOBEC3B, could be useful to predict response to this agent. While CCT244747 is not included in the recent GDSC1000 pharmacogenomic dataset, we did not observe a relationship between APOBEC3B expression and either AZD7762 or Calbiochem 681640, which inhibit CHK1  are distinct from all of the other members of the APOBEC3 family, which are very strongly associated with a STAT1/interferon signature . This obIn conclusion, Kanu and colleagues provide important insights into our understanding of the APOBEC phenomenon. Their careful experimentation complements the growing body of genomics-based analyses that seek to fully decrypt how and why these immune defenders turn against our genomes. Well-conducted experimental studies and continued interrogation of the genomes of nascent and late-stage cancers, both before and following treatment, will undoubtedly reveal much about this enemy within and should clarify the potential of translating this knowledge for the prevention or treatment of cancers where APOBEC operates.


Cells robustly reprogram gene expression during stress generated by protein misfolding and aggregation. In this condition, cells assemble the bulk of mRNAs into translationally silent stress granules (SGs), while they sustain the translation of specific mRNAs coding for proteins that are needed to overcome cellular stress. Alterations of this process are deeply associated to neurodegeneration. This is the case of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder caused by a selective loss of motor neurons. Indeed, impairment of protein homeostasis as well as alterations of RNA metabolism are now recognized as major players in the pathogenesis of ALS. In particular, evidence shows that defective mRNA transport and translation are implicated. Here, we provide a review of what is currently known about altered mRNA translation in ALS and how this impacts on the ability of affected cells to cope with proteotoxic stress. Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease. The most significant feature of ALS is the preferential loss of motor neurons from brain and spinal cord. Yet, a huge heterogeneity characterizes ALS manifestations, and it is now accepted that ALS is a complex multi-systemic syndrome with important aspects that overlap with other neurodegenerative disorders , small ribosomal subunits and a great number of RBPs , two RBPs whose mutations are associated to rare forms of familial ALS  by high levels of unfolded or misfolded proteins, the PERK kinase phosphorylates eIF2α. This decreases the active pool of the ternary complex with the consequent inhibition of global translation. This pathway is indeed involved in ALS pathology, since ER stress markers, including phosphorylated eIF2α, have been detected in tissues from ALS patients and animal models (Matus et al., Drosophila the knockdown of PERK or GADD34 fly homologs respectively suppresses or enhances motility defects caused by TDP-43 toxicity (Kim et al., Drosophila and in primary rat cortical neurons followed by treatment with a specific PERK inhibitor (GSK2606414; Kim et al., Genetic approaches have been used to modulate the eIF2α-P levels in mice overexpressing mutated G85R-SOD1. In particular, PERK haploinsufficiency accelerates SOD1 misfolding, causes an earlier disease onset and shortens survival (Wang et al., In conclusion, an increasing amount of genetic and mechanistic indications point to alterations in the proper control of mRNA translation as critical players in ALS pathogenesis Figure . ClearlyGC and MC formulated the concept of the manuscript. GC, SR and MC wrote the manuscript. SR and MDS executed complete drawing of the figure. All authors reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2–8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a “housekeeping” activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on  Due to a quirk in human evolution, SMN is also encoded by the highly homologous SMN2 gene. Nonetheless, a single nucleotide substitution (C/T) in exon 7, converts an exon splicing enhancer to a silencer, hence inducing the omission of exon 7 from most of the SMN2-derived mRNA transcripts. This alteration leads to the production of an unstable truncated protein isoform (SMNΔ7) that is rapidly degraded, although in the absence of complete penetrance, full-length, functional SMN is still encoded by a small portion of SMN2 transcripts that evade exon 7 skipping  is a neuromuscular disorder that can afflict both infants and adults. Patients present with loss of lower motor neurons and profound muscle weakness leading to immobility and, in severe cases, respiratory failure and death , core elements of the spliceosome. In this review, we present a refined view of the key snRNP assembly events taking place within the crowded environment of cells, and evaluate the evidence favoring the classification of SMA as a chaperonopathy or a disorder arising from a disturbance in the chaperoning of snRNP assembly with the consequential transcriptome abnormalities as the primary drivers of neuromuscular degeneration in SMA patients. A better understanding of the mechanisms underpinning the disease can open up novel therapeutic routes that complement or accentuate the effect of the mainstream approach.Interestingly, ASOs and other therapeutic approaches that treat SMA by augmenting SMN expression, including chief amongst others viral-mediated SMN gene delivery, and orally bioavailable small molecules that correct Schizosaccharomyces pombe  and Gemin2 (Yip1p), a situation that is typical in the fission yeast It has long been known that loss of SMN is incompatible with life  bound to a heptameric Sm/Lsm protein ring  cap of nuclear-exported snRNAs via the first and second WD40 repeat domains, respectively  cap of assembled snRNPs to a 2,2,7-trimethylguanosine (TMG) cap  (Cauchi, The ample evidence linking defective chaperoning of snRNP assembly to neuromuscular dysfunction is not only consistent with SMA being a chaperonopathy but also sets the scene for the discovery of therapies that target this pathway. Inhibition of RNA decay pathways to correct snRNP levels (Shukla and Parker,  Cauchi, , such thRC conceived the review focus; ML, NV, and RC conducted the literature review, wrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Long non-coding RNAs (lncRNAs) are critical regulators in a multitude of biological processes. Recent evidences demonstrate potential pathogenetic implications of lncRNAs in diabetic cardiomyopathy (DCM); however, the majority of lncRNAs have not been comprehensively characterized. While the precise molecular mechanisms underlying the functions of lncRNAs remain to be deciphered in DCM, emerging data in other pathophysiological conditions suggests that lncRNAs can have versatile features such as genomic imprinting, acting as guides for certain histone-modifying complexes, serving as scaffolds for specific molecules, or acting as molecular sponges. In an effort to better understand these features of lncRNAs in the context of DCM, our review will first summarize some of the key molecular alterations that occur during fibrosis in the diabetic heart , followed by a review of the current knowledge on the crosstalk between lncRNAs and major epigenetic mechanisms  within this fibrotic process. With the incidence of diabetic cardiomyopathy (DCM) increasing at an alarming rate, the need for broadening the therapeutic scope for disease management becomes fundamental. In order to develop new therapeutic agents to successfully impede the progression of DCM, a thorough understanding of the complex pathogenetic mechanisms implicated in DCM progression is an absolute requirement. There are currently several known metabolic pathway alterations that occur in a hyperglycemic environment; however, recent advances in genomic technology have identified that a significant number of epigenetic alterations contribute to the development and progression of DCM. Long non-coding RNAs (lncRNAs), which are involved in altering gene expression without modifying the underlying nucleotide composition of the genome, are beginning to emerge as key epigenetic regulators in various diseases . DespiteCardiovascular complications are responsible for the majority of diabetes-related morbidity and mortality . Such coMultiple mechanisms have been proposed to explain the pathogenesis of DCM. These include autonomic dysfunction, defects in lipid metabolism, abnormalities in ion homeostasis, alterations in structural proteins, increased oxidative stress, interstitial fibrosis and alterations in myocardial substrates and energy metabolism –20. As cCurrently, there is no single therapy for treating DCM. Treatment options revolve around dietary glycemic control, direct and indirect regulators of fatty acid metabolism, and inhibitors of factors that trigger heart failure symptoms , 23. MedStructural and functional alterations in the vasculature arise in the presence of chronic diabetes. Among these alterations, modifications to the extracellular matrix (ECM) and basement membrane (BM) are the structural hallmarks in target organs of diabetic complications . First rThe entire circulatory system is lined by ECs, forming a boundary between circulating blood in the lumen and all vessel walls from the heart to small capillaries . ECs all Genetic factors are thought to be important for the development of diabetes and its various complications. In addition to genetics, environmental factors such as sedentary lifestyle, age and obesity are important for elevating the risk for the disease. In fact, there is considerable evidence indicating that the interaction between genes and the environment can influence an individual’s susceptibility to develop a chronic complication –71. The With the emergence of genome-wide association studies (GWAS) in the early to late 2000s, nearly 88% of trait/disease-associated single nucleotide polymorphisms were identified to reside in non-protein coding regions ; which, LncRNAs are defined as transcripts that are greater than 200 nucleotides in length and do not possess protein-coding potential . Based oFollowing the findings from GWAS, recent transcriptomic analyses revealed that lncRNA expression profiles differed considerably between failing and non-failing human hearts . In factin vitro that global DNA hypermethylation and elevated activities of DMNTs (DNMT1 and DMNT3B) were associated with hypoxic and pro-fibrotic human cardiac fibroblasts  and DNA demethylases. Typically, gene silencing, via the elevated activity of DMNTs, is associated with aberrant methylation patterns of CpG dinucleotide clusters (CpG islands) in certain genes . In the roblasts . In factroblasts . On the roblasts . They coroblasts . The subroblasts . Xu and roblasts , 108. OvAlthough the link between DNA methyltransferases and lncRNAs in cardiac fibrosis has not been made clear, previous evidence in lung fibrosis suggests that miRs  exhibit a complex regulatory relationship with DMNTs . In factHistone methylation involves the transfer of methyl groups from the methyl donor S-adenosyl methionine (SAM) to amino acid residues  by histone methyltransferases , 115. MeFendrr is known to bind to both PRC2 and TrxG/MLL complexes in order to facilitate proper cardiac development (Chaer (cardiac-hypertrophy-associated epigenetic regulator) directly interacts with EZH2 to alter PRC2 targeting, which ultimately inhibits H3K27me3 at the promoter regions of genes implicated in cardiac hypertrophy (Bvht interacts with SUZ12 of PRC2 to mediate epigenetic regulation of cardiovascular lineage commitment (Mhrt is a cardioprotective lncRNA that is capable of protecting the heart from hypertrophy and failure by sequestering a stress-induced chromatin-remodelling factor (Brg1)— this factor is then unable to activate aberrant gene expressions  in glucose-treated ECs  activity is significantly reduced under chronic hyperglycemic environments in ECs and the subsequent reduction of SIRT1 drove the formation of reactive oxygen species (ROS), which is mediated by FOXO1(forkhead box protein O1) acetylation through elevated p300 activity  and histone deacetylases (HDACs), respectively , 137. Thactivity . SIRT1 iactivity . Rizk anactivity . Along wactivity . Other sactivity –149.ANRIL (Khps1 (Sirt1 antisense (AS) lncRNA can inhibit muscle formation by activating Sirt1 and impeding the function of miR-34a by competitively interacting with the 3’ UTR of the Sirt1 transcript  has been shown to block the actions of miR-539 by acting as an endogenous sponge that consequently augments the expression of PHB2 (a miR-539 target) and prevents cardiomyocyte apoptosis and mitochondrial fission (NRF (necrosis-related factor) can regulate necrosis in cardiomyocytes by sponging miR-873, which is an important miR implicated in the translational repression of RIPK1/RIPK3  can block the actions of miR-24  by its sponging capabilities, and induce cardiac fibrosis  can act as a competitive endogenous RNA for miR let-7d . The figures and table presented in this review were drawn by Saumik Biswas and Subrata Chakrabarti. We provide permission to Writing of manuscript: SB, AT, SC. Figure drawings: SB, SC.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Schwann cell incredible plasticity is a hallmark of the utmost importance following nerve damage or in demyelinating neuropathies. After injury, Schwann cells undergo dedifferentiation before redifferentiating to promote nerve regeneration and complete functional recovery. This review updates and discusses the molecular mechanisms involved in the negative regulation of myelination as well as in the reprogramming of Schwann cells taking place early following nerve lesion to support repair. Significant advance has been made on signaling pathways and molecular components that regulate SC regenerative properties. These include for instance transcriptional regulators such as c-Jun or Notch, the MAPK and the Nrg1/ErbB2/3 pathways. This comprehensive overview ends with some therapeutical applications targeting factors that control Schwann cell plasticity and highlights the need to carefully modulate and balance this capacity to drive nerve repair. The peripheral nervous system (PNS) shows a surprising capacity of regeneration compared to the central nervous system (CNS). This ability of peripheral nerves to recover quickly following damage is to a large extent due to the remarkable plasticity of Schwann cells (SCs), the glial cells of the PNS , POU domain class 3 transcription factor 1 (Pou3f1 or Oct-6), myelin protein zero (MPZ) or myelin basic protein (MBP) as well as an up-regulation of markers of immature, de-differentiated SCs such as c-Jun, low affinity neurotrophin receptor (p75NTR) or glial fibrillary acidic protein (GFAP) but also specific repair-supportive genes  or glial cell line-derived neurotrophic factor (GDNF)  raises the question on the precise function of c-Jun in these diseases. Does c-Jun counteract the pathology, attenuate its symptoms and promote repair or does its up-regulation cause the disease? In two models of demyelinating diseases, CMT1A and CMT1X, c-Jun is increased in SCs that retain myelin differentiation  is a transmembrane receptor protein that, upon ligand binding, is cleaved and generates an intracellular domain (NICD), which acts as a transcriptional regulator. Notch controls SC proliferation and promotes the generation of immature SCs from Schwann cell precursors (SCPs) More recently, the function of a transcriptional repressor, Zeb2, has been investigated in SC myelination and nerve repair by two different teams  transcription factor regulates a lot of physiological processes and mediates the physiopathological inflammatory response in many diseases. Several studies suggest that NF-κB activation is essential for the differentiation and myelination of SCs In vitro, Sox2, Pax3, and Id2 decrease or increase myelin gene expression when overexpressed or depleted, respectively  family proteins in the regulation of SC plasticity. Extracellular signal regulated kinase (Erk), c-jun N-terminal kinase (JNK) and p38 MAP kinase are rapidly and highly activated in the SCs of the distal stump following a nerve lesion and play specific, overlapping or complementary roles in the SC response after injury  treatment in SC-DRG neuron co-cultures , a downstream effector of Rac/Cdc42/Rho , also called p57Kip2, is a protein first known to block GYamauchi and co-workers reported that the atypical guanine-nucleotide exchange factor dedicator of cytokinesis protein 7 (Dock7), activates Rac/Cdc42/JNK signaling in SCs to positively regulate migration and negatively regulate differentiation and myelination  is another protein that has been linked to Rac activation in SCs. Apra and colleagues investigated Cthrc1 function in SCs both All these data confirm that Rac/JNK signaling is essential for SC plasticity, proliferation and migration following nerve injury. However, stimulating this pathway for nerve repair therapy must be cautioned as its upregulation has also been observed in primary human schwannoma cells  in SCs revealed a role for this protein as a negative regulator of myelination through the activation of p38 MAPK signaling  signaling has been implicated in the regulation of proliferation, survival and differentiation of different cell types  has been suggested to promote SC proliferation by enhancing the PI3K/Akt pathway and to act on regeneration following sciatic nerve crush  inhibits PI3K/Akt signaling via its interaction with the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). This mechanism is necessary to transiently inhibit the axonal stimulation of myelination and to limit myelin sheath thickness. Myelin outfoldings and overmyelination followed later by pathologic demyelination are actually observed after Dlg1 silencing via RNA interference in mouse sciatic nerves  necessary for growth and proliferation  or monocyte chemoattractant protein-1 (MCP-1) but this effect is reduced in SCs from mice lacking TLR3  are a class of proteins that play a key role in initiating the immune and inflammatory response. After nerve injury, damage-associated molecular patterns and ligands released from or expressed by activated or necrotic damaged cells result in the activation of TLRs in different cell types including SCs  have been demonstrated to be implicated in SC differentiation. These are Gpr126, Gpr44, and lysophosphatidic acid receptor 1 (LPA1) , previously known to affect SC migration and myelination in situ (Marquardt and Sakiyama-Elbert, in vitro (Lee et al., Other approaches that are based on SC regenerative properties and improve nerve repair can also be addressed. First, exercise and electrical stimulation have been demonstrated to promote SC-driven peripheral nerve regeneration in both animal models and in human patients (Gordon and English, The different therapeutic options that are built on or that stimulate SC plasticity represent new avenues for nerve regeneration but should be considered with prudence for different reasons. First, a prolonged stimulation of SC dedifferentiation could disrupt the remyelination of the regenerated axons, necessary for rapid nerve conduction and complete functional recovery. Also, the aberrant activation of some pathways including Notch, NF-κB, Ras/Raf/Erk, Rac/JNK, or Nrg1/ErbB can lead to abnormal cell proliferation and the development of peripheral nerve tumors. The better understanding of the molecular mechanisms regulating SC plasticity is thus necessary to set up therapies that modulate both temporally and quantitatively SC capacity to drive nerve repair without affecting remyelination and increasing the chances of triggering tumor development.The remarkable capacity of regeneration of the PNS compared to the CNS is mainly due to the fantastic plasticity of SCs. The molecular components involved in the negative regulation of myelination and in the reprogramming of SCs in response to nerve injury provide important mechanistic insights and new therapeutic approaches into peripheral neuropathies as well as in peripheral nerve regeneration. However, this review demonstrates the complexity of the molecular signaling pathways and reveals that little is known about the interactions between them. Moreover, the temporal and quantitative activation of the different signals identified is of great importance but is not completely elucidated. Future studies are thus required to better understand the cross-talks, networks and activation patterns and timings between the different molecular mechanisms controlling SC plasticity.Manuscript writing: AB; Manuscript revision: VD, AC, and RF.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Despite multimodal treatments comprising, radiation therapy (RT) and chemotherapy with temozolomide (TMZ), the prognosis of glioblastoma multiforme (GBM) remains dismal and consolidated therapy yields a median survival of 14.6 months.Blood Brain Barrier (BBB) mediated chemoresistance and high dose related toxicity make necessary the development of new therapeutic approach to sensitize GBM to TMZ.plus TMZ metronmic doses  in GBM therapy.The aim of the present study was to investigate the potential of the treatment morphine in vitro models.The effect of morphine, on tumor cell growth and P-glycoprothein (P-gp) activity, was investigate in The results demonstrated that GBM cells growth is not influenced by morphine treatment and, for the first time, we show that morphine is an inhibitor of the activity of P-gp efflux transporter who is markedly expressed on BBB.In vivo, response to the treatments TMZ plus morphine was investigated in an orthotopic nude mice model of GBM.Animals treated with TMZ metronomic doses showed a significant tumor growth inhibition compared to untreated mice and association with morphine appears to improve TMZ efficacy.Moreover, the combination of morphine with lower dose of TMZ result in a cytostatic effect on tumor growth over the period of the pharmacological treatments.In conclusion this novel approach could be a successful strategy to overcome chemoresistance and side effects TMZ mediated, reducing drug dosage and improving long term response, in GBM therapy. GBM is the most common and aggressive primary brain tumor derived from glial progenitors of the central nervous system (CNS) , 2.TMZ, the current standard care for GBM , 4, showResistance to TMZ has shown to be multifactorial, including changes in the cell cycle, up regulation of mismatch repair genes and MGMT  and addiP-gp belongs to the ATP binding cassette (ABC) transporters and plays the major role in the failure of cancer therapy, limiting the accumulation of a wide range of molecules in numerous tissue including the brain .Different studies have shown that brain concentrations of TMZ are only 17–20 % of the blood levels , 13 and in vivo frequent administration of low doses of chemotherapeutic drugs, known as metronomic chemotherapy, could affect tumor endothelium and inhibit tumor angiogenesis, reducing significant side effects  – 100. Measurements were carried out biweekly and, as humane endpoint, animals showing a BW reduction ≥ 15% were sacrificed by COData were expressed as mean ± SD. Statistical analyses were performed using U-Test between two groups while comparison between multiple groups were performed using 1 or 2 way ANOVA followed by post hoc corrections, as appropriate. All analyses were done using GraphPad Prism 5 and P<0,05 was considered statistically significant.


Cancers are an extraordinarily heterogeneous collection of diseases with distinct genetic profiles and biological features that directly influence response patterns to various treatment strategies as well as clinical outcomes. Nevertheless, our growing understanding of cancer cell biology and tumor progression is gradually leading towards rational, tailored medical treatments designed to destroy cancer cells by exploiting the unique cellular pathways that distinguish them from normal healthy counterparts. Recently, inhibition of the activity of phosphodiesterase type 5 (PDE5) is emerging as a promising approach to restore normal intracellular cyclic guanosine monophosphate (cGMP) signalling, and thereby resulting into the activation of various downstream molecules to inhibit proliferation, motility and invasion of certain cancer cells. In this review, we present an overview of the experimental and clinical evidences highlighting the role of PDE5 in the pathogenesis and prevention of various malignancies. Current data are still not sufficient to draw conclusive statements for cancer patient management, but could provide further rational for testing PDE5-targeting drugs as anticancer agents in clinical settings. The current global demographic, epidemiologic and nutritional transitions signal an enormous cancer burden on society in countries of all income levels. The incidence of cancer cases is on continuing growth also because of an increasing prevalence of established risk factors, such as tobacco use, excess body weight, physical inactivity, infection and changes in the reproductive patterns connected with urbanization and economic development. Based on data from GLOBOCAN 2012, an estimated 14.1 million new cancer cases and 8.2 million deaths were recorded in 2012 globally –6. In th2+/calmodulin), protein partners , or molecular scaffolds . In addition, N-terminal regulatory regions include dimerization domains and autoinhibitory modules as several PDEs exist as asymmetric homo- or heterodimers . Informations from the crystal structures of isolated catalytic cores of PDEs have revealed that these domains exhibit the same topography, composed of aminoacids folded into 16 helices , 7675, 7The human PDE5A gene is located on chromosome 4q264,5 and contains about 23 exons spanning approximately 100 kilobases, with the first three exons being alternative exons encoding the isoform-specific 5’-ends of the PDE5 sequences , 81. CloHuman PDE5A1 and A2 transcripts are found to be expressed in almost all tissues, with PDE5A2 being more common, and identifiable in almost all cells cultured from aortic smooth muscle, bladder smooth muscle, urethra smooth muscle, penile smooth muscle, penile endothelium, aortic endothelium, etc. On the contrary, the distribution of human PDE5A3 appears to be restricted to tissues with smooth and/or cardiac muscle component . The thrIn catalysing the hydrolysis of cGMP, PDE5 plays critical roles in controlling its intracellular levels, the compartmentalization of its signalling pathways and its downstream biological responses. cGMP signalling is schematically shown in Figure Since the discovery and characterization of PDE5, a collection of molecules able to inhibit its enzymatic activity have been conceived. The first drugs, such as IBMX (3-isobutyl-1-methylxanthine), dipyridamole and coffee, have been shown to be potent but non selective inhibitors. Later, zaprinast was described as a more specific molecule , but it in vitro and in vivo models of pulmonary hypertension following PDE5 inhibition has provided the rationale to recommend also PDE5 as a target for the treatment of pulmonary hypertension and respiratory distress [Data from reports using selective PDE5 inhibitors have been essential for a robust understanding of the cellular functions that are regulated by PDE5 in physiological states as well as under pathological conditions. For instance, sildenafil, originally designed as an antihypertensive molecule or a coronary vasodilator, was shown to induce responses in off-target tissues, such as in penis, changing the focus of this agent to erectile dysfunction (ED) and proposing PDE5 as a target for the treatment of ED. In addition, the improvement of pulmonary vascular physiology observed in distress , 123.At the present time, the orally administrated PDE5 inhibitors sildenafil and tadalafil have Food and Drug Administration approval for the treatment of ED as well as pulmonary arterial hypertension (PAH); whereas vardenafil and avanafil are approved only for ED. However, a great number of papers published over the last decade highlighted the potential clinical use of PDE5 inhibitors in other applications, for which current therapies are limited and in which the mechanism of action does not necessarily rely on their known vasodilatatory effects . Table 2http://www.clinicaltrials.gov). The list of the studies focused on the effects of PDE5 inhibition in cancer patients is reported in Table There has been a remarkable interest in identifying new clinical use of PDE5 inhibitors as potent anticancer drugs with a novel mechanism of action Figure . Since 2Lung cancer has emerged as the most common cancer in the world, both in terms of new cases and deaths (1.82 million diagnoses and 1.6 million deaths recorded in 2012) with the highest rates in Central/Eastern Europe and Eastern Asia . Despitein vivo by co-treatment with the mTOR inhibitor temsirolimus [Over the last years, the apoptotic and growth inhibition activities of PDE5 inhibitors have been demonstrated in numerous lung cancer cell lines. Most of the experiments were performed by using exisulind (sulindac sulfone), a sulfone metabolite of the nonsteroidal anti-inflammatory drug (NSAID) sulindac. Exisulind, which lacks the hallmark cyclooxygenase inhibitory activities of NSAIDs, acts as a cGMP PDE inhibitors, causing a persistent increase in cellular cGMP, and inducing PKG –203. It irolimus . The comirolimus .However, the clinical evidences do not support experimental findings. In 2006, a phase I/II study was designed to evaluate the safety and efficacy of exisulind in combination with gemcitabine as second-line therapy in NSCLC patients whose disease progressed more than 3 months from completion of first-line chemotherapy . AlthougProstate cancer represents the second most frequently diagnosed solid malignancy among men worldwide, accounting for about 1.1 million cases in 2012 [in vitro cell culture and in vivo xenograft approaches, it was clearly demonstrated that PDE5/cGMP/PKG signal targets to Hippo/TAZ pathway in maintaining stemness of prostate cancer stem cells, evidencing a novel role of PDE5 in governing stem cell features [In support of PDE5 inhibitors’ ability to affect prostate carcinogensis, it was reported that exisulind suppressed the growth of metastatic, human prostate cancer cells in a nude mouse xenograft model by increasing apoptosis . In contfeatures . Moreovefeatures . Tadalaffeatures  and revifeatures ).n = 4752) with a median follow-up of 60.3 months, it was shown that the use of PDE5 inhibitors after radical prostatectomy may adversely impact biochemical recurrence (BCR), defined as a PSA of 0.2 ng/ml or greater and increasing after radical prostatectomy [A retrospective analysis including a total of 4974 men revealed that the use of PDE5 inhibitors over a 7-year period was associated to a decreased incidence rate of prostate cancer among men with ED compared to men with ED of the same age and with similar risk factors who were not treated with these agents . It was atectomy . Howeveratectomy .On the basis of these findings, there is no strong evidence to modify current clinical practice, and therapy with PDE5 inhibitors still remains the more recommended option for many postprostatectomy patients for penile rehabilitation programs .Breast carcinoma is the most common malignancy and the leading cause of cancer-related death in women worldwide. Breast cancer is a complex and highly heterogeneous disease classified on the basis of global gene expression analyses into at least five biologically different intrinsic subtypes -enriched, basal-like, and normal-like) with distinct morphologic features, variable clinical outcomes and disparate therapeutic responses .in vitro and of lung metastasis formations in an experimental metastasis assay in vivo [Increased PDE5 expression has also been reported in various cell lines deriving from breast cancer  , giving  in vivo . This we in vivo .n = 35), but the synergism between these two drugs at the doses tested appears to be modest [In breast cancer clinical samples, increased PDE5 expression was verified by both RT-PCR and immunohistochemistry analyses, and was correlated with tumor grade stage and lymph node involvement , 234. Moe modest .Colorectal cancer is the third most commonly diagnosed cancer in men and the second in women worldwide, with an estimated 1.4 million cases and 693,900 deaths occurring in 2012 [in vitro and caused the reduction of xenograft tumor growth in nude mice [In several colon tumor cell lines , exisulind and analogs/derivatives were able to inhibit the oncogenic activity of β-catenin through a direct suppression of its transcription or increased proteosomal degradation, thereby promoting cell death , 235–238ude mice . Recentlude mice .In clinical studies, exisulind prevented colorectal polyp formation in patients with familial adenomatous polyposis (FAP) over 24 months , 244. MoCancers of the brain and central nervous system accounted for 256,000 new cases and 189,000 deaths in 2012, with the highest incidence and mortality rates in more developed regions [in vitro and in vivo [In both neuroblastoma N18TG2 and hybrid neuroblastoma-glioma NG108–15 cells, the presence and regulation of PDE5 mRNA during cell differentiation was previously demonstrated . In medu in vivo . PDE5 in in vivo . Tadalaf in vivo . In cont in vivo .Analysis of a cohort of 69 patients affected by glioblastoma multiforme (GBM) who underwent chemotherapy and radiotherapy following surgical resection of the tumor revealed that PDE5 was strongly expressed in 50% of cancer cases . RetrospCarcinoma of the thyroid is the most common malignancy of endocrine organs, representing 2.1% of the new cancer cases  . Over thThe role of cGMP levels and PDE5 in thyroid cancer are still not well defined. Analysis of the mRNA expression of members of the 11 known families of PDEs has revealed the expression of PDE4, PDE5, PDE7 and PDE8 subtypes in normal thyroid tissues . Previouin vitro, sildenafil and tadalafil determined a reduction of proliferation and at lower doses, they were also able to reduce cellular migration [in vivo, a valuable novel formulation for the treatment of thyroid carcinomas and other types of cancers.In papillary and anaplastic thyroid cancer cells igration . The effigration , that ma2+, a stimulation of actin-myosin contractility and a subsequent increase in cell invasion in vitro and in vivo [Cutaneous melanoma accounted for almost 5% of all new diagnosed cancer cases, with a reported mortality of approximately 2%, making it the deadliest form of skin cancer. Although early detection carries an excellent prognosis, with surgical excision often being curative, the long-term survival rate for patients with metastatic melanoma is only 5% . The dis in vivo . Accordi in vivo . More re in vivo .Clinically, in a prospective cohort study, men who used sildenafil for ED had a statistically significant elevated risk of developing melanoma, without affecting the risk of squamous or basal cell carcinomas, and this correlation was maintained in the models controlling for the major host characteristics, such as age, body mass index, family history, sun exposure, and UV index in the state of residence . A subsein vivo in a model of rat urinary bladder tumorigenesis [in vivo [A possible role of PDE5 inhibition has been suggested also in the management of other cancers. Immunohistochemistry showed that PDE5 was overexpressed in human squamous and transitional cell carcinomas compared with normal urothelium and accordingly, exisulind exhibited antineoplastic activity igenesis . The addigenesis . In humaigenesis . Sildena[in vivo . Sildena[in vivo . Recentl[in vivo , 277. In[in vivo . In 2015[in vivo . ResultsOver the last decades, researchers have elucidated the roles that impairment of cGMP signaling pathway by PDE5 activity inhibition plays in the regulation of tumor development, and progression. As a consequence, our knowledge on the link between PDE5 inhibitors and cancer biology has expanded, holding great promise for future use of these agents in several cancers. Although evident clinical controversial data come from patients affected by melanoma and glioblastoma multiforme, studies discussed in this literature review show that PDE5 inhibition could be associated with a decreased risk of cancer development and suppression of tumor progression in several malignancies including those of the lung, prostate, breast and colorectum. PDE5 inhibitors may also provide an additional antitumor immune response in patients affected by myeloma and head and neck squamous cell carcinomas. In addition, a synergistic effect with current chemotherapeutic regimens and monoclonal antibodies has been reported. However, this research suffered from the weakness of the clinical studies conducted until now that make difficult to draw a general conclusion. First, it would be important to distinguish class effects of PDE5 inhibitors versus effects unique to selective agents within the class, also in relation to non-specific inhibition of other PDEs as well as to potential off-target effects that can both positively and negatively influence the risk-benefit profile of PDE5 inhibitors. Secondly, we will need information concerning the optimal dosages of these molecules in the various applications, their monitoring, and the potential interactions with other agents regularly used in each patient population. Moreover, major clinical benefits will come from more definitive specifications of individual patient variables that may point toward the use of PDE5 inhibitors in general and each specific drug of this class, providing antitumor therapy with reduced adverse effects. Certainly, the clarification of additional molecular processes of potential oncogenic function of PDE5 as well as further clinical trials including PDE5 inhibitors will help to facilitate better applications of PDE5 targeting drugs in the area of cancer treatment.