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Atopic dermatitis (AD) therapeutic approach calls for a long-term treatment. Treatment options for AD have recently undergone a revolutionary change by the introduction of the first biologic drug. Availability in daily practice of the last version of international AD guidelines, taking peculiarities of the country into account, can contribute to good clinical practice in Italy. To adapt European Dermatology Forum (EDF) guidelines for AD to the Italian medical–legal context, the EDF guidelines were assessed independently by two independent Italian renowned experts in the field and further integrated with articles published and systematically reviewed before May 2019. The first draft was collegially corrected and updated by the members of the SIDEMAST, ADOI, and SIDAPA. Recommendation levels (A; B; C; D) were graded based on the evidence levels (1–4). The adapted guidelines presented here focus on topical and systemic therapies in AD patients, both children and adults. As opposed to previous Italian guidelines, they include indications about biologics. New relevant evidence available from very recent literature and peculiarities of the Italian medical and legal context have been integrated in the revision process. If compared to general guidelines for AD not adapted to a specific national and cultural context, a revision for specific Italian needs is now available: It comprises the option of implementing the new biologic treatments and is likely to provide an important contribution to the improvement of clinical practice in Italy. Cooperation between patients, dermatologists, allergologists, and pediatricians remains mandatory in AD management. The authors of the present revision recommend an update of the Italian guidelines to be performed at least every second year.

[Image: see text] Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD(+) to modify substrate proteins via the attachment of poly(ADP-ribose) chains. PARP-1 is a well established target in oncology, as testified by the number of marketed drugs (e.g., Lynparza, Rubraca, Zejula, and Talzenna) used for the treatment of ovarian, breast, and prostate tumors. Efforts in investigating an uncharted region of the previously identified isoindolinone carboxamide series delivered (S)-13 (NMS-P515), a potent inhibitor of PARP-1 both in biochemical (K(d): 0.016 μM) and cellular (IC(50): 0.027 μM) assays. Cocrystal structure allowed explaining NMS-P515 stereospecific inhibition of the target. After having ruled out potential loss of enantiopurity in vitro and in vivo, NMS-P515 was synthesized in an asymmetric fashion. NMS-P515 ADME profile and its antitumor activity in a mouse xenograft cancer model render the compound eligible for further optimization.

Patch testing is the standard procedure used to diagnose allergic contact dermatitis. It is an in-vivo test, which reproduces the reaction to a contact allergen. This in-vivo test aims to reproduce the elicitation phase of allergic contact dermatitis and is performed applying allergens under occlusion on the skin under standardized conditions. These guidelines for the best practice in performing patch test have been developed by an Italian group of experts taking in account the Italian legislation and local pharmacological governance. Guidelines are adapted from the original article under the guidance of the European Society of Contact Dermatitis (ESCD) and on the basis of the SIDAPA guidelines.

Objectives To determine the prevalence of ocular fundus abnormalities in cats with a diagnosis of systemic hypertension, to characterize the abnormalities observed, and to evaluate ophthalmoscopic evolution during treatment with amlodipine besylate. Animals studied Cats diagnosed as affected by SHP in a 2-year period. Procedures Systemic hypertension was assessed by oscillometric blood pressure measurement, and its etiology was also established. All the cats received an ophthalmic examination, and ocular lesions were classified with a score from 0 (no abnormalities) to 4 (severe abnormalities). All cats received amlodipine besylate by mouth, and those that showed fundus abnormalities were regularly rechecked from 7 to 365 days after diagnosis. Data were statistically analyzed to compare Psys and Pdia with all the variables and to correlate Psys and Pdia with the fundus score. Results A total of 225 cats were enrolled in the study, and the prevalence of fundus abnormalities was 58.6% (21.2%: grade 1; 18.2%: grade 2; 36.4%: grade 3; and 24.2%: grade 4). Systemic hypertension was diagnosed concurrently with chronic renal failure (60.4%), hyperthyroidism (28.9%), both chronic renal failure and hyperthyroidism (7.6%), and hypertrophic myocardiopathy (3.1%). A significant effect of Psys values on the fundus score was detected. Amlodipine therapy improved fundus abnormalities in 50% of cases at the 21-day follow-up. Conclusions This study showed that fundus abnormalities are common in hypertensive cats at the time of the systemic diagnosis, and most of the abnormalities are moderate to severe. Treatment with amlodipine appeared to improve ophthalmic lesions over time.

A four-year-old Scottish Shepherd dog was referred for acute onset of disorientation, blindness and chronic diarrhoea. The neurological examination was consistent with a multifocal neurolocalisation involving the prosencephalon and the brainstem. The ophthalmological exam showed bilateral chorioretinitis with retinal detachment. The brain MRI showed periventricular and left caudate nucleus lesions, increased thickness of the left III, IV, VI and opthalmic branch of V cranial nerves and bilateral multifocal lesions in the temporal and masseter muscles. Cerebrospinal fluid examination showed mild mixed pleocytosis. Faecal and urine cultures were positive for Prototheca zopfii genotype 2. Despite starting itraconazole therapy, the dog’s conditions deteriorated and the owner elected euthanasia. Protothecosis should be suspected in young dogs with multifocal neurological signs, blindness and chronic diarrhoea. MRI study of the central nervous system (CNS), together with blood exam, cytology and cultures, is a useful tool to evaluate the CNS in disseminated form of Prototheca infection.

The purpose of this study was to evaluate the diagnostic value of imaging-guided core needle biopsy for canine orbital mass diagnosis. A second excisional biopsy obtained during surgery or necropsy was used as the reference standard. A prospective feasibility study was conducted in 23 canine orbital masses at a single centre. A complete ophthalmic examination was always followed by orbital ultrasound and computed tomography (CT) examination of the head. All masses were sampled with the patient still on the CT table using ultrasound (US) guided automatic tru-cut device. The most suitable sampling approach to the orbit was chosen each time based on the CT image analysis. One of the following different approaches was used: trans-orbital, trans-conjunctival or trans-masseteric. In all cases, the imaging-guided biopsy provided a sufficient amount of tissue for the histopathological diagnosis, which concurred with the biopsies obtained using the excisional technique. CT examination was essential for morphological diagnosis and provided detailed topographic information that allowed us to choose the safest orbital approach for the biopsy. US guided automatic tru-cut biopsy based on CT images, performed with patient still on the CT table, resulted in a minimally invasive, relatively easy, and accurate diagnostic procedure in dogs with orbital masses.Keywords: Computed tomography, Core-needle biopsy, Dogs, Orbital mass, Ultrasound

OBJECTIVES: To validate a retinal imaging software named VAMPIRE® (Vascular Assay and Measurement Platform for Images of the Retina) in feline patients and test the clinical utility in hypertensive cats. ANIMALS STUDIED: One hundred and five healthy cats were enrolled. They represented the normal dataset used in the validation (group 1). Forty‐three hypertensive cats with no noticeable retinal abnormalities were enrolled for the clinical validity of the software (group 2). PROCEDURES: Eleven points (4 veins, 4 arteries, and 3 arterial bifurcations) were measured for each digital image. Repeatability and reproducibility of measurements were assessed using two independent operators. Data were statistically analyzed by the Mann‐Whiney and Tukey box plot. Significance was considered when P

To validate a retinal imaging software named VAMPIREOne hundred and five healthy cats were enrolled. They represented the normal dataset used in the validation (group 1). Forty-three hypertensive cats with no noticeable retinal abnormalities were enrolled for the clinical validity of the software (group 2).Eleven points (4 veins, 4 arteries, and 3 arterial bifurcations) were measured for each digital image. Repeatability and reproducibility of measurements were assessed using two independent operators. Data were statistically analyzed by the Mann-Whiney and Tukey box plot. Significance was considered when P 0.05.Two hundred and ten retinal images were analyzed for a total of 2310 measurements. Total mean was 9.1 and 6.1 pixels for veins and arteries, respectively. First, second, and third arteriolar bifurcations angles were 73.6°, 76.9°, and 85.4°, respectively. A comparison between groups 1 and 2 showed a statistically significant reduction in arteriolar diameter (mean 3.3 pixels) and branch angle (55°, 47.8° and 59.9°) associated with increasing vein diameter (mean 24.15 pixels).Current image analysis techniques used in human medicine were investigated in terms of extending their use to veterinary medicine. The VAMPIRE

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

A group of 56 employees exposed to postural risk due to sedentary activity in offices and aged 40 to 60 years underwent a training of ergomotricity. The schedule was based on six simple exercises to be self-managed during the work time. The efficacy was verified by questionnaire before and after 3 months and musculo-skeletal complaints resulted to be improved for 21 out of 56 workers, depending from diligence. The training was realized by an occupational doctor and a physiotherapist; the compliance of this method was good by the trainees, but a recalling intervention was planned to reach better results in the whole group.

Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.

RET chromosomal rearrangements initially identified in a subset of papillary thyroid cancers, as well as gain-of-function point mutations present in ca. 70% of medullary thyroid carcinomas, are well established as oncogenic events that induce constitutive RET activation. More recently, recurring activating RET gene rearrangements have also been found to be expressed in 1-2% of lung adenocarcinomas and subsets of other solid tumors, including colorectal and salivary gland carcinomas. RET kinase is therefore a validated actionable therapeutic target in multiple tumor types, and several small-molecule inhibitors targeting RET are being explored in clinical settings. A common feature of most advanced agents is their lack of selectivity and in particular their potent cross-reactivity against VEGFR2, a receptor tyrosine kinase whose inhibition has been described to be associated with dose-limiting cardiovascular toxicity. Indeed, the high homology between the two kinases renders identification of ATP competitive compounds that selectively inhibit RET over VEGFR2 a highly challenging task. Here we describe the preclinical activity of NMS-E668, a potent and selective ATP-competitive RET inhibitor characterized by favorable activity, selectivity and ADME profiles. NMS-E668 has low nM potency on RET and excellent biochemical selectivity when tested against a kinome panel, notably including circa 30-fold selectivity over VEGFR2. Importantly, 30-fold selectivity of NMS-E668 for RET vs. VEGFR2 was confirmed at the cellular level using NIH-3T3 cells engineered to express activated forms of the two receptors. NMS-E668 potently and selectively inhibited the proliferation of RET-dependent tumor cells, including TT medullary carcinoma cells harboring a RET C634W activating point mutation and LC-2/ad lung carcinoma cells bearing the oncogenic fusion protein CCDC6-RET. NMS-E668 also potently inhibited IL3-independent growth of Ba/F3 cells expressing KIF5B-RET, the RET rearrangement most commonly found in lung adenocarcinomas. Importantly, the proliferation of circa 100 non-RET-dependent tumor cell lines was not significantly affected by NMS-E668, confirming again its selectivity. Tested in vivo against the TT xenograft tumor model NMS-E668 displayed an excellent tumor growth inhibition with complete tumor regression achieved in all animals treated at the higher dose and with confirmed ex vivo target modulation. Good activity was also observed in additional RET-dependent models following oral administration of the compound. Thus NMS-E668, a potent and VEGFR2-sparing RET inhibitor, is an innovative and highly promising candidate for clinical development. Citation Format: Elena Ardini, Patrizia Banfi, Nilla Avanzi, Marina Ciomei, Paolo Polucci, Alessandra Cirla, Matteo D'Anello, Andrea Lombardi Borgia, Ilaria Motto, Cinzia Cristiani, Dario Ballinari, Eduard Felder, Daniele Donati, Arturo Galvani, Antonella Isacchi, Maria Menichincheri. NMS-E668, a highly potent orally available RET inhibitor with selectivity towards VEGFR2 and demonstrated antitumor efficacy in multiple RET-driven cancer models [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 4785.

Objectives To assess dermal exposure to 16 polycyclic aromatic hydrocarbons (PAHs) in asphalt workers by applying polypropylene pads to six body sites (neck, shoulder, upper arm, wrist, groin, ankle), to identify the compounds and exposure sites most representative, and to integrate dermal exposure results with environmental and biological data. Methods Twenty-four asphalt workers were recruited. Dermal exposure was assessed during a single work shift. Sixteen PAHs (from naphthalene to indeno[1,2,3-cd]pyrene) were quantified via gas chromatography-mass spectrometry. Airborne exposure, urinary PAHs and monohydroxy metabolites were also investigated. Results Phenanthrene (PHE), present in all samples, was the most abundant compound (median 0.805–1.825 ng/cm 2 ). Benzo[a]pyrene (BaP) was present in 75% of the samples (0.046–0.101 ng/cm 2 ). Wrist had the highest contamination, with median PHE, pyrene (PYR), and BaP concentrations of 1.825, 0.527, and 0.063 ng/cm 2 . PHE and PYR on wrist correlated with almost all 3- to 4-ring PAHs (0.405≤r≤0.856), but not with BaP; BaP correlated with almost all 4- to 6- ring PAHs (0.584≤r≤0.633). Significant correlations were observed between PHE level, airborne exposure, and the corresponding urinary PHE and monohydroxy metabolites. For PYR, significant correlations existed only between urinary PYR and monohydroxy metabolites. Multiple linear regression analysis revealed that 42% of the end-of-shift monohydroxy metabolites were the result of airborne exposure, dermal exposure, and baseline levels of biomarkers. Conclusions Dermal exposure to PAHs was in the low ng/cm 2 range. PHE or PYR and BaP were the most representative compounds and the wrist was the best location to perform dermal exposure assessments. Both dermal and airborne exposure contributed to the total body burden of PAHs, though the relative contribution was analyte-dependent.