Surfactants, nanomedicines and nanocarriers: a critical evaluation on clinical trials

Advances, perspectives and innovation in drug delivery have increased in recent years; however, there is limited information available regarding the actual presence of surfactants, nanomed-icines and nanocarriers in investigational medicinal products submitted as part of a request for authorization of clinical trials, particularly for those authorized in the European Economic Area. We retrieve, analyze and report data available at the Clinical Trial Office of the Italian Medicines Agency (AIFA), increasing the transparency and availability of relevant information. An analysis of quality documentation submitted along with clinical trials authorized by the AIFA in 2018 was carried out, focusing on the key terms “surfactant”, “nanomedicine” and “nanocarrier”. Results suggest potential indications and inputs for further reflection and actions for regulators to actively and safely drive innovation from a regulatory perspective and to transpose upcoming evolution of clinical trials within a strong regulatory framework

Laryngectomized patients caregivers' life experience: A phenomenological study

Background: Laryngectomized patients often depend on their caregivers who have a central and difficult role in supporting them dealing with financial, social, and relational issues. In fact, they feel very responsible and committed, especially considering the time devoted to take care of their beloved. Besides, providing care induces caregivers high stress levels, emotional distress, anxiety and the fear of cancer recurrence or progress. Few studies investigated laryngectomized patients caregivers\u2019 life experience during both the whole course of illness and at the end of the treatment. Therefore, the purpose of our study was to explore, through a phenomenological approach, the lived-experience of primary family caregivers of laryngectomized patients undergoing radical surgery. Methods: Qualitative semi-structured and audiotaped interviews were held with 12 laryngectomized patients\u2019 primary family caregivers. Data were analysed using the descriptive phenomenological approach outlined by Colaizzi. Results: Three key themes emerged: the caregivers lived experience of illness; the change of caregivers\u2019 daily life and how they support their sick beloved. The experience of caregivers\u2019 lived relations changes from being a family member to a supportive carer, and the illness of their beloved negatively affects their psychological lived experience. Their perception of time and Quality of Life change as their perception of the future becomes uncertain. Finally, they feel guilty mainly because of the limited amount of time they can devote to their beloved. Conclusions: The study findings allowed to understand in depth how the presence of a laryngectomized person in the family may affect the life of the caregiver, even after the treatment phase. This suggests the need for healthcare professionals to support caregivers throughout the whole care journey and especially in dealing with the perception of time during the diagnosis and care phases. Further research should be conducted on factors contributing to time perception alteration and possible interventions to support caregivers to cope with it

Differential habitat use between demographic states of black bears in managed timber forests

The long‐term effects of intensive forest harvest on sensitive demographic stages of the American black bear (Ursus americanus) have been often overlooked. Much of Maine, USA, is covered in forests that are hospitable to bears and commercial timber harvest. To investigate the potential effects of differing intensities of disturbance on black bears, and on females with cubs particularly, we designed a large‐scale natural experiment with 197 motion‐sensitive camera sites dispersed over representative forest stands in northern and central Maine. Using multi‐state occupancy models, we distinguished the overall trends in space use by females with young versus adult bears without young. Forest disturbance at large spatial scales was positively associated with the probability of use for both demographic groups and the availability of hardwood trees was an additional important factor for habitat use by females with young. Our study illustrates the use of motion‐sensitive cameras to monitor and understand habitat use by distinct life‐history stages of animals living in human‐modified landscapes, and results indicate that managers can maintain black bear habitat in areas of active forest harvest by ensuring the availability of hardwood specie

Massively parallel computing on an organic molecular layer

Current computers operate at enormous speeds of ~10^13 bits/s, but their principle of sequential logic operation has remained unchanged since the 1950s. Though our brain is much slower on a per-neuron base (~10^3 firings/s), it is capable of remarkable decision-making based on the collective operations of millions of neurons at a time in ever-evolving neural circuitry. Here we use molecular switches to build an assembly where each molecule communicates-like neurons-with many neighbors simultaneously. The assembly's ability to reconfigure itself spontaneously for a new problem allows us to realize conventional computing constructs like logic gates and Voronoi decompositions, as well as to reproduce two natural phenomena: heat diffusion and the mutation of normal cells to cancer cells. This is a shift from the current static computing paradigm of serial bit-processing to a regime in which a large number of bits are processed in parallel in dynamically changing hardware.Comment: 25 pages, 6 figure

Breaking barriers in triple negative breast cancer (TNBC) – Unleashing the power of antibody-drug conjugates (ADCs)

Antibody-drug conjugates (ADCs) represent a novel class of molecules composed of a recombinant monoclonal antibody targeted to a specific cell surface antigen, conjugated to a cytotoxic agent through a cleavable or non-cleavable synthetic linker. The rationale behind the development of ADCs is to overcome the limitations of conventional chemotherapy, such as the narrow therapeutic window and the emergence of resistance mechanisms. ADCs had already revolutionized the treatment algorithm of HER2-positive breast cancer. Currently, emergent non-HER2 targeted ADCs are gaining momentum, with special focus on triple-negative disease therapeutic landscape. Sacituzumab govitecan (SG) is an ADC consisting of a humanized monoclonal antibody hRS7 targeting trophoblast cell surface antigen 2 (Trop2), linked to the topoisomerase I inhibitor SN-38 by a hydrolysable linker. It currently stands as the only non-HER2 targeted ADC that already received approval for the treatment of unresectable locally advanced or metastatic triple negative breast cancer (TNBC) in patients who had received two or more prior systemic therapies, with at least one for advanced disease. The purpose of these review is to analyze the available evidence regarding ADCs in TNBC, alongside with providing an overview on the ongoing and future research horizons in this field

Instrumental activities of daily living in older patients with metastatic prostate cancer: results from the meet-URO network ADHERE prospective study

Instrumental activities of daily living (IADL) are significant health indicators closely related to executive functions and able to detect mild cognitive impairment. A decline in IADL usually precedes ADL limitation, including taking medications, and may therefore predict a cognitive decline. We aimed to investigate the association of patients’ IADL score with other clinical factors, with a particular focus on the presence of a caregiver, and the impact on adherence to androgen receptor pathway inhibitors (ARPIs) and survival outcomes within the Meet-URO 5—ADHERE study. It was a large prospective multicentre observational cohort study monitoring adherence to ARPIs in 234 metastatic castrate-resistant PC (mCRPC) patients aged ≥ 70. We observed an association between impaired IADL and lower geriatric G8 scores (p < 0.01), and lower adherence to ARPIs whether assessed by pill counting (p = 0.01) or self-reported by the patient himself (p = 0.03). The combination of an IADL < 6 and the absence of a caregiver resulted in a significantly high risk of non-adherence to the ARPIs at the multivariable analysis (HR 9.23, 95% confidence interval 2.28–37.43, p = 0.01). IADL alongside the geriatric G8 scales represent essential tools to identify frail and less auto-sufficient patients who are extremely vulnerable particularly if not supported by a caregiver and have the highest risk of nonadherence to ARPIs

The Geriatric G8 Score Is Associated with Survival Outcomes in Older Patients with Advanced Prostate Cancer in the ADHERE Prospective Study of the Meet-URO Network

Introduction: Androgen receptor pathway inhibitors (ARPIs) have been increasingly offered to older patients with prostate cancer (PC). However, prognostic factors relevant to their outcome with ARPIs are still little investigated. Methods and Materials: The Meet-URO network ADHERE was a prospective multicentre observational cohort study evaluating and monitoring adherence to ARPIs metastatic castrate-resistant PC (mCRPC) patients aged ≥70. Cox regression univariable and multivariable analyses for radiographic progression-free (rPFS) and overall survival (OS) were performed. Unsupervised median values and literature-based thresholds where available were used as cut-offs for quantitative variables. Results: Overall, 234 patients were enrolled with a median age of 78 years (73–82); 86 were treated with abiraterone (ABI) and 148 with enzalutamide (ENZ). With a median follow-up of 15.4 months (mo.), the median rPFS was 26.0 mo. (95% CI, 22.8–29.3) and OS 48.8 mo. (95% CI, 36.8–60.8). At the MVA, independent prognostic factors for both worse rPFS and OS were Geriatric G8 assessment ≤ 14 (p < 0.001 and p = 0.004) and PSA decline ≥50% (p < 0.001 for both); time to castration resistance ≥ 31 mo. and setting of treatment (i.e., post-ABI/ENZ) for rPFS only (p < 0.001 and p = 0.01, respectively); age ≥78 years for OS only (p = 0.008). Conclusions: Baseline G8 screening is recommended for mCRPC patients aged ≥70 to optimise ARPIs in vulnerable individuals, including early introduction of palliative care

Regional actorness and interregional relations:ASEAN, the EU and Mercosur

The European Union (EU) has a long tradition of interregional dialogue mechanisms with other regional organisations and is using these relations to project its own model of institutionalised actorness. This is partly motivated by the emerging actorness of the EU itself, which benefits from fostering capable regional counterparts in other parts of the world. This article advances the argument that actorness, which we conceptualise in terms of institutions, recognition and identity, is a relational concept, dependent on context and perception. Taking the Association of Southeast Asian Nations (ASEAN) and the Common Market of the South (Mercosur) and their relations with the EU as case studies, this article demonstrates that the actorness capabilities of all three organisations have been enhanced as result of ASEAN-EU and Mercosur-EU relations. However, there are clear limits to the development of the three components of regional actorness and to the interregional relations themselves. These limits stem both from the type of interregionalism at play and from the different regional models the actors incorporate. While there is evidence of institutional enhancement in ASEAN and Mercosur, these formal changes have been grafted on top of firmly entrenched normative underpinnings. Within the regional organisations, interactions with the EU generate centrifugal forces concerning the model to pursue, thus limiting their institutional cohesion and capacity. In addition, group-to-group relations have reinforced ASEAN and Mercosur identities in contrast to the EU. The formation of such differences has narrowed the scope of EU interregionalism despite the initial success of improved regional actorness

CLIPR-59 regulates TNF-α-induced apoptosis by controlling ubiquitination of RIP1

Tumor necrosis factor-α (TNF-α) has important roles in several immunological events by regulating apoptosis and transcriptional activation of cytokine genes. Intracellular signaling mediated by TNF-receptor-type 1 (TNFR1) is constituted by two sequential protein complexes: Complex-I containing the receptor and Complex-II-containing Caspase-8. Protein modifications, particularly ubiquitination, are associated with the regulation of the formation of these complexes. However, the underlying mechanisms remain poorly defined. Here, we identified CLIP-170-related 59 kDa protein (CLIPR-59) as a novel adaptor protein for TNFR1. Experimental reduction of CLIPR-59 levels prevented induction of apoptosis and activation of caspases in the context of TNF-α signaling. CLIPR-59 binds TNFR1 but dissociates in response to TNF-α stimulation. However, CLIPR-59 is also involved in and needed for the formation of Complex-II. Moreover, CLIPR-59 regulates TNF-α-induced ubiquitination of receptor-interacting protein 1 (RIP1) by its association with CYLD, a de-ubiquitinating enzyme. These findings suggest that CLIPR-59 modulates ubiquitination of RIP1, resulting in the formation of Complex-II and thus promoting Caspase-8 activation to induce apoptosis by TNF-α