Structural Chemistry of Intermetallic Compounds of Beryllium and Magnesium with Late Transition Metals

This work is dedicated to the investigation on intermetallic compounds of beryllium and magnesium with late transition metals. By conducting fundamental research, the objective is to unveil novel intermetallic compounds possessing distinctive chemical bonding and interesting physical properties, with the aim to identify potential semiconductor materials for further thermoelectric applications. Following the recent discovery of the semiconducting properties of Be5Pt, it was initially hypothesised that replacing Be with Mg, while preserving the semiconducting properties, could enhance the widespread applicability of said material considering the lower toxicity of magnesium compared to that of beryllium. The study of the already well-investigated Mg–Pt system, revealed that a phase with composition Mg5Pt does not exist, instead two new phases, Mg3Pt2 and Mg29-xPt4+y (x = 0.47, y = 0.07), were discovered. Mg3Pt2 can be synthesised by direct reaction of its constituent elements or through spark plasma sintering (SPS) using MgH2 and PtCl2 as precursors. An in-depth analysis of the chemical bonding in Mg3Pt2 allowed to conclude that belonging to the same structural prototype (Eu3Ga2) does not necessarily indicate the same chemical bonding scenario. The isolation of single crystals for diffraction experiments combined with atomic-resolution transmission electron microscopy (TEM), enabled the determination and examination of the crystal structure of Mg29-xPt4+y, the existence of which had previously only been hinted on the basis of powder diffraction or metallography analysis. The investigation of the chemical bonding in Mg29-xPt4+y revealed a unique characteristic, that distinguishes it from other complex intermetallic compounds (CMAs). Notably, a spatial separation of regions with different bonding features was observed, explaining a distinctive mixed Mg/Pt site occupancy near the origin of the unit cell. Beryllium has garnered considerable interest due to its versatile behaviour when combined with other elements. These combinations can give rise to materials exhibiting distinctive physical properties and intriguing chemical bonding characteristics. However, the high toxicity associated with beryllium and its compounds as well as difficulties in characterisation, e.g. very low X-ray scattering power, has limited systematic investigations of Be–based intermetallic compounds. This comprehensive study focuses on the binary Be–Ru system. The redetermination of the Be3Ru crystal structure, showed that it crystallises with TiCu3–type structure. The crystal structure can be derived by ‘colouring’ the hexagonal closest packing of spheres characteristic for large groups of intermetallic compounds. Be3Ru exhibits diamagnetic properties, and its metallic electrical resistivity is in good agreement both with electronic structure calculations and experimental measurements. Be2Ru crystallises with Fe2P–type structure, instead of the previously reported MgZn2–type one. Detailed investigations using single crystal X-ray diffraction experiments together with atomic-resolution electron microscopy have revealed the presence of minor orthorhombic inclusions dispersed within the hexagonal Fe2P–type matrix crystal structure. Despite these structural variations, both atomic arrangements primarily consist of similar structural layers and exhibit comparable chemical bonding characteristics. It has been also discovered that Be3Ru2 crystallises with U3Si2–type structure, in contrast to the previously reported (Mn0.5Fe0.5)2O3–type structure. Be7Ru4 and Be12Ru7 represent two new phases in the Be–Ru system. They possess a very close atomic composition (63.6 at. % Be and 63.2 at. % Be, respectively) and are situated between Be2Ru and Be3Ru2 in the Be–Ru phase diagram. Together with Be2Ru, these two new phases form a series of two-dimensional intergrowth structures, incorporating building blocks of Be2Ru and Be3Ru2 (Fe2P– and U3Si2– type structure). The first one is comprised of hexagonal channels of Ru atoms accompanied by embedded columns of [Be@Be6] trigonal prisms, while the second structure consists of columns composed of tetragonal [Be@Ru8] and trigonal [Be@Ru6] prisms. The structural organisation observed in Be7Ru4 and Be12Ru7 has not been documented previously, indicating that these two phases represent novel structural prototypes. A careful investigation of the crystal structure of Be17Ru3, revealed that the center of a cage [X@Be12] around at the origin of the unit cell, is not completely empty, but rather partly occupied by either Be or Ru. Furthermore, it was observed that this cage can be filled by rare earth and actinide elements giving rise to a novel family of ternary compounds with composition RBe68Ru12 (R = U, Th, Ce, Pr, Gd, Ho). Finally, two new Be–based Laves phases C15–Be2Fe1-xRux (x = 0.52) and C14–Be2Fe1-xOsx (x= 0.57) were discovered through alloying Ru and Os to C14–Be2Fe Laves phase. This study confirmed that the stability of C15 or C14 AB2 Laves phases cannot be predicted by simple reasoning such as atomic size ratio between the A and B atoms, difference in electronegativity or valence electron concentration (VEC), particularly when all three elements, Fe, Ru and Os, belong to the same group of the periodic table. Despite their different chemical behaviour, the investigation of chemical bonding using quantum chemical techniques in the Be– and Mg–based intermetallic compounds with late transition metals, unveiled shared characteristics whereby their crystal structures are stabilised by the formation of polar multiatomic bonds. The observed charge transfer not only serves a decisive role in stabilising the atomic configurations, but also contributes to the emergence of distinct structuring of the calculated electronic density of states of states, DOS, i.e. appearance of more or less prominent dips in the vicinity of the Fermi level, implying their proximity to a semiconducting state, in particular as far as Be–based intermetallic compounds are concerned

Incorporating immunotherapy in the management of gastric cancer: molecular and clinical implications

Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a clinical strategy that enhances the host’s immune system against cancer cells may be a successful approach to improve clinical outcomes. Additionally, there has been an increasing amount of translational evidence highlighting the relevance of PD-L1 expression in gastric cancer cells, indicating that PD-1/PD-L1 inhibitors may be useful. Several molecular subgroups of gastric cancer have been identified to respond with excellent outcomes to immunotherapy, including microsatellite instable tumours, tumours bearing a high tumour mutational burden, and tumours related to a chronic EBV infection. In gastric cancer, immunotherapy has produced durable responses in chemo-refractory patients; however, most recently there has been a lot of enthusiasm as several large-scale clinical trials highlight the improved survival noted from the incorporation of immunotherapy in the first line setting for advanced gastric cancer. Our review aims to discuss current pre-clinical and clinical data supporting the innovative role of immunotherapy in gastric cancer

Cell-specific pattern of berberine pleiotropic effects on different human cell lines

The natural alkaloid berberine has several pharmacological properties and recently received attention as a potential anticancer agent. In this work, we investigated the molecular mechanisms underlying the anti-Tumor effect of berberine on glioblastoma U343 and pancreatic carcinoma MIA PaCa-2 cells. Human dermal fibroblasts (HDF) were used as non-cancer cells. We show that berberine differentially affects cell viability, displaying a higher cytotoxicity on the two cancer cell lines than on HDF. Berberine also affects cell cycle progression, senescence, caspase-3 activity, autophagy and migration in a cell-specific manner. In particular, in HDF it induces cell cycle arrest in G2 and senescence, but not autophagy; in the U343 cells, berberine leads to cell cycle arrest in G2 and induces both senescence and autophagy; in MIA PaCa-2 cells, the alkaloid induces arrest in G1, senescence, autophagy, it increases caspase-3 activity and impairs migration/invasion. As demonstrated by decreased citrate synthase activity, the three cell lines show mitochondrial dysfunction following berberine exposure. Finally, we observed that berberine modulates the expression profile of genes involved in different pathways of tumorigenesis in a cell line-specific manner. These findings have valuable implications for understanding the complex functional interactions between berberine and specific cell types

Phosphorus and sulfur SAD phasing of the nucleic acid-bound DNA-binding domain of interferon regulatory factor 4

Pivotal to the regulation of key cellular processes such as the transcription, replication and repair of DNA, DNA-binding proteins play vital roles in all aspects of genetic activity. The determination of high-quality structures of DNA-binding proteins, particularly those in complexes with DNA, provides crucial insights into the understanding of these processes. The presence in such complexes of phosphate-rich oligonucleotides offers the choice of a rapid method for the routine solution of DNA-binding proteins through the use of long-wavelength beamlines such as I23 at Diamond Light Source. This article reports the use of native intrinsic phosphorus and sulfur single-wavelength anomalous dispersion methods to solve the complex of the DNA-binding domain (DBD) of interferon regulatory factor 4 (IRF4) bound to its interferon-stimulated response element (ISRE). The structure unexpectedly shows three molecules of the IRF4 DBD bound to one ISRE. The sole reliance on native intrinsic anomalous scattering elements that belong to DNA-protein complexes renders the method of general applicability to a large number of such protein complexes that cannot be solved by molecular replacement or by other phasing methods

Protopine/Gemcitabine Combination Induces Cytotoxic or Cytoprotective Effects in Cell Type-Specific and Dose-Dependent Manner on Human Cancer and Normal Cells

The natural alkaloid protopine (PRO) exhibits pharmacological properties including anticancer activity. We investigated the effects of PRO, alone and in combination with the chemotherapeutic gemcitabine (GEM), on human tumor cell lines and non-tumor human dermal fibroblasts (HDFs). We found that treatments with different PRO/GEM combinations were cytotoxic or cytoprotective, depending on concentration and cell type. PRO/GEM decreased viability in pancreatic cancer MIA PaCa-2 and PANC-1 cells, while it rescued the GEM-induced viability decline in HDFs and in tumor MCF-7 cells. Moreover, PRO/GEM decreased G1, S and G2/M phases, concomitantly with an increase of subG1 phase in MIA PaCa-2 and PANC-1 cells. Differently, PRO/GEM restored the normal progression of the cell cycle, altered by GEM, and decreased cell death in HDFs. PRO alone increased mitochondrial reactive oxygen species (ROS) in MIA PaCa-2, PANC-1 cells and HDFs, while PRO/GEM increased both intracellular and mitochondrial ROS in the three cell lines. These results indicate that specific combinations of PRO/GEM may be used to induce cytotoxic effects in pancreatic tumor MIA PaCa-2 and PANC-1 cells, but have cytoprotective or no effects in HDFs

Dissecting the impact of bromodomain inhibitors on the IRF4-MYC oncogenic axis in multiple myeloma

B-cell progenitor fate determinant interferon regulatory factor 4 (IRF4) exerts key roles in the pathogenesis and progression of multiple myeloma (MM), a currently incurable plasma cell malignancy. Aberrant expression of IRF4 and the establishment of a positive auto-regulatory loop with oncogene MYC, drives a MM specific gene-expression programme leading to the abnormal expansion of malignant immature plasma cells. Targeting the IRF4-MYC oncogenic loop has the potential to provide a selective and effective therapy for MM. Here we evaluate the use of bromodomain inhibitors to target the IRF4-MYC axis through combined inhibition of their known epigenetic regulators, BRD4 and CBP/EP300. Although all inhibitors induced cell death, we found no synergistic effect of targeting both of these regulators on the viability of MM cell-lines. Importantly, for all inhibitors over a time period up to 72 hours, we detected reduced IRF4 mRNA, but a limited decrease in IRF4 protein expression or mRNA levels of downstream target genes. This indicates that inhibitor-induced loss of cell viability is not mediated through reduced IRF4 protein expression, as previously proposed. Further analysis revealed a long half-life of IRF4 protein in MM cells. In support of our experimental observations, gene network modelling of MM suggests that bromodomain inhibition is exerted primarily through MYC and not IRF4. These findings suggest that despite the autofeedback positive regulatory loop between IRF4 and MYC, bromodomain inhibitors are not effective at targeting IRF4 in MM and that novel therapeutic strategies should focus on the direct inhibition or degradation of IRF4. This article is protected by copyright

IRF4 in multiple myeloma—biology, disease and therapeutic target

Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by abnormal proliferation of plasma cells. Interferon Regulatory Factor 4 (IRF4), a member of the interferon regulatory family of transcription factors, is central to the genesis of MM. IRF4 is highly expressed in B cells and plasma cells where it plays essential roles in controlling B cell to plasma cell differentiation and immunoglobulin class switching. Overexpression of IRF4 is found in MM patients’ derived cells, often as a result of activating mutations or translocations, where it is required for their survival. In this review, we rst describe the roles fi of IRF4 in B cells and plasma cells and then analyse the subversion of the IRF4 transcriptional network in MM. Moreover, we discuss current therapies for MM as well as direct targeting of IRF4 as a potential new therapeutic strategy

Structural Chemistry of Intermetallic Compounds of Beryllium and Magnesium with Late Transition Metals

This work is dedicated to the investigation on intermetallic compounds of beryllium and magnesium with late transition metals. By conducting fundamental research, the objective is to unveil novel intermetallic compounds possessing distinctive chemical bonding and interesting physical properties, with the aim to identify potential semiconductor materials for further thermoelectric applications. Following the recent discovery of the semiconducting properties of Be5Pt, it was initially hypothesised that replacing Be with Mg, while preserving the semiconducting properties, could enhance the widespread applicability of said material considering the lower toxicity of magnesium compared to that of beryllium. The study of the already well-investigated Mg–Pt system, revealed that a phase with composition Mg5Pt does not exist, instead two new phases, Mg3Pt2 and Mg29-xPt4+y (x = 0.47, y = 0.07), were discovered. Mg3Pt2 can be synthesised by direct reaction of its constituent elements or through spark plasma sintering (SPS) using MgH2 and PtCl2 as precursors. An in-depth analysis of the chemical bonding in Mg3Pt2 allowed to conclude that belonging to the same structural prototype (Eu3Ga2) does not necessarily indicate the same chemical bonding scenario. The isolation of single crystals for diffraction experiments combined with atomic-resolution transmission electron microscopy (TEM), enabled the determination and examination of the crystal structure of Mg29-xPt4+y, the existence of which had previously only been hinted on the basis of powder diffraction or metallography analysis. The investigation of the chemical bonding in Mg29-xPt4+y revealed a unique characteristic, that distinguishes it from other complex intermetallic compounds (CMAs). Notably, a spatial separation of regions with different bonding features was observed, explaining a distinctive mixed Mg/Pt site occupancy near the origin of the unit cell. Beryllium has garnered considerable interest due to its versatile behaviour when combined with other elements. These combinations can give rise to materials exhibiting distinctive physical properties and intriguing chemical bonding characteristics. However, the high toxicity associated with beryllium and its compounds as well as difficulties in characterisation, e.g. very low X-ray scattering power, has limited systematic investigations of Be–based intermetallic compounds. This comprehensive study focuses on the binary Be–Ru system. The redetermination of the Be3Ru crystal structure, showed that it crystallises with TiCu3–type structure. The crystal structure can be derived by ‘colouring’ the hexagonal closest packing of spheres characteristic for large groups of intermetallic compounds. Be3Ru exhibits diamagnetic properties, and its metallic electrical resistivity is in good agreement both with electronic structure calculations and experimental measurements. Be2Ru crystallises with Fe2P–type structure, instead of the previously reported MgZn2–type one. Detailed investigations using single crystal X-ray diffraction experiments together with atomic-resolution electron microscopy have revealed the presence of minor orthorhombic inclusions dispersed within the hexagonal Fe2P–type matrix crystal structure. Despite these structural variations, both atomic arrangements primarily consist of similar structural layers and exhibit comparable chemical bonding characteristics. It has been also discovered that Be3Ru2 crystallises with U3Si2–type structure, in contrast to the previously reported (Mn0.5Fe0.5)2O3–type structure. Be7Ru4 and Be12Ru7 represent two new phases in the Be–Ru system. They possess a very close atomic composition (63.6 at. % Be and 63.2 at. % Be, respectively) and are situated between Be2Ru and Be3Ru2 in the Be–Ru phase diagram. Together with Be2Ru, these two new phases form a series of two-dimensional intergrowth structures, incorporating building blocks of Be2Ru and Be3Ru2 (Fe2P– and U3Si2– type structure). The first one is comprised of hexagonal channels of Ru atoms accompanied by embedded columns of [Be@Be6] trigonal prisms, while the second structure consists of columns composed of tetragonal [Be@Ru8] and trigonal [Be@Ru6] prisms. The structural organisation observed in Be7Ru4 and Be12Ru7 has not been documented previously, indicating that these two phases represent novel structural prototypes. A careful investigation of the crystal structure of Be17Ru3, revealed that the center of a cage [X@Be12] around at the origin of the unit cell, is not completely empty, but rather partly occupied by either Be or Ru. Furthermore, it was observed that this cage can be filled by rare earth and actinide elements giving rise to a novel family of ternary compounds with composition RBe68Ru12 (R = U, Th, Ce, Pr, Gd, Ho). Finally, two new Be–based Laves phases C15–Be2Fe1-xRux (x = 0.52) and C14–Be2Fe1-xOsx (x= 0.57) were discovered through alloying Ru and Os to C14–Be2Fe Laves phase. This study confirmed that the stability of C15 or C14 AB2 Laves phases cannot be predicted by simple reasoning such as atomic size ratio between the A and B atoms, difference in electronegativity or valence electron concentration (VEC), particularly when all three elements, Fe, Ru and Os, belong to the same group of the periodic table. Despite their different chemical behaviour, the investigation of chemical bonding using quantum chemical techniques in the Be– and Mg–based intermetallic compounds with late transition metals, unveiled shared characteristics whereby their crystal structures are stabilised by the formation of polar multiatomic bonds. The observed charge transfer not only serves a decisive role in stabilising the atomic configurations, but also contributes to the emergence of distinct structuring of the calculated electronic density of states of states, DOS, i.e. appearance of more or less prominent dips in the vicinity of the Fermi level, implying their proximity to a semiconducting state, in particular as far as Be–based intermetallic compounds are concerned

Targeting the IRF4 transcriptional network to subvert multiple myeloma

EMBARGOED - expected end date 21.12.202

Structural Chemistry of Intermetallic Compounds of Beryllium and Magnesium with Late Transition Metals

This work is dedicated to the investigation on intermetallic compounds of beryllium and magnesium with late transition metals. By conducting fundamental research, the objective is to unveil novel intermetallic compounds possessing distinctive chemical bonding and interesting physical properties, with the aim to identify potential semiconductor materials for further thermoelectric applications. Following the recent discovery of the semiconducting properties of Be5Pt, it was initially hypothesised that replacing Be with Mg, while preserving the semiconducting properties, could enhance the widespread applicability of said material considering the lower toxicity of magnesium compared to that of beryllium. The study of the already well-investigated Mg–Pt system, revealed that a phase with composition Mg5Pt does not exist, instead two new phases, Mg3Pt2 and Mg29-xPt4+y (x = 0.47, y = 0.07), were discovered. Mg3Pt2 can be synthesised by direct reaction of its constituent elements or through spark plasma sintering (SPS) using MgH2 and PtCl2 as precursors. An in-depth analysis of the chemical bonding in Mg3Pt2 allowed to conclude that belonging to the same structural prototype (Eu3Ga2) does not necessarily indicate the same chemical bonding scenario. The isolation of single crystals for diffraction experiments combined with atomic-resolution transmission electron microscopy (TEM), enabled the determination and examination of the crystal structure of Mg29-xPt4+y, the existence of which had previously only been hinted on the basis of powder diffraction or metallography analysis. The investigation of the chemical bonding in Mg29-xPt4+y revealed a unique characteristic, that distinguishes it from other complex intermetallic compounds (CMAs). Notably, a spatial separation of regions with different bonding features was observed, explaining a distinctive mixed Mg/Pt site occupancy near the origin of the unit cell. Beryllium has garnered considerable interest due to its versatile behaviour when combined with other elements. These combinations can give rise to materials exhibiting distinctive physical properties and intriguing chemical bonding characteristics. However, the high toxicity associated with beryllium and its compounds as well as difficulties in characterisation, e.g. very low X-ray scattering power, has limited systematic investigations of Be–based intermetallic compounds. This comprehensive study focuses on the binary Be–Ru system. The redetermination of the Be3Ru crystal structure, showed that it crystallises with TiCu3–type structure. The crystal structure can be derived by ‘colouring’ the hexagonal closest packing of spheres characteristic for large groups of intermetallic compounds. Be3Ru exhibits diamagnetic properties, and its metallic electrical resistivity is in good agreement both with electronic structure calculations and experimental measurements. Be2Ru crystallises with Fe2P–type structure, instead of the previously reported MgZn2–type one. Detailed investigations using single crystal X-ray diffraction experiments together with atomic-resolution electron microscopy have revealed the presence of minor orthorhombic inclusions dispersed within the hexagonal Fe2P–type matrix crystal structure. Despite these structural variations, both atomic arrangements primarily consist of similar structural layers and exhibit comparable chemical bonding characteristics. It has been also discovered that Be3Ru2 crystallises with U3Si2–type structure, in contrast to the previously reported (Mn0.5Fe0.5)2O3–type structure. Be7Ru4 and Be12Ru7 represent two new phases in the Be–Ru system. They possess a very close atomic composition (63.6 at. % Be and 63.2 at. % Be, respectively) and are situated between Be2Ru and Be3Ru2 in the Be–Ru phase diagram. Together with Be2Ru, these two new phases form a series of two-dimensional intergrowth structures, incorporating building blocks of Be2Ru and Be3Ru2 (Fe2P– and U3Si2– type structure). The first one is comprised of hexagonal channels of Ru atoms accompanied by embedded columns of [Be@Be6] trigonal prisms, while the second structure consists of columns composed of tetragonal [Be@Ru8] and trigonal [Be@Ru6] prisms. The structural organisation observed in Be7Ru4 and Be12Ru7 has not been documented previously, indicating that these two phases represent novel structural prototypes. A careful investigation of the crystal structure of Be17Ru3, revealed that the center of a cage [X@Be12] around at the origin of the unit cell, is not completely empty, but rather partly occupied by either Be or Ru. Furthermore, it was observed that this cage can be filled by rare earth and actinide elements giving rise to a novel family of ternary compounds with composition RBe68Ru12 (R = U, Th, Ce, Pr, Gd, Ho). Finally, two new Be–based Laves phases C15–Be2Fe1-xRux (x = 0.52) and C14–Be2Fe1-xOsx (x= 0.57) were discovered through alloying Ru and Os to C14–Be2Fe Laves phase. This study confirmed that the stability of C15 or C14 AB2 Laves phases cannot be predicted by simple reasoning such as atomic size ratio between the A and B atoms, difference in electronegativity or valence electron concentration (VEC), particularly when all three elements, Fe, Ru and Os, belong to the same group of the periodic table. Despite their different chemical behaviour, the investigation of chemical bonding using quantum chemical techniques in the Be– and Mg–based intermetallic compounds with late transition metals, unveiled shared characteristics whereby their crystal structures are stabilised by the formation of polar multiatomic bonds. The observed charge transfer not only serves a decisive role in stabilising the atomic configurations, but also contributes to the emergence of distinct structuring of the calculated electronic density of states of states, DOS, i.e. appearance of more or less prominent dips in the vicinity of the Fermi level, implying their proximity to a semiconducting state, in particular as far as Be–based intermetallic compounds are concerned