An empowered, clinically-viable hematopoietic stem cell gene therapy approach for the treatment of multisystemic Mucopolysaccharidosis Type II

: Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked recessive lysosomal storage disorder due to a mutation in the lysosomal enzyme iduronate-2-sulfatase (IDS) gene. IDS-deficiency leads to a progressive, multisystem accumulation of glycosaminoglycans (GAGs) and results in central nervous system (CNS) manifestations in the severe form. We developed up to clinical readiness a new Hematopoietic Stem Cell (HSC) gene therapy approach for MPS II that benefits from a novel highly effective transduction protocol. We first provided proof-of-concept of efficacy of our approach aimed at enhanced IDS enzyme delivery to the CNS in a murine study of immediate translational value, employing a lentiviral vector (LV) encoding a codon optimized human IDS cDNA. Then the therapeutic LV was tested for its ability to efficiently and safely transduce bona fide human HSCs in clinically relevant conditions according to a standard versus a novel protocol that demonstrated superior ability to transduce bona fide long-term repopulating HSCs. Overall, these results provide strong proof-of-concept for the clinical translation of this approach for the treatment of Hunter syndrome

Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer

Abstract Background In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up. Methods Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized. Results At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69–78 %) reported being bothered “a little bit” or “not at all” by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline. Conclusion PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer

Addressing timber (il)legality in the Western Balkan: Stakeholder perspectives on the EUTR and the new Regulation on Deforestation-free Products

Some Western Balkan countries are among high-risk timber exporting countries as they are considered to comprise the corridor of illegal timber and timber products from the East to the West. In general, research on deforestation and illegal forest activities in Balkan countries received less attention compared to other high-risk regions and countries, such as tropical ones. Although some studies focus on the legality aspects associated to forest management, timber harvesting and processing in the Balkan countries, they mostly target the topic just partially (e.g., focusing on trade data and trends) or pay attention to the role of existing policy tools (e.g. forest certification) in coping with the problem. This paper aims to approach timber legality issues in the Western Balkans from a different angle. Building on public policy and environmental governance studies, we approach the issue of timber legality in the Western Balkans by investigating the transposition of European Union Timber Regulation (EUTR) requirements into the national policy frameworks of five selected Western Balkan countries (i.e., Slovenia, Croatia, Serbia Montenegro and the Republic of Srpska, BH). By adopting a multiple embedded case study design, we collected national policies and regulations related to the prevention and tackling of illegal logging, as well as those dealing with the trade in timber and timber products in targeted countries and conducted qualitative content analysis of retrieved documents to check the extent to which EUTR requirements are covered. Moreover interviews with more than 30 key informants were performed across selected countries. We analyzed interviewees’ perceptions about EUTR and the forthcoming Regulation on Deforestation-free Products (EUDR) looking into five main dimensions, i.e., awareness, transparency, information, resources, and challenges of ensuring timber legality. Following actor-centered institutionalism we further distinguished institutional and actors-oriented factors influencing the transposition of EUTR requirements into national policies and forestry practice. Our contribution will offer a comparative gap analysis about EUTR incorporation within the national policy frameworks of targeted countries as well as an overview of common and opposing perceptions on timber legality and legitimate forestry practices of key stakeholders in five Western Balkan countries

Application of short-term analysis of skin temperature variability in prediction of survival in patients with cirrhosis

: Background: Liver cirrhosis is a complex disorder, involving several different organ systems and physiological network disruption. Various physiological markers have been developed for survival modelling in patients with cirrhosis. Reduction in heart rate variability and skin temperature variability have been shown to predict mortality in cirrhosis, with the potential to aid clinical prognostication. We have recently reported that short-term skin temperature variability analysis can predict survival independently of the severity of liver failure in cirrhosis. However, in previous reports, 24-h skin temperature recordings were used, which are often not feasible in the context of routine clinical practice. The purpose of this study was to determine the shortest length of time from 24-h proximal temperature recordings that can accurately and independently predict 12-month survival post-recording in patients with cirrhosis. Methods: Forty individuals diagnosed with cirrhosis participated in this study and wireless temperature sensors (iButtons) were used to record patients' proximal skin temperature. From 24-h temperature recordings, different length of recordings (30 min, 1, 2, 3 and 6 h) were extracted sequentially for temperature variability analysis using the Extended Poincaré plot to quantify both short-term (SD1) and long-term (SD2) variability. These patients were then subsequently followed for a period of 12 months, during which data was gathered concerning any cases of mortality. Results: Cirrhosis was associated with significantly decreased proximal skin temperature fluctuations among individuals who did not survive, across all durations of daytime temperature recordings lasting 1 hour or more. Survival analysis showcased 1-h daytime proximal skin temperature time-series to be significant predictors of survival in cirrhosis, whereby SD2, was found to be independent to the Model for End-Stage Liver Disease (MELD) score and thus, the extent of disease severity. As expected, longer durations of time-series were also predictors of mortality for the majority of the temperature variability indices. Conclusion: Crucially, this study suggests that 1-h proximal skin temperature recordings are sufficient in length to accurately predict 12-month survival in patients with cirrhosis, independent from current prognostic indicators used in the clinic such as MELD

Safety parameters and stability diagram of hydroxylamine hydrochloride and sulphate

The thermal instability of hydroxylamine (HA) poses severe concerns in the process industry, while preventive and mitigative strategies are required to reduce the frequency and magnitude of associated decomposition phenomena. From this perspective, formulating an aqueous solution or using derived salts could be a solution for risk reduction. Nevertheless, the effect of HA-derived salt addition on HA/water solutions has yet to be reported in the literature. For this reason, the scope of the present work is to examine experimentally whether salt addition can reduce the occurrence and severity of HA thermal degradation. Samples containing HA and hydroxylamine sulphate (HAS) or hydroxylamine hydrochloride (HH) were analysed. During the experimental campaign, a calorimeter was used for the assessment of reaction kinetic, thermodynamic, and onset features. The determined parameters were used for safety purposes to understand the related thermal hazards and to provide stability diagrams. The results show, under certain conditions, that the type and amount of HA-derived salt determines an attenuation of the decomposition of HA/water solutions. Moreover, increasing the amount of salt enhances the susceptibility to decomposition of the HA/water solution, while lower salts content could help stabilise the HA mixtures. According to the developed stability diagram, an inherently safe zone for reaction or storage has been established. Eventually, the proposed structured approach can be intended as a strategic procedure to involve the reaction parameters gathered, which is helpful for drawing general guidelines for establishing safer processes and reaction conditions

KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas

Introduction: Paradoxical increase of GH following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expression in somatotroph pituitary adenomas. Methods: We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-CGH on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expression. Results: 146 patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (p = 0.0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, p < 0.0001) and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, p = 0.0012) in adenomas from patients with KDM1A haploinsufficiency compared to those with two KDM1A copies. Discussion: Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus

Distance in depth: A comparison of explicit and implicit numerical distances in the horizontal and radial dimensions

: Numbers are a constant presence in our daily lives: A brain devoid of the ability to process numbers would not be functional in its external environment. Comparing numerical magnitudes is a fundamental ability that requires the processing of numerical distances. From magnitude comparison tasks, a comparison distance effect (DE) emerges: It describes better performance when comparing numerically distant rather than close numbers. Unlike other signatures of number processing, the comparison DE has been assessed only implicitly, with numerical distance as nonsalient task property. Different assessments permit identification of different cognitive processes underlying a specific effect. To investigate whether explicit and implicit assessment of the comparison DE influences numerical cognition differently, we introduced the distance classification task, involving explicit classification of numbers as close or far from a reference. N = 93 healthy adults classified numbers either by magnitude or by numerical distance. To investigate associations between numerical and physical distance, response buttons were positioned horizontally (Experiment 1) or radially (Experiment 2). In both experiments, there was an advantage for both the closest and farthest numbers with respect to the reference during distance classification, but not during magnitude classification. In Experiment 2, numerically close/far numbers were classified faster with the close/far response button, respectively, suggesting radial correspondence between physical and representational distances. These findings provide new theoretical and methodological insights into the mental representation of numbers. (PsycInfo Database Record (c) 2024 APA, all rights reserved)