Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a stem cell (SC) neoplasm characterized by the BCR/ABL1 oncogene. Although mechanisms of BCR/ABL1-induced transformation are well-defined, little is known about effector-molecules contributing to malignant expansion and the extramedullary spread of leukemic SC (LSC) in CML. We have identified the cytokine-targeting surface enzyme dipeptidylpeptidase-IV (DPPIV/CD26) as a novel, specific and pathogenetically relevant biomarker of CD34+/CD38─ CML LSC. In functional assays, CD26 was identified as target enzyme disrupting the SDF-1-CXCR4-axis by cleaving SDF-1, a chemotaxin recruiting CXCR4+ SC. CD26 was not detected on normal SC or LSC in other hematopoietic malignancies. Correspondingly, CD26+ LSC decreased to low or undetectable levels during successful treatment with imatinib. CD26+ CML LSC engrafted NOD-SCID-IL-2Rγ−/− (NSG) mice with BCR/ABL1+ cells, whereas CD26─ SC from the same patients produced multilineage BCR/ABL1– engraftment. Finally, targeting of CD26 by gliptins suppressed the expansion of BCR/ABL1+ cells. Together, CD26 is a new biomarker and target of CML LSC. CD26 expression may explain the abnormal extramedullary spread of CML LSC, and inhibition of CD26 may revert abnormal LSC function and support curative treatment approaches in this malignancy

Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia (AML)

Acute myeloid leukemia (AML) is a life-threatening stem cell disease characterized by uncontrolled proliferation and accumulation of myeloblasts. Using an advanced RNAi screen-approach in an AML mouse model we have recently identified the epigenetic ‘reader’ BRD4 as a promising target in AML. In the current study, we asked whether inhibition of BRD4 by a small-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosis in primary human AML stem- and progenitor cells. Primary cell samples were obtained from 37 patients with freshly diagnosed AML (n=23) or refractory AML (n=14). BRD4 was found to be expressed at the mRNA and protein level in unfractionated AML cells as well as in highly enriched CD34+/CD38− and CD34+/CD38+ stem- and progenitor cells in all patients examined. In unfractionated leukemic cells, submicromolar concentrations of JQ1 induced major growth-inhibitory effects (IC50 0.05-0.5 μM) in most samples, including cells derived from relapsed or refractory patients. In addition, JQ1 was found to induce apoptosis in CD34+/CD38− and CD34+/CD38+ stem- and progenitor cells in all donors examined as evidenced by combined surface/Annexin-V staining. Moreover, we were able to show that JQ1 synergizes with ARA-C in inducing growth inhibition in AML cells. Together, the BRD4-targeting drug JQ1 exerts major anti-leukemic effects in a broad range of human AML subtypes, including relapsed and refractory patients and all relevant stem- and progenitor cell compartments, including CD34+/CD38− and CD34+/CD38+ AML cells. These results characterize BRD4-inhibition as a promising new therapeutic approach in AML which should be further investigated in clinical trials

Immature Cryopreserved Ovary Restores Puberty and Fertility in Mice without Alteration of Epigenetic Marks

BACKGROUND: Progress in oncology could improve survival rate in children, but would probably lead to impaired fertility and puberty. In pre-pubertal girls, the only therapeutic option is the cryopreservation of one ovary. Three births have been reported after reimplantation of cryopreserved mature ovary. Conversely, reimplantation of ovary preserved before puberty (defined as immature ovary) has never been performed in humans. METHODOLOGY/PRINCIPAL FINDINGS: In order to analyze ovarian function, we performed transplantation using fresh or cryopreserved immature grafts in pre-pubertal or adult mice. Puberty as well as cyclic hormonal activity was restored. All follicle populations were present although a significant reduction in follicle density was observed with or without cryopreservation. Although fertility was restored, the graft is of limited life span. Because ex vivo ovary manipulation and cryopreservation procedure, the status of genomic imprinting was investigated. Methylation status of the H19 and Lit1 Imprinting Control Regions in kidney, muscle and tongue of offsprings from grafted mice does not show significant alteration when compared to those of unoperated mice. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that immature ovarian grafting can restore spontaneous puberty and fertility. However, these data suggest that follicle depletion leads to premature ovarian failure. This study addresses the very important epigenetics issue, and provides valuable information to the study of ovarian transplantation suggesting that these procedures do not perturb normal epigenetics marks. These results are highly relevant to the reimplantation question of immature cortex in women

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involvedSupplementary Information: Supplementary Data 1; Supplementary Data 2; Reporting Summary.NHMRC; Women’s and Children’s Hospital Research Foundation; Muir Maxwell Trust; Epilepsy Society; The European Fund for Regional Development; The province of Friesland, Dystonia Medical Research Foundation; Stichting Wetenschapsfonds Dystonie Vereniging; Fonds Psychische Gezondheid; Phelps Stichting; The Italian Ministry of Health; Istituto Superiore di Sanità, Italy; Undiagnosed Disease Network Italy; The Fondation maladies rares, University Hospital Essen and UK Department of Health’s NIHR.https://www.nature.com/ncommspm2020Neurolog

Probing dielectrophoretic force fields with metallic carbon nanotubes

The authors show that single-walled carbon nanotubes are effective probes for dielectrophoretic force fields by studying their deposition pattern on surfaces. Different force fields were generated by electrodes on insulating oxides, with or without conducting substrates underneath. The patterns were recorded by scanning electron microscopy and simulated by finite element calculations. The data show that a sign change of the normal component of the dielectrophoretic force close to the substrate surface can lead to a repulsion of metallic carbon nanotubes from the surface. The authors present geometrical constraints to avoid such a sign change in the dielectrophoretic force

Reversible metal-insulator transitions in metallic single-walled carbon nanotubes

We report on reversible metal to insulator transitions in metallic single-walled carbon nanotube devices induced by repeated electron irradiation of a nanotube segment. The transition from a low-resistive, metallic state to a high-resistive, insulating state by 3 orders of magnitude was monitored by electron transport measurements. Application of a large voltage bias leads to a transition back to the original metallic state. Both states are stable in time, and transitions are fully reversible and reproducible. The data is evidence for a local perturbation of the nanotube electronic system by removable trapped charges in the underneath substrate and excludes structural damage of the nanotube. The result has implications for using electron-beam lithography in nanotube device fabrication

Imaging electronic structure of carbon nanotubes by voltage-contrast scanning electron microscopy

We review recent progress in the measurement and understanding of the electrical properties of individual metal and semiconducting single-wall carbon nanotubes. The fundamental scattering mechanisms governing the electrical transport in nanotubes are discussed, along with the properties of p–n and Schottky-barrier junctions in semiconductor tubes. The use of advanced nanotube devices for electronic, high-frequency, and electromechanical applications is discussed. We then examine quantum transport in carbon nanotubes, including the observation of quantized conductance, proximity-induced supercurrents, and spin-dependent ballistic transport. We move on to explore the properties of single and coupled carbon-nanotube quantum dots. Spin and orbital (isospin) magnetic moments lead to fourfold shell structure and unusual Kondo phenomena. We conclude with a discussion of unanswered questions and a look to future research directions

Influence of structural and dielectric anisotropy on the dielectrophoresis of single-walled carbon nanotubes

We report on a carbon nanotube network which is composed of aligned metallic and randomly oriented semiconducting single-walled carbon nanotubes. The material is formed by using a novel radio frequency dielectrophoresis setup, which generates very large dielectrophoretic force fields and allows dielectrophoretic assembling of nanotube films up to 100 nm thickness. Polarization dependent absorption measurements provide experimental evidence for the electronic type specific alignment behavior. We explain the experimental data with an advanced model for nanotube dielectrophoresis, which explicitly takes into account both the longitudinal and transversal polarizability. On the basis of this model, we calculate the dielectrophoretic force fields and show that semiconducting nanotubes deposit under very large fields due to their transversal polarizability even for high field frequencies