Publications by authors named "Stefania Palumbo"

5 Publications

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Growth Hormone Receptor (GHR) 6Ω Pseudoexon Activation: a Novel Cause of Severe Growth Hormone Insensitivity.

J Clin Endocrinol Metab 2021 Jul 28. Epub 2021 Jul 28.

Centre for Endocrinology, William Harvey Research Institute: Barts and The London School of Medicine and Dentistry William Harvey Research Institute, London EC1M 6BQ, UK.

Context: Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.

Objective: This work aims to identify the genetic cause of growth failure in 3 "classical" GHI individuals.

Methods: A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.

Results: We identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation.

Conclusion: Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
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http://dx.doi.org/10.1210/clinem/dgab550DOI Listing
July 2021

Growth Hormone Receptor (Ghr) 6ω Pseudoexon Activation: A Novel Cause Of Severe Growth Hormone Insensitivity (Ghi).

J Clin Endocrinol Metab 2021 Jul 28. Epub 2021 Jul 28.

Centre for Endocrinology, William Harvey Research Institute: Barts and The London School of Medicine and Dentistry William Harvey Research Institute.

Context: Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies.

Objective: Identification of the genetic cause of growth failure in 3 'classical' GHI subjects.

Design: A novel intronic GHR variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.

Results: We identified a novel homozygous intronic GHR variant (g.5:42700940T>G, c.618 + 836T> G), 44bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C>T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a non-functional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following growth hormone stimulation.

Conclusion: Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
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http://dx.doi.org/10.1210/clinem/dgab550DOI Listing
July 2021

A lesson from earthquake engineering for selectively damaging cancer cell structures.

J Mech Behav Biomed Mater 2021 07 19;119:104533. Epub 2021 Apr 19.

Laboratory of Bio-inspired, Bionic, Nano, Meta Materials and Mechanics, Department of Civil, Environmental and Mechanical Engineering, University of Trento, Italy; School of Engineering and Materials Science, Queen Mary University of London, UK. Electronic address:

The progressive falling of barriers among disciplines is opening unforeseen scenarios in diagnosis and treatment of cancer diseases. By sharing models and mature knowledge in physics, engineering, computer sciences and molecular biology, synergistic efforts have in fact contributed in the last years to re-think still unsolved problems, shedding light on key roles of mechanobiology in tumors and envisaging new effective strategies for a precise medicine. The use of ultrasounds for altering cancer cells' program is one of the most attracting grounds to be explored in oncophysics, although how to administer mechanical energy to impair selected cell structures and functions simultaneously overcoming the critical trade-off between the impact of the cure and the patient risk still remains an open issue. Within this framework, by starting from the theoretical possibility of selectively attacking malignant cells by exploiting the stiffness discrepancies between tumor and healthy single cells, first proposed by Fraldi et al. (2015), we here investigate the in-frequency response of an overall spherical close-packing of geometrically equal polyhedral cells to gain insights into how mechanical resonance and vibration-induced failure phenomena can be oriented to destroy specific target units when both the cell populations coexist, as it happens for in vivo cases. Inspired by the dynamic action of earthquakes - which fracture only selected elements among adjacent ones in the same structure or damage individual constructions in contiguous buildings - we study the harmonic response of hierarchically architectured cell agglomerates, inhabited by both tumor and healthy cells that interact mutually throughout the extra-cellular matrix and whose cytoskeleton is modeled as a nonlinear soft-tensegrity structure. Numerical Finite Element results show that, at frequencies compatible with low intensity therapeutic ultrasounds, mechanical resonance and possible fatigue cycles of the pre-stressed actin filaments and microtubules can be selectively induced in cancer cells as a function of the global volume fraction of the cell species, paving the way for future engineered treatment protocols.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104533DOI Listing
July 2021

Competition between delamination and tearing in multiple peeling problems.

J R Soc Interface 2019 11 27;16(160):20190388. Epub 2019 Nov 27.

Laboratory of Bio-Inspired and Graphene Nanomechanics, Department of Civil, Environmental and Mechanical Engineering, Università di Trento, via Mesiano, 77, I-38123 Trento, Italy.

Adhesive attachment systems consisting of multiple tapes or strands are commonly found in nature, for example in spider web anchorages or in mussel byssal threads, and their structure has been found to be ingeniously architected in order to optimize mechanical properties: in particular, to maximize dissipated energy before full detachment. These properties emerge from the complex interplay between mechanical and geometric parameters, including tape stiffness, adhesive energy, attached and detached lengths and peeling angles, which determine the occurrence of three main mechanisms: elastic deformation, interface delamination and tape fracture. In this paper, we introduce a formalism to evaluate the mechanical performance of multiple tape attachments in different parameter ranges, where an optimal (not maximal) adhesion energy emerges. We also introduce a numerical model to simulate the multiple peeling behaviour of complex structures, illustrating its predictions in the case of the staple-pin architecture. Finally, we present a proof-of-principle experiment to illustrate the predicted behaviour. We expect the presented formalism and the numerical model to provide important tools for the design of bioinspired adhesive systems with tuneable or optimized detachment properties.
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http://dx.doi.org/10.1098/rsif.2019.0388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893497PMC
November 2019

A New APEH Cluster with Antioxidant Functions in the Antarctic Hemoglobinless Icefish Chionodraco hamatus.

PLoS One 2015 6;10(5):e0125594. Epub 2015 May 6.

National Research Council, Institute of Biosciences and BioResources (CNR-IBBR), Napoli, Italy.

Acylpeptide hydrolase (APEH) is a ubiquitous cytosolic protease that plays an important role in the detoxification of oxidised proteins. In this work, to further explore the physiological role of this enzyme, two apeh cDNAs were isolated from the Chionodraco hamatus icefish, which lives in the highly oxygenated Antarctic marine environment. The encoded proteins (APEH-1(Ch) and APEH-2(Ch)) were characterised in comparison with the uniquely expressed isoform from the temperate fish Dicentrarchus labrax (APEH-1Dl) and the two APEHs from the red-blooded Antarctic fish Trematomus bernacchii (APEH-1(Tb) and APEH-2(Tb)). Homology modelling and kinetic characterisation of the APEH isoforms provided new insights into their structure/function properties. APEH-2 isoforms were the only ones capable of hydrolysing oxidised proteins, with APEH-2(Ch) being more efficient than APEH-2(Tb) at this specific function. Therefore, this ability of APEH-2 isoforms is the result of an evolutionary adaptation due to the pressure of a richly oxygenated environment. The lack of expression of APEH-2 in the tissues of the temperate fish used as the controls further supported this hypothesis. In addition, analysis of gene expression showed a significant discrepancy between the levels of transcripts and those of proteins, especially for apeh-2 genes, which suggests the presence of post-transcriptional regulation mechanisms, triggered by cold-induced oxidative stress, that produce high basal levels of APEH-2 mRNA as a reserve that is ready to use in case of the accumulation of oxidised proteins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0125594PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422685PMC
April 2016
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