Training the "clinical eye". Rubens' Three Graces: how many pathologies?

Art can serve as a powerful resource for medical students to both train the so called “clinical eye” and to better understand disease [1]. Herein a paleopathological analysis is performed on one of Ruben’s final artworks, “The Three Graces” (1630- 1635; oil on oak panel; 220.5 x 182 cm; Museo del Prado, Madrid). Rubens depicts the three Graces beside a fountain, under a garland of flowers in a landscape. The circular rhythm and elegant undulation are based on classical sculpture. Painted shortly after his marriage, it bears witness to the happiness of the artist’s life. The figure on the left is directly inspired by his second wife, Hélène Fourment (23 years old); the central and right Graces probably illustrate Rubens’ sisters-in-law. Besides overweight, scoliosis, and hyperlordosis observed in all three Graces, the left Grace evidences flat feet; hyperextension of the right metacarpal joints; signs of rheumatoid arthritis (even fibromyalgia has been proposed); lateral deviation of the nipple (Mondor’s disease?); varicose thighs, and right hallux vagus. The central Grace (Clara Fourment?), in turn, shows cellulite and, interestingly, positive Trendelenburg sign. Finally, the Grace on the right -Susanna Fourment- has been subject of a long debate on signs of a locally advanced breast cancer in the left external upper quadrant. In fact, several specialists agree in the observation of signs of an open ulcer; redness of the surrounding skin (an inflammatory sign); nipple retraction; reduction of the left breast volume, and enlarged axillary lymph nodes [2-3]. Rubens was one of main Baroque and realist painters, i.e. he painted whatever his eyes captured. If the Graces were sisters, then they are likely to share genetic traits. The latter, together with all the other signs described, favour the working diagnosis of familial benign hypermobility syndrome. Observation has a key role in clinical medicine; the paleopathological observation in art show us how artists could record abnormalities long before doctors did [2]. Therefore, artworks still represent useful teaching tools for refining visual skills in traditional and innovative medical education. References [1] Hinojosa-Azaloa A. & Alcocer-Varela J. (2014) Art and rheumatology: the artist and the rheumatologist’s perspective. Rheumatology 53: 1725-1731. [2] Dequeker J. (2007) Medicine and the artist. Age and Ageing 37: 4-5. [3] Grau et al. (2001) Breast cancer in Rubens paintings. Breast Ca Res Treat 68: 89-93

Loss of the tumour suppressor LKB1/STK11 uncovers a leptin-mediated sensitivity mechanism to mitochondrial uncouplers for targeted cancer therapy

Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers

Estimating the economic impact of a long–term hunting ban on local businesses in rural areas in Greece: a hypothetical scenario

In December 2009, hunting was banned for a few days in Greece following the decision of the Council of State. The decision was issued when an animal rights organization claimed to the Court that there was no updated evidence about the impact of hunting on wild populations. This case prompted the present study, which focused on examining the hypothetical scenario of the possible impact of a long–term hunting ban on local businesses in rural areas in Greece. We carried out face–to–face interviews with entrepreneurs from the accommodation and food service sectors. Our results showed that most business owners interviewed considered the impact would be significant for their annual earnings. This finding should be taken into account by environmental decision makers because rural and mountainous areas in Greece are sparsely populated, and the few small businesses that still operate would not withstand drastic changes in rural tourism.Estimación del impacto económico de una veda de caza a largo plazo sobre los negocios locales en las zonas rurales de Grecia: una situación hipotética.— En diciembre del 2009, en Grecia se prohibió la caza durante unos pocos días, siguiendo la decisión del Consejo de Estado. Esta se tomó cuando una organización defensora de los derechos de los animales recurrió a la Corte argumentando que no existían pruebas actualizadas sobre el impacto de la caza sobre las poblaciones de animales salvajes. Estas circunstancias promovieron el presente estudio, que se enfocó hacia el examen de unas hipotéticas circunstancias del posible impacto de la veda de caza a largo plazo sobre los negocios locales de las zonas rurales de Grecia. Llevamos a cabo entrevistas cara a cara con los empresarios de los servicios de alojamiento y gastronomía. Nuestros resultados mostraron que la mayoría de propietarios de negocios entrevistados consideraban que el impacto sería significativo para sus ingresos anuales. Los gestores del medio ambiente deberían tener en cuenta este resultado, dado que las áreas rurales montañosas de Grecia están escasamente pobladas, y los pocos negocios que aún funcionan en ellas no podrían soportar cambios drásticos en el turismo rural.Estimación del impacto económico de una veda de caza a largo plazo sobre los negocios locales en las zonas rurales de Grecia: una situación hipotética.— En diciembre del 2009, en Grecia se prohibió la caza durante unos pocos días, siguiendo la decisión del Consejo de Estado. Esta se tomó cuando una organización defensora de los derechos de los animales recurrió a la Corte argumentando que no existían pruebas actualizadas sobre el impacto de la caza sobre las poblaciones de animales salvajes. Estas circunstancias promovieron el presente estudio, que se enfocó hacia el examen de unas hipotéticas circunstancias del posible impacto de la veda de caza a largo plazo sobre los negocios locales de las zonas rurales de Grecia. Llevamos a cabo entrevistas cara a cara con los empresarios de los servicios de alojamiento y gastronomía. Nuestros resultados mostraron que la mayoría de propietarios de negocios entrevistados consideraban que el impacto sería significativo para sus ingresos anuales. Los gestores del medio ambiente deberían tener en cuenta este resultado, dado que las áreas rurales montañosas de Grecia están escasamente pobladas, y los pocos negocios que aún funcionan en ellas no podrían soportar cambios drásticos en el turismo rural

Escape from senescence:molecular basis and therapeutic ramifications

Cellular senescence constitutes a stress response mechanism in reaction to a plethora of stimuli. Senescent cells exhibit cell-cycle arrest and altered function. While cell-cycle withdrawal has been perceived as permanent, recent evidence in cancer research introduced the so-called escape-from-senescence concept. In particular, under certain conditions, senescent cells may resume proliferation, acquiring highly aggressive features. As such, they have been associated with tumour relapse, rendering senescence less effective in inhibiting cancer progression. Thus, conventional cancer treatments, incapable of eliminating senescence, may benefit if revisited to include senolytic agents. To this end, it is anticipated that the assessment of the senescence burden in everyday clinical material by pathologists will play a crucial role in the near future, laying the foundation for more personalised approaches. Here, we provide an overview of the investigations that introduced the escape-from-senescence phenomenon, the identified mechanisms, as well as the major implications for pathology and therapy.</p

AKT regulates NPM dependent ARF localization and p53mut stability in tumors

Nucleophosmin (NPM) is known to regulate ARF subcellular localization and MDM2 activity in response to oncogenic stress, though the precise mechanism has remained elusive. Here we describe how NPM and ARF associate in the nucleoplasm to form a MDM2 inhibitory complex. We find that oligomerization of NPM drives nucleolar accumulation of ARF. Moreover, the formation of NPM and ARF oligomers antagonizes MDM2 association with the inhibitory complex, leading to activation of MDM2 E3-ligase activity and targeting of p53. We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. We also show that ARF promotes p53 mutant stability in tumors and suppresses p73 mediated p21 expression and senescence. We demonstrate that AKT and PI3K inhibitors may be effective in treatment of therapeutically resistant tumors with elevated AKT and carrying gain of function mutations in p53. Our results show that the clinical candidate AKT inhibitor MK-2206 promotes ARF nucleolar localization, reduced p53(mut) stability and increased sensitivity to ionizing radiation in a xenograft model of pancreatic cancer. Analysis of human tumors indicates that phospho-S48-NPM may be a useful biomarker for monitoring AKT activity and in vivo efficacy of AKT inhibitor treatment. Critically, we propose that combination therapy involving PI3K-AKT inhibitors would benefit from a patient stratification rationale based on ARF and p53(mut) status

Postgraduate eLearning satellite-based tutorials as a new approach to “teaching to teach” anatomy

Modern educational trends approach in a more innovative, learner-centered programs that rely on a combination of interactive didactic tools and individualized tutoring. In response to the increasing need for new professionals in the health sciences who are able to apply academic eLearning in Medicine, since 2005 Sapienza University of Rome is involved in and coordinates a multidisciplinary network formed by 11 Italian universities, aimed to deliver a Master (postgraduate) course on teleteaching applied to the health sciences (Matam). This program forms highly qualified professionals for distance teaching/eLearning in health sciences and management. University sites are activated through earth and satellite-based modules, thus creating real/virtual class-rooms or didactic communities. Matam is delivered in two semesters as either synchronous satellite-based or asynchronous pre-registered tutorials (posted on an intranet site). Learners can actively and autonomously follow these modules, interacting with teachers and colleagues, whereas teachers/tutors, in turn, are in a studio at the university. The program considers a total of 60 CFU and admits a maximum of 20 participants per site. The integrated course “Multimedia technologies and virtual reality in imaging diagnostics” (8 CFU) includes 3 two-hour tutorials of human gross and microscopic anatomy (digestive and reproductive tracts), of which one is sent synchronously and two asynchronously. Matam is a sharing of knowledge, allowing teachers and learners to have a continuous and real-time update. The use of eLearning as an innovative integration within a course considering either ex cathedra and tutorial teaching may be useful for the improvement of students’ motivation and self assessment aptitudes, specially in young undergraduate ones. In addition, eLearning can favour a wider use of computer animations, thus representing a valid complement to courses particularly belonging to health sciences degrees

Looking is not seeing: visual art as a useful eLearning tool for teaching clinical anatomy

An old Chinese proverb reads “A picture paints a thousand words…”. Even though arts were used as a pedagogical tool as early as 1902, arts have not traditionally been part of medical education. Anatomy teaching is undergoing significant changes; long-distance education associated to web 2.0 tools have enlarged communication and interaction possibilities between users and virtual communities (1,2). We are developing a project consisting of a series of asynchronous (pre-registered) short video tutorials covering a wide range of clinical anatomy-related topics which can be posted on an internet/intranet site and then actively and autonomously be followed. Videos include short introductory remarks and legends which might be developed in different languages and which make them useful even to disable eLearners. The relationship between Art and: anatomy, thyroid gland, osteomuscular alterations, breast, ageing, artists’ diseases, as well as the presence of anatomists and physicians in Art, are some of the topics developed. Each tutorial considers numerous paintings and some sculptures covering a long time span, from Prehistory to the Classical period, Late Middle Ages, the rich Renaissance period up until modern times. Artworks were chosen in order to be narrative in nature and rich in detail, thus stimulating reflection and self-discussion. These video tutorials could be a valuable teaching/learning complement to theoretical knowledge within medical students’ education or even within a larger “art-loving” audience. eLearners are guided by the teacher’s voice and then get immersed in an artwork, discovering it. Clear and/or hidden clinical anatomical features can be enhanced and made easier to assimilate. This nontraditional format brings a new lens through which students can learn valuable visual skills on human clinical anatomy. It may favor critical thinking, opening the mind to alternative ways of seeing, thus enhancing medical students’ abilities to more deeply observe and to better understand real clinical situations

Training the “clinical eye”. Rubens’ Three Graces: how many pathologies?

Art can serve as a powerful resource for medical students to both train the so called “clinical eye” and to better understand disease [1]. Herein a paleopathological analysis is performed on one of Ruben’s final artworks, “The Three Graces” (1630-1635; oil on oak panel; 220.5 x 182 cm; Museo del Prado, Madrid). Rubens depicts the three Graces beside a fountain, under a garland of flowers in a landscape. The circular rhythm and elegant undulation are based on classical sculpture. Painted shortly after his marriage, it bears witness to the happiness of the artist’s life. The figure on the left is directly inspired by his second wife, Hélène Fourment (23 years old); the central and right Graces probably illustrate Rubens’ sisters-in-law. Besides overweight, scoliosis, and hyperlordosis observed in all three Graces, the left Grace evidences flat feet; hyperextension of the right metacarpal joints; signs of rheumatoid arthritis (even fibromyalgia has been proposed); lateral deviation of the nipple (Mondor’s disease?); varicose thighs, and right hallux vagus. The central Grace (Clara Fourment?), in turn, shows cellulite and, interestingly, positive Trendelenburg sign. Finally, the Grace on the right -Susanna Fourment- has been subject of a long debate on signs of a locally advanced breast cancer in the left external upper quadrant. In fact, several specialists agree in the observation of signs of an open ulcer; redness of the surrounding skin (an inflammatory sign); nipple retraction; reduction of the left breast volume, and enlarged axillary lymph nodes [2-3]. Rubens was one of main Baroque and realist painters, i.e. he painted whatever his eyes captured. If the Graces were sisters, then they are likely to share genetic traits. The latter, together with all the other signs described, favour the working diagnosis of familial benign hypermobility syndrome. Observation has a key role in clinical medicine; the paleopathological observation in art show us how artists could record abnormalities long before doctors did [2]. Therefore, artworks still represent useful teaching tools for refining visual skills in traditional and innovative medical education

Idiopathic Effusive-Constrictive Pericarditis

We herein describe the case of a 71-year-old man, who presented with clinical manifestations of congestive heart failure, in whom non-invasive imaging techniques played a decisive role in arriving at the correct diagnosis of effusive-constrictive pericarditis

Decoding of translation-regulating entities reveals heterogeneous translation deficiency patterns in cellular senescence

Cellular senescence constitutes a generally irreversible proliferation barrier, accompanied by macromolecular damage and metabolic rewiring. Several senescence types have been identified based on the initiating stimulus, such as replicative (RS), stress-induced (SIS) and oncogene-induced senescence (OIS). These senescence subtypes are heterogeneous and often develop subset-specific phenotypes. Reduced protein synthesis is considered a senescence hallmark, but whether this trait pertains to various senescence subtypes and if distinct molecular mechanisms are involved remain largely unknown. Here, we analyze large published or experimentally produced RNA-seq and Ribo-seq datasets to determine whether major translation-regulating entities such as ribosome stalling, the presence of uORFs/dORFs and IRES elements may differentially contribute to translation deficiency in senescence subsets. We show that translation-regulating mechanisms may not be directly relevant to RS, however uORFs are significantly enriched in SIS. Interestingly, ribosome stalling, uORF/dORF patterns and IRES elements comprise predominant mechanisms upon OIS, strongly correlating with Notch pathway activation. Our study provides for the first time evidence that major translation dysregulation mechanisms/patterns occur during cellular senescence, but at different rates depending on the stimulus type. The degree at which those mechanisms accumulate directly correlates with translation deficiency levels. Our thorough analysis contributes to elucidating crucial and so far unknown differences in the translation machinery between senescence subsets.</p