A new player in the development of TRAIL based therapies for hepatocarcinoma treatment: ATM kinase

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCCs are genetically and phenotypically heterogeneous tumors characterized by very poor prognosis, mainly due to the lack, at present, of effective therapeutic options, as these tumors are rarely suitable for radiotherapy and often resistant to chemotherapy protocols. In the last years, agonists targeting the Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) death receptor, has been investigated as a valuable promise for cancer therapy, based on their selectivity for malignant cells and low toxicity for healthy cells. However, many cancer models display resistance to death receptor induced apoptosis, pointing to the requirement for the development of combined therapeutic approaches aimed to selectively sensitize cancer cells to TRAIL. Recently, we identified ATM kinase as a novel modulator of the ability of chemotherapeutic agents to enhance TRAIL sensitivity. Here, we review the biological determinants of HCC responsiveness to TRAIL and provide an exhaustive and updated analysis of the molecular mechanisms exploited for combined therapy in this context. The role of ATM kinase as potential novel predictive biomarker for combined therapeutic approaches based on TRAIL and chemotherapeutic drugs will be closely discussed

Targeting the DNA damage response to overcome cancer drug resistance in glioblastoma

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness

Targeting the DNA damage response to overcome cancer drug resistance in glioblastoma

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness

H2 from biofuels and carriers: A concerted homo-heterogeneous kinetic model of ethanol partial oxidation and steam reforming on Rh/Al2O3

Investigating bioethanol as a renewable energy source is crucial in the context of H2-based economy. Ethanol partial oxidation and steam reforming on Rh/Al2O3 represent promising processes that have already proved to be highly tangled reacting systems. In this work, a significant step forward has been done towards the development of an engineering tool that can capture all the relevant features of the process; a combined homo-heterogeneous kinetic scheme was developed and validated against experimental data, informative of the catalytic and thermal activation of the C2-alcohol. In particular, a 36-species reduced homogeneous scheme was developed, able to cap -ture observed trends with a limited computational load. On the other side, a macro-kinetic heterogeneous scheme with six molecular reactions (ethanol oxidative dehydrogenation, total oxidation, decomposition, dehydrogenation, steam reforming and acetaldehyde post -reforming) was tuned to accurately describe ethanol/O2 and ethanol/H2O reacting systems.& COPY; 2023 Hydrogen Energy Publications LLC. Published by Elsevier Ltd. All rights reserved

Tug of war between survival and death: exploring ATM function in cancer.

Ataxia-telangiectasia mutated (ATM) kinase is a one of the main guardian of genome stability and plays a central role in the DNA damage response (DDR). The deregulation of these pathways is strongly linked to cancer initiation and progression as well as to the development of therapeutic approaches. These observations, along with reports that identify ATM loss of function as an event that may promote tumor initiation and progression, point to ATM as a bona fide tumor suppressor. The identification of ATM as a positive modulator of several signalling networks that sustain tumorigenesis, including oxidative stress, hypoxia, receptor tyrosine kinase and AKT serine-threonine kinase activation, raise the question of whether ATM function in cancer may be more complex. This review aims to give a complete overview on the work of several labs that links ATM to the control of the balance between cell survival, proliferation and death in cancer

Fully Ir(iii) tetrazolate soft salts: the road to white-emitting ion pairs

The first examples of anionic Ir(iii) bis-tetrazolate complexes and their combination with a cationic Ir(iii)tetrazole derivative forming "fully tetrazolate" Ir(iii) based soft salts as O2-sensitive white emitters are described herein

Methodological factors affecting joint moments estimation in clinical gait analysis: A systematic review

Quantitative gait analysis can provide a description of joint kinematics and dynamics, and it is recognized as a clinically useful tool for functional assessment, diagnosis and intervention planning. Clinically interpretable parameters are estimated from quantitative measures (i.e. ground reaction forces, skin marker trajectories, etc.) through biomechanical modelling. In particular, the estimation of joint moments during motion is grounded on several modelling assumptions: (1) body segmental and joint kinematics is derived from the trajectories of markers and by modelling the human body as a kinematic chain; (2) joint resultant (net) loads are, usually, derived from force plate measurements through a model of segmental dynamics. Therefore, both measurement errors and modelling assumptions can affect the results, to an extent that also depends on the characteristics of the motor task analysed (i.e. gait speed). Errors affecting the trajectories of joint centres, the orientation of joint functional axes, the joint angular velocities, the accuracy of inertial parameters and force measurements (concurring to the definition of the dynamic model), can weigh differently in the estimation of clinically interpretable joint moments. Numerous studies addressed all these methodological aspects separately, but a critical analysis of how these aspects may affect the clinical interpretation of joint dynamics is still missing. This article aims at filling this gap through a systematic review of the literature, conducted on Web of Science, Scopus and PubMed. The final objective is hence to provide clear take-home messages to guide laboratories in the estimation of joint moments for the clinical practice

Luminescent protein staining with Re(i) tetrazolato complexes

Within the general framework of our past and current studies dealing with the investigation of the photophysical properties and the biological behavior of the family of tetrazolato and tetrazole Re(i) complexes, we have endeavored to investigate their potential in the luminescent staining of proteins purified by acrylamide gel electrophoresis. With the aim to provide the first examples of luminescent Re(i) complexes to be exploited for this specific purpose, we have designed and prepared four new Re(i)-based species with the general formula fac-[Re(CO)3(N^N)(Tph)]2-/0, where Tph is the 5-(phenyl)tetrazolato anion and N^N is in turn represented by bathophenanthroline disulfonate (BPS), bathocuproine disulfonate (BCS) or by the SO3-free bathocuproine (BC). In this latter case, the neutral complex fac-[Re(CO)3(BC)(Tph)] served as a model species for the characterization of the former disulfonate complexes. Its cationic analogue fac-[Re(CO)3(BC)(Tph-Me)]+was also prepared by a straightforward methylation reaction. All complexes displayed bright phosphorescence in organic media and, relative to their water solubility, the dianionic species fac-[Re(CO)3(BPS)(Tph)]2-and fac-[Re(CO)3(BCS)(Tph)]2-were also highly emissive in aqueous solution. The sulfonate groups played a key role in promoting and significantly enhancing the luminescent staining performances of both the Re(i) complexes fac-[Re(CO)3(BPS)(Tph)]2-and fac-[Re(CO)3(BCS)(Tph)]2-for proteins. Highlighting a response superior to that of Coomassie Blue and comparable to the one obtained by the well-known silver staining method, these dianionic Re(i)-complexes could efficiently detect up to 50 ng of pure Bovine Serum Albumin (BSA), as well as all proteins found in a Standard Protein Marker mix and from a total protein extract. A lower but still good response for luminescent protein staining was surprisingly obtained by employing the-SO3-free neutral and cationic complexes fac-[Re(CO)3(BC)(Tph)] and fac-[Re(CO)3(BC)(Tph-Me)]+, respectively. These preliminary results open up new possibilities for the further widening of the use of Re(i)-based complexes as luminescent protein staining agents

Targeting divalent metal cations with Re(I) tetrazolato complexes

© 2015 The Royal Society of Chemistry. In order to exploit their potential as versatile luminescent sensors, four new Re(i)-tetrazolato complexes with the general formula fac-[Re(CO)3(diim)(L)], where diim is 2,2'-bipyridine (bipy) or 1,10-phenanthroline (phen) and L- is either the anion 5-(2'-pyridyl)tetrazolato (2-PTZ-) or 5-(2'-quinolyl)tetrazolato (2-QTZ-), were prepared and fully characterized. In all cases, the regioselective coordination of the Re(i) center through the N2 atom of the tetrazolato ring was observed. This particular feature ensures the availability of the diiminic (N^N) site that was systematically incorporated into the structure of the 2-PTZ- and 2-QTZ- ligands for further coordination with metal cations. Such a diimine-type coordination mode was preliminarily tested by using the mononuclear Re(i) complexes as N^N ligands for the preparation of two [(N^N)Cu(POP)] cationic species, where POP is the chelating diphosphine bis[2-(diphenylphosphino)phenyl]ether. The X-ray structures of the resulting Re(i)-Cu(i) dyads revealed that the Re(i) mononuclear complexes effectively behaved as chelating N^N ligands with respect to the [Cu(POP)]+ fragment, the coordination of which also resulted in significant modification of the Re(i)-centered luminescence. With these data in hand, the luminescent sensing abilities of the four new Re(i) tetrazolato complexes were screened with respect to divalent metal ions of toxicological and biological importance such as Zn(ii), Cd(ii) and Cu(ii). The interaction of the Re(i) complexes with Zn(ii) and Cd(ii) was witnessed by the evident blue shift (??max = 22-36 nm) of the emission maxima, which was also accompanied by a significant elongation of the emission lifetimes. On the contrary, the addition of the cupric ion caused substantial quenching of the radiative processes originating from the Re(i) luminophores