Kaposi sarcoma in an HIV-negative Tunisian patient: A rare cause of metatarsalgia

AbstractBackgroundKaposi sarcoma (KS) is an angioproliferative neoplasm that is commonly associated with human herpes virus-8 (HHV-8) and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). KS with osseous involvement is a rare occurrence, and is far more common in acquired immunodeficiency syndrome (AIDS)-related KS.Case presentationWe present a 32-year-old Tunisian man, HIV negative, who presented with a 4-year history of atraumatic mechanical metatarsalgia that progressively worsened with a limping gait. Physical examination revealed marked symmetrical forefoot lymphedema and a painful restricted left knee joint movement. Physical examination showed purple-blue plaques and nodules on the feet and ankles. Serologic tests for HIV and syphilis were negative. Plain radiography of the feet revealed numerous small lytic lesions. There were also scattered lytic lesions in the metaphysis of the proximal tibia and fibula. Osteolysis was predominantly left. Magnetic resonance imaging of the feet showed abnormal bone marrow signal of metatarsals and phalanges. Skin lesion biopsy yielded the diagnosis of Kaposi sarcoma. The disease was managed with chemotherapy including vinblastine.ConclusionIn a patient presenting with metatarsalgia without a commonly detected cause, it is mandatory to search for other lesions that may point to a rare diagnosis as KS which is famous for involvement of the metatarsal bone

Spondylodiscite tuberculeuse : 12 ans d'expérience dans un centre hospitalier en Tunisie

Objectifs : Décrire les particularités épidémiologiques, cliniques et paracliniques des spondylodiscites tuberculeuses et déterminer les facteurs prédictifs d’une évolution défavorable. Patients et Méthode: Etude rétrospective sur une période de 12 ans. Le diagnostic a été porté sur des preuves bactériologiques, anatomopathologiques ou sur un faisceau d’arguments. Résultats : Il s’agissait de 49 patients (26F/23H), âgés en moyenne de 51,84 ans. Le délai moyen de diagnostic était de 6,65 mois. Un facteur prédisposant à l’infection a été relevé chez 38,7% des patients. L’étage lombaire était le plus touché (67,3%). L’imagerie par résonnance magnétique était pathologique dans tous les cas où elle a été effectuée. Le diagnostic de certitude a été porté dans 9 cas sur une preuve histologique. La ponction biopsie disco-vertébrale a permis de confirmer le diagnostic dans 6/36 cas. Tous les patients ont reçu un traitement anti-tuberculeux d’une durée moyenne de 13,59 mois associé à un geste interventionnel dans 8 cas. L’évolution était favorable dans 84,2% des cas. Nous avons identifiés quatre facteurs prédictifs d’une évolution défavorable: une hyperleucocytose initiale ≥11500 éléments/mm3 (p=0,031), la présence d’abcès ou de collection à l’imagerie (p=0,018); un tassement vertébral à l’IRM (p=0,018) et l’existence de déformation osseuse avant correction chirurgicale (p<0,001). Conclusion: La spondylodiscite tuberculeuse devrait être suspectée devant toute rachialgie inflammatoire. Une prise en charge précoce est la clé pour éviter les complications neurologiques et ostéo-articulaires

Non-Fourier effect and inertia effect analysis of a strip with an induced crack under thermal shock loading

In this paper, the transient temperature fields and the dynamic stress intensity factors of a thermo-elastic strip containing an inner crack parallel to the heated surface under thermal shock are studied. The Biot number of the crack gap, hyperbolic heat conduction theory and equation of motion are considered to investigate the behavior of the temperature fields around the crack and the stress intensity factors. Fourier transform and Laplace transform are used to reduce this mixed boundary value problem. Numerical methods are used to solved the singular integrate equations. Finally, the numerical results are presented illustrating the influence of Biot number, non-Fourier effect and inertia effect on temperature field and stress intensity factors. It is found that the Biot number strongly affect the uniformity of the temperature field and the magnitude of the stress intensity factors. The stress intensity factors have higher amplitude and an oscillating feature comparing to those obtained under conventional Fourier thermal conduction condition and quasi-static hypothesis, which can help to better understand the crack behaviors of advanced materials under thermal impact loading. (C) 2016 Elsevier Ltd. All rights reserved

A unique subset of glycolytic tumour-propagating cells drives squamous cell carcinoma

Head and neck squamous cell carcinoma (SCC) remains among the most aggressive human cancers. Tumour progression and aggressiveness in SCC are largely driven by tumour-propagating cells (TPCs). Aerobic glycolysis, also known as the Warburg effect, is a characteristic of many cancers; however, whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood. Here, we show that the NAD+-dependent histone deacetylase sirtuin 6 is a robust tumour suppressor in SCC, acting as a modulator of glycolysis in these tumours. Remarkably, rather than a late adaptation, we find enhanced glycolysis specifically in TPCs. More importantly, using single-cell RNA sequencing of TPCs, we identify a subset of TPCs with higher glycolysis and enhanced pentose phosphate pathway and glutathione metabolism, characteristics that are strongly associated with a better antioxidant response. Together, our studies uncover enhanced glycolysis as a main driver in SCC, and, more importantly, identify a subset of TPCs as the cell of origin for the Warburg effect, defining metabolism as a key feature of intra-tumour heterogeneity

Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma

Therapeutic options for the treatment of glioblastoma remain inadequate despite concerted research efforts in drug development. Therapeutic failure can result from poor permeability of the blood-brain barrier, heterogeneous drug distribution, and development of resistance. Elucidation of relationships among such parameters could enable the development of predictive models of drug response in patients and inform drug development. Complementary analyses were applied to a glioblastoma patient-derived xenograft model in order to quantitatively map distribution and resulting cellular response to the EGFR inhibitor erlotinib. Mass spectrometry images of erlotinib were registered to histology and magnetic resonance images in order to correlate drug distribution with tumor characteristics. Phosphoproteomics and immunohistochemistry were used to assess protein signaling in response to drug, and integrated with transcriptional response using mRNA sequencing. This comprehensive dataset provides simultaneous insight into pharmacokinetics and pharmacodynamics and indicates that erlotinib delivery to intracranial tumors is insufficient to inhibit EGFR tyrosine kinase signaling.National Institutes of Health (U.S.) (U54 CA210180)MIT/Mayo Physical Sciences Center for Drug Distribution and Drug Efficacy in Brain TumorsDana-Farber Cancer Institute (PLGA Fund)Lundbeck FoundationNovo Nordisk Foundatio

Increasing gene dosage greatly enhances recombinant expression of aquaporins in Pichia pastoris

<p>Abstract</p> <p>Background</p> <p>When performing functional and structural studies, large quantities of pure protein are desired. Most membrane proteins are however not abundantly expressed in their native tissues, which in general rules out purification from natural sources. Heterologous expression, especially of eukaryotic membrane proteins, has also proven to be challenging. The development of expression systems in insect cells and yeasts has resulted in an increase in successful overexpression of eukaryotic proteins. High yields of membrane protein from such hosts are however not guaranteed and several, to a large extent unexplored, factors may influence recombinant expression levels. In this report we have used four isoforms of aquaporins to systematically investigate parameters that may affect protein yield when overexpressing membrane proteins in the yeast <it>Pichia pastoris</it>.</p> <p>Results</p> <p>By comparing clones carrying a single gene copy, we show a remarkable variation in recombinant protein expression between isoforms and that the poor expression observed for one of the isoforms could only in part be explained by reduced transcript levels. Furthermore, we show that heterologous expression levels of all four aquaporin isoforms strongly respond to an increase in recombinant gene dosage, independent of the amount of protein expressed from a single gene copy. We also demonstrate that the increased expression does not appear to compromise the protein folding and the membrane localisation.</p> <p>Conclusions</p> <p>We report a convenient and robust method based on qPCR to determine recombinant gene dosage. The method is generic for all constructs based on the pPICZ vectors and offers an inexpensive, quick and reliable means of characterising recombinant <it>P. pastoris </it>clones. By using this method we show that: (1) heterologous expression of all aquaporins investigated respond strongly to an increase in recombinant gene dosage (2) expression from a single recombinant gene copy varies in an isoform dependent manner (3) the poor expression observed for AtSIP1;1 is mainly caused by posttranscriptional limitations. The protein folding and membrane localisation seems to be unaffected by increased expression levels. Thus a screen for elevated gene dosage can routinely be performed for identification of <it>P. pastoris </it>clones with high expression levels of aquaporins and other classes of membrane proteins.</p

A year of genomic surveillance reveals how the SARS-CoV-2 pandemic unfolded in Africa

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The evolving SARS-CoV-2 epidemic in Africa: insights from rapidly expanding genomic surveillance

Investment in SARS-CoV-2 sequencing in Africa over the past year has led to a major increase in the number of sequences generated, now exceeding 100,000 genomes, used to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence domestically, and highlight that local sequencing enables faster turnaround time and more regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and shed light on the distinct dispersal dynamics of Variants of Concern, particularly Alpha, Beta, Delta, and Omicron, on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve, while the continent faces many emerging and re-emerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century