Treating Prostate Cancer by Antibody–Drug Conjugates

Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP–ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called “antibody–drug conjugates” (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells’ surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.     

In-plane behavior of perforated brick masonry walls

This paper reports the results of experimental and theoretical research conducted on perforated brick masonry walls under in-plane loading. The walls?? structural behavior depends strongly on their specific features, e.g. geometry, mechanical properties of the masonry material, brick arrangement and loading conditions. The experimental program was designed to study the incidence of brick arrangement in the spandrels and piers, and of the acting vertical load on the failure mode and load-bearing capacity of the walls. Six specimens of brick masonry wall with a central opening were submitted to a constant vertical load and a monotonic horizontal force that was gradually increased until the kinematic mechanism condition was reached. The object of the theoretical research was to develop a simplified analytical model for describing the kinematic mechanism of the walls. The results of the experiments indicate that brick arrangement strongly influences the failure mode and load-bearing capacity of the walls. Proper a priori assessment of the failure mode of walls becomes fundamental to an accurate evaluation of their load-bearing capacity using the proposed model.     

Evidence for Biological Age Acceleration and Telomere Shortening in COVID-19 Survivors

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).     

Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors

The approval of the first HIV-1 protease inhibitors (HIV-1 PRIs) marked a fundamental step in the control of AIDS, and this class of agents still represents the mainstay therapy for this illness. Despite the undisputed benefits, the necessary lifelong treatment led to numerous severe side-effects (metabolic syndrome, hepatotoxicity, diabetes, etc.). The HIV-1 PRIs are capable of interacting with “secondary” targets (off-targets) characterized by different biological activities from that of HIV-1 protease. In this scenario, the in-silico techniques undoubtedly contributed to the design of new small molecules with well-fitting selectivity against the main target, analyzing possible undesirable interactions that are already in the early stages of the research process. The present work is focused on a new mixed-hierarchical, ligand-structure-based protocol, which is centered on an on/off-target approach, to identify the new selective inhibitors of HIV-1 PR. The use of the well-established, ligand-based tools available in the DRUDIT web platform, in combination with a conventional, structure-based molecular docking process, permitted to fast screen a large database of active molecules and to select a set of structure with optimal on/off-target profiles. Therefore, the method exposed herein, could represent a reliable help in the research of new selective targeted small molecules, permitting to design new agents without undesirable interactions.     

An updated numerical model of the Larderello–Travale geothermal system, Italy

Larderello–Travale is one of the few geothermal systems in the world that is characterized by a reservoir pressure much lower than hydrostatic. This is a consequence of its natural evolution from an initial liquid-dominated to the current steam-dominated system. Beneath a nearly impermeable cover, the geothermal reservoir consists of carbonate-anhydrite formations and, at greater depth, by metamorphic rocks. The shallow reservoir has temperatures in the range of 220–250 °C, and pressures of about 20 bar at a depth of 1000 m, while the deep metamorphic reservoir has temperatures of 300–350 °C, and pressures of about 70 bar at a depth of 3000 m. The 3D numerical code “TOUGH2” has been used to conduct a regional modeling study to investigate the production mechanism of superheated steam, the interactions between the geothermal field and the surrounding deep aquifers, and the field sustainability. All the available geoscientific data collected in about one century of exploration and exploitation have been used to provide the necessary input parameters for the model, which covers an area (4900 km²) about 10 times wider than the Larderello–Travale geothermal field (400 km²). The numerical model explains the origin of the steam extracted in about one century of exploitation and shows that, at the current level, the production is sustainable at least for the next 100 years.     

From Precursor Chemistry to Gas Sensors: Plasma‐Enhanced Atomic Layer Deposition Process Engineering for Zinc Oxide Layers from a Nonpyrophoric Zinc Precursor for Gas Barrier and Sensor Applications

The identification of bis‐3‐(N,N‐dimethylamino)propyl zinc ([Zn(DMP)₂], BDMPZ) as a safe and potential alternative to the highly pyrophoric diethyl zinc (DEZ) as atomic layer deposition (ALD) precursor for ZnO thin films is reported. Owing to the intramolecular stabilization, BDMPZ is a thermally stable, volatile, nonpyrophoric solid compound, however, it possesses a high reactivity due to the presence of Zn‐C and Zn‐N bonds in this complex. Employing this precursor, a new oxygen plasma enhanced (PE)ALD process in the deposition temperature range of 60 and 160 °C is developed. The resulting ZnO thin films are uniform, smooth, stoichiometric, and highly transparent. The deposition on polyethylene terephthalate (PET) at 60 °C results in dense and compact ZnO layers for a thickness as low as 7.5 nm with encouraging oxygen transmission rates (OTR) compared to the bare PET substrates. As a representative application of the ZnO layers, the gas sensing properties are investigated. A high response toward NO₂ is observed without cross‐sensitivities against NH₃ and CO. Thus, the new PEALD process employing BDMPZ has the potential to be a safe substitute to the commonly used DEZ processes.