The Evaluation of Mefloquine Drug Repurposing on Acute Myeloid Leukemia

The aim of this study is to observe cell proliferation, cell viability, apoptosis, and autophagy on acute myeloid leukemia (AML) cell lines, NB4 and U937, with the drug repurposing of mefloquine (MQ). Methods such as the 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay and trypan blue staining have shown a decrease in live cells with high concentrations of mefloquine. Using their average perspective IC50 values of MQ concentration, Western blotting was applied by means of apoptosis and autophagy markers to determine if the induction of apoptosis and inhibition of autophagy was present in MQ-treated AML cells. The experiment will be continued with more cell lines, drugs, and other means of protocol in order to contribute to cancer therapy.https://scholarscompass.vcu.edu/uresposters/1285/thumbnail.jp

Massive tubercular pseudo-tumor of the thigh: a case report

Psoas abscess in cases of tuberculosis originates from the primary lesion in the lower dorsal or the lumbar spine. From the spinal origin of the Psoas muscle, this abscess tracks down its sheath and may be palpable in the iliac fossa, in the lumbar triangle, in the upper part of thigh below the inguinal ligament. We present a rare case, where patient presented with thigh swelling, which on first look gave an impression of a malignant origin. But subsequent investigation revealed it to be one of tuberculous origin, and that to, tracking down of a Psoas abscess. According to best of our knowledge, there has been no reported case of a Psoas abscess tracking down to the thigh and knee and mimicking a tumour.Pan African Medical Journal 2012; 12:2

A Prospective, Multicentric, Open label and Post Marketing Clinical Follow up Study to Monitor the Safety and Performance of Light Cured Limb Orthosis - FlexiOH® (Short Arm Immobilizer) in Fractures Distal Radius

Background: Distal forearm fracture is the most common fracture encountered in daily life. Patients with this type of injury suffer from meaningful pain after Emergency Department discharge. Various studies reported that short-arm, below-the-elbow casts perform as well as long-arm, above-the-elbow casts for maintaining a reduction of distal forearm fractures demonstrated with a comparable risk of complication. Consequently, short casts are the commonly used method of immobilization however, short casts carry a potential disadvantage. Objective: To evaluate the safety and efficacy of the next-generation FlexiOH® (Short Arm Immobilizer). Settings and Design: This is a prospective, multicentre, and open-label clinical trial conducted in 5 different sites in India by recruiting a total of 137 subjects who were presented with distal forearm fractures. Materials and M ethods: Vital signs, concomitant medication taken by subjects during the study, X-ray results, and adverse events caused during all three visits were evaluated. Results: Overall patients showed normal vital signs, minimal adverse events, and relatively less concomitant medication consumption during the study period and at the end of the study, 100% healing was noted among all the study participants in the X-ray investigation. This clearly demonstrates the benefits over the conventional methods. Conclusion: For uncomplicated care of fractures and sports injuries of the limbs, FlexiOH® (Short Arm Immobilizer) technology offers more than just reliable immobilization and has advantages over contemporary plaster and cast bandages. This product is the most advanced orthopaedic immobilization technology and has the potential to be used and adopted worldwide. Keywords: FlexiOH®, Distal radius fractures, Short arm immobilizer, Adverse event

Ewing's Sarcoma of the Sacroiliac Joint Presenting as Tubercular Sacroiliitis: A Diagnostic Dilemma

We report a case of Ewing's sarcoma of the sacroiliac joint in a 21-year-old male mimicking tubercular sacroiliitis, a rare entity not reported in literature. He presented with pain in the lower back radiating to the right lower limb along with constitutional symptoms of 3 months duration. On examination, the right sacroiliac joint was tender. The laboratory investigations showed anaemia, leukocytosis and raised erythrocyte sedimentation rate. On X-ray, features of right sacroiliitis were seen. This was further investigated with magnetic resonance imaging (MRI), which showed features consistent with tubercular sacroiliitis. Patient was then started on antitubercular treatment, but the improvement was not consistent. So, a contrast MRI was done, which indicated features of primary sarcoma. It was then further confirmed by a computed tomography-guided biopsy, which showed features consistent with Ewing's sarcoma of the sacroiliac joint

Integrative genomic and proteomic approaches for identification of therapeutic vulnerabilities in human melanoma

Die Lebenserwartung von Melanompatienten hat sich durch große Fortschritte im Bereich der Therapiermöglichkeiten, unter anderem durch den enormen Fortschritt bioinformatischer Ansätze, stark erhöht. Obwohl es zahlreiche Durchbrüche auf dem Gebiet der Krebstherapie gab, sind das Nicht-Ansprechen auf und die Resistenz gegen eine Behandlung immer noch problematisch in der Melanomtherapie. Um diese Punkte zu adressieren, haben wir eine Methode entwickelt, die sowohl die in silico Analyse von Daten als auch in vitro Experimente umfasst. Bis jetzt generierten wir für eine genomische Analyse das Tool INtegrated DEtection of Genomic Outliers (INDEGO) und für eine Substanzsffinitäts-basierte proteomische Analyse das Programm Drug-EFfected Integrative Identification of Target(s)(DEFINIT). Das Melanom stellt eine sehr heterogene Tumorspezies dar, deshalb haben wir versucht Gene, die ein Ausreißer-Expressionsprofil in einer kleinen Untergruppe von Melanomen zeigen, zu identifizieren. Mit Hilfe von INDEGO wurden solche Gene, die zusätzlich eine starke negative prognostische Korrelation zeigen, bestimmt. In dieser Arbeit zeigen wir, dass Signal Sequence Receptor 2 (SSR2) in einer kleinen Untergruppe von Melanomen positiv mit der Überlebensdauer von Patienten korreliert. SSR2, ein Teil des Signal Sequence Receptor Komplexes, spielt eine große Rolle im effizienten Schleusen von Proteinen mit einer schwachen Signalsequenz. Diese Funktion ist besonders wichtig in Melanomen mit einer hohe Rate an Peptidsequenz-verändernder genetischen Veränderungen Dadurch wird die Proteintranslokation beeinträchtigt, was zu Stress im Endoplasmatischen Retikulum (ER) führt. Und tatsächlich konnten wir zeigen, dass SSR2 eine protektive Rolle gegen die ER Stress Antwort hat, was weiters durch eine Hochregulation von SSR2 in BRAF Inhibitor resistenten Melanomzellen bestätigt wurde. Wir fanden eine Veränderung des sogenannten Unfolded Protein Response (UPR) Signalweges, im Besonderen von dessen XBP1-IRE1 Arm, der für die SSR2 Regulierung verantwortlich ist. Die Rolle des Onkogens MITF im Melanom wird seit Jahren stark erforscht. Vor allem die expressionslevel-abhängigen, sehr unterschiedlichen Rollen in der Zellbiologie des Melanoms, und seine Neigung zur Erzeugung von Resistenzen gegen Therapien, machen es zu einem interessanten Ziel im Prozess der Melanombehandlung. Doch da die Proteinoberfläche keine Angriffspunkte für Inhibitoren hat, ist eine direkte therapeutische Intervention zur Zeit ausgeschlossen. Um diese Bedenken zu dressieren, wollen wir direkt auf die durch MITF ausgelöste Resistenz und den Tumorphänotyp abzielen, anstatt auf die MITF Levels selbst. Wir verwenden ein System isogener Zelllinien, die MITF normal- oder überexprimieren. Unsere DEFINIT x Analyse und funktionelle Analysen haben offenbart, dass Aurora Kinase A (AURKA) ein mögliches Kinase-Ziel sein könnte, um einen MITF-abhängigen Tumorphänotypen zu bekämpfen. Interessanterweise führte die Inhibierung von AURKA durch seinen Inhibitor MLN8237 zu einer Aktivierung und Hochregulation des MEK-ERK Signalwegesunabhängig vom genetischen Hintergrund der Zellen. Durch die AURKA-Inhibierung wird ein Resistenzprogramm gestartet, das zur Erhöhung pro-proliferativer Molekülewie auch anti-apoptotischer Moleküle führt. Eine Kombination aus AURKA und MAPK Signalweg Inhibierung wirkt diesem Phänomen entgegen und wirkt wachstumhemmend. Diese Resultate könnten wichtig für den Erfolg des AURKA Inhibitors MLN8237, der sich gerade in Phase II klinischer Versuche für Melanome befindet, sein. Zusammenfassend haben wir in einer kleinen Gruppe von Melanomen ein ‚Ausreißergen‘ gefunden und beschrieben, das eine wichtige Rolle im Melanomzellwachstum spielen könnte. Zusätzlich haben wir das in der Melanombiologie sehr gut beschriebene Gen MITF adressiert und eine stichfeste mechanistische Erklärung für therapeutische Kombinationsstrategien abgegeben.Advancement in melanoma therapeutics assisted by the progress in genomics and proteomics approaches has led to increased survival in melanoma patients. In spite of many breakthroughs, major problem of unresponsiveness to therapy and resistance to therapy persists in melanoma. To address these concerns we worked upon a framework of systematic algorithms consisting of both in silico analysis as well as in vitro experiments. To this end we developed INtegrated DEtetion of Genomic Outliers (INDEGO) for genomic analysis and Drug-EFfected INtegrative Identification of Target(s) (DEFINIT) for drug affinity based proteomic analysis. In lieu of highly heterogeneous nature of melanoma and the inability of conventional frequentist based computational approaches to cover all melanoma patients; we sought to identify the genes with an outlier expression profile in a small subset of melanoma patients. Using INDEGO we identified such genes, which were additionally backed by a strong negative prognostic correlation. In this study we show a prosurvival role of Signal Sequence Receptor 2 (SSR2) in a small subset of melanomas and a high SSR2 expression association with a poor prognosis. SSR2 as a part of the Signal Sequence Receptor (SSR) complex plays a crucial role in efficient gating of the proteins with a poor signal sequence. This is particularly important in melanomas having high rate of genomic alterations and mutations which might affect peptide signal sequences as well. Together this effects the protein translocation and causes ER stress. In conformity to above reasoning SSR2 indeed seems to play a protective role against ER stress response which is further endorsed by upregulation of SSR2 in BRAF inhibitor resistant melanoma cells. Using complementary gain and loss of function analysis we observe an Unfolded Protein Response (UPR) pathway as the one responsible for SSR2 regulation. In this case, UPR acts via transcription factor XBP1s emanating from its IRE1 branch. MITF, a lineage specific oncogene in melanoma, has been at the center of research for its role in melanoma. Confounded by its differential roles in melanoma cell biology depending on its levels and its propensity towards resistance against therapy via multiple mechanisms, makes it an enviable target in the process of melanoma treatment. Additional layer of complexity is added by a lack of target site for its inhibition thus keeping it out of the purview of therapeutic intervention. To address these concerns, instead to countering MITF levels we targeted MITF conferred resistance and tumorigenic phenotype. Using a system of isogenic cell lines with or without MITF overexpression we demonstrate a general resistance phenomenon against different inhibitors affecting multiple pathways. Secondly, our approach DEFINIT involving drug affinity based chemical proteomics upon on functional analysis for anchorage independent growth revealed Aurora Kinase A (AURKA) as a possible kinase target to overcome MITF dependent tumorigenic phenotype. Interestingly, AURKA inhibition by its inhibitor MLN8237 led to MEK-ERK pathway activation as well upregulation in all the tested melanoma cell lines irrespective of their genetic background. This initiated a resistance program involving a pro-proliferation signature. A combination of AURKA and MAPK pathway inhibition counteracted this phenomenon and also led to a heightened response. These results could be of great importance for the success of AURKA inhibitor, MLN8237 which is currently undergoing phase 2 clinical trials for melanoma. Taken together we identified and characterized a small subset associated outlier gene which could play an important role in melanoma cell progression and development of resistance to therapeutics. Additionally, we targeted a previously well characterized gene, MITF, in melanoma biology and forwarded a profound mechanistic rationale for a therapeutic combination strategy.submitted by Bhavuk Garg, M.Sc.Zusammenfassung in deutscher SpracheAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Dissertation, 2016OeBB(VLID)171453