The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML

A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1−/− HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML

Mechanical force induces mitochondrial fission.

Eukaryotic cells are densely packed with macromolecular complexes and intertwining organelles, continually transported and reshaped. Intriguingly, organelles avoid clashing and entangling with each other in such limited space. Mitochondria form extensive networks constantly remodeled by fission and fusion. Here, we show that mitochondrial fission is triggered by mechanical forces. Mechano-stimulation of mitochondria - via encounter with motile intracellular pathogens, via external pressure applied by an atomic force microscope, or via cell migration across uneven microsurfaces - results in the recruitment of the mitochondrial fission machinery, and subsequent division. We propose that MFF, owing to affinity for narrow mitochondria, acts as a membrane-bound force sensor to recruit the fission machinery to mechanically strained sites. Thus, mitochondria adapt to the environment by sensing and responding to biomechanical cues. Our findings that mechanical triggers can be coupled to biochemical responses in membrane dynamics may explain how organelles orderly cohabit in the crowded cytoplasm

High myeloperoxidase positive cell infiltration in colorectal cancer is an independent favorable prognostic factor

BACKGROUND Colorectal cancer (CRC) infiltration by adaptive immune system cells correlates with favorable prognosis. The role of the innate immune system is still debated. Here we addressed the prognostic impact of CRC infiltration by neutrophil granulocytes (NG). METHODS A TMA including healthy mucosa and clinically annotated CRC specimens (n = 1491) was stained with MPO and CD15 specific antibodies. MPO+ and CD15+ positive immune cells were counted by three independent observers. Phenotypic profiles of CRC infiltrating MPO+ and CD15+ cells were validated by flow cytometry on cell suspensions derived from enzymatically digested surgical specimens. Survival analysis was performed by splitting randomized data in training and validation subsets. RESULTS MPO+ and CD15+ cell infiltration were significantly correlated (p<0.0001; r = 0.76). However, only high density of MPO+ cell infiltration was associated with significantly improved survival in training (P = 0.038) and validation (P = 0.002) sets. In multivariate analysis including T and N stage, vascular invasion, tumor border configuration and microsatellite instability status, MPO+ cell infiltration proved an independent prognostic marker overall (P = 0.004; HR = 0.65; CI:±0.15) and in both training (P = 0.048) and validation (P = 0.036) sets. Flow-cytometry analysis of CRC cell suspensions derived from clinical specimens showed that while MPO+ cells were largely CD15+/CD66b+, sizeable percentages of CD15+ and CD66b+ cells were MPO-. CONCLUSIONS High density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC

Versorgung von Hautdefekten des Kopfes mit einem Vakuumverband

Einleitung: Große Hautdefekte der Stirn und des Kopfe gleich welcher Entität sind in vielen Fällen nicht durch einen primären Wundverschluss zu versorgen, da die Haut in diesem anatomischen Bereich wenig elastisch ist. Traditionelle Rekonstruktionsmöglichkeiten umfassen die Vollhauttransplantation, lokale gestielte Lappen wie beispielsweise transpositions- und Rotationslappen, Implantation von Haut- und Gewebeexpandern mit anschliessendem Wundverschluss sowie freie Lappen.Hautdefekte bei älteren Patienten sind in den meisten Fällen posttraumatisch oder postoperativ. Bei großen postoperativen Defekten wird in vielen Fällen die sekundäre Wundheilung angestrebt. Diese wird teilweise mit Granulationsanreizen, wie dem Anbohren der Kalotte, unterstützt. Die Wundheilung ist langfristig, mehrfache Verbandswechsel sind notwendig und das kosmetische Ergebnis ist meist nicht optimal.Material und Methoden: Um Entfernung und Rekonstruktion von großen Basaliomen der Kopfhaut bei 3 älteren männlichen Patienten (Durchschnittsalter 78,4 Jahre) so schonend und angenehm wie möglich zu gestalten, erfolgte die histographische Resektion unter Lokalanästhesie, wobei Defekte zwischen 5 und 8 cm Durchmesser entstanden. Anschließend wurde das V.A.C.-System (KCI) als Wundverband genutzt.Ergebnisse: Bei allen 3 Patienten zeigte sich die nach 3 Wochen die gesamte Wunde mit vitalem Granulationsgewebe ausgefüllt. So konnte bei 2 Patienten der Wundverschluss mittels Vollhauttransplantat aus der Leiste erfolgen. Der dritte Patient lehnte die Defektdeckung ab.Diskussion: Das V.A.C.-System zur Behandlung von größeren Defekten im Kopfbereich stellt eine einfach und nach unserer Erfahrung für den Patienten gut tolerierbare Behandlungsform dar. Es zeigte sich eine rasche und effiziente Wundheilung mit einer somit erhöhten Lebensqualität der Patienten. Zusätzlich können Kosten durch kurze Krankenhausaufenthalte und ambulante Verbandswechsel gespart werden.Der Erstautor gibt keinen Interessenkonflikt an