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International audience; To ensure successful offspring ploidy, vertebrate oocytes must halt the cell cycle in meiosis II until sperm entry. Emi2 is essential to keep oocytes arrested until fertilization. However, how this arrest is implemented exclusively in meiosis II and not prematurely in meiosis I has until now remained enigmatic. Using mouse and frog oocytes, we show here that cyclin B3, an understudied B-type cyclin, is essential to keep Emi2 levels low in meiosis I. Direct phosphorylation of Emi2 at an evolutionarily highly conserved site by Cdk1/cyclin B3 targets Emi2 for degradation. In contrast, Cdk1/cyclin B1 is inefficient in Emi2 phosphorylation, and this provides a molecular explanation for the requirement of different B-type cyclins for oocyte maturation. Cyclin B3 degradation at exit from meiosis I enables Emi2 accumulation and thus timely arrest in meiosis II. Our findings illuminate the evolutionarily conserved mechanisms that control oocyte arrest for fertilization at the correct cell-cycle stage, which is essential for embryo viability.

Cohesin is a conserved, ring-shaped protein complex that topologically entraps DNA. This ability makes this member of the structural maintenance of chromosomes (SMC) complex family a central hub of chromosome dynamics regulation. Besides its essential role in sister chromatid cohesion, cohesin shapes the interphase chromatin domain architecture and plays important roles in transcriptional regulation and DNA repair. Cohesin is loaded onto chromosomes at centromeres, at the promoters of highly expressed genes, as well as at DNA replication forks and sites of DNA damage. However, the features that determine these binding sites are still incompletely understood. We recently described a role of the budding yeast RSC chromatin remodeler in cohesin loading onto chromosomes. RSC has a dual function, both as a physical chromatin receptor of the Scc2/Scc4 cohesin loader complex, as well as by providing a nucleosome-free template for cohesin loading. Here, we show that the role of RSC in sister chromatid cohesion is conserved in fission yeast. We discuss what is known about the broader conservation of the contribution of chromatin remodelers to cohesin loading onto chromatin.

Introduction: The Integrated Care Pathway (ICP) represents a multidisciplinary outline of anticipated care, placed in an appropriate timeframe, to support patients with specific conditions or symptoms. The aim of this paper is to define the ICP for patients with melanoma referring to the “Istituto Dermopatico dell’Immacolata-IRCCS di Roma e Villa Paola” (“Center”). Methods and results: A multidisciplinary group (oncologists, dermatologists, surgeons, pathologists etc.) was defined as well as a facilitator to act as a link between all experts. The first step of ICP development was a review of current practice for patients with melanoma referring to the Center. This first step had the scope to define the multidisciplinary process map (a “picture” of the care plan) for patients with melanoma. The process map defined: i) the activities performed during delivery of care to the patients, ii) the responsibilities for these activities and iii) potential problem areas or opportunities for improvements. The process map formed the basis of the final ICP document. Conclusion: The adoption of melanoma ICP will allow the multidisciplinary group to ensure that clinical guidelines and available evidence are incorporated into everyday practice. (Oncology, HTA & Market Access)

The coronavirus disease (COVID‐19), during its course, may involve several organs, including the skin with a petechial skin rash, urticaria and erythematous rash, or varicella‐like eruption, representing an additional effect of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, as commonly observed in other viral diseases. Considering that symptomatic patients with COVID‐19 generally undergo multidrug treatments, the occurrence of a possible adverse drug reaction presenting with cutaneous manifestations should be contemplated. Pleomorphic skin eruptions occurred in a 59‐year‐old Caucasian woman, affected by a stable form of chronic lymphocytic leukemia, and symptomatic SARS‐CoV‐2 infection, treated with a combination of hydroxychloroquine sulfate, darunavir, ritonavir, sarilumb, omeprazole, ceftriaxone, high‐flow oxygen therapy devices, filgrastim (Zarzio®) as a single injection, and enoxaparin. The patient stopped all treatment but oxygen and enoxaparin were continued and the patient received a high‐dose Desametasone with complete remission of dermatological impairment in 10 days. It is very important to differentially diagnose COVID‐19 disease‐related cutaneous manifestations, where is justified to continue the multidrug antiviral treatment, from those caused by an adverse drug reaction, where it would be necessary to identify the possible culprit drug and to start appropriate antiallergic treatment., The coronavirus disease (COVID‐19), during its course, may involve several organs, including the skin with a petechial skin rash, urticaria and erythematous rash, or varicella‐like eruption, representing an additional effect of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, as commonly observed in other viral diseases. Considering that symptomatic patients with COVID‐19 generally undergo multidrug treatments, the occurrence of a possible adverse drug reaction presenting with cutaneous manifestations should be contemplated. Pleomorphic skin eruptions occurred in a 59‐year‐old Caucasian woman, affected by a stable form of chronic lymphocytic leukemia, and symptomatic SARS‐CoV‐2 infection, treated with a combination of hydroxychloroquine sulfate, darunavir, ritonavir, sarilumb, omeprazole, ceftriaxone, high‐flow oxygen therapy devices, filgrastim (Zarzio®) as a single injection, and enoxaparin. The patient stopped all treatment but oxygen and enoxaparin and received a high‐dose Desametasone with complete remission of dermatological impairment in 10 days. It is very important to differentially diagnose COVID‐19 disease‐related cutaneous manifestations, where is justified to continue the multi‐drug antiviral treatment, from those caused by an adverse drug reaction, where it would be necessary to identify the possible culprit drug and to start appropriate antiallergic treatment.

The incidence of non-melanoma skin cancers (NMSC) is increasing worldwide and these skin cancers have become an important health issue. An integrated care pathway (ICP) is a multidisciplinary outline of anticipated care, placed in an appropriate timeframe, to help a patient with a specific condition. The aim of this paper is to define the ICP for patients affected by NMSC referring to the Istituto Dermopatico dell'Immacolata - IRCCS of Rome and Villa Paola, Italy. This ICP is multidisciplinary and included various specialists like dermatologist, oncologist, general surgeon, plastic surgeon, anatomopathologist, molecular biologist and epidemiologist. This ICP is based on the most recent acquisitions in the literature, referring in particular to the national (EADO and SIDEMAST) and international guidelines (EDF and NCCN). We firstly valued the current practice for patients affected by NMSC referring to our Institute to define the multidisciplinary process map. This process delineated the activities and the responsibilities performed during delivery of care to the patients and the potential problem areas or opportunities for improvements. Subsequently, we defined the final ICP process. This ICP of NMSC represents an innovative strategy to provide high quality healthcare. This allows to ensure all the necessary procedures for the patient, optimizing the "continuum" of care and the use of health services, and improving the organization of the Institute regarding an important health issue.

The coronavirus disease (COVID-19), during its course, may involve several organs, including the skin with a petechial skin rash, urticaria and erythematous rash, or varicella-like eruption, representing an additional effect of the SARS-CoV-2 infection, as commonly observed in other viral diseases. Considering that symptomatic COVID-19 patients generally undergo multi-drug treatments, the occurrence of a possible adverse drug reaction (ADR) presenting with cutaneous manifestations should be contemplated. Pleomorphic skin eruptions occurred in a 59-year-old Caucasian woman, affected by a stable form of Chronic lymphocytic leukaemia, and symptomatic SARS-CoV.2 infection, treated with a combination of hydroxychloroquine sulphate, darunavir, ritonavir, sarilumb, omeprazole, ceftriaxone, high-flow oxygen therapy devices, filgrastim (Zarzio®) as a single injection, and enoxaparin. The patient stopped all treatment but oxygen and enoxaparin and received a high-dose Desametasone with complete remission of dermatological impairment in 10 days. It is very important to differentially diagnose COVID-19 disease-related cutaneous manifestations, where is justified to continue the multi-drug antiviral treatment, from those caused by an adverse drug reaction, where it would be necessary to identify the possible culprit drug and to start an appropriate treatment.

Variably reduced expression of the basement membrane component laminin-332 (α3aβ3γ2) causes junctional epidermolysis bullosa generalized intermediate (JEB-GI), a skin fragility disorder with an increased susceptibility to squamous cell carcinoma (SCC) development in adulthood. Laminin-332 is highly expressed in several types of epithelial tumors and is central to signaling pathways that promote SCC tumorigenesis. However, laminin-332 mutations and expression in individuals affected by JEB-GI and suffering from recurrent SCCs have been poorly characterized. We studied a JEB-GI patient who developed over a hundred primary cutaneous SCCs. Molecular analysis combined with gene expression studies in patient skin and primary keratinocytes revealed that the patient is a functional hemizygous for the p.Cys1171* mutant allele which is transcribed in a stable mRNA encoding for a β3 chain shortened of the last two C-terminal amino acids (Cys1171-Lys1172). The lack of the Cys1171 residue involved in the C-terminal disulphide bond to γ2 chain did not prevent assembly, secretion, and proteolytic processing of the heterotrimeric molecule. Immunohistochemistry of SCC specimens revealed accumulation of mutant laminin-332 at the epithelial-stromal interface of invasive front. We conclude that the C-terminal disulphide bond is a structural element crucial for laminin-332 adhesion function in-vivo. By saving laminin-332 amount, processing, and signaling role the p.Cys1171* mutation may allow intrinsic pro-tumorigenic properties of the protein to be conveyed, thus contributing to invasiveness and recurrence of SCCs in this patient.

Factors that are most associated with positive lymph node status in melanoma are Breslow thickness and ulceration. However, there are other factors that have been little explored and could help in the identification of “at risk patients” harbouring occult metastasis. The objective of this study was to determine whether intensity of tumour-infiltrating lymphocytes (TILs) in a cohort study (N = 4133) is an independent predictor of sentinel lymph node (SLN) status in patients with primary cutaneous melanoma. Of the patients with cutaneous melanoma who resulted negative for nodal metastasis, 50.7% had moderate/marked TILs versus 27.7% among those patients who resulted positive for nodal metastasis. In the multivariate analysis, controlling for sex, age, mitotic rate, ulceration and Breslow, high levels of TILs in primary invasive melanoma was associated with a lower risk of developing SLN metastasis (OR 0.46; 95% CI 0.23–0.95, p = 0.037). When the analysis was stratified by sex, the protective effect of moderate/marked TIL remained only for women (OR 0.30; 95% CI 0.10–0.93, p = 0.037) but not for men (OR 0.51; 95% CI 0.19–1.34, p = 0.172). Other independent predictors of negative lymph node were low Breslow thickness (≤ 2.0 mm) and low mitotic rate. Besides predicting a negative lymph node response, TILs were also associated with a decreased risk of 10-year mortality among females with positive lymph node. Our findings suggest that high level of TILs is an independent predictor of negative SLN status among women. Further research is warranted to confirm our findings.

Breast asymmetry can be congenital or developmental, however a tumorous growth may be the cause of this condition after puberty. A 19-year-old female presented with a slowly developing breast asymmetry pre-operatively diagnosed as Pseudoangiomatous Stromal Hyperplasia (PASH). The patient underwent tumour excision with breast gland remodelling. Postoperative course was uneventful.

Sezary syndrome (SS) is a rare and aggressive variant of Cutaneous T-Cell Lymphoma characterized by neoplastic distribution mainly involving blood, skin, and lymph-node. Although a role of the skin microenvironment in SS pathogenesis has long been hypothesized, its function in vivo is poorly characterized. To deepen this aspect, here we compared skin to blood-derived SS cells concurrently obtained from SS patients highlighting a greater proliferation-index and a PI3K/AKT/mTORC1 pathway activation level, particularly of mTOR protein, in skin-derived-SS cells. We proved that SDF-1 and CCL21 chemokines, both overexpressed in SS tissues, induce mTORC1 signaling activation, cell proliferation and Ki67 up-regulation in a SS-derived cell line and primary-SS cells. In a cohort of 43 SS cases, we observed recurrent copy number variations (CNV) of members belonging to this cascade, namely: loss of LKB1 (48%), PTEN (39%) and PDCD4 (35%) and gains of P70S6K (30%). These alterations represent druggable targets unraveling new therapeutic treatments as metformin here evaluated in vitro. Moreover, CNV of PTEN, PDCD4, and P70S6K, evaluated individually or in combination, are associated with reduced survival of SS patients. These data shed light on effects in vivo of skin-SS cells interaction underlying the prognostic and therapeutic relevance of mTORC1 pathway in SS.

We develop a new theory of vote switching by legislators that defect from party line voting. In our model, ideological candidates select their party label and, once elected, vote in parliament. Political parties select their policy platform as to maximize votes while preserving their candidates’ loyalty. We find that legislators that defect from party line voting arise within the majority party. Besides, the more legislators care about their ideology and the less about their own reputation, the more they defect from party line voting. Interestingly, when a party has larger electoral advantage and its candidates sufficiently care about their reputation, such a party can propose a more polarized policy to avoid party defectors. Our model suggests that polarization incentivizes loyalty. Finally, we discuss the robustness of our results in multi-party systems and multi-constituency systems.

Background Whether timing of sentinel lymph node biopsy (SLNB) in cutaneous melanoma improves survival is not yet clear. The aim of this study was to investigate if the timing of SLNB influences long-term melanoma mortality. Methods A 10-year retrospective cohort study was conducted on 748 cutaneous melanoma patients who underwent excision of the SLN. Hazard ratios and 95% confidence intervals were estimated from Cox proportional hazards models. Results After adjusting for sex, age, Breslow thickness, mitotic rate, ulceration, and histologic type, patients who underwent early SLNB (≤30 days) and resulted positive on final pathology had a 3 times decreased risk of melanoma mortality (hazard ratio = .29; 95%confidence interval = .11 to .77) in comparison to patients who underwent delayed SLNB (≥31 days) and resulted positive on final pathology. Conclusions Our findings suggest that early SLNB (≤30 days) improves melanoma survival.

Human keratinocytes were recently shown to respond to anti-EGFR (epidermal growth factor receptor) drugs with activation of an interferon-&kappa, driven autocrine loop, leading to enhanced expression of innate antiviral effectors and of the pro-inflammatory chemokines CXCL10 (C-X-C motif chemokine 10) and CCL2 (C-C motif ligand 2). Here we showed active type I interferon signaling in the skin lesions of cancer patients undergoing treatment with the anti-EGFR drug cetuximab. Strong nuclear positivity for Interferon Regulatory Factor 1 and phosphorylated Signal Transducer and Activator of Transcription 1, enhanced interferon-&kappa, expression and CXCL10 was associated to the epidermal compartment. Notably, 50 micromolar resveratrol and quercetin fully suppressed the low constitutive levels of type I interferon signaling and prevented its activation by the anti-EGFR cetuximab or gefitinib in cultured keratinocytes. In sensitized mice undergoing DNFB (2,4-dinitro-1-fluorobenzene)-induced contact hypersensitivity, local administration of gefitinib prior to elicitation further amplified hapten-induced type I interferon activation, tissue edema, and infiltration by T cells, whereas resveratrol or quercetin suppressed this inflammatory cascade. Overall, these data suggest that topical application of resveratrol or quercetin could be potentially effective in preventing pathological conditions due to overactivation of type I IFN (interferon)-driven circuits in the skin, including the inflammatory manifestations of anti-EGFR drug-induced skin-targeted toxicity.

Key Clinical Message We report on a case of Sweet's syndrome associated with multiple myeloma, as harbinger for disease relapse.

Brain serotonin 7 (5-HT7) receptors play an important functional role in learning and memory, in regulation of mood and motivation, and for circadian rhythms. Recently, we have studied the modulatory effects of a developmental exposure (under subchronic regimen) in rats with LP-211, a brain-penetrant and selective 5-HT7 receptor agonist. We aimed at further deciphering long-term sequelae into adulthood. LP-211 (0.250 mg/kg i.p., once/day) was administered for 5 days during the adolescent phase (postnatal days 43-45 to 47-49). When adult (postnatal days >70), forebrain areas were obtained for ex vivo immunohistochemistry, whose results prompted us to reconsider the brain connectivity maps presented in our previous study (Canese et al., Psycho-Pharmacol 2015;232:75-89.) Significant elevation in levels of 5-HT7 receptors were evidenced due to adolescent LP-211 exposure, in dorsal striatum (which also shows an increase of dopaminergic D2 auto-receptors) and-unexpectedly-in piriform cortex, with no changes in ventral striatum. We observed that functional connectivity from a seed on the right hippocampus was more extended than reported, also including the piriform cortex. As a whole, the cortical loop rearranged by adolescent LP-211 exposure consisted in a hippocampus receiving connections from piriform cortex and dorsal striatum, the latter both directly and through functional control over the 'extended amygdala'. Such results represent a starting point to explore neurophysiology of 5-HT7 receptors. Further investigation is warranted to develop therapies for sleep disorders, for impaired emotional and motivational regulation, for attentive and executive deficit. The 5-HT7 agonist LP-211 (0.250 mg/kg i.p., once/day) was administered for 5 days during adolescence (postnatal days 43-45 to 47-49) in rats. When adult (postnatal days >70), a significant elevation in levels of 5-HT7 receptors were evidenced in dorsal striatum and-unexpectedly-in piriform cortex.

Understanding differences in survival across distinct subgroups of melanoma patients may help with the choice of types of therapy. Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response to tumor, but the role of TILs in melanoma mortality is controversial. The aim of this study was to investigate independent prognostic factors for melanoma mortality. We carried out a 10-year cohort study on 4133 melanoma patients from the same geographic area (Lazio) with primary cutaneous melanoma diagnosed between January 1998 and December 2008. The probability of survival was estimated using Kaplan-Meier methods and prognostic factors were evaluated by multivariate analysis (Cox proportional hazards model). The 10-year survival rate for melanoma decreased with increasing Breslow thickness (Pfor trend

Interleukin-17 (IL-17) and IL-22 have been reported to play critical roles in autoimmunity and inflammation but information about their role in cancer is limited. In this study, we investigated the role of IL-17 and IL-22 in the progression of human skin basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC). We found that both tumor types are infiltrated with an high number of IL-17(+) and IL-22(+) T lymphocytes, as demonstrated by immunohistochemistry and by FACS analysis performed on peritumoral T-cell lines isolated from skin biopsies. In vitro studies demonstrated that proliferation and migration of the BCC- and SCC-cell lines M77015 and CAL27 were increased by IL-17 and IL-22. Moreover, IL-17, alone or in combination with TNF-α, was able to induce the production of two cytokines important for tumor progression, IL-6 and IL-8, in CAL27. We also showed that IL-17 upregulated NF-κB signaling, while IL-22 activated the STAT3 pathway and the antiapoptotic AKT protein in M77015 and CAL27. Finally, in vivo experiments demonstrated that IL-17 and IL-22 enhanced tumor growth in nude mice injected with CAL27. Altogether, our findings indicate that high levels of IL-22 and IL-17 in the BCC and SCC microenvironment promote tumor progression.

Caralluma fimbriata Wall. is currently used as a “natural slimming” food supplement, likely due to its content in pregnane glycosides. In the present study, a commercially available Caralluma fimbriata extract (Slimaluma®; CFE, 100 mg/kg) has been evaluated for its ability to affect the ingestive behaviour in female rats, also with reference to the modulation of the brain neuropeptides NPY and ORX.The interference of CFE with α-amylase and lipase enzymes has been investigated in vitro, as possible peripheral mechanism of action. Also, the chemical composition of CFE has been assessed by NMR and spectrophotometric analysis. Results from in vivo study showed that CFE induced effects neither on blood parameters, nor on liver and gut histomorphology. Interestingly, a reduction in body weight gain with an increase in water intake and hypothalamic levels of NPY and ORX peptides were found. Phytochemical analysis, showed CFE contained about 12% of pregnane glycosides and 1.3% of polyphenols. Present results suggest possible effects of C. fimbriata on ingestive behaviour, likely mediated by central and peripheral mechanisms.

Objectives: The outcome of patients with primary melanoma (PM) cannot be completely explained based on currently adopted clinical-histopathologic criteria. In this study, we evaluated the potential prognostic value of mismatch repair protein expression in PMs. Methods: We examined the immunohistochemical staining of mismatch repair proteins in 18 benign nevi and 101 stage I to III PMs and investigated their association with tumor clinicopathologic variables and melanoma mortality. Results: Expression of MSH2, MLH1, and PMS2 was high in benign nevi and reduced in a subset of PMs. Conversely, MSH6 expression was absent or extremely low in benign nevi and increased in a subset of PMs. In the multivariate analysis, including sex, age, Breslow thickness, and ulceration, high MSH6 expression in PMs (ie, immunostaining in >20% of tumor cells) was significantly associated with an increased risk of melanoma mortality (relative risk, 3.76; 95% confidence interval, 1.12–12.70). Conclusions: MSH6 protein expression can be a valuable marker to improve prognosis assessment in PMs.

An autoimmune hypothesis has been suggested for several disorders in childhood. The aim of the study was to clarify the role of the cerebellum in ADHD and to evaluate the possible association between anti-Yo antibodies and ADHD. The presence/absence of antibodies was tested by indirect immunofluorescence assay on 30 combined subtype ADHD children, on 19 children with other psychiatric disorders (Oppositional-defiant and Conduct Disorders, Dyslexia) and 27 healthy controls. Results showed a significant positive response to the anti-Yo antibody immunoreactivity in the Purkinje cells of the cerebellum of ADHD children, compared with the control group and the psychiatric non-ADHD children. This association points to an immune dysregulation and the involvement of the cerebellum in ADHD.

Fortes, Cristina Mastroeni, Simona Bonamigo, Renan Mannooranparampil, Thomas Marino, Claudia Michelozzi, Paola Passarelli, Francesca Boniol, Mathieu eng England 2015/02/04 06:00 Eur J Cancer Prev. 2016 Jan;25(1):34-40. doi: 10.1097/CEJ.0000000000000127.; International audience; Some studies have suggested that sun exposure plays a protective role in melanoma survival. This created a paradox as the known carcinogen can act as a cancer promoter and also as a survival enhancer. The aim of this study was to investigate the effect of sun exposure on melanoma mortality using both ambient sun exposure and individual data. A 10-year cohort study was carried out on primary cutaneous melanoma cases (n=972). Residential data were coupled with levels of ultraviolet radiation (UV) to provide a measure of individual exposure. Demographic, histological and clinical data were obtained for all participants. In a subsample, information on pigmentary characteristics, diet, medical history, phenotype and self-reported sun exposure was also collected. Survival analysis and Cox proportional hazards models were used to examine associations. No protective effect was found for UVB or individual sun exposure variables on melanoma mortality. However, an increased risk of mortality was found among patients with cutaneous melanoma located on the lower limbs and in the highest decile of UVB exposure (>/=3.298 J/cm) after controlling for sex, age and Breslow thickness (relative risk: 4.78; 95% confidence interval: 1.30-17.5). The increased risk of mortality for the highest decile of UVB was also confirmed in the subsample after controlling for sex, age, education, use of sun lamps, pigmentary characteristics and diet. The results of the study suggested no protective effect of sun exposure for melanoma mortality and showed that high sun exposure increases the risk of melanoma mortality among patients with melanomas located on the lower limbs.

Genetic variation in the human serotonin system has long been studied because of its functional consequences and links to various neuropsychiatric and behavior-related disorders. Among non-human primates, the common marmosets (Callithrix jacchus) and tufted capuchins monkeys (Cebus apella) are becoming increasingly used as models to study the effects of genes, environments, and their interaction on physiology and complex behavior. In order to investigate the independent functions of and potential interactions between serotonin-related genes, anxiety and neuropsychiatric disorders, we analyzed the presence and variability of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in marmoset and capuchin monkeys. By PCR and using heterologous primers from the human sequence, we amplified and then sequenced the corresponding 5-HTT region in marmosets and capuchins. The resulting data revealed the presence of a tandem repeat sequence similar to that described in humans, but unlike humans and other Old World primates, no variable length alleles were detected in these New World monkeys, suggesting that if serotonin transporter is involved in modulating behavior in these animals it does so through different molecular mechanisms. Am. J. Primatol. 74:1028-1034, 2012. © 2012 Wiley Periodicals, Inc.

Background Vascular endothelial growth factor-C (VEGF-C), a lymphatic vessel growth factor, has been involved in the formation of lymph nodal metastases in different tumor types. Early evidences indicate that VEGF-C expression in human primary melanoma could be predictive of lymph nodal metastases, whereas the role of lymphangiogenesis is still controversial. Methods By immunohistochemical analysis, we investigated VEGF-C or CC chemokine receptor 7 expression, together with the lymphatic and blood vessel network, in 36 patients with primary skin melanomas and metastases at the sentinel lymph node biopsy (SLN-positive), and 26 melanoma patients with negative SLN biopsy (SLN-negative). Results We found that VEGF-C expression in primary melanoma specimens was significantly associated with SLN-positive (p

Purpose We aimed to evaluate reliability of self-reported information on skin cancer among individuals aged >65 years with cutaneous squamous cell carcinoma (SCC). Methods A test-retest was performed with patients completing two questionnaires one month apart. Results Among 102 recruited patients the response rate was 97.1% (mean age 80.9 years, 74.8% men). The majority of items showed substantial agreement: history of skin cancer screening (k=0.88), past skin cancer in general (k=0.92), basal cell carcinoma (k=0.75), patient delay (k=0.64) and total delay (k=0.86). Agreement was high also for ages >80 years. Recall of past SCCs (k=0.48) and sunscreen use (k=0.38) was less accurate. Conclusions Our study provided evidence on the reliability of patient reported skin cancer information among elderly individuals, who represent the majority of affected cases.

Pascale E, Passarelli E, Purcaro C, Vestri AR, Fakeri A, Guglielmi R, Passarelli F, Meco G. Lack of association between IL-1β, TNF-α, and IL-10 gene polymorphisms and sporadic Parkinson’s disease in an Italian cohort. Acta Neurol Scand: 2011: 124: 176–181. © 2010 John Wiley & Sons A/S. Objective – There is increasing evidence suggesting that neuroinflammation and microglia activation may play important roles in the pathway leading to neuronal cell death in Parkinson’s disease (PD). Chronic activation of microglia may cause neuronal damage through the release of potentially cytotoxic molecules, such as pro-inflammatory cytokines. Different functional promoter polymorphisms within genes coding pro- or anti-inflammatory cytokines involved in the immune reactions in the brain might influence the risk of developing PD or the age of disease onset. Aim – To investigate the interleukin (IL)-1β-511, tumor necrosis factor alpha (TNF-α)-308, and interleukin (IL)-10-1082 gene polymorphisms as susceptibility factors for PD. Methods;– We analyzed genotype and allele distributions of these polymorphisms in146 Italian patients with PD and 156 healthy controls. Results – None of the polymorphisms we investigated was found to be associated with PD or with age of disease onset. No significant differences between patients with PD and controls were found as regards the concomitant presence of variant alleles in the three polymorphisms studied. We found that only the combined genotype TNF-α-308GG/IL-1β-511T(+) is associated with a decreased risk of PD. Conclusion – Our results indicate that the cytokine gene polymorphisms we investigated are not related to the development of PD in the Italian population; further studies are warranted to clarify the role of the TNF-α-308GG/IL-1β-511T(+) combined genotype.

Sezary Syndrome (SS) is an aggressive variant of cutaneous T cell lymphoma (CTCL) characterized by an accumulation of malignant T lymphocytes - the Sezary (SS) cells - in the skin, lymph nodes and blood. Until now, most studies on the characterization of this lymphoma have been performed on circulating SS cells because of the easy availability of tumor material from this compartment. For this reason, the role of skin microenvironment has not been characterized although it might play a fundamental role in the pathogenesis and in the disease progression of this neoplasia. According to this view, we recently demonstrated that PTEN downregulation, due to genetic loss and microRNA deregulation, commonly observed in SS patients, mainly activates AKT in skin-resident respect to blood-derived SS cells. This data underline how microenvironment signals amplify genetic abnormalities. Based on these observations, we investigated the effect of the skin microenvironment on SS cells in vivo. Comparing skin and blood-derived SS cells concurrently obtained from SS patients, we demonstrate that skin milieu promotes proliferation and PI3K/AKT/mTORC1 activation, a pathway that we prove to have multiple copy number (CN) alterations in our cohort of forty-three patients, thus indicating these genetic lesions as valid therapeutic targets to treat SS. At the end, we also demonstrate that the progressive increase of these CN alterations is associated to the shortening of overall survival of SS patients. Citation Format: Cristina Cristofoletti, Antonella Bresin, Mario Picozza, Maria Cristina Picchio, Francesca Passarelli, Francesca Monzo, Mauro Helmer Citterich, Alessandro Monopoli, Roberto Benucci, Maria Cantonetti, Alessandra Frezzolini, Enrico Scala, Elisabetta Caprini, Giandomenico Russo, Maria Grazia Narducci. The role of PI3 kinase pathway in the the skin of Sezary syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 761.

Aims: To evaluate skin cancer knowledge and preventive behaviors of patients recently treated for cutaneous squamous cell carcinoma (SCC) and to examine the factors associated with the adoption of preventive behaviors. Methods: Telephone survey on 315 SCC patients treated at a large dermatological hospital in Italy, evaluating skin cancer knowledge, sun protection and skin examination practices as well as medical recommendations received after SCC removal. Results: Skin cancer knowledge was fair/low for 48.9% of the participants. Doctors were the main source of skin cancer information for 24.4% of the patients. Of the patients assessed ≧12 months after SCC removal, 32.7% reported a total skin examination after removal. Of the participants, 41.6% never/rarely used sunscreens. In a multivariate analysis, the likelihood of having complete skin examinations was associated with a doctor’s advice to have an examination (odds ratio, OR = 2.29; 95% confidence interval, CI = 1.2–4.4), a higher knowledge level (OR = 2.05; 95% CI = 1.1–3.8) and past skin examinations (OR = 3.62; 95% CI = 1.9–7.0). Doctor’s recommendations increased the likelihood of adopting preventive behaviors. Conclusions: We found substantial knowledge gaps and limited adoption of skin cancer prevention, highlighting the need for interventions promoting knowledge and preventive behaviors, particularly among higher-risk patients.

Summary We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF , mutant RAS , mutant NF1 , and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

Aims: The role of the serotonin transporter gene (SLC6A4) in alcohol dependence (AD) is still unclear. In this paper,we have evaluated the association of theSLC6A4gene polymorphisms5-HTTLPR and rs25531 in AD and assessed the polymorphic patterns both in alcoholics and in healthy people of an Italian population. Methods: Genotyping of the 5-HTTLPR (L/S) and rs25531 (A/G) polymorphisms of the SLC6A4 gene was performed on 403 alcoholics outpatients and 427 blood donors. Results: Comparing AD and control populations and taking into account statistical correction for multiple testing, we found no statisticallysignificant differences for 5-HTTLPR (L/S) and rs25531 polymorphisms in terms of either genotypes or alleles frequencies. By univariate ANOVA, a statistically significant differencewas found in the onset of AD: the mean age of onset resulted to be of 25.4 years in males in respect to 28.1 in females. In particular in males, the early AD onset was different, in a statisticallysignificant manner, depending on the presence of at least one S or Lg allele (24.6 years) in respect to La homozygotes (27.5 years) (P= 0.03). Conclusions: These findings suggest that genetic factors contribute, together with gender and age, to the onset differences in alcohol-dependent phenotypes.

It has been proposed that S100B can be a marker for several pathological conditions including brain traumas, blood-brain barrier disruption, and ischemia. Because the hypothalamo-pituitary-adrenal axis is activated in these conditions, we investigated the role of glucocorticoids in the effects of stress on serum S100B. Restraint stress increased S100B levels in control and in adrenalectomized but not in corticosterone-injected rats. Adrenalectomy did not alter basal S100B. These results indicate a glucocorticoid-independent relationship between stress and S100B.

The aim of the present work was to verify whether an impairment of subtype 5 metabotropic glutamate receptor-mediated neurotransmission did occur in the aged striatum. To this end, the ability of the subtype 5 metabotropic glutamate receptor agonist, RS-2-chloro-5-hydroxyphenylglycine, to stimulate phosphoinositide hydrolysis and to potentiate N-methyl-d-aspartate-induced effects in striatal slices from young (3 months) and aged (24 months) rats was compared. The ability of RS-2-chloro-5-hydroxyphenylglycine to induce maximal phosphoinositide turnover and to potentiate N-methyl-d-aspartate effects was significantly reduced in slices from old vs. young rats. These changes were associated with a significant reduction in the expression of subtype 5 metabotropic glutamate receptor protein (-28.8%) and phospholipase C-beta1 (-55.8%) in old striata, while receptor messenger ribonucleic acid expression was unchanged. These results show that the signalling associated with subtype 5 metabotropic glutamate receptors undergoes significant age-related changes and that a reduced expression of subtype 5 metabotropic glutamate receptors and, more importantly, phospholipase C-beta1 may account for the functional decline of subtype 5 metabotropic glutamate receptors.

Interleukin-17 (IL-17) and IL-22 have been reported to play critical roles in autoimmunity and inflammation but information about their role in cancer is limited. In this study, we investigated the role of IL-17 and IL-22 in the progression of human skin basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC). We found that both tumor types are infiltrated with an high number of IL-17(+) and IL-22(+) T lymphocytes, as demonstrated by immunohistochemistry and by FACS analysis performed on peritumoral T-cell lines isolated from skin biopsies. In vitro studies demonstrated that proliferation and migration of the BCC- and SCC-cell lines M77015 and CAL27 were increased by IL-17 and IL-22. Moreover, IL-17, alone or in combination with TNF-α, was able to induce the production of two cytokines important for tumor progression, IL-6 and IL-8, in CAL27. We also showed that IL-17 upregulated NF-κB signaling, while IL-22 activated the STAT3 pathway and the antiapoptotic AKT protein in M77015 and CAL27. Finally, in vivo experiments demonstrated that IL-17 and IL-22 enhanced tumor growth in nude mice injected with CAL27. Altogether, our findings indicate that high levels of IL-22 and IL-17 in the BCC and SCC microenvironment promote tumor progression.

Objective: To explore the impact of early-onset bipolar disorder (pediatric bipolar disorder [PBD]) on ADHD. Method: We compared ADHD symptom severity, ADHD subtype distribution, and rates of comorbid and familial psychiatric disorders between 49 ADHD children with comorbid PBD and 320 ADHD children without PBD. Results: Children with ADHD and PBD showed higher scores in the Hyperactive and Inattentive subscales of the ADHD Rating Scale, than children with ADHD alone. The frequency of combined subtype was significantly higher in ADHD children with PBD, than in those with ADHD alone. ADHD children with PBD showed a higher rate of familial psychiatric disorders than ADHD children without PBD. The rate of conduct disorder was significantly greater in children with PBD and ADHD compared with children with ADHD alone. Conclusion: ADHD along with PBD presents with several characteristics that distinguish it from ADHD alone, suggesting that these may be distinct disorders.

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG-binding protein 2 gene (MECP2) cause >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiological regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R density is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2–308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacological targeting of 5-HT7R improves specific behavioral and molecular manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders associated with intellectual disability.

The H1 haplotype of the MAPT gene influences the risk of PD and has been related to the development of PDD. We evaluated the influence of MAPT haplotypes on the expression of motor features in PD patients. We genotyped, for the MAPT haplotypes H1 and H2, a sample of 181 PD patients with distinct clinical subtypes: tremor dominant and non-tremor dominant (NTD). Our results indicate that the MAPT haplotypes contribute to the expression of motor features of PD. H1 homozygous PD patients are significantly more likely to present a NTD phenotype, a clinical subtype characterized by widespread pathological degeneration, than H2 carriers.

The serotonin receptor 7 (5-HT7-R), is very abundant in the thalamus, hypothalamus, dorsal raphe nucleus and hippocampus; at lower levels it is found also in the cortex, striatum and amygdala. This neurochemical receptor system plays important functional roles in learning and memory, in regulation of mood and circadian rhythmicity. Recently, many agonist drugs selective for this receptor have been developed and their effects reported. Presently, we review some recent studies we have conducted aimed to evaluate the modulatory effect of a subchronic regimen with LP-211, a new selective agonist compound belonging to 1-arylpiperazine category, on behavioural and molecular parameters. At low dose (0.25 mg/kg, i.p.), LP-211 induced in adult mice a six-hour anticipated wake up with no temporal landmark (constant light) acting as non-photic stimulus for “internal clock” resetting. In standard 12:12h L/D cycle, we observed a subchronic effect (5-6 days at 0.25 mg/kg, once/day), on delay of wake up associated with a reduction of peak locomotor activity and any evidence for a real cellular proliferation after ex vivo analysis. The other studies, conduct on rats, were aimed to investigate long-term effects of subchronic LP-211 administration into adulthood development. Subchronic LP-211 (0.125 mg/kg, i.p. once/day) during the prepuberal phase reduced L-Glutamate, NMDAR1 and DAT, within the ventral striatum. Moreover, we observed a clear reduction of the immunoreactivity of serotonin transporter (SERT) and dopaminergic D2 receptors at dorsal striatum. These results represent a starting point to explore the neurophysiology of 5-HT7-R: subchronic LP-211 in rats and mice appears a suitable tool for studying the role of 5-HT7-R in sleep disorders, emotional and motivational regulations, attentive processes and executive functions.

Previous studies have identified the mammalian homologue of Bv8 (mBv8), a small protein originally isolated from skin secretions of the frog, Bombina variegata. In situ hybridization showed that mBv8 RNA was widely expressed in the rodent CNS, with high levels being detected in layer II of the cerebral cortex, limbic regions, cerebellar Purkinje cells, and dorsal and ventral horns of the spinal cord. A similar pattern of distribution was found by examining the presence of mBv8 protein by immunocytochemistry. Addition of frog Bv8 to cultured cerebellar granule cells reduced the extent of apoptotic death induced by switching the growing medium from 25 to 5 mM K+. Bv8 could also protect cultured cortical neurons against excitotoxic death. Both effects were prevented by PD98059 and LY294002, which inhibit the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI-3-K) pathways, respectively. In cultured cerebellar granule cells, Bv8 stimulated both the MAPK and the PI-3-K pathways, as revealed by Western blot analysis of phosphorylated p44/p42 MAPKs and phosphorylated Akt, respectively. We conclude that mBv8 acts as an endogenous neurotrophic factor and supports neuronal survival through the activation of the MAPK/PI-3-K pathways.

The purpose of this paper was to present our 4-year experience with sentinel node biopsy in the treatment of malignant melanoma. We will present technical details that influence the efficacy of the procedure and discuss the clinical, therapeutic and prognostic advantages of this technique. A total of 259 consecutive patients with primary skin melanoma (T2–3 N0 M0) underwent sentinel node biopsy between March 1996 and May 2000. All patients underwent previous excisional biopsy of the primary lesion and clinical and radiographic examination to exclude lymphatic or systemic macroscopic spread of the disease. Preoperative lymphoscintigraphy (99mTc-nanocoll) was routinely performed in the last 184 patients. Intraoperative detection of the sentinel node was performed by perilesional, intradermal injection of blue dye associated with a gamma probe (Neoprobe 2000) in the last 141 patients. For each anatomical site of dissection (inguinal, axillary, head and neck), detection rates with or without gamma probe were compared, focusing on the main reasons for failure. Sentinel nodes, serially sectioned, were all hematoxylin-eosin and immunohistochemically stained. All patients positive for micrometastasis underwent radical lymphadenectomy. Comparative analysis was performed between the incidence of metastasis in sentinel and non-sentinel nodes, according to the clinical stage of the disease. The overall detection rate of sentinel nodes was 96%. Relevant differences were found according to the site of dissection and the use of a gamma probe. The gamma probe makes the procedure more effective, less invasive, and less expensive. Timing and accuracy of the preoperative lymphoscintigraphy are basic steps in the procedure. The overall incidence of positive sentinel node was 14.6% with differences correlated with thickness of primary lesion (0.75–1.5 mm: 7.3%; 1.5–3 mm: 14.9%; 3–4 mm: 30.5%). Metastasis in other non- sentinel nodes was found only with primary tumor thickness exceeding 2 mm. Correlation between sentinel node metastasis and prognosis as well as adjuvant therapy will be discussed. Sentinel node biopsy is a procedure requiring a multidisciplinary approach (surgery, nuclear medicine, and pathology). A specific learning phase (>30 patients) is recommended for reliable results. An improvement in survival rates by sentinel node biopsy has not yet been demonstrated, but this more accurate N-staging procedure offers clear advantages in terms of the patient’s quality of life, prognosis, and indication for adjuvant therapy.

We employed the [14C]2-deoxyglucose method in order to map local brain metabolic activity of rats administered 1, 5, or 20 mg/kg of clozapine, or 0.5 mg/kg of haloperidol, as compared to saline. Clozapine produced a dose-dependent reduction of glucose utilization. At the dose of 1 mg/kg, the effects were limited to limbic areas. An additional number of structures were significantly affected following administration of 5 mg/kg (the whole hippocampal formation and septal area, and cortical limbic areas). The dose of 20 mg/kg markedly reduced glucose utilization in most of the areas examined. Haloperidol (0.5 mg/kg) reduced glucose utilization of the orbital cortex, hippocampal formation and septal area, globus pallidus, amygdala, ventral thalamus, and substantia nigra reticulata. The results show that acute administration of clozapine or haloperidol are associated with different distribution patterns of altered cerebral energy metabolism. Clozapine differently from haloperidol, reduces energy metabolism of the nucleus accumbens and other limbic areas. Haloperidol, but not clozapine (1 or 5 mg/kg), affects the substantia nigra reticulata.