Over the last decade, liquid biopsy has gained much attention as a powerful tool in personalized medicine, since it enables monitoring cancer evolution and follow-up of cancer patients in real time. ...Through minimally invasive procedures, liquid biopsy provides important information through the analysis of Circulating Tumor Cells (CTCs), and circulating tumor-derived material like circulating tumor DNA (ctDNA), circulating miRNAs (cfmiRNAs) and extracellular vehicles (EVs). CTCs and ctDNA analysis has already an important impact on the prognosis, detection of minimal residual disease (MRD), treatment selection and monitoring of cancer patients, while recent data show also its potential for early cancer diagnosis (Figure 1). Numerous clinical trials include now a liquid biopsy arm, and functional studies mainly based on CTC derived cell-lines and CTC derived explants (CDx) provide important insight on the metastatic process. The recent findings in the field of liquid biopsy and the benefits and main clinical applications of CTC and ctDNA analysis in solid tumors are summarized in this review.
The field-line description of the electric field, proposed by Faraday, accepted by Maxwell and used by Dirac, is utilized here in order to try to understand the origin of the electric charge ...quantization. This origin could be the result of the discrete nature of the field lines in conjunction
with the requirement for spherical symmetry of the field. Under the hypothesis that for elementary particles, the electric field is consisting of only a few field lines, the d-quark could be composed of four field lines, the u-quark of eight, and the electron of 12. The proton would
also exhibit a 12 field line structure. For electrons and protons, such a structure could eventually be observed with the here proposed experimental techniques. New particles with charges 1/2e, 5/3e, and 2.5e would be allowed in this context.
Abstract
Interacting electrons confined to their lowest Landau level in a high magnetic field can form a variety of correlated states, some of which manifest themselves in a Hall effect. Although ...such states have been predicted to occur in three-dimensional semimetals, a corresponding Hall response has not yet been experimentally observed. Here, we report the observation of an unconventional Hall response in the quantum limit of the bulk semimetal HfTe
5
, adjacent to the three-dimensional quantum Hall effect of a single electron band at low magnetic fields. The additional plateau-like feature in the Hall conductivity of the lowest Landau level is accompanied by a Shubnikov-de Haas minimum in the longitudinal electrical resistivity and its magnitude relates as 3/5 to the height of the last plateau of the three-dimensional quantum Hall effect. Our findings are consistent with strong electron-electron interactions, stabilizing an unconventional variant of the Hall effect in a three-dimensional material in the quantum limit.
Abstract
The quantum Hall effect (QHE) is traditionally considered to be a purely two-dimensional (2D) phenomenon. Recently, however, a three-dimensional (3D) version of the QHE was reported in the ...Dirac semimetal ZrTe
5
. It was proposed to arise from a magnetic-field-driven Fermi surface instability, transforming the original 3D electron system into a stack of 2D sheets. Here, we report thermodynamic, spectroscopic, thermoelectric and charge transport measurements on such ZrTe
5
samples. The measured properties: magnetization, ultrasound propagation, scanning tunneling spectroscopy, and Raman spectroscopy, show no signatures of a Fermi surface instability, consistent with in-field single crystal X-ray diffraction. Instead, a direct comparison of the experimental data with linear response calculations based on an effective 3D Dirac Hamiltonian suggests that the quasi-quantization of the observed Hall response emerges from the interplay of the intrinsic properties of the ZrTe
5
electronic structure and its Dirac-type semi-metallic character.
Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv(+)) fast-spiking interneurons, have been proposed as underlying causes of ...several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv(+) GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv(+) interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv(+) interneurons resulted in reduced numbers of Pv(+) neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv(+) neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders.
•Topological Hall effect found in Pt/Co/W multilayers with different signs of anisotropy.•Negative topological Hall contribution due to nucleated isolated skyrmions.•Positive topological Hall ...contribution isolated non-annihilated skyrmions.•Skyrmion numbers of complex domain structures reproduced micromagmetically.
The chirality of non-coplanar magnetic configurations, in magnetic materials with interfacial Dzyaloshinskii–Moriya interaction, gives rise to a local magnetic field generating an extra contribution to the anomalous Hall effect. This contribution, termed topological Hall effect (THE), is studied in three Pt/Co/W multi-layered samples with different effective anisotropy. A particularity of this system, compared to similar systems which show THE, is the existence of magnetically inactive layers at the Co/W interfaces. This implies that the coupling between the layers in this series of samples is mainly magnetostatic. The samples with positive or almost zero effective anisotropy show the same characteristics. These are reproduced by micromagnetic simulations. The sample with negative effective anisotropy shows a qualitatively different behaviour that can be assigned to its radically different domain structure. The values of THE are in the range 0.1–0.25 μΩ cm.
Abstract Early life adversity or parental neglect is linked to the development of a number of psychiatric illnesses, including major depression and substance use disorder. These two disorders are ...often comorbid and characterized by anhedonia, defined as the reduced ability to experience pleasure or reward. The aim of the present study was to determine the effects of neonatal maternal separation in Long Evans rats, a model of early life stress, on anhedonia under baseline conditions and in response to drug and stress exposure during adulthood. Three hours of daily maternal separation from postnatal day 1 to 14 led to marked decreases in arched-back nursing, licking, and grooming of pups by their dams. In adulthood, brain reward function was assessed using intracranial self-stimulation of the lateral hypothalamus. Lowered current thresholds derived from this procedure are interpreted as reward-enhancing effects, whereas elevations in thresholds are an operational measure of anhedonia. Maternally separated rats did not exhibit anhedonia under baseline conditions compared with non-handled controls but exhibited a greater reward-enhancing effect of acute amphetamine administration. Acute social defeat produced anhedonia in non-handled controls, but not in maternally separated rats. Conversely, control rats habituated to 7 days of repeated social defeat, whereas maternally separated rats developed an increased anhedonic response to the repeated stressor. One week after termination of stress exposure, maternally separated rats still exhibited an increased reward-enhancing effect of acute amphetamine administration compared with non-handled controls, regardless of prior social defeat experience. These data indicate that early life stress increases the reward-enhancing properties of amphetamine, protects against the anhedonic effects of acute stress exposure, and exacerbates the anhedonic response to repeated stress. Thus, early life stress may increase an individual's vulnerability to depressive or addictive disorders when confronted with stress or drug challenge in adulthood.
Abstract Deregulation of miRNAs expression levels has been detected in many human tumor types, and recent studies have demonstrated the critical roles of miRNAs in cancer pathogenesis. Numerous ...recent studies have shown that miRNAs are rapidly released from tissues into the circulation in many pathological conditions. The high relative stability of miRNAs in biofluids such as plasma and serum, and the ability of miRNA expression profiles to accurately classify discrete tissue types and disease states have positioned miRNAs as promising non-invasive new tumor biomarkers. In this study, we used liquid bead array technology (Luminex) to profile the expression of 320 mature miRNAs in a pilot testing group of 19 matched fresh frozen cancerous and non-cancerous tissues from NSCLC patients. We further validated our results by RT-qPCR for differentially expressed miRNAs in an independent group of 40 matched fresh frozen tissues, 37 plasma samples from NSCLC patients and 28 healthy donors. We found that eight miRNAs ( miR-21 , miR-30d , miR-451 , miR-10a , miR-30e-5p and miR-126* , miR-126 , miR-145 ) were differentially expressed by three different statistical analysis approaches. Two of them ( miR-10a and miR-30e-5p ) are reported here for the first time. Bead-array results were further verified in an independent group of 40 matched fresh frozen tissues by RT-qPCR. According to RT-qPCR miR-21 was significantly up-regulated ( P = 0.010), miR-126* ( P = 0.002), miR-30d ( P = 0.012), miR-30e-5p ( P < 0.001) and miR-451 ( P < 0.001) were down-regulated, while miR-10a was not differentiated ( P = 0.732) in NSCLC tissues. However, in NSCLC plasma samples, only three of these miRNAs ( miR-21 , miR-10a , and miR-30e-5p ) displayed differential expression when compared to plasma of healthy donors. High expression of miR-21 was associated with DFI and OS both in NSCLC tissues ( P = 0.022 and P = 0.037) and plasma ( P = 0.045 and P = 0.065), respectively. Moreover, we report for the first time that low expression of miR-10a in NSCLC plasma samples was associated with worse DFI ( P = 0.050) and high expression of miR-30e-5p was found to be associated with shorter OS ( P = 0.048). In conclusion, circulating miR-21 , miR-10a and miR-30e-5p in plasma should be further evaluated as potential non-invasive biomarkers in NSCLC.
We assessed whether preoperativemutational analyses of circulating tumor cells (CTCs) and plasma-cfDNA could be used as minimally invasive biomarkers and as complimentary tools for early prediction ...of relapse in early-stage non-small -cell lung cancer (NSCLC).
Using ddPCR assays, hotspot mutations of
and
were identified in plasma-cfDNA samples and size-based enriched CTCs isolated from the same blood samples of 49 early-stage NSCLC patients before surgery and in a control group of healthy blood donors (
= 22). Direct concordance of the mutational spectrum was further evaluated in 27 patient-matched plasma-cfDNA and CTC-derived DNA in comparison to tissue-derived DNA.
The prevalence of detectable mutations of the four tested genes was higher in CTC-derived DNA than in the corresponding plasma-cfDNA (38.8% and 24.5%, respectively).The most commonly mutated gene was PIK3CA, in both CTCs and plasma-cfDNA at baseline and at the time of relapse. Direct comparison of the mutation status of selected drug-responsive genes in CTC-derived DNA, corresponding plasma-cfDNA and paired primary FFPE tissues clearly showed the impact of heterogeneity both within a sample type, as well as between different sample components. The incidence of relapse was higher when at least one mutation was detected in CTC-derived DNA or plasma-cfDNA compared with patients in whom no mutation was detected (
=0.023). Univariate analysis showed a significantly higher risk of progression (HR: 2.716; 95% CI, 1.030-7.165;
=0.043) in patients with detectable mutations in plasma-cfDNA compared with patients with undetectable mutations, whereas the hazard ratio was higher when at least one mutation was detected in CTC-derived DNA or plasma-cfDNA (HR: 3.375; 95% CI, 1.098-10.375;
=0.034).
Simultaneous mutational analyses of plasma-cfDNA and CTC-derived DNA provided complementary molecular information from the same blood sample and greater diversity in genomic information for cancer treatment and prognosis. The detection of specific mutations in ctDNA and CTCs in patients with early-stage NSCLC before surgery was independently associated with disease recurrence, which represents an important stratification factor for future trials.
PDF
