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IntroductionAATF/Che-1 over-expression in different tumors is well known and its effect on tumorigenicity is mainly due to its central role demonstrated in the oncogenic pathways of solid tumors, where it controls proliferation and viability. The effect exerted by tumors overexpressing Che-1 on the immune response has not yet been investigated.MethodsStarting from ChIP-sequencing data we confirmed Che-1 enrichment on Nectin-1 promoter. Several co-cultures experiments between NK-cells and tumor cells transduced by lentiviral vectors carrying Che-1-interfering sequence, analyzed by flow-cytometry have allowed a detailed characterization of NK receptors and tumor ligands expression.ResultsHere, we show that Che-1 is able to modulate the expression of Nectin-1 ligand at the transcriptional level, leading to the impairment of killing activity of NK-cells. Nectin-1 down-modulation induces a modification in NK-cell ligands expression able to interact with activating receptors and to stimulate NK-cell function. In addition, NK-cells from Che-1 transgenic mice, confirming a reduced expression of activating receptors, exhibit impaired activation and a preferential immature status.DiscussionThe critical equilibrium between NK-cell ligand expression on tumor cells and the interaction with NK cell receptors is affected by Che-1 over-expression and partially restored by Che-1 interference. The evidence of a new role for Che-1 as regulator of anti-tumor immunity supports the necessity to develop approaches able to target this molecule which shows a dual tumorigenic function as cancer promoter and immune response modulator.

Local inversion symmetry breaking in centrosymmetric materials can lead to large spin polarization of the electronic band structure in separate sectors of the unit cell. Here, the authors reveal such hidden spin polarisation in ZrSiTe using spin and angle resolved photoemission spectroscopy in combination with ab initio band structure calculations and investigate the resultant spin polarised bulk and surface properties

We investigated the Phase Change Memory (PCM) capabilities of In-doped Sb nanowires (NWs) with diameters of (20-40) nm, which were self-assembled by Metalorganic Chemical Vapor Deposition (MOCVD) via the vapor-liquid-solid (VLS) mechanism. The PCM behavior of the NWs was proved, and it was shown to have relatively low reset power consumption (~ 400 μW) and fast switching capabilities with respect to standard Ge-Sb-Te based devices. In particular, reversible set and reset switches by voltage pulses as short as 25 ns were demonstrated. The obtained results are useful for understanding the effects of downscaling in PCM devices and for the exploration of innovative PCM architectures and materials. Keywords: Phase change memories, Nanowires, MOCVD, In-Sb, TEM, XRD

Abstract The underlying mechanism driving the structural amorphous-to-crystalline transition in Group VI chalcogenides is still a matter of debate even in the simplest GeTe system. We exploit the extreme sensitivity of 57Fe emission Mössbauer spectroscopy, following dilute implantation of 57Mn (T½ = 1.5 min) at ISOLDE/CERN, to study the electronic charge distribution in the immediate vicinity of the 57Fe probe substituting Ge (FeGe), and to interrogate the local environment of FeGe over the amorphous-crystalline phase transition in GeTe thin films. Our results show that the local structure of as-sputtered amorphous GeTe is a combination of tetrahedral and defect-octahedral sites. The main effect of the crystallization is the conversion from tetrahedral to defect-free octahedral sites. We discover that only the tetrahedral fraction in amorphous GeTe participates to the change of the FeGe-Te chemical bonds, with a net electronic charge density transfer of ~ 1.6 e/a0 between FeGe and neighboring Te atoms. This charge transfer accounts for a lowering of the covalent character during crystallization. The results are corroborated by theoretical calculations within the framework of density functional theory. The observed atomic-scale chemical-structural changes are directly connected to the macroscopic phase transition and resistivity switch of GeTe thin films.

Inα-GeTe, ferroelectric polarization acts to break inversion symmetry of the lattice and induce a strong Rashba-type spin splitting of the electronic band structure. Here, the authors study how this effect competes with Zeeman splitting due to ferromagnetic exchange coupling in Mn-doped GeTe.

The main feature of amorphous materials is the presence of excess vibrational modes at low energies, giving rise to the so-called “boson peak” in neutron and optical spectroscopies. These same modes manifest themselves as two-level systems (TLSs) causing noise and decoherence in qubits and other sensitive devices. Here, we present an experiment that uses the spin relaxation of dangling bonds at the Si/(amorphous)SiO_{2} interface as a probe of TLSs. We introduce a model that is able to explain the observed nonexponential electron spin inversion recovery and provides a measure of the degree of spatial localization and concentration of the TLSs close to the interface, their maximum energy, and its temperature dependence.

The control of the electron spin by external means is a key issue for spintronic devices. Using spin- and angle-resolved photoemission spectroscopy (SARPES) with three-dimensional spin detection, we demonstrate operando electrostatic spin manipulation in ferroelectric α-GeTe and multiferroic Ge_{1−x}Mn_{x}Te. We demonstrate for the first time electrostatic spin manipulation in Rashba semiconductors due to ferroelectric polarization reversal. Additionally, we are also able to follow the switching pathway in detail. In multiferroic Ge_{1−x}Mn_{x}Te operando SARPES reveals switching of the perpendicular spin component due to electric-field-induced magnetization reversal. This provides firm evidence of magnetoelectric coupling which opens up functionality with a multitude of spin-switching paths in which the magnetic and electric order parameters are coupled through ferroelastic relaxation paths. This work thus provides a new type of magnetoelectric switching intertwined with Rashba-Zeeman splitting in a multiferroic system.

We study the oxidation mechanism of silicon in the presence of a thin HfO2layer. We performed a set of annealing in 18O2atmosphere on HfO2/SiO2/Si stacks observing the 18O distribution in the SiO2layer with time-of-flight secondary ion mass spectrometry (ToF-SIMS). The 18O distribution in HfO2/SiO2/Si stacks upon 18O2annealing suggests that what is responsible for SiO2growth is the molecular O2, whereas no contribution is found of the atomic oxygen to the oxidation. By studying the dependence of the oxidation velocity from oxygen partial pressure and annealing temperature, we demonstrate that the rate-determining step of the oxidation is the oxygen exchange at the HfO2/SiO2interface. When moisture is chemisorbed in HfO2films, the oxidation of the underlying silicon substrate becomes extremely fast and its kinetics can be described as a wet silicon oxidation process. The silicon oxidation during O2annealing of the atomic layer deposited HfO2/Si is fast in its early stage due to chemisorbed moisture and becomes slow after the first 10 s. [ABSTRACT FROM AUTHOR]

The evolution of microstructure and phase structure of ultrathin HfO2 films on Si(100) under ultrahigh-vacuum annealing is investigated in situ by x-ray photoelectron spectroscopy (XPS) and low-energy ion scattering (LEIS). The onset temperature of degradation is found to depend on film thickness. It is established that, for HfO2 (4 nm)/SiO2 (1 nm)/Si(100) specimens, 5-min annealing at about 900°C causes silicon (LEIS evidence) to appear on the surface, the silicon being uncombined with oxygen or the metal (XPS evidence). A longer annealing at the same temperature produces HfSix; annealing at 950°C converts the entire HfO2 film into polycrystalline silicide whose grains are partly oriented as the Si substrate. With respect to annealing in a low-oxygen environment, the experimental results support a model whereby the degradation of an ultrathin HfO2 film starts with the formation of nanopores by clustering of oxygen vacancies, whose density increases sharply due to partial desorption of oxygen; HfOx with x < 2 then forms in the vicinity of vacancy clusters. It is concluded that the formation of hafnium silicide, the end product of HfO2 degradation, starts in Si surface areas at the bottom of nanopores. [ABSTRACT FROM AUTHOR]

Reliability issues have hampered the adoption of ferroelectric thin films by the microelectronics industry. One of these is imprint, an important problem affecting the performance of ferroelectric non-volatile memories. This paper presents the effects of the low temperature pyrolysis step on the chemical and physical properties of SrBi2Ta2O9 films. A comparison of the hysteretic properties and composition profiles shows that control of the oxidising conditions during pyrolysis is critical to the dielectric properties. Data from this work and from the literature have been used to construct a model that explains the origin of surface depletion and segregation, self poling and as-grown imprint in ferroelectric films. [ABSTRACT FROM AUTHOR]

We present a universal set of quantum gate operations based on exchange-only spin qubits in a double quantum dot, where each qubit is obtained by three electrons in the (2,1) filling. Gate operations are addressed by modulating electrostatically the tunneling barrier and the energy offset between the two dots, singly and doubly occupied respectively. We propose explicit gate sequences of single qubit operations for arbitrary rotations, and the two-qubit controlled NOT gate, to complete the universal set. The unswitchable interaction between the two electrons of the doubly occupied quantum dot is taken into account. Short gate times are obtained by employing spin density functional theory simulations. [ABSTRACT FROM AUTHOR]

Magnetite (Fe3O4) is predicted to be half metallic at room temperature (RT) and it shows the highest Curie temperature among oxides. The use of Fe3O4 thin films is therefore promising for spintronic devices such as magnetic tunnel junctions (MTJs) and magnetoresistive sensors. The structural, magnetic and magnetotransport properties of magnetite are reported to be strongly dependent on the growth conditions. We have developed a very simple deposition chamber for growing thin magnetite films via a chemical vapour deposition (CVD) process based on the Fe3(CO)12 carbonyl precursor. The structural, morphological, and magnetic properties of the as deposited Fe3O4 films have been investigated by means of time of flight secondary ion mass spectrometry, grazing incidence x-ray diffraction, x-ray reflectivity, atomic force microscopy, conversion electron Mossbauer spectroscopy and superconducting quantum interference device magnetometry. Magnetotransport measurements show magnetoresistance up to [?]2.4% at RT at the maximum applied field of 1.1 T. Resistivity measurements in the 100-300 K temperature range reveal that the magnetotransport properties of the Fe3O4 films are governed by inter-granular tunnelling of the spin-polarized electrons. The spin polarization is estimated to be around [?]16%. A possible route for increasing the spin-polarized performances of our magnetite films is proposed. We have also deposited Fe3O4/MgO/Co stacks by using a combined CVD and atomic layer-deposition process. The trilayer's hysteresis curve evidences the presence of two distinct switching fields making it promising for magnetite-based MTJ applications. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM), a hematologic malignancy characterized by the clonal expansion of plasma cells within the bone marrow, is associated with severe health complications, including osteolytic bone lesions that significantly increase the risk of fractures, leading to higher morbidity and mortality rates. One intriguing protein in this context is the RNA polymerase binding factor Che-1/AATF (Che-1), which has emerged as a potential player in the survival and proliferation of myeloma cells. Hippo pathway has been shown to be an important mediator of oncogenesis in solid tumors, especially for its role in shaping a tumor microenvironment favorable to cancer maintenance and spread. The Hippo pathway is also implicated in the pathogenesis of the osteolytic lesions that occurs in MM, since it deregulates the activities of mesenchymal populations of the bone matrix. In this commentary we wish to highlight some new molecular aspects elucidated in the paper by Bruno et al. regarding the proliferation of MM and the onset of bone lesions [Leukemia 38:877-882, 1]. A series of recent findings has revealed a crosstalk between the RNA polymerase binding factor Che-1 and the HIPPO downstream co-transcriptional factor TAZ, bringing to light new emerging molecular targets in MM to limit the development of bone lesions., Competing Interests: Declarations. Ethics approval: Not applicable. Consent for publication: All authors have commented on and approved the manuscript for publication. Conflict of interest: No potential conflict of interest was reported by the authors., (© 2024. The Author(s).)

Acute myeloid leukemia (AML) with inv(16) is typically associated with a favourable prognosis. However, up to 40 % of patients will eventually experience disease relapse. Herein, we dissected the genomic and transcriptomic profile of inv(16) AML to identify potential prognostic markers and therapeutic vulnerabilities. Sequencing data from 222 diagnostic samples, including 44 relapse/refractory patients, revealed a median of 1 concomitant additional mutation, cooperating with inv(16) in leukemogenesis. Notably, the mutational landscape at diagnosis did not differ significantly between patients experiencing primary induction failure or relapse when compared to the rest of the cohort, except for an increase in the mutational burden in the relapse/refractory group. RNA-Seq of unpaired diagnostic(n=7) and relapse(n=6) samples allowed the identification of oxidative phosphorylation (OXPHOS) as one of the most significantly downregulated pathways at relapse. Considering that OXPHOS could be targeted by Venetoclax/Azacitidine combination, we explored its biological effects on an inv(16) cell-line ME-1, but there was no additional advantage in terms of cell death over Azacitidine alone. To enhance Venetoclax efficacy, we tested in vitro effects of Metformin as a potential drug able to enhance chemosensitivity of AML cells by inhibiting the mitochondrial transfer. By challenging ME-1 with this combination, we observed a significant synergistic interaction at least similar to that of Venetoclax/Azacitidine. In conclusions, we identified a downregulated expression of oxidative phosphorylation (OXPHOS) at relapse in AML with inv(16), and explored the in vitro effects of metformin as a potential drug to enhance chemosensitivity in this setting., Competing Interests: Declaration of Competing Interest Conflict-of-interest disclosure: The authors declare no competing financial interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Co-occurring mutations in KEAP1 and STK11/KRAS have emerged as determinants of survival outcomes in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. However, these mutational contexts identify a fraction of nonresponders to immune checkpoint inhibitors. We hypothesized that KEAP1 wild-type tumors recapitulate the transcriptional footprint of KEAP1 mutations and that this KEAPness phenotype can determine immune responsiveness with higher precision compared to mutation-based models., Experimental Design: The Cancer Genome Atlas was used to infer the KEAPness phenotype and explore its immunological correlates at the pan-cancer level. The association between KEAPness and survival outcomes was tested in two independent cohorts of patients with advanced NSCLC treated with immunotherapy and profiled by RNA sequencing (SU2C n = 153; OAK/POPLAR n = 439). The NSCLC TRACERx421 multiregion sequencing study (tumor regions, n = 947) was used to investigate evolutionary trajectories., Results: KEAPness-dominant tumors represented 50% of all NSCLCs and were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAPness-free cases in independent cohorts of patients with NSCLC treated with immunotherapy (SU2C PFS P = 0.042, OS P = 0.008; OAK/POPLAR PFS P = 0.0014, OS P < 0.001). Patients with KEAPness tumors had survival outcomes comparable to those with KEAP1-mutant tumors. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and immune exclusion, resembling the KEAP1-mutant disease. This phenotypic state occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared to KEAP1-mutant tumors., Conclusions: We identified a KEAPness phenotype across evolutionary divergent tumors. KEAPness outperforms mutation-based classifiers as a biomarker of inferior survival outcomes in patients with NSCLC treated with immunotherapy., (©2024 American Association for Cancer Research.)

In recent years, research on hyperdoped semiconductors has accelerated, displaying dopant concentrations far exceeding solubility limits to surpass the limitations of conventionally doped materials. Nitrogen defects in silicon have been extensively investigated for their unique characteristics compared to other pnictogen dopants. However, previous practical investigations have encountered challenges in achieving high nitrogen defect concentrations due to the low solubility and diffusivity of nitrogen in silicon, and the necessary non-equilibrium techniques, such as ion implantation, resulting in crystal damage and amorphisation. In this study, we present a single-step technique called high-pressure gas immersion excimer laser doping (HP-GIELD) to manufacture nitrogen-hyperdoped silicon. Our approach offers ultrafast processing, scalability, high control, and reproducibility. Employing HP-GIELD, we achieved nitrogen concentrations exceeding 6 at% (3.01 × 10 21 at/cm 3 ) in intrinsic silicon. Notably, nitrogen concentration remained above the liquid solubility limit to ~1 µm in depth. HP-GIELD's high-pressure environment effectively suppressed physical surface damage and the generation of silicon dangling bonds, while the well-known effects of pulsed laser annealing (PLA) preserved crystallinity. Additionally, we conducted a theoretical analysis of light-matter interactions and thermal effects governing nitrogen diffusion during HP-GIELD, which provided insights into the doping mechanism. Leveraging excimer lasers, our method is well-suited for integration into high-volume semiconductor manufacturing, particularly front-end-of-line processes., (© 2024. The Author(s).)

Background: Enhancer reprogramming plays a significant role in the heterogeneity of cancer. However, we have limited knowledge about the impact of chromatin remodeling in B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) patients, and how it affects tumorigenesis and drug response. Our research focuses on investigating the role of enhancers in sustaining oncogenic transformation in children with BCP-ALL., Methods: We used ATAC-seq to study the accessibility of chromatin in pediatric BCP-ALL at three different stages-onset, remission, and relapse. Using a combination of computational and experimental methods, we were able to analyze the accessibility landscape and focus on the most significant cis-regulatory sites. These sites were then functionally validated through the use of Promoter capture Hi-C in a primary cell line model called LAL-B, followed by RNA-seq and genomic deletion of target sites using CRISPR-Cas9 editing., Results: We found that enhancer activity changes during cancer progression and is mediated by the production of enhancer RNAs (eRNAs). CRISPR-Cas9-mediated validation of previously unknown eRNA productive enhancers demonstrated their capability to control the oncogenic activities of the MYB and DCTD genes., Conclusions: Our findings directly support the notion that productive enhancer engagement is a crucial determinant of the BCP-ALL and highlight the potential of enhancers as therapeutic targets in pediatric BCP-ALL., (© 2024. The Author(s).)

N 6 -methyladenosine (m 6 A) is one of the most prevalent and conserved RNA modifications. It controls several biological processes, including the biogenesis and function of circular RNAs (circRNAs), which are a class of covalently closed-single stranded RNAs. Several studies have revealed that proteotoxic stress response induction could be a relevant anticancer therapy in Acute Myeloid Leukemia (AML). Furthermore, a strong molecular interaction between the m 6 A mRNA modification factors and the suppression of the proteotoxic stress response has emerged. Since the proteasome inhibition leading to the imbalance in protein homeostasis is strictly linked to the stress response induction, we investigated the role of Bortezomib (Btz) on m 6 A regulation and in particular its impact on the modulation of m 6 A-modified circRNAs expression. Here, we show that treating AML cells with Btz downregulated the expression of the m 6 A regulator WTAP at translational level, mainly because of increased oxidative stress. Indeed, Btz treatment promoted oxidative stress, with ROS generation and HMOX-1 activation and administration of the reducing agent N-acetylcysteine restored WTAP expression. Additionally, we identified m 6 A-modified circRNAs modulated by Btz treatment, including circHIPK3, which is implicated in protein folding and oxidative stress regulation. These results highlight the intricate molecular networks involved in oxidative and ER stress induction in AML cells following proteotoxic stress response, laying the groundwork for future therapeutic strategies targeting these pathways., (© 2024. The Author(s).)

Scientific literature supports the evidence that cancer stem cells (CSCs) retain inside low reactive oxygen species (ROS) levels and are, therefore, less susceptible to cell death, including ferroptosis, a type of cell death dependent on iron-driven lipid peroxidation. A collection of lung adenocarcinoma (LUAD) primary cell lines derived from malignant pleural effusions (MPEs) of patients was used to obtain 3D spheroids enriched for stem-like properties. We observed that the ferroptosis inducer RSL3 triggered lipid peroxidation and cell death in LUAD cells when grown in 2D conditions; however, when grown in 3D conditions, all cell lines underwent a phenotypic switch, exhibiting substantial resistance to RSL3 and, therefore, protection against ferroptotic cell death. Interestingly, this phenomenon was reversed by disrupting 3D cells and growing them back in adherence, supporting the idea of CSCs plasticity, which holds that cancer cells have the dynamic ability to transition between a CSC state and a non-CSC state. Molecular analyses showed that ferroptosis resistance in 3D spheroids correlated with an increased expression of antioxidant genes and high levels of proteins involved in iron storage and export, indicating protection against oxidative stress and low availability of iron for the initiation of ferroptosis. Moreover, transcriptomic analyses highlighted a novel subset of genes commonly modulated in 3D spheroids and potentially capable of driving ferroptosis protection in LUAD-CSCs, thus allowing to better understand the mechanisms of CSC-mediated drug resistance in tumors., (© 2024. The Author(s).)

HAX1 is a multifunctional protein involved in the antagonism of apoptosis in cellular response to oxidative stress. In the present study we identified HAX1 as a novel binding partner for Che-1/AATF, a pro-survival factor which plays a crucial role in fundamental processes, including response to multiple stresses and apoptosis. HAX1 and Che-1 proteins show extensive colocalization in mitochondria and we demonstrated that their association is strengthened after oxidative stress stimuli. Interestingly, in MCF-7 cells, resembling luminal estrogen receptor (ER) positive breast cancer, we found that Che-1 depletion correlates with decreased HAX1 mRNA and protein levels, and this event is not significantly affected by oxidative stress induction. Furthermore, we observed an enhancement of the previously reported interaction between HAX1 and estrogen receptor alpha (ERα) upon H 2 O 2 treatment. These results indicate the two anti-apoptotic proteins HAX1 and Che-1 as coordinated players in cellular response to oxidative stress with a potential role in estrogen sensitive breast cancer cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In a previous investigation, the authors proposed nitrogen as a possible candidate for exploiting the donor spin in silicon quantum devices. This system is characterized by a ground state deeper than the other group V impurities in silicon, offering less stringent requirements on the device temperature necessary to access the unionized state. The nitrogen donor is slightly displaced from the substitutional site, and upon heating, the system undergoes a motional transition. In the present article, we show the results from our investigation on the spin-relaxation times in nat Si and 28 Si substrates and discuss the motional effects on relaxation. The stretched exponential relaxation observed is interpreted as a distribution of spin-lattice relaxation times, whose origin is also discussed. This information greatly contributes to the assessment of a nitrogen-doped silicon system as a potential candidate for quantum devices working at temperatures higher than those required for other group V donors in silicon.

Properly tuning the Fermi level position in topological insulators is of vital importance to tailor their spin-polarized electronic transport and to improve the efficiency of any functional device based on them. Here, we report the full in situ metal organic chemical vapor deposition (MOCVD) and study of a highly crystalline Bi 2 Te 3 /Sb 2 Te 3 topological insulator heterostructure on top of large area (4″) Si(111) substrates. The bottom Sb 2 Te 3 layer serves as an ideal seed layer for the growth of highly crystalline Bi 2 Te 3 on top, also inducing a remarkable shift of the Fermi level to place it very close to the Dirac point, as visualized by angle-resolved photoemission spectroscopy. To exploit such ideal topologically protected surface states, we fabricate the simple spin-charge converter Si(111)/Sb 2 Te 3 /Bi 2 Te 3 /Au/Co/Au and probe the spin-charge conversion (SCC) by spin pumping ferromagnetic resonance. A large SCC is measured at room temperature and is interpreted within the inverse Edelstein effect, thus resulting in a conversion efficiency of λ IEEE ∼ 0.44 nm. Our results demonstrate the successful tuning of the surface Fermi level of Bi 2 Te 3 when grown on top of Sb 2 Te 3 with a full in situ MOCVD process, which is highly interesting in view of its future technology transfer.

Background: Molecular Tumor Boards (MTB) operating in real-world have generated limited consensus on good practices for accrual, actionable alteration mapping, and outcome metrics. These topics are addressed herein in 124 MTB patients, all real-world accrued at progression, and lacking approved therapy options., Methods: Actionable genomic alterations identified by tumor DNA (tDNA) and circulating tumor DNA (ctDNA) profiling were mapped by customized OncoKB criteria to reflect diagnostic/therapeutic indications as approved in Europe. Alterations were considered non-SoC when mapped at either OncoKB level 3, regardless of tDNA/ctDNA origin, or at OncoKB levels 1/2, provided they were undetectable in matched tDNA, and had not been exploited in previous therapy lines., Results: Altogether, actionable alterations were detected in 54/124 (43.5%) MTB patients, but only in 39 cases (31%) were these alterations (25 from tDNA, 14 from ctDNA) actionable/unexploited, e.g. they had not resulted in the assignment of pre-MTB treatments. Interestingly, actionable and actionable/unexploited alterations both decreased (37.5% and 22.7% respectively) in a subset of 88 MTB patients profiled by tDNA-only, but increased considerably (77.7% and 66.7%) in 18 distinct patients undergoing combined tDNA/ctDNA testing, approaching the potential treatment opportunities (76.9%) in 147 treatment-naïve patients undergoing routine tDNA profiling for the first time. Non-SoC therapy was MTB-recommended to all 39 patients with actionable/unexploited alterations, but only 22 (56%) accessed the applicable drug, mainly due to clinical deterioration, lengthy drug-gathering procedures, and geographical distance from recruiting clinical trials. Partial response and stable disease were recorded in 8 and 7 of 19 evaluable patients, respectively. The time to progression (TTP) ratio (MTB-recommended treatment vs last pre-MTB treatment) exceeded the conventional Von Hoff 1.3 cut-off in 9/19 cases, high absolute TTP and Von Hoff values coinciding in 3 cases. Retrospectively, 8 patients receiving post-MTB treatment(s) as per physician's choice were noted to have a much longer overall survival from MTB accrual than 11 patients who had received no further treatment (35.09 vs 6.67 months, p = 0.006)., Conclusions: MTB-recommended/non-SoC treatments are effective, including those assigned by ctDNA-only alterations. However, real-world MTBs may inadvertently recruit patients electively susceptible to diverse and/or multiple treatments., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The interplay between spin-orbit interaction and magnetic order is one of the most active research fields in condensed matter physics and drives the search for materials with novel, and tunable, magnetic and spin properties. Here we report on a variety of unique and unexpected observations in thin multiferroic Ge 1-x Mn x Te films. The ferrimagnetic order parameter in this ferroelectric semiconductor is found to switch direction under magnetostochastic resonance with current pulses many orders of magnitude lower as for typical spin-orbit torque systems. Upon a switching event, the magnetic order spreads coherently and collectively over macroscopic distances through a correlated spin-glass state. Utilizing these observations, we apply a novel methodology to controllably harness this stochastic magnetization dynamics., (© 2023. Springer Nature Limited.)

We performed spin-, time- and angle-resolved extreme ultraviolet photoemission spectroscopy of excitons prepared by photoexcitation of inversion-symmetric 2H-WSe&#95;{2} with circularly polarized light. The very short probing depth of XUV photoemission permits selective measurement of photoelectrons originating from the top-most WSe&#95;{2} layer, allowing for direct measurement of hidden spin polarization of bright and momentum-forbidden dark excitons. Our results reveal efficient chiroptical control of bright excitons' hidden spin polarization. Following optical photoexcitation, intervalley scattering between nonequivalent K-K^{'} valleys leads to a decay of bright excitons' hidden spin polarization. Conversely, the ultrafast formation of momentum-forbidden dark excitons acts as a local spin polarization reservoir, which could be used for spin injection in van der Waals heterostructures involving multilayer transition metal dichalcogenides.

Background: Approximately 20-50% of patients presenting with localized colorectal cancer progress to stage IV metastatic disease (mCRC) following initial treatment and this is a major prognostic determinant. Here, we have interrogated a heterogeneous set of primary colorectal cancer (CRC), liver CRC metastases and adjacent liver tissue to identify molecular determinants of the colon to liver spreading. Screening Food and Drug Administration (FDA) approved drugs for their ability to interfere with an identified colon to liver metastasis signature may help filling an unmet therapeutic need., Methods: RNA sequencing of primary colorectal cancer specimens vs adjacent liver tissue vs synchronous and asynchronous liver metastases. Pathways enrichment analyses. The Library of Integrated Network-based Cellular Signatures (LINCS)-based and Connectivity Map (CMAP)-mediated identification of FDA-approved compounds capable to interfere with a 22 gene signature from primary CRC and liver metastases. Testing the identified compounds on CRC-Patient Derived Organoid (PDO) cultures. Microscopy and Fluorescence Activated Cell Sorting (FACS) based analysis of the treated PDOs., Results: We have found that liver metastases acquire features of the adjacent liver tissue while partially losing those of the primary tumors they derived from. We have identified a 22-gene signature differentially expressed among primary tumors and metastases and validated in public databases. A pharmacogenomic screening for FDA-approved compounds capable of interfering with this signature has been performed. We have validated some of the identified representative compounds in CRC-Patient Derived Organoid cultures (PDOs) and found that pentoxyfilline and, to a minor extent, dexketoprofen and desloratadine, can variably interfere with number, size and viability of the CRC -PDOs in a patient-specific way. We explored the pentoxifylline mechanism of action and found that pentoxifylline treatment attenuated the 5-FU elicited increase of ALDHhigh cells by attenuating the IL-6 mediated STAT3 (tyr705) phosphorylation., Conclusions: Pentoxifylline synergizes with 5-Fluorouracil (5-FU) in attenuating organoid formation. It does so by interfering with an IL-6-STAT3 axis leading to the emergence of chemoresistant ALDHhigh cell subpopulations in 5-FU treated PDOs. A larger cohort of CRC-PDOs will be required to validate and expand on the findings of this proof-of-concept study., (© 2023. The Author(s).)

The transcription factor ΔNp63 regulates epithelial stem cell function and maintains the integrity of stratified epithelial tissues by acting as transcriptional repressor or activator towards a distinct subset of protein-coding genes and microRNAs. However, our knowledge of the functional link between ∆Np63 transcriptional activity and long non-coding RNAs (lncRNAs) expression is quite limited. Here, we show that in proliferating human keratinocytes ∆Np63 represses the expression of the lncRNA NEAT1 by recruiting the histone deacetylase HDAC1 to the proximal promoter of NEAT1 genomic locus. Upon induction of differentiation, ∆Np63 down-regulation is associated by a marked increase of NEAT1 RNA levels, resulting in an increased assembly of paraspeckles foci both in vitro and in human skin tissues. RNA-seq analysis associated with global DNA binding profile (ChIRP-seq) revealed that NEAT1 associates with the promoter of key epithelial transcription factors sustaining their expression during epidermal differentiation. These molecular events might explain the inability of NEAT1-depleted keratinocytes to undergo the proper formation of epidermal layers. Collectively, these data uncover the lncRNA NEAT1 as an additional player of the intricate network orchestrating epidermal morphogenesis., (© 2023. The Author(s).)

An essential function of the epidermis is to provide a physical barrier that prevents the loss of water. Essential mediators of this barrier function include ceramides, cholesterol, and very long chain fatty acids, and their alteration causes human pathologies, including psoriasis and atopic dermatitis. A frameshift mutation in the human ZNF750 gene, which encodes a zinc finger transcription factor, has been shown to cause a seborrhea-like dermatitis. Here, we show that genetic deletion of the mouse homolog ZFP750 results in loss of epidermal barrier function, which is associated with a substantial reduction of ceramides, nonpolar lipids. The alteration of epidermal lipid homeostasis is directly linked to the transcriptional activity of ZFP750. ZFP750 directly and/or indirectly regulates the expression of crucial enzymes primarily involved in the biosynthesis of ceramides. Overall, our study identifies the transcription factor ZFP750 as a master regulator epidermal homeostasis through lipid biosynthesis and thus contributing to our understanding of the pathogenesis of several human skin diseases.

Background: This study aimed to characterize the genetic profile of patients with glioma and discuss the impact of next-generation sequencing in glioma diagnosis and treatment., Methods: Between 2019 and 2022, we analyzed the genetic profile of 99 patients with glioma through the Oncomine Focus Assay. The assay enables the detection of mutations in 52 driver genes, including single nucleotide variants (SNVs), copy number variants (CNVs), and gene fusions. We also collected and analyzed patients' clinic characteristics and treatment outcomes., Results: Over a period of 35 months, 700 patients with glioma followed by our neuro-oncology unit were screened, and 99 were enrolled in the study; most of the patients were excluded for inadequate non-morphological MRI or lack/inadequacy of the tissue samples. Based on our findings, most patients with glioma present mutations, such as SNVs, CNVs or gene fusions. Our data were similar to those reported by The Cancer Genome Atlas Program in terms of frequency of SNVs and CNVs, while we observed more cases of gene fusions. Median overall survival, progression-free survival, and time to progression were significantly lower for patients with grade VI glioblastoma than those with other gliomas. Only four patients were offered a targeted treatment based on the mutation detected; however, only one received treatment, the others could not receive the selected treatment because of worsening clinical status., Conclusion: Routine timely molecular profiling in patients with glioma should be implemented to offer patients an individualized diagnostic approach and provide them with advanced targeted therapy options if available., (© 2023. The Author(s).)

Background: Metastases are the major cause of cancer-related morbidity and mortality. By the time cancer cells detach from their primary site to eventually spread to distant sites, they need to acquire the ability to survive in non-adherent conditions and to proliferate within a new microenvironment in spite of stressing conditions that may severely constrain the metastatic process. In this study, we gained insight into the molecular mechanisms allowing cancer cells to survive and proliferate in an anchorage-independent manner, regardless of both tumor-intrinsic variables and nutrient culture conditions., Methods: 3D spheroids derived from lung adenocarcinoma (LUAD) and breast cancer cells were cultured in either nutrient-rich or -restricted culture conditions. A multi-omics approach, including transcriptomics, proteomics, and metabolomics, was used to explore the molecular changes underlying the transition from 2 to 3D cultures. Small interfering RNA-mediated loss of function assays were used to validate the role of the identified differentially expressed genes and proteins in H460 and HCC827 LUAD as well as in MCF7 and T47D breast cancer cell lines., Results: We found that the transition from 2 to 3D cultures of H460 and MCF7 cells is associated with significant changes in the expression of genes and proteins involved in metabolic reprogramming. In particular, we observed that 3D tumor spheroid growth implies the overexpression of ALDOC and ENO2 glycolytic enzymes concomitant with the enhanced consumption of glucose and fructose and the enhanced production of lactate. Transfection with siRNA against both ALDOC and ENO2 determined a significant reduction in lactate production, viability and size of 3D tumor spheroids produced by H460, HCC827, MCF7, and T47D cell lines., Conclusions: Our results show that anchorage-independent survival and growth of cancer cells are supported by changes in genes and proteins that drive glucose metabolism towards an enhanced lactate production. Notably, this finding is valid for all lung and breast cancer cell lines we have analyzed in different nutrient environmental conditions. broader Validation of this mechanism in other cancer cells of different origin will be necessary to broaden the role of ALDOC and ENO2 to other tumor types. Future in vivo studies will be necessary to assess the role of ALDOC and ENO2 in cancer metastasis., (© 2023. The Author(s).)

In vitro and in vivo stimulation and recording of neuron action potential is currently achieved with microelectrode arrays, either in planar or 3D geometries, adopting different materials and strategies. IrO 2 is a conductive oxide known for its excellent biocompatibility, good adhesion on different substrates, and charge injection capabilities higher than noble metals. Atomic layer deposition (ALD) allows excellent conformal growth, which can be exploited on 3D nanoelectrode arrays. In this work, we disclose the growth of nanocrystalline rutile IrO 2 at T = 150 °C adopting a new plasma-assisted ALD (PA-ALD) process. The morphological, structural, physical, chemical, and electrochemical properties of the IrO 2 thin films are reported. To the best of our knowledge, the electrochemical characterization of the electrode/electrolyte interface in terms of charge injection capacity, charge storage capacity, and double-layer capacitance for IrO 2 grown by PA-ALD was not reported yet. IrO 2 grown on PtSi reveals a double-layer capacitance ( C dl ) above 300 µF∙cm -2 , and a charge injection capacity of 0.22 ± 0.01 mC∙cm -2 for an electrode of 1.0 cm 2 , confirming IrO 2 grown by PA-ALD as an excellent material for neuroelectronic applications.

Background: KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11/KRAS alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs., Patients and Methods: Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation [KEAP1 clonal diploid-subclonal (KEAP1 CD-SC)] in the Memorial Sloan Kettering Cancer Center (MSK) MetTropism cohort (N = 2550). Clonality/LOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAF/TP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSK/Rome N = 237; DFCI N = 461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort)., Results: Clonality/LOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAF/TP ratio. In the ICI-treated MSK/Rome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P = 0.001; OS log-rank P < 0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P = 0.006; OS log-rank P = 0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features., Conclusions: KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs., Competing Interests: Disclosure PV reports travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili. RDM reports serving as a scientific advisory board member at Exosomics SpA (Siena IT), HiberCell Inc. (New York, NY), Kiromic Inc. (Houston, TX) and Exiris Inc. (Rome, IT). FC reports personal fees from Roche/Genentech, AstraZeneca, Takeda, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, Lilly, and Bayer. MMA reported serving as a consultant for Achilles, AbbVie, Neon, Maverick, Nektar, and Hegrui; receiving grants and personal fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, and Lilly; and receiving personal fees from Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDx, Mirati, NextCure, Novartis, EMD Serono, and NovaRx. All other authors have declared no conflicts of interest. Data sharing Data concerning the Rome cohort are disclosed in our previous work.(8) MSK studies are available at www.cbioportal.org. The DFCI cohort is available from the authors upon reasonable request (B. Ricciuti and M.M. Awad)., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Precision medicine has driven a major change in the treatment of many forms of cancer. The discovery that each patient is different and each tumor mass has its own characteristics has shifted the focus of basic and clinical research to the singular individual. Liquid biopsy (LB), in this sense, presents new scenarios in personalized medicine through the study of molecules, factors, and tumor biomarkers in blood such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes and circulating tumor microRNAs (ct-miRNAs). Moreover, its easy application and complete absence of contraindications for the patient make this method applicable in a great many fields. Melanoma, given its highly heterogeneous characteristics, is a cancer form that could significantly benefit from the information linked to liquid biopsy, especially in the treatment management. In this review, we will focus our attention on the latest applications of liquid biopsy in metastatic melanoma and possible developments in the clinical setting.

Two-dimensional (2D) van der Waals (vdW) ferromagnetic metals Fe x GeTe 2 with x = 3-5 have raised significant interest in the scientific community. Fe 5 GeTe 2 shows prospects for spintronic applications since the Curie temperature T c has been reported near or higher than 300 K. In the present work, epitaxial Fe 5- δ GeTe 2 (FGT) heterostructures were grown by Molecular Beam Epitaxy (MBE) on insulating crystalline substrates. The FGT films were combined with Bi 2 Te 3 topological insulator (TI) aiming to investigate the possible beneficial effect of the TI on the magnetic properties of FGT. FGT/Bi 2 Te 3 films were compared to FGT capped only with AlO x to prevent oxidation. SQUID and MOKE measurements revealed that the growth of Bi 2 Te 3 TI on FGT films significantly enhances the saturation magnetization of FGT as well as the T c well above room temperature (RT) reaching record values of 570 K. First-principles calculations predict a shift of the Fermi level and an associated enhancement of the majority spin (primarily) as well as the total density of states at the Fermi level suggesting that effective doping of FGT from Bi 2 Te 3 could explain the enhancement of ferromagnetism in FGT. It is also predicted that strain induced stabilization of a high magnetic moment phase in FGT/Bi 2 Te 3 could be an alternative explanation of magnetization and T c enhancement. Ferromagnetic resonance measurements evidence an enhanced broadening in the FGT/Bi 2 m 3 heterostructure when compared to FGT. We obtain a large spin mixing conductance of g ↑↓eff = 4.4 × 10 20 m -2 , which demonstrates the great potential of FGT/Bi 2 Te 3 systems for spin-charge conversion applications at room temperature.

Caspase-8 is a cysteine protease that plays an essential role in apoptosis. Consistently with its canonical proapoptotic function, cancer cells may genetically or epigenetically downregulate its expression. Unexpectedly, Caspase-8 is often retained in cancer, suggesting the presence of alternative mechanisms that may be exploited by cancer cells to their own benefit. In this regard, we reported that Src tyrosine kinase, which is aberrantly activated in many tumors, promotes Caspase-8 phosphorylation on Tyrosine 380 (Y380) preventing its full activation. Here, we investigated the significance of Caspase-8 expression and of its phosphorylation on Y380 in glioblastoma, a brain tumor where both Caspase-8 expression and Src activity are often aberrantly upregulated. Transcriptomic analyses identified inflammatory response as a major target of Caspase-8, and in particular, NFκB signaling as one of the most affected pathways. More importantly, we could show that Src-dependent phosphorylation of Caspase-8 on Y380 drives the assembly of a multiprotein complex that triggers NFκB activation, thereby inducing the expression of inflammatory and pro-angiogenic factors. Remarkably, phosphorylation on Y380 sustains neoangiogenesis and resistance to radiotherapy. In summary, our work identifies a novel interplay between Src kinase and Caspase-8 that allows cancer cells to hijack Caspase-8 to sustain tumor growth., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

BRAF-mutated melanoma relapsing after targeted therapies is an aggressive disease with unmet clinical need. Hence the need to identify novel combination therapies able to overcome drug resistance. miRNAs have emerged as orchestrators of non-genetic mechanisms adopted by melanoma cells to challenge therapies. In this context we previously identified a subset of oncosuppressor miRNAs downregulated in drug-resistant melanomas. Here we demonstrate that lipid nanoparticles co-encapsulating two of them, miR-199-5p and miR-204-5p, inhibit tumor growth both in vitro and in vivo in combination with target therapy and block the development of drug resistance. Mechanistically they act by directly reducing melanoma cell growth and also indirectly by hampering the recruitment and reprogramming of pro-tumoral macrophages. Molecularly, we demonstrate that the effects on macrophages are mediated by the dysregulation of a newly identified miR-204-5p-miR-199b-5p/CCL5 axis. Finally, we unveiled that M2 macrophages programs are molecular signatures of resistance and predict response to therapy in patients. Overall, these findings have strong translational implications to propose new combination therapies making use of RNA therapeutics for metastatic melanoma patients., (© 2022. The Author(s).)

Artificial intelligence (AI), a field of research in which computers are applied to mimic humans, is continuously expanding and influencing many aspects of our lives. From electric cars to search motors, AI helps us manage our daily lives by simplifying functions and activities that would be more complex otherwise. Even in the medical field, and specifically in oncology, many studies in recent years have highlighted the possible helping role that AI could play in clinical and therapeutic patient management. In specific contexts, clinical decisions are supported by "intelligent" machines and the development of specific softwares that assist the specialist in the management of the oncology patient. Melanoma, a highly heterogeneous disease influenced by several genetic and environmental factors, to date is still difficult to manage clinically in its advanced stages. Therapies often fail, due to the establishment of intrinsic or secondary resistance, making clinical decisions complex. In this sense, although much work still needs to be conducted, numerous evidence shows that AI (through the processing of large available data) could positively influence the management of the patient with advanced melanoma, helping the clinician in the most favorable therapeutic choice and avoiding unnecessary treatments that are sure to fail. In this review, the most recent applications of AI in melanoma will be described, focusing especially on the possible finding of this field in the management of drug treatments.

New evidence on the impact of dysregulation of the CDK4/6 pathway on breast cancer (BC) cell proliferation has led to the development of selective CDK4/6 inhibitors, which have radically changed the management of advanced BC. Despite the improved outcomes obtained by CDK4/6 inhibitors, approximately 10% of tumors show primary resistance, whereas acquired resistance appears to be an almost ubiquitous occurrence, leading to treatment failure. The identification of differentially expressed genes or genomic mutational signatures able to predict sensitivity or resistance to CDK4/6 inhibitors is critical for medical decision making and for avoiding or counteracting primary or acquired resistance against CDK4/6 inhibitors. In this review, we summarize the main mechanisms of resistance to CDK4/6 inhibitors, focusing on those associated with potentially relevant biomarkers that could predict patients' response/resistance to treatment. Recent advances in biomarker identification are discussed, including the potential use of liquid biopsy for BC management and the role of multiple microRNAs as molecular predictors of cancer cell sensitivity and resistance to CDK4/6 inhibitors.

Several kinds of stress promote the formation of three-stranded RNA:DNA hybrids called R-loops. Insufficient clearance of these structures promotes genomic instability and DNA damage, which ultimately contribute to the establishment of cancer phenotypes. Paraspeckle assemblies participate in R-loop resolution and preserve genome stability, however, the main determinants of this mechanism are still unknown. This study finds that in Multiple Myeloma (MM), AATF/Che-1 (Che-1), an RNA-binding protein fundamental to transcription regulation, interacts with paraspeckles via the lncRNA NEAT1&#95;2 (NEAT1) and directly localizes on R-loops. We systematically show that depletion of Che-1 produces a marked accumulation of RNA:DNA hybrids. We provide evidence that such failure to resolve R-loops causes sustained activation of a systemic inflammatory response characterized by an interferon (IFN) gene expression signature. Furthermore, elevated levels of R-loops and of mRNA for paraspeckle genes in patient cells are linearly correlated with Multiple Myeloma progression. Moreover, increased interferon gene expression signature in patients is associated with markedly poor prognosis. Taken together, our study indicates that Che-1/NEAT1 cooperation prevents excessive inflammatory signaling in Multiple Myeloma by facilitating the clearance of R-loops. Further studies on different cancer types are needed to test if this mechanism is ubiquitously conserved and fundamental for cell homeostasis., (© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

In this work, we report the hot-injection synthesis of Cs 3 ZnCl 5 colloidal nanocrystals (NCs) with tunable amounts of Cu + and Mn 2+ substituent cations. All the samples had a rodlike morphology, with a diameter of ∼14 nm and a length of ∼30-100 nm. Alloying did not alter the crystal structure of the host Cs 3 ZnCl 5 NCs, and Cu ions were mainly introduced in the oxidation state +1 according to X-ray photoelectron and electron paramagnetic resonance spectroscopies. The spectroscopic analysis of unalloyed, Cu-alloyed, Mn-alloyed, and Cu, Mn coalloyed NCs indicated that (i) the Cs 3 ZnCl 5 NCs have a large band gap of ∼5.35 eV; (ii) Cu(I) aliovalent alloying leads to an absorption shoulder/peak at ∼4.8 eV and cyan photoluminescence (PL) peaked at 2.50 eV; (iii) Mn(II) isovalent alloying leads to weak Mn PL, which intensifies remarkably in the coalloyed samples, prompted by an energy transfer (ET) process between the Cu and Mn centers, favored by the overlap between the lowest ( 6 A 1 → 4 T 1 ) transition for tetrahedrally coordinated Mn 2+ and the PL profile from Cu(I) species in the Cs 3 ZnCl 5 NCs. The efficiency of this ET process reaches a value of 61% for the sample with the highest extent of Mn alloying. The PL quantum yield (QY) values in these Cu, Mn coalloyed NCs are lower at higher Mn contents. The analysis of the Mn PL dynamics in these samples indicates that this PL drop stems from inter-Mn exciton migration, which increases the likelihood of trapping in defect sites, in agreement with previous studies., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy., (© 2022. The Author(s).)

Acute Myeloid Leukaemia (AML) is a haematological malignancy showing a hypervariable landscape of clinical outcomes and phenotypic differences, explainable by heterogeneity at the cellular and molecular level. Among the most common genomic alterations, CBFB-MYH11 rearrangement and FLT3-ITD gene mutations, have opposite clinical significance and are unfrequently associated. We present here a Molecular Case Report in which these two events co-exist an ultra-aggressive phenotype resulting in death in 4 days from hospital admittance. Somatic and germline Whole Exome Sequencing analysis was performed to uncover other putative driver mutations, de-novo genomic structural events or germline clusters increasing cancer insurgence. Only three mutations in LTK, BCAS2 and LGAS9 were found, unlikely causative of the exhibited phenotype, prompting to additional investigation of the rare CBFB-MYH11/ FLT3-ITD scenario., (© 2022. The Author(s).)

Background: Immune checkpoint inhibitors are still unable to provide clinical benefit to the large majority of non-small cell lung cancer (NSCLC) patients. A deeper characterization of the tumor immune microenvironment (TIME) is expected to shed light on the mechanisms of cancer immune evasion and resistance to immunotherapy. Here, we exploited malignant pleural effusions (MPEs) from lung adenocarcinoma (LUAD) patients as a model system to decipher TIME in metastatic NSCLC., Methods: Mononuclear cells from MPEs (PEMC) and peripheral blood (PBMC), cell free pleural fluid and/or plasma were collected from a total of 24 LUAD patients and 12 healthy donors. Bulk-RNA sequencing was performed on total RNA extracted from PEMC and matched PBMC. The DEseq2 Bioconductor package was used to perform differential expression analysis and CIBERSORTx for the regression-based immune deconvolution of bulk gene expression data. Cytokinome analysis of cell-free pleural fluid and plasma samples was performed using a 48-Plex Assay panel. THP-1 monocytic cells were used to assess macrophage polarization. Survival analyses on NSCLC patients were performed using KM Plotter (LUAD, N=672; lung squamous cell carcinoma, N=271)., Results: Transcriptomic analysis of immune cells and cytokinome analysis of soluble factors in the pleural fluid depicted MPEs as a metastatic niche in which all the components required for an effective antitumor response are present, but conscripted in a wound-healing, proinflammatory and tumor-supportive mode. The bioinformatic deconvolution analysis revealed an immune landscape dominated by myeloid subsets with the prevalence of monocytes, protumoral macrophages and activated mast cells. Focusing on macrophages we identified an MPEs-distinctive signature associated with worse clinical outcome in LUAD patients., Conclusions: Our study reports for the first time a wide characterization of MPEs LUAD microenvironment, highlighting the importance of specific components of the myeloid compartment and opens new perspectives for the rational design of new therapies for metastatic NSCLC., Competing Interests: Competing interests: All the authors with the exception of LA have nothing to disclose. LA is an employee of Takis srl., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)