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Fabio Turco,1,* Lavinia Di Prima,1,* Chiara Pisano,1 Stefano Poletto,1 Marco De Filippis,1 Veronica Crespi,1 Giovanni Farinea,1 Massimiliano Cani,1 Mariangela Calabrese,1 Isabella Saporita,1 Rosario Francesco Di Stefano,1 Marcello Tucci,2 Consuelo Buttigliero1 1Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy; 2Department of Medical Oncology, Cardinal Massaia Hospital, Asti, Italy*These authors contributed equally to this workCorrespondence: Marcello Tucci, Department of Medical Oncology, Cardinal Massaia Hospital, Corso Dante Alighieri 202, Asti, 14100, Italy, Tel +393286754734, Email marcello.tucci@gmail.comAbstract: Prostate cancer (PC) is a hormone-sensitive tumor. Androgen deprivation therapy (ADT) is the cornerstone of systemic therapy for patients with intermediate or high-risk localized, recurrent, and metastatic prostate cancer. Although generally well tolerated, ADT can lead to short- and long-term adverse events that can worsen the quality of life of patients with PC. In the last decade, the introduction of novel generation androgen receptor pathway inhibitors (ARPI) has resulted in an improvement in the prognosis of patients with metastatic PC when used in combination with ADT. The use of ARPI in increasingly early stages of the disease determines a longer exposure of patients to these treatments. Although ARPIs are normally well-tolerated drugs, they generally cause an increase in toxicity compared to ADT alone, being able to worsen some adverse events already induced by ADT or leading to the development of specific side effects. Although there are no specific treatments for all the adverse events induced by hormonal therapies, it is essential to know the possible toxicities induced by the different treatments and to start procedures to prevent and/or recognize and consequently treat them early in order to not compromise the quality of life of the patients with PC. The aim of this review is to describe the adverse events induced by hormonal therapies. We will first describe the side effects induced by both ADT and ARPI and then the specific adverse events of the different ARPIs. Furthermore, we will try to highlight the possible therapeutic options to prevent or mitigate the toxicity induced by hormone therapies in order to improve the quality of life of the patients with PC.Keywords: prostate cancer, androgen deprivation therapy, androgen pathway inhibitors, management of adverse events

Current images of the supermassive black hole (SMBH) candidates at the centre of our Galaxy and M87 have opened an unprecedented era for studying strong gravity and the nature of relativistic sources. Very-long-baseline interferometry data show images consistent with a central SMBH within General Relativity (GR). However, it is essential to consider whether other well-motivated dark compact objects within GR could produce similar images. Recent studies have shown that dark matter (DM) haloes modelled as self-gravitating systems of neutral fermions can harbour very dense fermionic cores at their centres, which can mimic the space–time features of a black hole (BH). Such dense, horizonless DM cores can satisfy the observational constraints: they can be supermassive and compact and lack a hard surface. We investigate whether such cores can produce similar observational signatures to those of BHs when illuminated by an accretion disc. We compute images and spectra of the fermion cores with a general-relativistic ray tracing technique, assuming the radiation originates from standard |$\alpha$| discs, which are self-consistently solved within the current DM framework. Our simulated images possess a central brightness depression surrounded by a ring-like feature, resembling what is expected in the BH scenario. For Milky Way-like haloes, the central brightness depressions have diameters down to |${\sim} 35\, \mu \text{as}$| as measured from a distance of approximately |$8\,$|  kpc. Finally, we show that the DM cores do not possess photon rings, a key difference from the BH paradigm, which could help discriminate between the models. [ABSTRACT FROM AUTHOR]

It has been recently demonstrated that both, a classical Schwarzschild black hole (BH), and a dense concentration of self-gravitating fermionic dark matter (DM) placed at the Galaxy centre, can explain the precise astrometric data (positions and radial velocities) of the S-stars orbiting Sgr A*. This result encompasses the 17 best resolved S-stars, and includes the test of general relativistic effects such as the gravitational redshift in the S2-star. In addition, the DM model features another remarkable result: The dense core of fermions is the central region of a continuous density distribution of DM whose diluted halo explains the Galactic rotation curve. In this Letter, we complement the above findings by analysing in both models the relativistic periapsis precession of the S2-star orbit. While the Schwarzschild BH scenario predicts a unique prograde precession for S2, in the DM scenario, it can be either retrograde or prograde, depending on the amount of DM mass enclosed within the S2 orbit, which, in turn, is a function of the DM fermion mass. We show that all the current and publicly available data of S2 cannot discriminate between the two models, but upcoming S2 astrometry close to next apocentre passage could potentially establish if Sgr A* is governed by a classical BH or by a quantum DM system. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is generally a hormone-dependent tumor. Androgen deprivation therapy ( has been the standard of care in metastatic disease for more than 80 years. Subsequent studies have highlighted the efficacy of ADT even in earlier disease settings such as in localized disease or in the case of biochemical recurrence (BCR). Improved knowledge of PC biology and ADT resistance mechanisms have led to the development of novel generation androgen receptor pathway inhibitors (ARPI). Initially used only in patients who became resistant to ADT, ARPI have subsequently shown to be effective when used in patients with metastatic hormone-naive disease and in recent years their effectiveness has also been evaluated in localized disease and in case of BCR. The objective of this review is to describe the current role of agents interfering with the androgen receptor in different stages of PC and to point out future perspectives., Competing Interests: Disclosure Fabio Turco: Travel support: Bayer. Silke Gillessen: (last 3 years) personal honoraria for participation in advisory boards from Amgen, MSD; other honoraria from Radio-televisione Svizzera Italiana (RSI), German-speaking European School of Oncology (DESO); invited speaker for ESMO, Swiss group for Clinical Cancer Research (SAKK), Swiss Academy of Multidisciplinary oncology (SAMO), Orikata academy research group, China Anticancer Association Genitourinary Oncology Committee (CACA-GU); Speaker's bureau for Janssen Cilag; travel grant from ProteoMEdiX and AstraZeneca. Institutional honoraria for participation in advisory boards or in Independent Data Monitoring Committees and Steering Committees from AAA International, Amgen, AstraZeneca, Astellas Pharma, Bayer, Bristol-Myers Squibb, DAIICHI Sankyo, Janssen, Modra Pharmaceuticals, MSD, Myriad Genetic, Novartis, Orion, Pfizer, Roche, Telixpharma, Tolermo Pharmaceutcials; invited speaker for Swiss group for Clinical Cancer Research (SAKK), Cold Spring Harbor Laboratory, ASCO GU; other honoraria from PeerVoice, Silvio Grasso Consulting, WebMD-Medscape. Patent royalties and other intellectual property for a research method for biomarker WO2009138392 Ursula Vogl: Advisory role (institutional): Janssen, Astellas, Merck, MSD, Pfizer, Roche, Bayer, BMS, Novartis AAA. Travel support: Janssen, Merck, Ipsen; Speakers Bureau (compensated, institutional): Janssen, Astellas, Pfizer, Roche, SAMO, BMS, Ipsen. Grant: Fond'Action The remaining authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

ABCB4 is located at the canalicular membrane of hepatocytes and is responsible for the secretion of phosphatidylcholine into bile. Genetic variations of this transporter are correlated with rare cholestatic liver diseases, the most severe being progressive familial intrahepatic cholestasis type 3 (PFIC3). PFIC3 patients most often require liver transplantation. In this context of unmet medical need, we developed a high-content screening approach to identify small molecules able to correct ABCB4 molecular defects. Intracellularly-retained variants of ABCB4 were expressed in cell models and their maturation, cellular localization and function were analyzed after treatment with the molecules identified by high-content screening. In total, six hits were identified by high-content screening. Three of them were able to correct the maturation and canalicular localization of two distinct intracellularly-retained ABCB4 variants; one molecule was able to significantly restore the function of two ABCB4 variants. In addition, in silico molecular docking calculations suggest that the identified hits may interact with wild type ABCB4 residues involved in ATP binding/hydrolysis. Our results pave the way for their optimization in order to provide new drug candidates as potential alternative to liver transplantation for patients with severe forms of ABCB4-related diseases, including PFIC3., (© 2024. The Author(s).)

ATP-binding cassette C-family drug membrane transporters play an important role in local pharmacokinetics, that is, drug concentration in cellular compartments. From the structural point of view, only the bovine ortholog of the multidrug resistance-associated protein 1 (bMRP1) has been resolved. We here used μs-scaled molecular dynamics simulations to investigate the structure and dynamics of the bovine multidrug resistance-associated protein 1 in pre- and post-hydrolysis functional states. The present work aims to examine the slight but likely relevant structural differences between pre- and post-hydrolysis states of outward-facing conformations as well as the interactions between the multidrug resistance-associated protein 1 and the surrounding lipid bilayer. Global conformational dynamics show unfavourable extracellular opening associated with nucleotide-binding domain dimerization indicating that the post-hydrolysis state adopts a close-cleft conformation rather than an outward-open conformation. Our present simulations also highlight persistent interactions with annular cholesterol molecules and the expected active role of lipid bilayer in the allosteric communication between distant domains of the transporter., (© 2023 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Considering the established contribution of environmental factors to the development of thoracic malignancies, the inherited susceptibility of these tumors has rarely been explored. However, the recent introduction of next-generation sequencing-based tumor molecular profiling in the real-word setting enabled us to deeply characterize the genomic background of patients with lung cancer with or without smoking-related history, increasing the likelihood of detecting germline mutations with potential prevention and treatment implications. Pathogenic germline variants have been detected in 2% to 3% of patients with NSCLC undergoing next-generation sequencing analysis, whereas the proportion of germline mutations associated with the development of pleural mesothelioma widely varies across different studies, ranging between 5% and 10%. This review provides an updated summary of emerging evidence about germline mutations in thoracic malignancies, focusing on pathogenetic mechanisms, clinical features, therapeutic implications, and screening recommendations for high-risk individuals., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Multidrug resistance-associated proteins are ABC C-family exporters. They are crucial in pharmacology as they transport various substrates across membranes. However, the role of the degenerate nucleotide-binding site (NBS) remains unclear likewise the interplay with the surrounding lipid environment. Here, we propose a dynamic and structural overview of MRP1 from ca. 110 μs molecular dynamics simulations. ATP binding to NBS1 is likely maintained along several transport cycles. Asymmetric NBD behaviour is ensured by lower signal transduction from NBD1 to the rest of the protein owing to the absence of ball-and-socket conformation between NBD1 and coupling helices. Even though surrounding lipids play an active role in the allosteric communication between the substrate-binding pocket and NBDs, our results suggest that lipid composition has a limited impact, mostly by affecting transport kinetics. We believe that our work can be extended to other degenerate NBS ABC proteins and provide hints for deciphering mechanistic differences among ABC transporters., (© 2023. The Author(s).)

Disclinations in a 2D sheet create regions of Gaussian curvature whose inversion produces a reconfigurable surface with many distinct metastable shapes, as shown by molecular dynamics of a disclinated graphene monolayer. This material has a near-Gaussian "density of shapes" and an effectively antiferromagnetic interaction between adjacent cones. A∼10  nm patch has hundreds of distinct metastable shapes with tunable stability and topography on the size scale of biomolecules. As every conical disclination provides an Ising-like degree of freedom, we call this technique "Isigami."

Background: Retrospective series suggest that bevacizumab-induced hypertension (HTN) is a prognostic and potentially predictive biomarker of efficacy of the antiangiogenic drug in the upfront treatment of metastatic colorectal cancer (mCRC) patients. The immortal-time bias and the effect of pre-existing HTN might affect these findings. We conducted a pooled, post hoc analysis of 2 prospective randomized trials of chemotherapy plus bevacizumab in mCRC, and performed a systematic review of the available literature focusing on how the immortal-time bias was taken into account and how pre-existing HTN potentially requiring the use of antihypertensive drugs was managed., Methods: The pooled-analysis included patients enrolled in the phase III TRIBE and TRIBE-2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively. Association between HTN and survival outcomes was assessed by incorporating a time-dependent Cox regression model to consider the time-dependency of the probability of HTN onset during the treatment. The systematic review was conducted according to PRISMA guidelines., Results: The systematic review retrieved 14 eligible and highly heterogeneous studies. A positive prognostic impact of bevacizumab-induced HTN was reported in the 58% of the analyses reporting Progression Free Survival (PFS) and in the 54% of the analyses reporting Overall Survival (OS) data. Immortal-time bias was incorporated in 4 studies (28%). In TRIBE and TRIBE-2 study populations (N = 1175), patients experiencing ≥ G2 HTN during first-line bevacizumab administration showed longer PFS (median: 14.7 versus 10.3 months, p < 0.001) and OS (median: 31.7 versus 24.2 months, p < 0.001). The association with OS retained statistical significance after correction for time-dependency (p = 0.003) and was confirmed in the multivariable model including HTN as a time-dependent variable (p = 0.02). Moreover, in patients with pre-existing HTN, no difference in terms of PFS and OS was observed compared with the subgroup of patients who never experienced ≥G2 HTN (HR 1.01, p = 0.86 and HR 1.02, p = 0.78 respectively., Conclusions: Bevacizumab-induced HTN during the first-line treatment of mCRC is an independent prognostic factor, also adopting a time-dependency correction. Toxicity should be interpreted as a time-dependent variable when exploring its association with clinical outcome., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Chemically stable quantum-confined 2D metals are of interest in next-generation nanoscale quantum devices. Bottom-up design and synthesis of such metals could enable the creation of materials with tailored, on-demand, electronic and optical properties for applications that utilize tunable plasmonic coupling, optical nonlinearity, epsilon-near-zero behavior, or wavelength-specific light trapping. In this work, it is demonstrated that the electronic, superconducting, and optical properties of air-stable 2D metals can be controllably tuned by the formation of alloys. Environmentally robust large-area 2D-In x Ga 1- x alloys are synthesized byConfinement Heteroepitaxy (CHet). Near-complete solid solubility is achieved with no evidence of phase segregation, and the composition is tunable over the full range of x by changing the relative elemental composition of the precursor. The optical and electronic properties directly correlate with alloy composition, wherein the dielectric function, band structure, superconductivity, and charge transfer from the metal to graphene are all controlled by the indium/gallium ratio in the 2D metal layer., (© 2021 Wiley-VCH GmbH.)