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Background: Search algorithms used to identify patients with alopecia areata (AA) need to be validated prior to use in large databases. Objectives: The aim of the study is to assess whether patients with an International Statistical Classification of Diseases and Related Health Problems (ICD) 9 or 10 code for AA have a true diagnosis of AA. Materials and Methods: A multicenter retrospective review was performed at Columbia University Irving Medical Center, Brigham and Women's Hospital, and Massachusetts General Hospital to determine whether patients with an ICD 9 codes (704.01 - AA) or ICD 10 codes (L63.0 -Alopecia Totalis, L63.1 - Alopecia Universalis, L63.2 - Ophiasis, L63.8 - other AA, and L63.9 - AA, unspecified) for AA met diagnostic criteria for the disease. Results: Of 880 charts, 97.5% had physical examination findings consistent with AA, and 90% had an unequivocal diagnosis. AA was diagnosed by a dermatologist in 87% of the charts. The positive predictive value (PPV) of the ICD 9 code 704.01 was 97% (248/255). The PPV for the ICD 10 codes were 64% (75/118) for L63.0, 86% (130/151) for L63.1, 50% (1/2) for L63.2, 91% (81/89) for L63.8, and 93% (247/265) for L63.9. Overall, 89% (782/880) of patients with an ICD code for AA were deemed to have a true diagnosis of AA. Conclusions: Patients whose medical records contain an AA-associated ICD code have a high probability of having the condition.

Introduction International guidelines recommend BRAF mutational status assessment in treatment-naive advanced non-squamous non-small cell lung carcinoma (NSCLC) patients since the presence of a BRAFV600 mutation enables specific BRAF inhibitor treatment. For this purpose, the mutational status needs to be obtained in 10 working days. Herein, we prospectively evaluated the feasibility of systematic assessment of the BRAF status using immunohistochemistry (IHC) in a single institution (LPCE, Nice) at baseline for NSCLC diagnosed. Methods 1317 NSCLC were evaluated using BRAF IHC from 2011 to 2019. Initially the BRAF status was prospectively assessed using NGS and/or pyrosequencing in 618 consecutively diagnosed NSCLC patients from 2012 to 2016; BRAFV600E and BRAF nonV600E mutated tumors detected in this cohort were retrospectively evaluated using BRAF IHC. Secondarily, 699 biopsies of NSCLC were prospectively analyzed between 2017 and 2019 using BRAF IHC. BRAF IHC positive tumors were tested using a rapid BRAF specific PCR based assay. Results Initially, 21/618 (3%) of tumors (15 early and 6 late stage tumors) were BRAFV600E mutated according to the results of NGS and/or pyrosequencing. BRAF IHC was positive in 21/21 of these cases and negative in 51/51 (100 %) BRAF non V600E mutated cases. In the prospective BRAF IHC tested cohort of patients, 24/699 (3%) tumors (13 early and 11 late stage tumors) were positive with VE1 IHC. The BRAF PCR assay was positive in 20/24 (83 %) of these cases. Conclusion BRAFV600E IHC screening of treatment-naive NSCLC patients is a rapid, specific and very sensitive method which can lead in advanced stage positive NSCLC tumors to a BRAF inhibitor treatment. This test can be routinely integrated into mandatory predictive biomarker ‘testing of NSCLC. According to the organization of patient care and the physician’s request, this practice can be proposed as an alternative to NGS-based tissue biopsy made at baseline.

Introduction: Deafness is the most frequent sensory deficit in humans. Incidence is estimated at 4:1000 births in Brazil. Specific programs for clinical care of patients with hearing loss are still scarce in Brazil and the issue is an important public health problem. Objective: To determine the frequency of 35delG and D13S1830 mutations in GJB2 and GJB6 genes respectively in patients with non-syndromic sensorineural hearing loss from Minas Gerais, Brazil. Methods: This research involved 53 individuals, who were assessed by a questionnaire for predicting the possibility of non-syndromic deafness and for data collecting. Samples were tested for the presence of the 35delG mutation in GJB2 gene and D13S1830 in GJB6 gene by polymerase chain reaction and restriction enzyme digestion. Results: Epidemiological research has shown that the majority of the subjects are unaware of the etiology and the pathogenesis of hearing loss. In 9 patients (16.98%), 35delG mutation was found in heterozygosis and the allele frequency was estimate to be around 8.5%. Although 9.61% of the patients reported having some degree of consanguinity between the parents and 12.08% reported other cases of deafness in their families, this mutation was not found in homozygosis. The D13S1830 mutation was not found in this study. Conclusion: This research describes for the first time the frequency of the 35delG and D13S1830 mutation in hearing-impaired individuals from Minas Gerais, Brazil, and the collected data reinforce the need for further studies in this population due to heterogeneity of hearing loss. Resumo Introdução: A surdez é o déficit sensorial mais frequente em humanos. Estima-se que a incidência seja de 4:1.000 nascimentos no Brasil. Programas específicos para atendimento clínico de pacientes com perda auditiva são escassos no Brasil e a questão é um importante problema de saúde pública. Objetivo: Determinar a frequência das mutações 35delG no gene GJB2 e D13S1830 no GJB6 em pacientes deficientes auditivos de origem neurossensorial e não sindrômica de Minas Gerais, Brasil. Método: A pesquisa envolveu 53 indivíduos selecionados por meio de questionário o qual avaliou a possibilidade de surdez não sindrômica entre outros dados. As amostras foram testadas quanto à presença da mutação 35delG no gene GJB2 e D13S1830 no gene GJB6 por reação em cadeia da polimerase e digestão com enzima de restrição. Resultados: A pesquisa epidemiológica mostrou que a maioria dos indivíduos desconhece a etiologia da perda auditiva. Em 9 pacientes (16,98%), a mutação 35delG foi encontrada em heterozigose e a frequência alélica foi estimada em 8,5%. Embora 9,61% das pessoas tenham relatado algum grau de consanguinidade entre os pais e 12,08% relatassem outros casos de surdez em suas famílias, essa mutação não foi encontrada em homozigose. A mutação D13S1830 não foi encontrada neste estudo. Conclusão: Este trabalho descreve pela primeira vez a frequência da mutação 35delG e D13S1830 em deficientes auditivos de Minas Gerais, Brasil, e os dados coletados reforçam a necessidade de mais estudos nessa população devido à heterogeneidade da perda auditiva.

Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are scarring alopecias that cause significant distress and psychological morbidity. Limited studies have been performed examining the epidemiology of FFA and LPP. We performed a retrospective case cohort analysis by querying for patients with the ICD 10 code L66.1 (LPP, FFA) between 2015 and 2018 using the Clinical Data Warehouse (CDW) at NewYork-Presbyterian Hospital and Columbia Doctors. We calculated the one-year incidence of LPP/FFA between January 1, 2018 to December 31, 2018 by identifying all patients without a previously recorded ICD code for L66.1 who presented as a new hair loss patient based on chart review. A total of 170 patients were identified with a new diagnosis of LPP or FFA in 2018 among 1,187,583 patients. The standardized incidence per 100,000 was 12.75 for LPP and FFA combined, 7.35 for LPP alone, and 5.41 for FFA alone. The incidence peaked in the 51 to 60 age range (3.36). The incidence was highest in non-Hispanic White patients (17.27), White patients of unknown ethnicity (26.26), and non-Hispanic Asian patients (17.27). In New York City, LPP and FFA are uncommon diseases that are most common in middle-aged females and non-Hispanic White patients.

Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematological cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class antibody drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leukemias and multiple myeloma by immunohistochemistry on tissue microarrays. Anti-tumor activity of MEN1309/OBT076 as single agent was then shown across 42 B-cell lymphoma cell lines with a median IC50 of 200 pM and induction of apoptosis in 25/42 (59.5%) of the cases. The activity appeared highly correlated with its target expression. After in vivo validation as the single agent, the antibody drug conjugate synergized with the BCL2 inhibitor venetoclax, and the anti-CD20 monoclonal antibody rituximab. The first-in-class antibody drug targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti-tumor activity in lymphoma, warranting further investigations as a single agent and in combination.

Objective: To assess the quality of life and functional status of patients subjected to debridement of ulcers in the posterior ankle who required complete Achilles tendon resection without any type of reconstruction or tendon transfer. Method: This is a case series of 5 (mostly diabetic) patients who underwent complete Achilles tendon resection due to an ulcer in the posterior ankle region. Preservation of the Achilles tendon was prevented due to tendon exposure, extensive degeneration and the need for infection control. Patients answered the Brazilian Portuguese version of the Achilles Tendon Total Rupture Score (ATRS-BR) questionnaire and the 36-item Short-Form Health Survey (SF-36) during the postoperative period, and follow-up varied between 6 and 24 months. The ATRS-BR ranges from 0 to 100, and higher scores indicate fewer symptoms and limitations. The SF-36 consists of 36 questions comprising 8 domains, which are independently assessed and given a score of up to 100 points, with higher scores indicating better health status. Results: The mean age of patients was 70 years. The mean score on the SF-36 physical functioning domain was 70 (50-95) points. The mean value of the ATRS-BR was 54.6 (31-88) points; however, the patients had few complaints about their functional status. Conclusion: Non-reconstruction of the Achilles tendon in predominantly diabetic elderly patients with posterior ankle ulcers presents encouraging functional outcomes. This study suggests that complete Achilles tendon resection is a viable option for ulcer treatment in this population. Level of Evidence IV; Therapeutic Studies; Cases Series.

Antibody-drug conjugates (ADC) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADC targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked via sulfo-SPDB to the potent DNA-alkylating agent DGN462. huB4-DGN462 had improved in vitro anti-proliferative and cytotoxic activity compared to SAR3419 across multiple B-cell lymphoma and human acute lymphoblastic leukemia cell lines. In vivo experiments using lymphoma xenografts models confirmed the in vitro data. The response of B-cell lymphoma lines to huB4-DGN462 was not correlated with CD19 expression, the presence of BCL2 or MYC translocations, TP53 inactivation or lymphoma histology. In conclusion, huB4-DGN462 is an attractive candidate for clinical investigation in patients with B-cell malignancies.

Copyright © 2020 Bordone and Barbosa-Morais. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms., Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders worldwide, with age being their major risk factor. The increasing worldwide life expectancy, together with the scarcity of available treatment choices, makes it thus pressing to find the molecular basis of AD and PD so that the causing mechanisms can be targeted. To study these mechanisms, gene expression profiles have been compared between diseased and control brain tissues. However, this approach is limited by mRNA expression profiles derived for brain tissues highly reflecting their degeneration in cellular composition but not necessarily disease-related molecular states. We therefore propose to account for cell type composition when comparing transcriptomes of healthy and diseased brain samples, so that the loss of neurons can be decoupled from pathology-associated molecular effects. This approach allowed us to identify genes and pathways putatively altered systemically and in a cell-type-dependent manner in AD and PD brains. Moreover, using chemical perturbagen data, we computationally identified candidate small molecules for specifically targeting the profiled AD/PD-associated molecular alterations. Our approach therefore not only brings new insights into the disease-specific and common molecular etiologies of AD and PD but also, in these realms, foster the discovery of more specific targets for functional and therapeutic exploration., This work was supported by European Molecular Biology Organization (EMBO Installation Grant 3057 to NB-M), Fundação para a Ciência e a Tecnologia (FCT Investigator Starting Grant IF/00595/2014 and CEEC Individual Assistant Researcher contract CEECIND/00436/2018 to NB-M, Ph.D.Studentship PD/BD/105854/2014 to MB), and Genome PT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 – Operational Programme for Competitiveness and Internationalization (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020),under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by Fundação para a Ciência e a Tecnologia (FCT).

A 52-year-old female patient was diagnosed with chronic periapical periodontitis associated with severely calcified lower central incisors. Radiographic examination revealed no visible root canal in the coronal-third of the root. After choosing the guided endodontic treatment, an intraoral scan (Trios, 3shape, Copenhagen, Denmark), in conjunction with a cone beam computed tomography (CBCT) scan, was taken in order to design and fabricate a printed guide. Virtual implant software was used to visualize the surgical access into the sclerosed root canals. After locating the canals, the guide was removed, and the teeth were treated under a rubber dam. The guided approach allows predictable, efficient endodontic treatment of teeth presenting calcified canals, with minimal removal of sound dentine and less risk of root perforations.

The objective of this study is to find a correlation between the abdominal aortic aneurysm (AAA) geometric parameters, wall stress shear (WSS), abdominal flow patterns, intraluminal thrombus (ILT), and AAA arterial wall rupture using computational fluid dynamics (CFD). Real AAA 3D models were created by three-dimensional (3D) reconstruction of in vivo acquired computed tomography (CT) images from 5 patients. Based on 3D AAA models, high quality volume meshes were created using an optimal tetrahedral aspect ratio for the whole domain. In order to quantify the WSS and the recirculation inside the AAA, a 3D CFD using finite elements analysis was used. The CFD computation was performed assuming that the arterial wall is rigid and the blood is considered a homogeneous Newtonian fluid with a density of 1050 kg/m3and a kinematic viscosity of4×10-3Pa·s. Parallelization procedures were used in order to increase the performance of the CFD calculations. A relation between AAA geometric parameters (asymmetry index (β), saccular index (γ), deformation diameter ratio (χ), and tortuosity index (ε)) and hemodynamic loads was observed, and it could be used as a potential predictor of AAA arterial wall rupture and potential ILT formation.

Background NGS from plasma samples in non-squamous cell lung carcinoma (NSCC) can aid in the detection of actionable genomic alterations. However, the absolute clinical value of NGS in liquid biopsy (LB) made at baseline is currently uncertain. We assessed the impact of plasma-based NGS using an in-house test and an outsourced test in comparison to a routine molecular pathology workflow. Methods Twenty-four advanced/metastatic treatment-naïve NSCC patients were prospectively included. NGS analyses were conducted both in-house using the Oncomine cfTNA Panel and in an external testing center using the Foundation Liquid assay. NGS analysis and/or specific molecular based assays were conducted in parallel on tissue or cytological samples. Results Both LB tests were well correlated. Tissue NGS results were obtained in 67% of patients and demonstrated good correlation with LB assays. Activating EGFR mutations were detected using LB tests in three patients. PD-L1 expression assessed in tissue sections enabled the initiation of pembrolizumab treatment in five patients. Conclusion NGS from LB is feasible in routine clinical practice using an in-house or an outsourced test at baseline. However, the impact on therapy selection was limited in this small series of patients and LB was not able to replace tissue-based testing in our hands.

// Marius Ilie 1, 2, 3 , Catherine Butori 1, 3 , Sandra Lassalle 1, 2, 3 , Simon Heeke 2 , Nicolas Piton 4 , Jean-Christophe Sabourin 4 , Virginie Tanga 3 , Kevin Washetine 1, 3 , Elodie Long-Mira 1, 2, 3 , Priscilla Maitre 3 , Nathalie Yazbeck 2 , Olivier Bordone 3 , Virginie Lespinet 3 , Sylvie Leroy 5 , Charlotte Cohen 6 , Jerome Mouroux 2, 6 , Charles Hugo Marquette 2, 5 , Veronique Hofman 1, 2, 3 and Paul Hofman 1, 2, 3 1 Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, FHU OncoAge, University Cote d’Azur, Nice, France 2 IRCAN Inserm U1081/CNRS 7284, FHU OncoAge, University Cote d’Azur, Nice, France 3 Hospital-related Biobank (BB-0033-00025), Pasteur Hospital, FHU OncoAge, University Cote d’Azur, Nice, France 4 Department of Pathology, Rouen University Hospital, Rouen, France 5 Department of Pulmonary Medicine and Thoracic Oncology, Pasteur Hospital, FHU OncoAge, University Cote d’Azur, Nice, France 6 Department of Thoracic Surgery, Pasteur Hospital, FHU OncoAge, University Cote d’Azur, Nice, France Correspondence to: Paul Hofman, email: hofman.p@chu-nice.fr Keywords: NSCLC, EGFR, targeted therapy, optimization, PCR Received: March 21, 2017 Accepted: September 19, 2017 Published: October 04, 2017 ABSTRACT Treatment with EGFR inhibitors is limited to patients with advanced/metastatic non-small cell lung cancer who have known EGFR mutations. Currently, patient care has to respond to several imperatives to make these inhibitors broadly available to all patients; fast and accurate detection of EGFR mutations by a sensitive and specific standardized cost-effective method, easy-to-implement in settings with limited expertise in molecular diagnostics. We evaluated the Idylla™ EGFR Mutation Assay (Biocartis) for the detection of EGFR mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples from a series of 55 patients with lung adenocarcinoma and compared these results with those obtained by a pyrosequencing ISO-15189 accredited laboratory method. The comparison was made on both whole surgical tumor sections and on three artificially constructed small biopsies (~1 mm) from the same FFPE blocks. Cost-effectiveness and turnaround time comparison between the two methods was performed. On both whole tissue sections and on biopsy cores, the Idylla™ and pyrosequencing had an agreement of 95% (52/55). The Idylla™ EGFR Assay produced results faster and more cost-effective than pyrosequencing. The Idylla™ system showed a good sensitivity and was cost-saving in our setting. Because of the easy workflow, the Idylla™ system has the potential to expand EGFR testing to more pathology laboratories in a reliable and fast manner.

Glaucoma is a leading cause of blindness, characterized by retinal ganglion cell (RGC) loss and optic nerve (ON) damage. Cumulative evidence suggests glial cell involvement in the degeneration of the ON and RGCs. We analyzed the contribution of microglial reactivity to early axoglial alterations of the ON in an induced model of ocular hypertension. For this purpose, vehicle or chondroitin sulfate (CS) were weekly injected into the eye anterior chamber from Wistar rats for different intervals. The amount of Brn3a(+) RGC significantly decreased in CS-injected eyes for 10 and 15 (but not 6) weeks. A reduction in anterograde transport of β-subunit cholera toxin (CTB) was observed in the superior colliculus and the lateral geniculate nucleus contralateral to CS-injected eyes for 6 and 15 weeks. A disruption of CTB transport was observed at the proximal myelinated ON. A significant decrease in phosphorylated neurofilament heavy chain (pNFH)-immunoreactivity, an increase in Iba-1(+), ED1(+) (microglial markers), and glial fibrillary acidic protein (GFAP, astrocytes) (+) area, and decreased luxol fast blue (LFB) staining were observed in the ON at 6 and 15 weeks of ocular hypertension. Microglial reactivity involvement was examined through a daily treatment with minocycline (30 mg/kg, i.p.) for 2 weeks, after 4 weeks of ocular hypertension. Minocycline prevented the increase in Iba-1(+), ED-1(+), and GFAP(+) area, the decrease in pNFH-immunoreactivity and LFB staining, and the deficit in anterograde transport induced by 6 weeks of ocular hypertension. Thus, targeting microglial reactivity might prevent early axoglial alterations in the glaucomatous ON. Fil: Bordone, Melina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: González Fleitas, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Pasquini, Laura Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina Fil: Bosco, Alejandra. University of Utah; Estados Unidos Fil: Sande Casal, Pablo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina

Recent findings have shown that maximum diameter of abdominal aortic aneurysm (AAA) and its growth rate are not entirely reliable indicators of rupture potential. The AAA geometrical shape and size may be related to the rupture risk which is a clinical manifestation of the balance between the forces generated by blood flow within the AAA and its strength. This study aims at assessing the hemodynamic features associated with the geometry of AAAs.

Visual Abstract, Dopamine replacement by levodopa (L-DOPA) is the most widely used therapy for Parkinson’s disease (PD), however patients often develop side effects, known as L-DOPA-induced dyskinesia (LID), that usually need therapeutic intervention. There are no suitable therapeutic options for LID, except for the use of the NMDA receptor (NMDA-R) antagonist amantadine, which has limited efficacy. The NMDA-R is indeed the most plausible target to manage LID in PD and recently the kinase Fyn, one of its key regulators, became a new putative molecular target involved in LID. The aim of this work was to reduce Fyn expression to alleviate LID in a mouse model of PD. We performed intrastriatal delivery of a designed micro-RNA against Fyn (miRNA-Fyn) in 6-OHDA-lesioned mice treated with L-DOPA. The miRNA-Fyn was delivered either before or after L-DOPA exposure to assess its ability to prevent or revert dyskinesia. Preadministration of miRNA-Fyn reduced LID with a concomitant reduction of FosB-ΔFosB protein levels, a marker of LID, as well as decreased phosphorylation of the NR2B-NMDA subunit, which is a main target of Fyn. On the other hand, post-L-DOPA delivery of miRNA-Fyn was less effective to revert already established dyskinesia, suggesting that early blocking of Fyn activity might be a more efficient therapeutic approach. Together, our results provide proof of concept about Fyn as a plausible therapeutic target to manage LID, and validate RNA silencing as a potential approach to locally reduce striatal Fyn, rising new perspectives for RNA therapy interventions in PD.

A dataset of XBT (eXpendable BathyThermograph) temperature profiles collected by ships of opportunity along the Genova–Palermo route, since September 1999, is analyzed, together with altimetric observations and model results, with the purpose of identifying and characterizing robust circulation features along the track and investigating their variability. An anticyclone is found in the Ligurian Sea, just north of the Corsica Channel, not present in previous descriptions of the Mediterranean Sea circulation. It appears to be a recurrent feature, better defined and stronger in summer and in the beginning of autumn. In the northern part of the Tyrrhenian Sea, the well-known Bonifacio dipole shows a similar seasonality, in agreement with previous observations. However, the Bonifacio anticyclone also displays a strong interannual variability, not previously recorded, with significant variations in position and shape. In fact, the data suggest the existence of two distinct summer circulation regimes related to the position and shape of the Ligurian anticyclone. When the latter is wider, filling the entire region north of the Corsica Channel, the circulation in the northern Tyrrhenian Sea is isolated from that in the Ligurian Sea, in agreement with the common picture. However, the altimeter maps show that there are several cases in the last two decades in which the Ligurian anticyclone is small and displaced to the west, allowing an inflow through the Corsica Channel into the Tyrrhenian Sea. The two regimes appear to result from a delicate balance between the forcings acting in the two sub-basins and the topographic constraints.

In the last few years, the treatment of patients with non-small cell lung cancer (NSCLC) has impressively benefitted from immunotherapy, in particular from the inhibition of immune checkpoints such as programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1). However, despite the significant survival benefit for some patients with advanced NSCLC, the objective response rates (ORRs) remain relatively low no more than 20-30% with a large proportion of patients demonstrating primary resistance. Although the selection of NSCLC patients for the first-line treatment is currently guided by the expression of PD-L1 in tumor cells as detected by immunohistochemistry, this is not the case for the second-line setting. Moreover, the sensitivity and specificity of PD-L1 expression is modest which has prompted the search for additional predictive biomarkers. In this context, the assessment of the tumor mutational burden (TMB), defined as the total number of nonsynonymous mutations in the coding regions of genes, has recently emerged as an additional powerful biomarker to select patients for immunotherapy. The purpose of our review is to highlight the recent advances as well as the challenges and perspectives in the field of TMB and immunotherapy for patients with NSCLC.

Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We have analyzed sixty NSCLC and thirty-six melanoma patients with ICI treatment, using the FoundationOne test (FO) in addition to in-house testing using the Oncomine TML (OTML) panel and evaluated the durable clinical benefit (DCB), defined by &gt, 6 months without progressive disease. Comparison of TMB values obtained by both tests demonstrated a high correlation in NSCLC (R2 = 0.73) and melanoma (R2 = 0.94). The association of TMB with DCB was comparable between OTML (area-under the curve (AUC) = 0.67) and FO (AUC = 0.71) in NSCLC. Median TMB was higher in the DCB cohort and progression-free survival (PFS) was prolonged in patients with high TMB (OTML HR = 0.35, FO HR = 0.45). In contrast, we detected no differences in PFS and median TMB in our melanoma cohort. Combining TMB with PD-L1 and CD8-expression by immunohistochemistry improved the predictive value. We conclude that in our cohort both approaches are equally able to assess TMB and to predict DCB in NSCLC.

International audience; Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation ofvascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology.

Hand-foot-and-mouth disease is a viral exanthem caused, primarily by Coxsackie A16 and enterovirus 71 with typical clinical features of fever, painful papules and blisters over the extremities and genitalia and an enanthem involving ulceration of the mouth, palate, and pharynx. Other enteroviruses have recently been noted to cause severe neurologic illness and paralysis (enterovirus 68) with variable cutaneous features. A recent outbreak of Coxsackie A6 infection has been seen worldwide with cases reported in the United States, Japan, Southeast Asia, and Europe. These cases have caused extensive cutaneous disease variants, some of which are not previously recognized in Coxsackie infection, namely vesicobullous and erosive eruptions, extensive cutaneous involvement, periorificial lesions, localization in areas of atopic dermatitis or in children with atopic dermatitis (the so-called eczema coxsackium), Gianotti-Crosti-like lesions, petechial/purpuric eruptions, delayed onychomadesis, and palmoplantar desquamation. Finally, adult cases appear to occur with this form of hand-foot-and-mouth disease, likely due to fecal-oral transmission in a household setting.

Aims.In recent years several warnings have been issued by regulatory authorities on the risk of electrocardiogram abnormalities in individuals exposed to psychotropic drugs. As a consequence of these warnings, monitoring of the QT interval corrected for heart rate (QTc) has become increasingly common. This study was conducted to measure the frequency of QTc prolongation in unselected psychiatric patients, and to document the associated factors using a cross-sectional approach.Method.The study was carried out in 35 Italian psychiatric services that are part of the STAR (Servizi Territoriali Associati per la Ricerca) Network, a research group established to produce scientific knowledge by collecting data under ordinary circumstances. During a three-month period, a consecutive unselected series of both in- and out-patients were enrolled if they performed an ECG during the recruitment period and were receiving psychotropic drugs on the day ECG was recorded.Results.During the recruitment period a total of 2411 patients were included in the study. The prevalence of QTc prolongation ranged from 14.7% (men) and 18.6% (women) for the cut-off of 450 ms, to 1.26% (men) and 1.01% (women) for the cut-off of 500 ms. In the multivariate model conducted in the whole sample of patients exposed to psychotropic drugs, female sex, age, heart rate, alcohol and/or substance abuse, cardiovascular diseases and cardiovascular drug treatment, and drug overdose were significantly associated with QTc prolongation. In patients exposed to antipsychotic drugs, polypharmacy was positively associated with QTc prolongation, whereas use of aripiprazole decreased the risk. In patients exposed to antidepressant drugs, use of citalopram, citalopram dose and use of haloperidol in addition to antidepressant drugs, were all positively associated with QTc prolongation.Conclusions.The confirmation of a link between antipsychotic polypharmacy and QTc prolongation supports the current guidelines that recommend avoiding the concurrent use of two or more antipsychotic drugs, and the confirmation of a link between citalopram and QTc prolongation supports the need for routine QTc monitoring. The relatively low proportion of patients with QTc prolongation not only suggests compliance with current safety warnings issued by regulatory authorities, but also casts some doubts on the clinical relevance of QTc prolongation related to some psychotropic drugs.

International audience; Collected specimens for research purposes may or may not be made available depending on their scarcity and/or on the project needs. Their protection against degradation or in the event of an incident is pivotal. Duplication and storage on a different site is the best way to assure their sustainability. The conservation of samples at room temperature (RT) by duplication can facilitate their protection. We describe a security system for the collection of non-small cell lung cancers (NSCLC) stored in the biobank of the Nice Hospital Center, France, by duplication and conservation of lyophilized (dried), encapsulated DNA kept at RT. Therefore, three frozen tissue collections from non-smoking, early stage and sarcomatoid carcinoma NSCLC patients were selected for this study. DNA was extracted, lyophilized and encapsulated at RT under anoxic conditions using the DNAshell technology. In total, 1974 samples from 987 patients were encapsulated. Six and two capsules from each sample were stored in the biobanks of the Nice and Grenoble (France) Hospitals, respectively. In conclusion, DNA maintained at RT allows for the conservation, duplication and durability of collections of interest stored in biobanks. This is a low-cost and safe technology that requires a limited amount of space and has a low environmental impact. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.

To assess the risk of adverse neonatal outcomes in women with gestational diabetes (GDM) by identifying subgroups of women at higher risk to recognize the characteristics most associated with an excess of risk. Observational, retrospective, multicenter study involving consecutive women with GDM. To identify distinct and homogeneous subgroups of women at a higher risk, the RECursive Partitioning and AMalgamation (RECPAM) method was used. Overall, 2736 pregnancies complicated by GDM were analyzed. The main outcome measure was the occurrence of adverse neonatal outcomes in pregnancies complicated by GDM. Among study participants (median age 36.8 years, pre-gestational BMI 24.8 kg/m2), six miscarriages, one neonatal death, but no maternal death was recorded. The occurrence of the cumulative adverse outcome (OR 2.48, 95% CI 1.59–3.87), large for gestational age (OR 3.99, 95% CI 2.40–6.63), fetal malformation (OR 2.66, 95% CI 1.00–7.18), and respiratory distress (OR 4.33, 95% CI 1.33–14.12) was associated with previous macrosomia. Large for gestational age was also associated with obesity (OR 1.46, 95% CI 1.00–2.15). Small for gestational age was associated with first trimester glucose levels (OR 1.96, 95% CI 1.04–3.69). Neonatal hypoglycemia was associated with overweight (OR 1.52, 95% CI 1.02–2.27) and obesity (OR 1.62, 95% CI 1.04–2.51). The RECPAM analysis identified high-risk subgroups mainly characterized by high pre-pregnancy BMI (OR 1.68, 95% CI 1.21–2.33 for obese; OR 1.38 95% CI 1.03–1.87 for overweight). A deep investigation on the factors associated with adverse neonatal outcomes requires a risk stratification. In particular, great attention must be paid to the prevention and treatment of obesity.

Dopamine replacement therapy with l-DOPA is the treatment of choice for Parkinson’s disease; however, its long-term use is frequently associated with l-DOPA-induced dyskinesia (LID). Many molecules have been implicated in the development of LID, and several of these have been proposed as potential therapeutic targets. However, to date, none of these molecules have demonstrated full clinical efficacy, either because they lie downstream of dopaminergic signaling, or due to adverse side effects. Therefore, discovering new strategies to reduce LID in Parkinson’s disease remains a major challenge. Here, we have explored the tyrosine kinase Fyn, as a novel intermediate molecule in the development of LID. Fyn, a member of the Src kinase family, is located in the postsynaptic density, where it regulates phosphorylation of the NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor in response to dopamine D1 receptor stimulation. We have used Fyn knockout and wild-type mice, lesioned with 6-hydroxydopamine and chronically treated with l-DOPA, to investigate the role of Fyn in the induction of LID. We found that mice lacking Fyn displayed reduced LID, ΔFosB accumulation and NR2B phosphorylation compared to wild-type control mice. Pre-administration of saracatinib (AZD0530), an inhibitor of Fyn activity, also significantly reduced LID in dyskinetic wild-type mice. These results support that Fyn has a critical role in the molecular pathways affected during the development of LID and identify Fyn as a novel potential therapeutic target for the management of dyskinesia in Parkinson’s disease. Fil: Sanz Blasco, Sara Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: Bordone, Melina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: Damianich, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: Gomez, Gimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: Bernardi, Maria Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: Isaja, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: Taravini, Irene Rita Eloisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Universidad Nacional de Entre Ríos. Facultad de Bromatología; Argentina Fil: Hanger, Diane P.. King's College London; Reino Unido Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: Gershanik, Oscar Samuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: Ferrario, Juan Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina

Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.Results: PQR309 had in vitro antilymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab. Sensitivity to PQR309 was associated with specific baseline gene-expression features, such as high expression of transcripts coding for the BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene-expression signatures induced by PQR309 and by other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib.Conclusions: On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. Clin Cancer Res; 24(1); 120–9. ©2017 AACR.

Antipsychotic (AP) drugs have the potential to cause prolongation of the QT interval corrected for heart rate (QTc). As this risk is dose-dependent, it may be associated with the number of AP drugs concurrently prescribed, which is known to be associated with increased cumulative equivalent AP dosage. This study analysed whether AP dose mediates the relationship between polypharmacy and QTc interval. We used data from a cross-sectional survey that investigated the prevalence of QTc lengthening among people with psychiatric illnesses in Italy. AP polypharmacy was tested for evidence of association with AP dose and QTc interval using the Baron and Kenny mediational model. A total of 725 patients were included in this analysis. Of these, 186 (26%) were treated with two or more AP drugs (AP polypharmacy). The mean cumulative AP dose was significantly higher in those receiving AP polypharmacy (prescribed daily dose/defined daily dose = 2.93, standard deviation 1.31) than monotherapy (prescribed daily dose/defined daily dose = 0.82, standard deviation 0.77) (z = -12.62, p < 0.001). Similarly, the mean QTc interval was significantly longer in those receiving AP polypharmacy (mean = 420.86 milliseconds, standard deviation 27.16) than monotherapy (mean = 413.42 milliseconds, standard deviation 31.54) (z = -2.70, p = 0.006). The Baron and Kenny mediational analysis showed that, after adjustment for confounding variables, AP dose mediates the association between polypharmacy and QTc interval. The present study found that AP polypharmacy is associated with QTc interval, and this effect is mediated by AP dose. Given the high prevalence of AP polypharmacy in real-world clinical practice, clinicians should consider not only the myriad risk factors for QTc prolongation in their patients, but also that adding a second AP drug may further increase risk as compared with monotherapy.

Type 2 Diabetes (T2DM) is a complex disease that is not limited to hyperglycemia. Anti-diabetic treatments aimed at preventing late onset complications and avoiding both hypo- and hyperglycemic events. Unfortunately, recently discovered anti-diabetic drugs only modestly impacted on disease clinical outcome. This article is protected by copyright. All rights reserved.

Diabetic retinopathy (DR) is a leading cause of acquired blindness in adults, mostly affected by type 2 diabetes mellitus (T2DM). We have developed an experimental model of early T2DM in adult rats which mimics some features of human T2DM at its initial stages and provokes significant retinal alterations. The aim of this work was to analyze the effect of melatonin on retinal changes induced by the moderate metabolic derangement. For this purpose, adult male Wistar rats received a control diet or 30% sucrose in the drinking water. Three weeks after this treatment, animals were injected with vehicle or streptozotocin (STZ, 25 mg/kg). One day or 3 wk after vehicle or STZ injection, animals were subcutaneously implanted with a pellet of melatonin. Fasting and postprandial glycemia, and glucose, and insulin tolerance tests were analyzed. At 12 wk of treatment, animals which received a sucrose-enriched diet and STZ showed significant differences in metabolic tests, as compared with control groups. Melatonin, which did not affect glucose metabolism in control or diabetic rats, prevented the decrease in the electroretinogram a-wave, b-wave, and oscillatory potential amplitude, and the increase in retinal lipid peroxidation, NOS activity, TNFα, Müller cells glial fibrillary acidic protein, and vascular endothelial growth factor levels. In addition, melatonin prevented the decrease in retinal catalase activity. These results indicate that melatonin protected the retina from the alterations observed in an experimental model of DR associated with type 2 diabetes. Fil: Salido, Ezequiel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Bordone, Melina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: de Laurentiis, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Chianelli, Monica Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Keller Sarmiento, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina

Objective This study aimed to evaluate the effectiveness of a nursing home (NH) staff education to manage apathy in older individuals with a diagnosis of dementia. Methods Sixteen NHs agreed to participate, and 230 demented apathetic residents were randomly assigned to the reference group (RG) or the intervention group (IG). IG received a month of weekly 4-h training. Qualitative evaluation was performed through interviews and questionnaires regarding work practices and knowledge about dementia. Quantitative evaluation was at baseline, at the end of the training program (week 4), and 3 months after the end of it with the use of the Neuropsychiatric Inventory (NPI), the Apathy Inventory, and two observation scales. Results In the qualitative evaluation, very few staff responded to the questionnaire. Concerning the difficulty that managing residents' behavioral symptoms presented, aggressiveness was ranked as the most difficult behavior to manage and apathy as the least difficult. In the quantitative evaluation, the results are as follows. NPI: the IG scores increased from baseline to week 4 more than the RG for symptoms belonging to the affective and the psychotic NPI item subgroup. Apathy Inventory: there was a significant decrease of the emotional blunting score dimension in the IG. Group Observation Scale: significant improvement was observed for the emotional blunting dimension in the IG only. Conclusions Apathy is rarely identified as a problem in NH. Emotional blunting was the only dimension sensitive to change. Failure to improve residents' level of interest could be explained by the difficulties encountered in accessing information regarding the subjects' personal interests. But it remains possible to modify residents' emotional reactivity and staff's perceptions of residents' behaviors and emotions. Copyright © 2012 John Wiley & Sons, Ltd.

Light-induced damage is a widely used model to study retinal degeneration. We examined whether bacterial lipopolysaccharide (LPS) protects the retina against light-induced injury. One day before intense light exposure for 24 h, rats were intravitreally injected with LPS in one eye and vehicle in the contralateral eye. At several time points after light exposure, rats were subjected to electroretinography and histological analysis. Bax, Bcl-xL, p-Akt, and p-Stat3 levels were assessed by Western blotting, and retinal thiobarbituric acid reactive substances levels were measured as an index of lipid peroxidation. One group of animals received injections of dexamethasone, aminoguanidine (an inducible NOS inhibitor), 5-hydroxydecanoic acid (a mitochondrial K(+) /ATP channel blocker), or wortmannin [a phosphoinositide-3-kinase (PI3K) inhibitor] in order to analyze their effect on the protection induced by LPS. LPS afforded significant morphologic and functional protection in eyes exposed to intense light. Light damage induced an increase in mitochondrial Bax/cytoplasmic Bax ratio, and lipid peroxidation which were prevented by LPS. Dexamethasone and wortmannin (but not aminoguanidine or 5-hydroxydecanoic acid) prevented the effect of LPS. Moreover, wortmannin prevented the effect of LPS on p-Akt levels. These results indicate that LPS provides retinal protection against light-induced stress, probably through a PI3K/Akt-dependent mechanism.

The term ‘thyroid tumors of uncertain malignant potential’ (TT-UMP) was coined by surgical pathologists to define well-differentiated tumors (WDT) showing inconclusive morphological evidence of malignancy or benignity. We have analyzed the expression of microRNA (miRNA) in a training set of 42 WDT of different histological subtypes: seven follicular tumors of UMP (FT-UMP), six WDT-UMP, seven follicular thyroid adenomas (FTA), 11 conventional papillary thyroid carcinomas (C-PTC), five follicular variants of PTC (FV-PTC), and six follicular thyroid carcinomas (FTC), which led to the identification of about 40 deregulated miRNAs. A subset of these altered miRNAs was independently validated by qRT-PCR, which included 18 supplementary TT-UMP (eight WDT-UMP and ten FT-UMP). Supervised clustering techniques were used to predict the first 42 samples. Based on the four possible outcomes (FTA, C-PTC, FV-PTC, and FTC), about 80% of FTA and C-PTC and 50% of FV-PTC and FTC samples were correctly assigned. Analysis of the independent set of 18 WDT-UMP by quantitative RT-PCR for the selection of the six most discriminating miRNAs was unable to separate FT-UMP from WDT-UMP, suggesting that the miRNA signature is insufficient in characterizing these two clinical entities. We conclude that considering FT-UMP and WDT-UMP as distinct and specific clinical entities may improve the diagnosis of WDT of the thyroid gland. In this context, a small set of miRNAs (i.e.miR-7,miR-146a,miR-146b,miR-200b,miR-221, andmiR-222) appears to be useful, though not sufficientper se, in distinguishing TT-UMP from other WDT of the thyroid gland.

Lichen planopilaris (LPP) is an inflammatory cicatricial alopecia for which many different therapies are attempted with varying success. The Janus kinase (JAK) inhibitor, tofacitinib, has been shown to be effective in treating the noncicatricial alopecia, alopecia areata. As in alopecia areata, upregulation of interferon and JAK signaling may play a role in LPP. We retrospectively reviewed the cases of 10 patients with recalcitrant LPP who were treated with oral tofacitinib. Patients received oral tofacitinib 5 mg twice or three times daily for 2–19 months as either monotherapy or adjunctive therapy to other ongoing treatments including intralesional triamcinolone, hydroxychloroquine, and tacrolimus ointment. Eight patients had clinical improvement in LPP with tofacitinib as either monotherapy (4/10) or adjunctive therapy (4/10). LPP Activity Index (LPPAI) before and after treatment was measured in seven patients and was significantly different (6.22 before treatment, 3.08 after treatment; p value = .0014). Reduction in LPPAI ranged from 30 to 94%. One patient complained of 10 pound (4.5 kg) weight gain after 12 months on tofacitinib. No other adverse effects were reported. Treatment with oral tofacitinib either as monotherapy or adjunctive therapy can lead to measurable improvement in recalcitrant LPP.

The advent of the targeted cancer therapies administered to patients, according to the results of molecular biology techniques (in particular, in situ hybridization, "polymerase chain reaction" amplification and sequencing), has modified the practice of the surgical pathology laboratories. The necessity to answer to the needs of physicians for optimizing the medical care for patients who develop cancer has led to a policy of national debate, spurred by the National Institute of Cancer (INCa), in order to implement new procedures in the pathology laboratories. Thus, in addition to the structuring of molecular biology platforms and their labeling by INCa, the upstream control of the steps present between resection of tumor samples and molecular analysis has proved to be crucial. Indeed, the quality of this upstream time, called "pre-analytical" phase, determines the reliability of the molecular biology results and therefore the therapeutic strategy. We describe here the main steps to be checked in the pre-analytical phase. The optimization of this pre-analytical phase within the surgical pathology laboratory aims to reduce or render insignificant the risk of errors of molecular biology tests. These errors can indeed lead to false negative or false positive results whose therapeutic consequences can be particularly harmful to patients with cancer.

Background: With the integration of various targeted therapies into the clinical management of patients with advanced lung adenocarcinoma, next-generation sequencing (NGS) has become the technology of choice and has led to an increase in simultaneously interrogated genes. However, the broader adoption of NGS for routine clinical practice is still hampered by sophisticated workflows, complex bioinformatics analysis and medical interpretation. Therefore, the performance of the novel QIAGEN GeneReader NGS system was compared to an in-house ISO-15189 certified Ion PGM NGS platform. Methods: Clinical samples from 90 patients (60 Retrospectively and 30 Prospectively) with lung adenocarcinoma were sequenced with both systems. Mutations were analyzed and EGFR, KRAS, BRAF, NRAS, ALK, PIK3CA and ERBB2 genes were compared and sampling time and suitability for clinical testing were assessed. Results: Both sequencing systems showed perfect concordance for the overlapping genes. Correlation of allele frequency was r2 = 0.93 for the retrospective patients and r2 = 0.81 for the prospective patients. Hands-on time and total run time were shorter using the PGM system, while the GeneReader platform provided good traceability and up-to-date interpretation of the results. Conclusion: We demonstrated the suitability of the GeneReader NGS system in routine practice in a clinical pathology laboratory setting.

The term thyroid tumours of uncertain malignant potential (TT-UMP) has been proposed for a subgroup of follicular-patterned thyroid tumours for which benignancy or malignancy cannot be assessed with certainty. The frequency, diagnostic reproducibility, immunohistochemistry and molecular genetic profiling of such tumours have been poorly explored. We, therefore, investigated (1) the frequency of TT-UMP diagnosed in a single institution (Nice, France: 2004-2008), (2) the observer variation among four pathologists, (3) whether immunohistochemical and molecular genetic profiling of TT-UMP provide additional information concerning such lesions. A series of 31 diagnosed TT-UMP (2.9%) out of 1,078 consecutive thyroidectomies were analysed. It comprised 15 follicular thyroid tumours of UMP (FT-UMP) and 16 well-differentiated tumours of UMP (WDT-UMP). Observer concordance was 70% for all TT-UMP. More than 50% of FT-UMP expressed galectin-3 and CK19, whereas more than 50% of WDT-UMP expressed HBME-1. Five cases of TT-UMP showed N-RAS mutations, while one showed H-RAS mutation and another PAX8/PPARgamma rearrangement. In conclusion, the frequency of TT-UMP is low in our institution. Diagnostic reproducibility is within the same range as other published data on follicular-patterned thyroid tumours. The ancillary methods have a low impact on aiding diagnosis of such lesions.

BACKGROUND: Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established. METHODS: In this multicenter, open-label trial, we randomly assigned 1818 patients with severe sepsis, in 100 intensive care units (ICUs), to receive either 20% albumin and crystalloid solution or crystalloid solution alone. In the albumin group, the target serum albumin concentration was 30 g per liter or more until discharge from the ICU or 28 days after randomization. The primary outcome was death from any cause at 28 days. Secondary outcomes were death from any cause at 90 days, the number of patients with organ dysfunction and the degree of dysfunction, and length of stay in the ICU and the hospital. RESULTS: During the first 7 days, patients in the albumin group, as compared with those in the crystalloid group, had a higher mean arterial pressure (P = 0.03) and lower net fluid balance (P

Translocation t(4;11)(q21;p15) is a rare recurrent change associated to T-cell acute leukemia. In most cases, this alteration appears as the only abnormality or as part of a simple karyotype. In this report, we present the first case of T acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) with the unbalanced translocation der(11)t(4;11)(q21;p15) as part of a very complex karyotype with multiple chromosome abnormalities, most of them not previously described in the literature. FISH (fluorescence in situ hybridization) and spectral karyotype (HiSKY) analysis confirmed the presence of complex alterations. The patient, a 16-year-old male, showed poor response to treatment and short survival (11 months). A detailed review of previously reported cases with t(4;11)(q21;p15) is also provided. The description of this type of alterations may contribute to the identification of new molecular mechanism associated to neoplastic development. Fil: Colli, Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Furforo, Lilian. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; Argentina Fil: Rojo Pisarello, Eduardo. Hospital de Alta Complejidad “Presidente Juan Domingo Perón"; Argentina Fil: Maidana, Marcela. Hospital de Alta Complejidad “Presidente Juan Domingo Perón"; Argentina Fil: Martín, Carlos. Consultorio de Hematopatología; Argentina Fil: Bordone, Javier. Hospital de Alta Complejidad “Presidente Juan Domingo Perón"; Argentina Fil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina

Inzucchi et al. (1) suggested that the newer class of hypoglycemic drugs should be preferred to sulfonylureas because of a safer profile with a superimposable hypoglycemic effect. In particular, they state that sulfonylureas are not indicated in chronic kidney disease because of an increased risk of hypoglycemia and potentially cardiovascular death. We challenge this conclusion, in main part, because sulfonylureas have been considered as a class, without taking into account specific properties of each drug—particularly gliclazide, which can be safely prescribed to patients with chronic kidney disease (2). Sulfonylureas have been prescribed to subjects with type 2 diabetes …