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Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome characterized by monocytic proliferation in the presence of dysplastic bone marrow changes, inflammatory symptoms, and propensity for transformation to acute myeloid leukemia (AML), with a poor prognosis and limited treatment options. Unlike the α and β isoforms, the phosphatidylinositol-3-kinase (PI3K)-δ signaling protein is predominantly expressed by hematopoietic cells and therefore has garnered interest as a potential target for the treatment of lymphomas and leukemias. We revealed a pattern of increased PIK3CD:PIK3CA ratio in monocytic M5 AML patients and cell lines, and this ratio correlated with responsiveness to pharmacological PI3K-δ inhibition in vitro. Because CMML is a disease defined by monocytic clonal proliferation, we tested the PI3K-δ inhibitor umbralisib as a single agent and in combination with the JAK1/2 inhibitor ruxolitinib, in CMML. Our ex vivo experiments with primary CMML patient samples revealed synergistic inhibition of viability and clonogenicity with this combination. Phospho-specific flow cytometry revealed that dual inhibition had the unique ability to decrease STAT5, ERK, AKT, and S6 phosphorylation simultaneously, which offers a mechanistic hypothesis for the enhanced efficacy of the combination treatment. These preclinical data indicate promising activity by co-inhibition of PI3K-δ and JAK1/2 and support the use of ruxolitinib + umbralisib combination therapy in CMML under active clinical investigation.

Bakterielles Alginat konnte in hoher Ausbeute aus dem Bakterium Azotobacter vinelandii biotechnologisch gewonnen, aufgereinigt und chemisch charakterisiert werden. Es wurde zu Fasern nassversponnen, zu Vliesen verarbeitet, und Stanzlinge daraus wurden auf Fl��ssigkeitsaufnahmeverm��gen, Zytokinbindung und Keiminaktivierung hin untersucht. Dabei wurde stets ein Vergleich zu kommerziellen Wundauflagen aus marinen Alginaten gezogen. Wundauflagen aus bakteriellem Alginat zeigten ein generell h��heres Fl��ssigkeitsaufnahmeverm��gen als Vergleichsproben aus marinem Alginat. Ebenso besa��en sie ein deutlich gesteigertes Absorptionsverhalten gegen��ber Zytokinen und Proteasen. Speziell die Konzentration der proinflammatorischen Zytokine TNF-�� (Tumornekrosefaktor ��) und IL-8 (Interleukin 8), der Proteasen MMP-2 (Matrix-Metalloproteinase 2) und PMN Elastase (polymorphnukle��re Elastase) sowie freier Radikale (ROS) konnte bakterielles Alginat st��rker reduzieren als marines. Dabei erzielten in der Mehrzahl der Absorptionsversuche bakterielle Alginatwundauflagen ohne Zus��tze noch bessere Ergebnisse als solche mit Nanosilberzusatz. In vitro erreichten sie damit in Bezug auf Absorptionsverm��gen und Zytokinbindung bessere Resultate als kommerzielle Produkte. Die Wundauflagen aus bakteriellem Alginat zeigten weiterhin eine erh��hte Keiminaktivierung gegen��ber Wundkeimen wie MRSA (Methicillin-resistenter Staphylokokkus aureus) und Pseudomonas aeruginosa, vermutlich durch Einbindung in das entstehende Gel; das Wachstum von Pseudomonas aeruginosa wurde vollst��ndig gehemmt, das von MRSA deutlich reduziert. Die Ergebnisse dieser Arbeit weisen darauf hin, dass Wundauflagen aus bakteriellem Alginat in der modernen Wundbehandlung k��nftig klinische Vorteile bieten: Gegen��ber marinem Alginat gelieren sie aufgrund ihrer Molekularstruktur besser und schlie��en bei Kontakt mit Fl��ssigkeiten vermehrt Wundexsudat, Detritus oder Bakterien ein. Die erh��hte Bindung von Entz��ndungsmediatoren wie proinflammatorische Zytokine, Proteasen und reaktiven Oxygenspezies sowie die Keiminaktivierung sind weitere Vorteile. Ihre Integrit��t bleibt nach Gelierung in ausreichendem Ma�� f��r klinische Anwendungen erhalten. Zusammengefasst ist bakterielles Alginat aufgrund der dargelegten Eigenschaften ein aussichtsreiches Material f��r die Weiterentwicklung der feuchten Wundbehandlung, das sich insbesondere f��r stark exsudierende chronische Wunden empfiehlt.

Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors.Comp. 2: 5IEZ; Comp. 5: 5IF4.

Andrew L Sochacki,1 Melissa A Fischer,1 Michael R Savona1,2 1Department of Internal Medicine, Vanderbilt University Medical Center, 2Vanderbilt-Ingram Cancer Center, Nashville, TN, USA Abstract: The discovery of JAK2V617F a decade ago led to optimism for a rapidly developing treatment revolution in Ph- myeloproliferative neoplasms. Unlike BCR–ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK–STAT inhibitors have changed this, drastically ameliorating symptoms and ultimately beginning to show evidence of impact on survival. Now, the genetic foundations of myelofibrosis and MDS/MPN are rapidly being elucidated and contributing to targeted therapy development. This has been empowered through updated response criteria for MDS/MPN and refined prognostic scoring systems in these diseases. The aim of this article is to summarize concisely the current and rationally designed investigational therapeutics directed at JAK–STAT, hedgehog, PI3K–Akt, bone marrow fibrosis, telomerase, and rogue epigenetic signaling. The revolution in immunotherapy and novel treatments aimed at previously untargeted signaling pathways provides hope for considerable advancement in therapy options for those with chronic myeloid disease. Keywords: MDS/MPN neoplasms, emerging therapy

Penile strangulation is an infrequent clinical condition that has widely been reported. It usually results following placement of a constriction device to enhance sexual stimulation. Early treatment is essential to avoid potential complications, including ischemic necrosis and autoamputation. We describe the use of a Large Orthopedic Pin Cutter to remove a metal penile constriction device in the Emergency Department (ED). This case report describes the relatively safe technique of using an instrument available in many hospitals that can be added to the physician’s arsenal in the removal of metal constriction devices.

Hybridization was evaluated among three Laricobius spp. involved in the biological control of hemlock woolly adelgid (Adelges tsugae Annand). Following lab mating studies, there was no evidence that Laricobius osakensis Montgomery and Yu could produce hybrid progeny with either Laricobius nigrinus Fender or Laricobius rubidus LeConte. Interaction between L. osakensis and L. nigrinus did not result in a lower production of progeny as a result of fitness costs associated with interspecific mating attempts. Laricobius nigrinus and L. rubidus hybrids were produced in the lab and collected in the field. Hybrid progeny showed very little evidence of decreased fitness. For example, there was no significant difference in the number of days it took for hybrids and pure parental species to develop from egg hatch to the prepupal stage, there was no difference among hybrids and pure parental species in the head capsule widths and larval lengths for the first through third instar, and there was evidence of an F2 generation from field collected specimens. Hybrids produced in the lab had intermediate shaped genital paramere angles compared with parental species, and had elytra coloration similar to that of L. rubidus. Hybrids showed no host preference in the lab, but a preference for Adelges tsugae in the field. Of 12 site factors examined, only the number of years that L. nigrinus was present at the site was found to be associated with percent hybrids. Contamination of the L. osakensis colony with Laricobius naganoensis Leschen resulted in the need to develop molecular methods to differentiate L. osakensis from L. naganoensis. Three restriction enzymes were found that correctly differentiated the two species. Ph. D.

In adult mice, haematopoietic stem cells are maintained in a quiescent state. The transcriptional repressor Myeloid Translocation Gene 16 (MTG16) is shown to govern this process.