Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma.

The advent of genomics has led to the identification of specific "driver" mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer. We discuss the promising concept of rational upfront polytherapy in lung cancer, which involves concurrently targeting multiple proteins in critical signaling pathways in a cancer cell to prevent or delay resistance

Two-color ionization of hydrogen by short intense pulses

Photoelectron energy spectra resulting by the interaction of hydrogen with two short pulses having carrier frequencies, respectively, in the range of the infrared and XUV regions have been calculated. The effects of the pulse duration and timing of the X-ray pulse on the photoelectron energy spectra are discussed. Analysis of the spectra obtained for very long pulses show that certain features may be explained in terms of quantum interferences in the time domain. It is found that, depending on the duration of the X-ray pulse, ripples in the energy spectra separated by the infrared photon energy may appear. Moreover, the temporal shape of the low frequency radiation field may be inferred by the breadth of the photoelectron energy spectra.Comment: 12 pages, 8 figure

Photodetachment o F- by a few-cycle circularly polarized laser field

We report on calculations of the above threshold detachment of F- by a few-cycle circularly polarized laser field, discussing the effects of both the carrier-envelope relative phase and the number of the cycle contained in a pulse on the angular distribution of ejected photoelectron. The results are analyzed in terms of a two-step semiclassical model: after the electrons are detached through tunnelling their motion is determined by the electric field pulse according to the classical dynamics laws. Anisotropies in the angular distributions of the electrons ejected on the plane perpendicular to the laser propagation direction are found that depend on the number of cycle of the laser pulse

Polarization and angular distribution of the radiation emitted in laser-assisted recombination

The effect of an intense external linear polarized radiation field on the angular distributions and polarization states of the photons emitted during the radiative recombination is investigated. It is predicted, on symmetry grounds, and corroborated by numerical calculations of approximate recombination rates, that emission of elliptically polarized photons occurs when the momentum of the electron beam is not aligned to the direction of the oscillating field. Moreover, strong modifications to the angular distributions of the emitted photons are induced by the external radiation field.Comment: 5 pages, 3 figure

Photoionization of hydrogen by a chirped, short X-ray pulse in the presence of a laser field

The ionization of hydrogen by a chirped XUV pulse in the presence of a few cycle infrared laser pulse is investigated. It is found that the combined action of the chirped pulse and the laser eld brings about asymmetries in the photoelectron momentum distribution that may be exploited for obtaining information on both the chirp and XUV pulse duration

Detecting significant features in modeling microRNA-target interactions

MicroRNAs (miRNAs) are small non-coding RNA molecules mediating the translational repression and degradation of target mRNAs in the cell. Mature miRNAs are used as a template by the RNA-induced silencing complex (RISC) to recognize the complementary mRNAs to be regulated. Up to 60% of human genes are putative targets of one or more miRNAs. Several prediction tools are available to suggest putative miRNA targets, however, only a small part of the interaction pairs has been validated by experimental approaches. The analysis of the expression profile of the RNA fraction immunoprecipitated (IP) with the RISC proteins is an established method to detect which genes are actually regulated by the RISC machinery. In fact, genes that result over-expressed in the IP sample with respect to the whole cell lysate RNA, are considered as involved in the RISC complex, then miRNA targets. Here, we aim to find the features useful to predict which genes are overexpressed in IP, i.e. miRNA targets, without actually performing the IP experiments. To this purpose, we compiled and analyzed a novel high throughput data set suitable to unravel the features involved in the miRNA regulatory activities. We analyzed IP samples obtained by the immunoprecipitation of two RISC proteins, AGO2 and GW182. The two proteins shows different behaviors, in terms of enriched genes and features characterizing the immunoprecipitated RNA fractio. Further analysis is needed to unravel the reason of such different behavior

Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming.

The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated transcriptomic and metabolomics profiling uncovering a central role for autocrine TGFβ2 in mediating cellular plasticity through profound cellular adaptive Omics reprogramming, with common mechanistic link to prosurvival mitochondrial priming. Cells undergoing early adaptive drug escape are in proliferative-metabolic quiescent, with enhanced EMT-ness and stem cell signaling, exhibiting global bioenergetics suppression including reverse Warburg, and are susceptible to glutamine deprivation and TGFβ2 inhibition. Our study further supports a preemptive therapeutic targeting of bioenergetics and mitochondrial priming to impact early drug-escape emergence using EGFR precision inhibitor combined with broad BH3-mimetic to interrupt BCL-2/BCL-xL together, but not BCL-2 alone

Study of hypothalamic metabolism in cluster headache by proton MR spectroscopy

The authors used 1H-MRS to investigate hypothalamic metabolism in 26 patients with cluster headache (CH) and 12 healthy subjects. Hypothalamic N-acetylaspartate/creatine was reduced in patients with CH vs controls (p < 0.01). Dividing the patients into episodic CH outside- and in-cluster periods and chronic CH, the hypothalamic N-acetylaspartate/creatine in all three subgroups of patients was reduced. The reduction of the neuronal marker N-acetylaspartate is consistent with hypothalamic neuronal dysfunction in patients with CH

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Vitamin K deficiency bleeding leading to a diagnosis of Crohn’s Disease

We report the case of a 45 year old man who came to Emergency Room of Polyclinic for sudden onset of localized ecchymosis and widespread hematomas. He was subjected to blood count and first level investigations to assess coagulation. Based on the results, second level investigations were performed. Endoscopy of the gastrointestinal tract with histological examination revealed a diagnosis of Crohn's disease. Vitamin K deficiency causes the formation of vitamin K-dependent clotting factors that cannot perform their pro-coagulant action. Consequently, patients present with hemorrhagic manifestations. Clinical and laboratory features observed in this patient show that the deficiency of vitamin K-dependent coagulation factors may reveal a complex clinical condition such as an inflammatory bowel disease