Bichromatic phase-control of interfering Autler-Townes spectra

We propose a new scheme to control the shape of the Autler-Townes (AT) doublet in the photoelectron spectrum from atomic resonance-enhanced multiphoton ionization (REMPI). The scheme is based on the interference of two AT doublets created by ionization of the strongly driven atom from the ground and the resonantly excited state using tailored bichromatic femtosecond (fs) laser pulses. In this scheme, the quantum phase of the photoelectrons is crucial for the manipulation of the AT doublet. The laser polarization state and the relative optical phase between the two colors are used to manipulate the interference pattern. We develop an analytical model to describe the bichromatic REMPI process and provide a physical picture of the control mechanism. To validate the model, the results are compared to an ab initio calculation based on the solution of the 2D time-dependent Schr\"odinger equation for the non-perturbative interaction of an atom with intense polarization-shaped bichromatic fs-laser pulses. Our results indicate that the control mechanism is robust with respect to the laser intensity facilitating its experimental observation.Comment: 13 pages, 5 figure

Orbital angular momentum superposition states in transmission electron microscopy and bichromatic multiphoton ionization

The coherent control of electron beams and ultrafast electron wave packets dynamics have attracted significant attention in electron microscopy as well as in atomic physics. In order to unify the conceptual pictures developed in both fields, we demonstrate the generation and manipulation of tailored electron orbital angular momentum (OAM) superposition states either by employing customized holographic diffraction masks in a transmission electron microscope or by atomic multiphoton ionization utilizing pulse-shaper generated carrier-envelope phase stable bichromatic ultrashort laser pulses. Both techniques follow similar physical mechanisms based on Fourier synthesis of quantum mechanical superposition states allowing the preparation of a broad set of electron states with uncommon symmetries. We describe both approaches in a unified picture based on an advanced spatial and spectral double slit and point out important analogies. In addition, we analyze the topological charge and discuss the control mechanisms of the free-electron OAM superposition states. Their generation and manipulation by phase tailoring in transmission electron microscopy and atomic multiphoton ionization is illustrated on a 7-fold rotationally symmetric electron density distribution.Comment: K. Eickhoff and C. Rathje contributed equally to this wor

A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men

Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD

Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability

Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme (acetyl CoA carboxylase 1, ACC1) as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified a mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to beta-oxidation indicating reprogramming of metabolism towards a reliance on fatty acids. Compared to mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ HSPCs or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in growth inhibition of mIDH1 cancers, not reversible by ivosidenib. Critically, pharmacologic targeting of ACC1 improved sensitivity of mIDH1 AML to venetoclax.Daniel Thomas, Manhong Wu, Yusuke Nakauchi, Ming Zheng, Chloe A.L. Thompson-Peach, Kelly Lim, Niklas Landberg, Thomas Köhnke, Nirmal Robinson, Satinder Kaur, Monika Kutyna, Melissa Stafford, Devendra Hiwase, Andreas Reinisch, Gary Peltz, Ravindra Majet

Monoamine related functional gene variants and relationships to monoamine metabolite concentrations in CSF of healthy volunteers

BACKGROUND: Concentrations of monoamine metabolites in human cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. CSF monoamine metabolite concentrations are partly determined by genetic influences. METHODS: We investigated possible relationships between DNA polymorphisms in the serotonin 2C receptor (HTR2C), the serotonin 3A receptor (HTR3A), the dopamine D(4 )receptor (DRD4), and the dopamine β-hydroxylase (DBH) genes and CSF concentrations of 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 90). RESULTS: The HTR3A 178 C/T variant was associated with 5-HIAA levels (p = 0.02). The DBH-1021 heterozygote genotype was associated with 5-HIAA (p = 0.0005) and HVA (p = 0.009) concentrations. Neither the HTR2C Cys23Ser variant, nor the DRD4 -521 C/T variant were significantly associated with any of the monoamine metabolites. CONCLUSIONS: The present results suggest that the HTR3A and DBH genes may participate in the regulation of dopamine and serotonin turnover rates in the central nervous system

Cancer stem cell drugs target K-ras signaling in a stemness context

Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC.Peer reviewe

Recent developments in immunotherapy of acute myeloid leukemia

The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML) is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years. Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1) antibody-drug conjugates, (2) T cell-recruiting antibody constructs, (3) chimeric antigen receptor (CAR) T cells, (4) checkpoint inhibitors, and (5) dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML, but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results. While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts