Trends of Phase I Clinical Trials in the Latest Ten Years across Five European Countries

Phase 1 clinical trials represent a critical phase of drug development because new candidate therapeutic agents are tested for the first time on humans. Therefore, international guidelines and local laws have been released to mitigate and control possible risks for human health in agreement with the declaration of Helsinki and the international Good Clinical Practice principles. Despite numerous scientific works characterizing the registered clinical trials on ClinicalTrials.gov, the main features and trends of registered phase 1 clinical trials in Europe have not been investigated. This study is aimed at assessing the features and the temporal trend of distribution of phase 1 clinical studies, carried out in the five largest European countries over a ten-year period (2012-2021), and to evaluate the impact of the Italian regulatory framework on the activation of such studies

A SPectroscopic Survey of Biased Halos in the Reionization Era (ASPIRE): A First Look at the Rest-frame Optical Spectra of z > 6.5 Quasars Using JWST

© 2023. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: https://creativecommons.org/licenses/by/4.0/Studies of rest-frame optical emission in quasars at z > 6 have historically been limited by the wavelengths accessible by ground-based telescopes. The James Webb Space Telescope (JWST) now offers the opportunity to probe this emission deep into the reionization epoch. We report the observations of eight quasars at z > 6.5 using the JWST/NIRCam Wide Field Slitless Spectroscopy as a part of the “A SPectroscopic survey of biased halos In the Reionization Era (ASPIRE)” program. Our JWST spectra cover the quasars’ emission between rest frame ∼4100 and 5100 Å. The profiles of these quasars’ broad Hβ emission lines span a full width at half maximum from 3000 to 6000 km s−1. The Hβ-based virial black hole (BH) masses, ranging from 0.6 to 2.1 billion solar masses, are generally consistent with their Mg ii-based BH masses. The new measurements based on the more reliable Hβ tracer thus confirm the existence of a billion solar-mass BHs in the reionization epoch. In the observed [O iii] λ λ 4960,5008 doublets of these luminous quasars, broad components are more common than narrow core components (≤ 1200 km s−1), and only one quasar shows stronger narrow components than broad. Two quasars exhibit significantly broad and blueshifted [O iii] emission, thought to trace galactic-scale outflows, with median velocities of −610 and −1430 km s−1 relative to the [C ii] 158 μm line. All eight quasars show strong optical Fe ii emission and follow the eigenvector 1 relations defined by low-redshift quasars. The entire ASPIRE program will eventually cover 25 quasars and provide a statistical sample for the studies of the BHs and quasar spectral properties.Peer reviewe

Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia

The identification of SERCA (sarco/endoplasmic reticulum calcium ATPase) as a target for modulating gain-of-function NOTCH1 mutations in Notch-dependent cancers has spurred the development of this compound class for cancer therapeutics. Despite the innate toxicity challenge associated with SERCA inhibition, we identified CAD204520, a small molecule with better drug-like properties and reduced off-target Ca2+ toxicity compared with the SERCA inhibitor thapsigargin. In this work, we describe the properties and complex structure of CAD204520 and show that CAD204520 preferentially targets mutated over wild-type NOTCH1 proteins in T cell acute lymphoblastic leukemia (T-ALL) and mantle cell lymphoma (MCL). Uniquely among SERCA inhibitors, CAD204520 suppresses NOTCH1-mutated leukemic cells in a T-ALL xenografted model without causing cardiac toxicity. This study supports the development of SERCA inhibitors for Notch-dependent cancers and extends their application to cases with isolated mutations in the PEST degradation domain of NOTCH1, such as MCL or chronic lymphocytic leukemia (CLL)

Awareness, discussion and non-prescribed use of HIV pre-exposure prophylaxis among persons living with HIV/AIDS in Italy: a Nationwide, cross-sectional study among patients on antiretrovirals and their treating HIV physicians

Background: Before Pre-Exposure Prophylaxis (PrEP) was officially recommended and made available, a few surveys among gay and bisexual men, and persons living with HIV/AIDS (PLWHA), identified an informal use of antiretrovirals (ARVs) for PrEP among HIV-negative individuals. Before PrEP availability in Italy, we aimed to assess whether PLWHA in Italy shared their ARVs with HIV-negative individuals, whether they knew people who were on PrEP, and describe the level of awareness and discussion on this preventive measure among them and people in their close circle. Methods: Two anonymous questionnaires investigating personal characteristics and PrEP awareness, knowledge, and experience were proposed to HIV specialists and their patients on ARVs in a one-week, cross-sectional survey (December 2013-January 2014). Among PLWHA, a Multivariable Logistic Regression analysis was conducted to identify factors associated with PrEP discussion with peers (close circle and/or HIV associations), and experience (use in close circle and/or personal ARV sharing). Results: Eighty-seven specialists in 31 representative Infectious Diseases departments administered the questionnaire to 1405 PLWHA. Among specialists, 98% reported awareness, 65% knew the dosage schedule, and 14% had previously suggested or prescribed PrEP. Among PLWHA, 45.6% were somehow aware, discussed or had direct or indirect experience of PrEP: 38% "had heard" of PrEP, 24% were aware of studies in HIV-negative individuals demonstrating a risk reduction through the use of ARVs, 22% had discussed PrEP, 12% with peers; 9% reported PrEP use in close circle and 1% personal ARV sharing. Factors predictive of either PrEP discussion with peers or experience differed between men and women, but across all genders were mainly related to having access to information, with HIV association membership being the strongest predictor. Conclusions: At a time and place where there were neither official information nor proposals or interventions to guide public policies on PrEP in Italy, a significant number of PLWHA were aware of it, and approximately 10% reported PrEP use in their close circle, although they rarely shared their ARVs with uninfected people for this purpose. Official policies and PrEP availability, along with implementation programs, could avoid risks from uncontrolled PrEP procurement and self-administration practices