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Background. Standard protocol to detect melanoma relies on visual assessment in which the sensitivity and specificity are low for early melanomas. Pigmented lesion assay (PLA) offers objective metrics to aid in determining suspicious lesions; however, the literature on the diagnostic accuracy is controversial. Methods. To assess the performance of PLA, we retrospectively assessed the diagnostic accuracy using two different cohorts, total (n = 426) and biopsied (n = 96), modifying the definition of true negative for each. Sensitivity, specificity, negative predictive value, positive predictive value, prevalence, and Cohen’s kappa were calculated. Results. 370 PLA (−) lesions and 56 in the PLA (+). Of the 40 PLA (−) lesions that were biopsied, 5 (12.5%) were diagnosed as melanoma and 16 (40.0%) were atypical melanocytic nevus. Of the 56 PLA (+) lesions, 14 (25.0%) were melanoma, of which 10 (71.4%) were double positive, 3 (21.4%) were PRAME only, and 1 (7.1%) was LINC only. For the total cohort (n = 426), sensitivity of 73.7%, specificity of 89.7%, NPV of 98.6%, PPV of 25.0%, prevalence of 4.5%, accuracy of 89.0%, and kappa agreement of 0.329 were calculated. The biopsied cohort revealed the same sensitivity and PPV; however, specificity was 45.5%, accuracy was 51.0%, NPV was 87.5%), and kappa agreement was 0.110. Conclusion. There differences in our study seen between cohorts highlight the importance to recognize that neither findings are perfect. The real value likely falls in between, but further studies are needed.

A 31-gene expression profile (31-GEP) test that predicts metastatic risk in patients with cutaneous malignant melanoma (CMM) has previously been validated and is available for clinical use. The test dichotomizes patients into lower risk and higher risk groups based on differences that correspond to unique genetic expression patterns. Although the impact of such a test on dermatology providers' clinical decision-making has been studied, little is known about whether there exists an association between certain clinical features, such as dermoscopy, and 31-GEP results.In this retrospective analysis of 31-GEP test results ordered by dermatologists, we evaluated the frequency of dermoscopic features, using a modified dermoscopy three-point checklist, in 17 cases (n=17) and compared these findings to other key clinicopathologic features including tumor thickness, ulceration, and mitotic rate to 31-GEP results. Additionally, we evaluated the dermatologist's perspective and incorporation of GEP testing as part of patient discussion on melanoma management.31-GEP stratified patients into 4 groups; groups 1A and 1B are considered low risk of metastasis or recurrence, while 2A and 2B are considered high risk. Of the 17 cases, we had fifteen group 1A (88.23%), one 1B (5.88%), and one 2B (5.88%) result. Overall frequency of dermoscopic features is as follows; 100% of lesions presented with asymmetry, 47% with round structures, and 70.6% with blue-white color. The average time providers spent explaining and ordering the test was 15 minutes, with a range of 10 to 20 minutes.This study represents our experience and understanding of the dermatologistrsquo;s role ordering 31-GEP in the care pathway of melanoma patients and we recommend that dermatology providers consider ordering the test for newly diagnosed CMM patients. J Drugs Dermatol. 2022;21(12): doi:10.36849/JDD.6889.

A partir de uma etnografia realizada entre usuários de tornozeleiras no sistema de monitoramento eletrônico no Sul do Brasil, exploramos a noção da “infraestrutura do cuidado” para entender por que, em certos casos, o dispositivo não parece alcançar os objetivos projetados nem do sistema judiciário nem dos apenados. Nossa análise inspira-se no trabalho de Maria Puig de la Bellacasa, que encoraja pesquisadores a resgatar a noção de cuidado das garras de perspectivas idealizadas – isto é, de visões normativas descrevendo um trabalho abnegado por cuidadores perfeitos. No intuito de restituir seu pleno potencial político, abraçamos uma abordagem não inocente da noção de cuidado que adentra os terrenos tóxicos das dinâmicas de poder e exclusão. Olhando em particular para a organização das atividades domésticas, atentamo-nos para os atos e atores normalmente invisibilizados dos presos em regime do semiaberto. Perguntamos quais as práticas que facilitam ou, pelo contrário, travam as engrenagens do sistema que rege a vida desses usuários de tornozeleiras. Com isso, esperamos realizar três objetivos: sublinhar o caráter coletivo da estrutura do cuidado, aumentar a visibilidade de coisas e pessoas previamente negligenciadas, e finalmente acrescentar densidade à nossa apreensão das consequências reais de certo artefato tecnológico para o universo heterogêneo de apenados. Through the ethnographic study in Southern Brazil of prisoners in semi-liberty subjected to electronic monitoring, we explore the notion of “infrastructures of care” to understand why, in certain cases, the device does not seem to achieve hoped-for objectives -- neither those of the judicial system nor those of the prisoners themselves. Our analysis is inspired by the work of Maria Puig de la Bellacasa, who exhorts researchers to rescue the notion of care from the clutches of idealized perspectives – that is, from normative perspectives describing selfless work by perfect caregivers. In order to restore the notion of care to its full political potential, we embrace a “non-innocent” approach that penetrates into the toxic terrains involved in the dynamics of power and exclusion. Focusing mainly on the organization of the anklet-wearers’ domestic activities, we highlight the often “invisible” acts and actors that facilitate or, on the contrary, gum up the gears of the system that governs their lives. Altogether, ours is a three-fold objective, aiming to underline the collective nature of the structures of care, to enhance the visibility of previously neglected people and things, and finally to add new layers to our understanding of the real-life consequences of a certain technological artifact for the heterogeneous universe of inmates.

Through the ethnographic study in Southern Brazil of prisoners in semi-liberty subjected to electronic monitoring, we explore the notion of “infrastructures of care” to understand why, in certain cases, the device does not seem to achieve hoped-for objectives -- neither those of the judicial system nor those of the prisoners themselves. Our analysis is inspired by the work of Maria Puig de la Bellacasa, who exhorts researchers to rescue the notion of care from the clutches of idealized perspectives – that is, from normative perspectives describing selfless work by perfect caregivers. In order to restore the notion of care to its full political potential, we embrace a “non-innocent” approach that penetrates into the toxic terrains involved in the dynamics of power and exclusion. Focusing mainly on the organization of the anklet-wearers’ domestic activities, we highlight the often “invisible” acts and actors that facilitate or, on the contrary, gum up the gears of the system that governs their lives. Altogether, ours is a three-fold objective, aiming to underline the collective nature of the structures of care, to enhance the visibility of previously neglected people and things, and finally to add new layers to our understanding of the real-life consequences of a certain technological artifact for the heterogeneous universe of inmates., A partir de uma etnografia realizada entre usuários de tornozeleiras no sistema de monitoramento eletrônico no Sul do Brasil, exploramos a noção da “infraestrutura do cuidado” para entender por que, em certos casos, o dispositivo não parece alcançar os objetivos projetados nem do sistema judiciário nem dos apenados. Nossa análise inspira-se no trabalho de Maria Puig de la Bellacasa, que encoraja pesquisadores a resgatar a noção de cuidado das garras de perspectivas idealizadas – isto é, de visões normativas descrevendo um trabalho abnegado por cuidadores perfeitos. No intuito de restituir seu pleno potencial político, abraçamos uma abordagem não inocente da noção de cuidado que adentra os terrenos tóxicos das dinâmicas de poder e exclusão. Olhando em particular para a organização das atividades domésticas, atentamo-nos para os atos e atores normalmente invisibilizados dos presos em regime do semiaberto. Perguntamos quais as práticas que facilitam ou, pelo contrário, travam as engrenagens do sistema que rege a vida desses usuários de tornozeleiras. Com isso, esperamos realizar três objetivos: sublinhar o caráter coletivo da estrutura do cuidado, aumentar a visibilidade de coisas e pessoas previamente negligenciadas, e finalmente acrescentar densidade à nossa apreensão das consequências reais de certo artefato tecnológico para o universo heterogêneo de apenados.

Background A pigmented lesion assay (PLA) is used to non-invasively detect the presence of three genes associated with melanoma (LINC00518, PRAME, and TERT) using adhesive patch testing and has the potential to reduce unnecessary biopsies. However, few studies have evaluated the clinical applicability of PLA testing and its potential limitations in real-world practice. We aim to identify possible barriers that inhibit the clinical utility of PLA testing by dermatologists. Methods Retrospective case-control study analyzing the PLA testing by two pigmented-lesion specialists that underwent PLA testing as part of clinical management. Data was collected from April 2021 to April 2022 from an academic tertiary-level center. Results The total cohort consists of 472 lesions. Genetic analysis failure for LINC00518 and PRAME occurred in 12.5% of cases and in 70.9% of cases for TERT. In 38.5% of cases, PLA results were discrepant with histopathology. The additional time associated with PLA use independent from the patient's visit was 15 min on average. Conclusion The high proportion of non-actionable results and discrepant cases highlights potential barriers to the widespread adoption of PLA testing. The high proportion of genetic analysis failure seen for TERT and limited influence on the proposed risk suggests TERT does not offer significant clinical value.

Environmental carcinogenic exposures are major contributors to global disease burden yet how they promote cancer is unclear. Over 70 years ago, the concept of tumour promoting agents driving latent clones to expand was first proposed. In support of this model, recent evidence suggests that human tissue contains a patchwork of mutant clones, some of which harbour oncogenic mutations, and many environmental carcinogens lack a clear mutational signature. We hypothesised that the environmental carcinogen

Long-term cognitive impairment (LTCI) is a phenomenon predominantly seen in patients within intensive care units (ICU) that causes chronic dysfunction, defined as new or worsening deficits in memory, attention, mental processing speed, executive function, intellectual function, and visual-spatial abilities for over 12 months, inhibiting the necessary return to baseline function without appropriate intervention. Our objective is to provide a guideline of nursing strategies to reduce LTCI through different studies that evaluate pharmacological and non-pharmacological methods. Current literature demonstrates that pharmacotherapy focused on neuronal protection as well as robust physical therapy regimens and regulated sleep schedules show promise in strengthening cognitive function and reducing LTCI. Future studies regarding LTCI should focus on the efficacy of specific pharmacological regimens, large-scale assessments of the implementation of physical therapy to reduce LTCI, as well as, specific interventions to reduce the incidence of delirium in the ICU.

Anticholinergics, such as benztropine and trihexyphenidyl, are a class of medications that have been used to treat several different conditions including antipsychotic-induced extrapyramidal side effects (EPS) that are most often associated with first-generation antipsychotics (FGAs), such as haloperidol and fluphenazine. Many other medications, including antimuscarinics, antipsychotics, and antidepressants, also have anticholinergic effects. In this report, we review the case of an 80-year-old male who experiences irreversible anticholinergic withdrawal effects following the discontinuation of trihexyphenidyl and trospium secondary to side effects. Discontinuation of anticholinergics must be approached with care as abrupt withdrawal can lead to cholinergic rebound and muscular rigidity, and in some cases can lead to acute hospitalization and an inability to return to baseline functioning, as seen in our elderly patient. Keywords: Anticholinergic withdrawal, trihexyphenidyl, trihexyphenidyl withdrawal, trospium, anticholinergic drugs, cholinergic rebound

The unprecedented onset of the COVID-19 crisis poses a significant challenge to all fields of medicine, including dermatology. Since the start of the coronavirus outbreak, a stark decline in new skin cancer diagnoses has been reported by countries worldwide. One of the greatest challenges during the pandemic has been the reduced access to face-to-face dermatologic evaluation and non-urgent procedures, such as biopsies or surgical excisions. Teledermatology is a well-integrated alternative when face-to-face dermatological assistance is not available. Teledermoscopy, an extension of teledermatology, comprises consulting dermoscopic images to improve the remote assessment of pigmented and non-pigmented lesions when direct visualisation of lesions is difficult. One of teledermoscopy’s greatest strengths may be its utility as a triage and monitoring tool, which is critical in the early detection of skin cancer, as it can reduce the number of unnecessary referrals, wait times, and the cost of providing and receiving dermatological care. Mobile teledermoscopy may act as a communication tool between medical practitioners and patients. By using their smartphone (mobile phone) patients can monitor a suspicious skin lesion identified by their medical practitioner, or alternatively self-detect concerning lesions and forward valuable dermoscopic images for remote medical evaluation. Several mobile applications that allow users to photograph suspicious lesions with their smartphones and have them evaluated using artificial intelligence technology have recently emerged. With the growing popularity of mobile apps and consumer-involved healthcare, this will likely be a key component of skin cancer screening in the years to come. However, most of these applications apply artificial intelligence technology to assess clinical images rather than dermoscopic images, which may lead to lower diagnostic accuracy. Incorporating the direct-to-consumer mobile dermoscopy model in combination with mole-scanning artificial intelligence as a mobile app may be the future of skin cancer detection.

Another way for GPCRs to signal G protein–coupled receptors (GPCRs) normally transmit signals by coupling to heterotrimeric guanine nucleotide–binding proteins (G proteins) or by binding β-arrestin proteins. Smith et al. provide evidence for another mechanism, an approximate combination of the two. They monitored the interaction of vasopressin type 2 receptors (V2Rs) and G α proteins in cultured cells using bioluminescent resonance energy transfer. Even though V2Rs do not signal canonically through G α i proteins, they promoted the formation of complexes containing β-arrestin and G α i , and this led to downstream signaling to extracellular signal-regulated kinase protein kinases. Science , this issue p. eaay1833

Introduction: High dimensional imaging approaches such as imaging mass cytometry (IMC) are becoming widely used in cancer research. Such methods allow simultaneous observation of many cell types and their functional states and can provide valuable spatial information on cancer disease states when applied to clinical tissue samples. For example, in-situ immune and tumor cell interactions can be interrogated in their spatial context within the tumor microenvironment (TME). Analysis methods for the resultant complex data are not well formalized, and bespoke methods are usually required to fully capitalize on the underlying richness of information made available by IMC. Deep learning [DL] approaches, while highly accurate for other imaging modalities, have been slow to be adopted in IMC, as public resources for deep learning tasks in IMC are not abundant. Methods: We developed multiple DL and ML-based analysis pipelines for the following tasks in IMC data processing: [1] nucleus and necrotic tissue segmentation, [2] quantitative nuclear and cellular morphometry, [3] identification of cell type-specific niches. We applied these protocols to images and derived single cell spatial data from the TRACERx IMC cohort (n=81 non-small cell lung cancer patients, 561 images). Results: [1] We created a 120 image, 46,000+ labelled nucleus segmentation dataset for IMC data with representative images from lung adenocarcinoma, squamous cell carcinoma and other tissues. We achieved state-of-the-art performance in nuclear instance segmentation using a custom U-net++ neural network architecture trained using this dataset, which we benchmarked against traditional image processing methods, as well as publicly available deep learning architectures. Subsequently, we exploited transfer learning to retrain this model on a restricted dataset of labelled necrotic domains, which produced predictions in good agreement with independent pathologist assessment. [2] We developed an IMC morphometry pipeline utilizing ML-informed partitions of nuclear and cellular shape descriptors through which we performed cell-type specific morphometric characterization of all mapped cells in the non-small cell lung cancer TME, and which enabled a comparative analysis of the morphometries of each distinct cellular phenotype. [3] We established a high throughput density-based spatial clustering pipeline capable of identifying locally enriched niches of a given cell type of interest, as well as probing the composition and phenotypes of other cells within these niches. Conclusions: These approaches enhanced the quality as well as the breadth of spatial information derivable from TRACERx IMC data. Applying such tools to other clinical and pre-clinical datasets can improve our understanding of the spatial organization of cells both in non-small cell lung cancer and other cancer types. Citation Format: Alastair Magness, Katey Enfield, Mihaela Angelova, Emma Colliver, Emer Daly, Kristiana Grigoriadis, Claudia Lee, Oriol Pich, Philip Hobson, Dina Levi, Takahiro Karasaki, David Moore, Julian Downward, Erik Sahai, Mariam Jamal-Hanjani, Charles Swanton, TRACERx Consortium. Machine learning-enhanced image and spatial analytic pipelines for imaging mass cytometry applied to the TRACERx non-small cell lung cancer study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1926.

Introduction. Studying cell-to-cell variation within the tumour’s native context is crucial for fully understanding tumour heterogeneity and its impact on disease progression and therapy response. Tumour cells and their surrounding stromal cells can be spatially profiled using multiplex imaging with a growing number of detectable proteins. The methods currently used for identification of cell phenotypes from multiplex imaging data have been initially developed for cells in suspension. Therefore, more accurate and robust approaches are required to account for spatial signal overlap and to automatically detect the presence of biomarkers in spatial proteomics. Methods. We performed imaging mass cytometry on 221 tumour and adjacent normal regions from 81 untreated, non-small cell lung cancer patients in the TRACERx study. Two antibody panels with 35 markers were applied to include a range of phenotypic, functional, and structural biomarkers. Single cells were segmented using deep learning-based approaches, and the measured biomarker intensities per cell were further used to identify cell types and functional states. Results. We developed a computational approach optimised for spatial proteomics for identification of cell types and functional states and automated detection of the presence of biomarkers on single cells. First, we demonstrated that current approaches for cell phenotyping lack reproducibility with subsampling and can produce ambiguous clusters of cells from different cell types. Using a multi-tiered analytical approach in combination with statistical tools, we showed reproducibility between technical and biological replicates. We estimated the performance using orthogonal measurements from flow cytometry and immunohistochemistry from matched tumour samples. This approach has been automated with a scalable and portable Nextflow-based implementation. Conclusions. We developed a streamlined approach that overcame limitations of current methods and quantified single-cell biomarker presence using multiplex imaging with TRACERx. Implemented as open-source, portable and customisable, this pipeline for spatially resolved TME characterisation will allow the study of drug targets expression within their spatial context for a better understanding of therapy efficacy. Citation Format: Mihaela Angelova, Katey Enfield, Alastair Magness, Emma Colliver, Masako Shimato, Claudia Lee, David A. Moore, Febe Van Maldegem, Philip Hobson, Dina Levi, James L. Reading, Crispin T. Hiley, Julian Downward, Erik Sahai, Charles Swanton. Spatially resolved biomarker detection on single cells in TRACERx using multiplex imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6113.

Por uma reflexão voltada para políticas de adoção infantil, procuro estabelecer uma ponte entre, por um lado, episódios etnográficos – densos e contextualmente situados – e, por outro, sistemas abrangentes com consequências em larga escala e de longo alcance. Operacionalizo essa proposta pela análise das infraestruturas administrativa, estatística e burocrática que conectam as filosofias políticas do momento às atitudes e ações dos variados atores (profissionais, servidores e usuários) sob observação. Essa abordagem permite rastrear através das últimas décadas os instrumentos tecnológicos – em particular, estatísticas, cadastros e formulários – cunhados para estabilizar determinadas políticas de adoção. Ao mesmo tempo, atento às “proliferações” (Tsing; Mathews; Bubandt, 2019) – produto e produtor de tensões do próprio sistema – que levam acontecimentos em direções inesperadas. Ao apreciar esses eventos que iniciam quase sempre em escala limitada e com consequências incertas, minha intenção é restituir o poder desses exemplos a alimentar certa esperança – profundamente pragmática, epistemologicamente ambivalente e subarticulada – em possibilidades futuras ainda sequer imaginadas. In the following reflection on child adoption policies, we seek to establish a bridge between, on the one hand, ethnographic episodes – dense and contextually situated – and, on the other hand, comprehensive systems with large-scale and far-reaching consequences. To carry out this endeavour we analyze the administrative, statistical and bureaucratic infrastructures connecting political philosophies of the moment to the attitudes and actions of the various actors (professionals, servants and users) under observation. This approach allows us to trace throughout the past few decades of technological instruments – in particular, statistics, registries and forms –, designed to stabilize certain adoption policies. At the same time, we pay close attention to “proliferations” (Tsing; Mathews; Bubandt, 2019) – product and producer of tensions in the system itself – that conduct matters in unexpected directions. In appreciating these events that almost always start on a limited scale and with uncertain consequences, our intention is to enhance the power of these examples to nurture a certain hope – deeply pragmatic, epistemologically ambivalent and subarticulated – in yet unfathomed possibilities.

The vascular endothelium is the innermost layer of blood vessels and is a key regulator of vascular tone. Endothelial function is controlled by receptor signaling through G protein-coupled receptors, receptor tyrosine kinases and receptor serine-threonine kinases. The β-arrestins, multifunctional adapter proteins, have the potential to regulate all of these receptor families, although it is unclear as to whether they serve to integrate signaling across all of these different axes. Notably, the β-arrestins have been shown to regulate signaling by a number of receptors important in endothelial function, such as chemokine receptors and receptors for vasoactive substances such as angiotensin II, endothelin-1 and prostaglandins. β-arrestin-mediated signaling pathways have been shown to play central roles in pathways that control vasodilation, cell proliferation, migration, and immune function. At this time, the physiological impact of this signaling has not been studied in detail, but a deeper understanding of it could lead to the development of novel therapies for the treatment of vascular disease.

Heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) are common drug targets and canonically couple to specific G(α) protein subtypes and β-arrestin adaptor proteins. G protein–mediated signaling and β-arrestin–mediated signaling have been considered separable. We show here that GPCRs promote a direct interaction between G(αi) protein subtype family members and β-arrestins regardless of their canonical G(αi) protein subtype coupling. G(αi):β-arrestin complexes bound extracellular signal-regulated kinase (ERK), and their disruption impaired both ERK activation and cell migration, which is consistent with β-arrestins requiring a functional interaction with G(αi) for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of G(αi):β-arrestin signaling complexes.

SummaryG-protein-coupled receptors (GPCRs) enable cells to sense and respond appropriately to hormonal and environmental signals, and are a target of ~30% of all FDA-approved medications. Canonically, each GPCR couples to distinct Gαproteins, such as Gαs, Gαi, Gαqor Gα12/13, as well as β-arrestins. These transducer proteins translate and integrate extracellular stimuli sensed by GPCRs into intracellular signals through what are broadly considered separable signalling pathways. However, the ability of Gαproteins to directly interact with β-arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between Gαiprotein family members and β-arrestin. Gαi:β-arrestin complexes were formed by all GPCRs tested, regardless of their canonical G protein isoform coupling, and could bind both GPCRs as well as the extracellular signal-regulated kinase (ERK). This novel paradigm of Gαi:β-arrestin scaffolds enhances our understanding of GPCR signalling.

Progesterone receptors (PR) are prognostic and predictive biomarkers in hormone-dependent cancers. Twomain PR isoforms have been described, PRB and PRA, that differ only in that PRB has 164 extra N-terminalamino acids. It has been reported that several antibodies empirically exclusively recognize PRA in formalinfixedparaffin-embedded (FFPE) tissues. To confirm these findings, we used human breast cancer xenograftmodels, T47D-YA and -YB cells expressing PRA or PRB, respectively, MDA-MB-231 cells modified to synthesizePRB, and MDA-MB-231/iPRAB cells which can bi-inducibly express either PRA or PRB. Cells were injectedinto immunocompromised mice to generate tumours exclusively expressing PRA or PRB. PR isoform expressionwas verified using immunoblots. FFPE samples from the same tumours were studied by immunohistochemistryusing H-190, clone 636, clone 16, and Ab-6 anti-PR antibodies, the latter exclusively recognizing PRB. Exceptfor Ab-6, all antibodies displayed a similar staining pattern. Our results indicate that clones 16, 636, and theH-190 antibody recognize both PR isoforms. They point to the need for more stringency in evaluating thetrue specificity of purported PRA-specific antibodies as the PRA/PRB ratio may have prognostic and predictivevalue in breast cancer. Fil: Fabris, Victoria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Abascal, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Giulianelli, Sebastian Jesus. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto de Biología de Organismos Marinos; Argentina Fil: May, María. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina Fil: Sequeira, Gonzalo Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Jacobsen, Britta. University of Colorado Anschutz Medical Campus; Estados Unidos Fil: Lombès, Marc. Inserm; Francia Fil: Han, Julie. Moore´s Cancer Center; Estados Unidos Fil: Tran, Luan. Moore´s Cancer Center; Estados Unidos Fil: Molinolo, Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naive MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (>200μg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z-score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z-score for those beginning treatment at 0-3, >3-6, >6-9, >9-12, and >12-15years of age (p

We describe three cases of pulmonary aspergillosis (PA) in three patients without traditional risk factors for invasive aspergillosis infection, such as prolonged neutropenia or high dose systemic corticosteroid therapy. All three patients developed PA while taking tyrosine kinase inhibitors (TKI) and sustained greater clinical improvement once TKI were withdrawn. Our case series supports the theory TKI treatment can increase susceptibility to PA without causing neutropenia. Recognition that TKI treatment may predispose to invasive aspergillosis will allow for rapid recognition of affected patients and more effective management of future cases.

Background The use of fluorescent proteins to label tumors is revolutionizing cancer research, enabling imaging of both primary and metastatic lesions, which is important for diagnosis, staging, and therapy. This report describes the use of fluorescence laparoscopy to image green fluorescent protein (GFP)-expressing tumors in an orthotopic mouse model of human pancreatic cancer. Methods The orthotopic mouse model of human pancreatic cancer was established by injecting GFP-expressing MiaPaCa-2 human pancreatic cancer cells into the pancreas of 6-week-old female athymic mice. On postoperative day 14, diagnostic laparoscopy using both white and fluorescent light was performed. A standard laparoscopic system was modified by placing a 480-nm short-pass excitation filter between the light cable and the laparoscope in addition to using a 2-mm-thick emission filter. A camera was used that allowed variable exposure time and gain setting. For mouse laparoscopy, a 3-mm 0° laparoscope was used. The mouse’s abdomen was gently insufflated to 2 mm Hg via a 22-gauge angiocatheter. After laparoscopy, the animals were sacrificed, and the tumors were collected and processed for histologic review. The experiments were performed in triplicate. Results Fluorescence laparoscopy enabled rapid imaging of the brightly fluorescent tumor in the pancreatic body. Use of the proper filters enabled simultaneous visualization of the tumor and the surrounding structures with minimal autofluorescence. Fluorescence laparoscopy thus allowed exact localization of the tumor, eliminating the need to switch back and forth between white and fluorescence lighting, under which the background usually is so darkened that it is difficult to maintain spatial orientation. Conclusion The use of fluorescence laparoscopy permits the facile, real-time imaging and localization of tumors labeled with fluorescent proteins. The results described in this report should have important clinical potential.

Tesis (Magister en Dirección y Liderazgo para la Gestión Educacional) El presente plan de mejoramiento institucional fue desarrollado para el Instituto Profesional IACC. Este instituto nace en el año 1981, bajo la figura de Centro de Formación Técnica, impartiendo carreras de Comunicación Audiovisual y Publicidad. Para el año 1987 obtiene el reconocimiento oficial del Ministerio de Educación Chileno (MINEDUC), lo que lo convierte en Instituto Profesional, a partir de este momento, aumenta la oferta académica del IACC incluyendo Relaciones Públicas Bilingüe, mención Secretariado Gerencial, Comunicación Escénica y Diseño Gráfico. Debido a la gran aceptación hasta el momento, y el auge existente a nivel nacional por aumentar el acceso a la educación superior, el IACC funda la Universidad de las Artes, Ciencias y Comunicaciones (UNIACC) en 1989, y con esto en el año 1990 se firma un Acuerdo de Colaboración Institucional entre ambas instituciones para así complementar la experiencia y el apoyo. Producto de su larga trayectoria, y aporte al campo laboral de técnicos y profesionales en las áreas de las Artes y Ciencias de la Comunicación, en el año 2006 IACC recibe su autonomía institucional por parte del MINEDUC. Un hito que marca la historia de IACC lo constituye el inicio de oferta de Programas de Diplomados y Cursos de Capacitación en la modalidad online, la cual para la época era muy poco conocida en el país, sumado a esto y en la búsqueda de innovación, hacia el año 2007, IACC pasa a formar parte de Apollo Global, corporación de Apollo Group líderes en educación online a nivel mundial, teniendo como principal referente la Universidad de Phoenix con más de 300.000 estudiantes en modalidad online tanto en pregrado como postgrado. Este hecho hace que IACC para el año 2008 decida emprender una transformación institucional y se convierta en el primer Instituto Profesional en ofrecer estudios 100% online de Chile. Ahora bien, el presente plan de mejoramiento nace a partir de un diagnóstico institucional y de los planes de optar a una acreditación institucional por parte del IACC; al realizar el diagnóstico se detectaron falencias que deben ser atendidas para así poder proseguir con los planes de acreditación que se tienen.

Neste artigo, com inspiração tanto nos estudos da ciência quanto na antropologia do parentesco, descrevemos um movimento político que exige do governo brasileiro reparação legal pela violação dos direitos humanos dos filhos de pessoas compulsoriamente internadas por causa da Hanseníase. Realizamos essa investigação através do exame de três tecnologias interconectadas – narrativas orais, documentos escritos e o teste de DNA – usadas pelos atores principais para “calcular” as conexões familiares no cerne desse drama. A noção de tecnologias permite destacar não só a materialidade de certos processos, mas também as temporalidades complexas em jogo. Ao responder a um desafio lançado por Janet Carsten, nosso objetivo último é demostrar como eventos políticos assim como estruturas institucionalizadas coletivas – mediadas por essas diversas tecnologias – produzem um tipo particular de socialidade, enredada em percepções novas de família e comunidade. In this paper, drawing on literature from both STS and the anthropology of kinship, we describe a political movement aimed at legal reparation for human rights violations perpetrated by the Brazilian government against children of the compulsorily institutionalized patients of Hansen’s disease. We conduct our investigation by exploring the action of intertwining technologies – narrated recollections, written documents, and the DNA test – employed by major actors to “reckon” the family connections at the core of this drama. The notion of technologies helps underline not only the materiality of certain processes, but also the complex temporalities at play. Responding to a challenge proposed by Janet Carsten, our ultimate aim is to show how political events as well as collective institutionalized structures – operating through the mediation of these diverse technologies – produce a particular kind of sociality, interwoven with perceptions of family and community.

Neste artigo, apoiando-me num conjunto de obras recentes, pretendo fornecer subsídios para “situar” os comitês universitários de ética (CEPs) no Brasil dentro dum contexto político e acadêmico mais amplo. Primeiro, ao rever a narrativa de origem dos CEPs, situando o surgimento deles nos EUA dos anos 1950 e 1960, sugiro que esse modelo seja mais adequado à resolução de riscos legais da pesquisa científi ca do que à garantia mais abrangente do proceder ético. Em segundo lugar, evoco estilos e espaços “alternativos” de participação popular no debate ético que permitem estranhar a ênfase dos CEPs em mecanismos de participação pontual e individualizada. Em terceiro lugar, considero a dimensão transnacional dos esforços para regular pesquisas científi cas envolvendo sujeitos humanos, especialmente na indústria farmacêutica. Finalmente, trato dos debates que circundam a aplicação do modelo dos CEPs à pesquisa em ciências humanas, sublinhando algumas provocações políticas que, especialmente na área de antropologia, têm levado a novas e desafi adoras perspectivas sobre a ética em pesquisa. Meu objetivo é contribuir para um arsenal de abordagens que combata receitas fáceis, garantindo que o debate sobre os modos de regulação da ética na pesquisa científi ca se mantenha aberto a uma diversidade de possibilidades criativas. In this article, drawing on recent studies, we propose to situate the university- related ethical review boards in Brazil within a wider political and academic context. First, by re-examining origin narratives, focusing now on the 50s and 60s in the USA, we suggest that these boards are better adapted to the resolution of legal risks concerning scientifi c research than to the broader aim of guaranteeing ethical procedures. Second, we consider alternative styles and spaces of popular participation in ethical debates that allow us to rethink the Review Boards’ emphasis on mechanisms of episodic and individualized participation. Third, we consider the transnational dimension of efforts to regulate scientifi c research involving human beings, especially in the pharmaceutical industry. Finally, we look at debates surrounding the application of the Review Board model to the social sciences, highlighting political provocations that, especially in the area of anthropology, have given rise to new and challenging perspectives on research ethics. By combatting simplistic solutions, this article’s ultimate objective is to assure ongoing debate on the creative diversity of possibilities for guaranteeing ethical procedures in scientifi c research.

There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters. Fil: Wargon, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Riggio, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Giulianelli, Sebastian Jesus. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Sequeira, Gonzalo Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Rojas, Paola Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: May, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Polo, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Gorostiaga, Maria Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Jacobsen, Britta. University of Colorado Anschutz Medical Campus; Estados Unidos Fil: Molinolo, Alfredo. Oral and Pharyngeal Cancer Branch; Estados Unidos Fil: Novaro, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

O seminário “Les sentiers de l’ethnologie urbaine, avec Colette Pétonnet” (“Pistas da etnologia urbana, com Colette Petonnet”), realizado entre 3 e 4 de outubro de 2013, no Muséum National d’Histoire Naturelle – Paris, reuniu diversos pesquisadores para uma homenagem póstuma a esta precursora da etnologia em meio urbano, fundadora, com Jacques Gutwirth, do Laboratoire d’Anthropologie Urbaine do Centre National de Recherche Scientifi que (LAU/CNRS). Este artigo é uma tradução do paper enviado por Claudia Fonseca, ex-orientanda da homenageada, apresentado, na ocasião, em forma de um vídeo, produzido em conjunto com Claudia Turra Magni e Mauro Bruschi, sob o título Colette Pétonnet au Brésil: les effets pédagogiques d’un exercice ethnographique. Aqui, as autoras evocam as marcas e repercussões dos ensinamentos da mestra, a partir de sua estada no Brasil, na última década do século passado. The seminar “Les sentiers de l’ethnologie urbaine, avec Colette Pétonnet” (Pathways of urban ethnology, with Colette Petonnet), held on October 3-4, 2013 at the Muséum National d’Histoire Naturelle in Paris, brought together diverse researchers in a posthumous homage to this precursor of ethnology in urban settings and founder – together with Jacques Gutwirth – of the Laboratoire d’Anthropologie Urbaine do Centre National de Recherche Scientifi que (LAU/CNRS). This article is inspired in the contribution solicited from Claudia Fonseca (one of Colette’s former students), presented at the seminar in the form of a video produced in co-authorship with Claudia Turra Magni and Mauro Bruschi, entitled Colette Pétonnet au Brésil: les effets pédagogiques d’un exercice ethnographique. Here, the authors outline the repercussions of the teachings of Colette, starting with her sojourn in Porto Alegre during the early 1990s.

This case study compares two different clinical outcomes for a patient with a long-standing psychotic disorder prescribed clozapine on two occasions. During the first trial, clozapine was used at a higher dose for this patient (350-450mg/day) and included clinically significant sialorrhea, pneumonia, and pneumonia-like illnesses requiring immediate medical intervention including hospitalization. There were also patient complaints of fatigue, cough, choking, and constipation leading to poor adherence. Clozapine was discontinued when the patient withdrew his consent due to side effects, despite his awareness of its benefits, including reduction of command hallucinations and irritability. The second clozapine trial was associated with lower daily doses and therapeutic serum blood levels. The patient was actively participating in and adhering to the medication plan. A very narrow window of clozapine dose was exceeded for two days and the patient complained of hypersalivation, cough, and lethargy. He was subsequently hospitalized for a two week period to treat aspiration pneumonia. This hospitalization helped establish the ideal daily dose of clozapine for this patient and also brought the relationship between aspiration pneumonia and clozapine to the attention of the psychiatrist and medical specialist. Once the appropriate dosage for this patient was established, his psychotic and affective symptoms were controlled, he was not hampered by adverse side effects, and he started to actively participate in social and recreational activities and plans that culminated in discharge from a state psychiatric facility to a supportive community residence. It is our hope that the lessons we have learned from our shared experience with this patient will be of benefit to other clinicians and patients.

Clozapine, the first atypical antipsychotic, is well known for superior efficacy in the treatment of refractory schizophrenia. Though the side effect most often associated with clozapine is the potential for causing blood dyscrasias, other lesser known side effects, including clozapine-induced incontinence, may result in the unnecessary discontinuation of this essential psychiatric medication in patients who otherwise have no alternative to treatment. Here we describe a case of pseudoephedrine used successfully as a therapeutic intervention for clozapine-induced incontinence.

In order to decrease the incidence of the development of ventral hernias along incision sites after midline abdominal laparotomies, it is critical that a relationship be established between tensile forces applied along the deep fascia and safety of closure. To quantify the tensile forces in the deep fascia, a pair of hemostats with articulating arms and beds and specially designed micro-hooks for attachment, were equipped with two strain gauges. The device was then successfully tested on swine cadavers at the University of Massachusetts Memorial Medical School. It is expected that future testing of the device will result in data that will ultimately allow doctors to select the optimal method for patient care.

Background The aim of this study was to improve fluorescence laparoscopy of pancreatic cancer in an orthotopic mouse model with the use of a light-emitting diode (LED) light source and optimal fluorophore combinations. Study Design Human pancreatic cancer models were established with fluorescent FG-RFP, MiaPaca2-GFP, BxPC-3-RFP, and BxPC-3 cancer cells implanted in 6-week-old female athymic mice. Two weeks postimplantation, diagnostic laparoscopy was performed with a Stryker L9000 LED light source or a Stryker X8000 xenon light source 24 hours after tail-vein injection of CEA antibodies conjugated with Alexa 488 or Alexa 555. Cancer lesions were detected and localized under each light mode. Intravital images were also obtained with the OV-100 Olympus and Maestro CRI Small Animal Imaging Systems, serving as a positive control. Tumors were collected for histologic analysis. Results Fluorescence laparoscopy with a 495-nm emission filter and an LED light source enabled real-time visualization of the fluorescence-labeled tumor deposits in the peritoneal cavity. The simultaneous use of different fluorophores (Alexa 488 and Alexa 555), conjugated to antibodies, brightened the fluorescence signal, enhancing detection of submillimeter lesions without compromising background illumination. Adjustments to the LED light source permitted simultaneous detection of tumor lesions of different fluorescent colors and surrounding structures with minimal autofluorescence. Conclusions Using an LED light source with adjustments to the red, blue, and green wavelengths, it is possible to simultaneously identify tumor metastases expressing fluorescent proteins of different wavelengths, which greatly enhanced the signal without compromising background illumination. Development of this fluorescence laparoscopy technology for clinical use can improve staging and resection of pancreatic cancer.