674 research outputs found
Homozygous mutation in the prokineticin-receptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: case report.
Prokineticin 2 (Prok2) or prokineticin-receptor2 (Prok-R2) gene mutations are associated with Kallmann syndrome
(KS). We describe a new homozygous mutation of Prok-R2 gene in a man displaying KS with an apparent reversal of
hypogonadism. The proband, offspring of consanguineous parents, presented at age 19 years with absent puberty, no
sense of smell, low testosterone and gonadotrophin levels. Magnetic resonance imaging showed olfactory bulb absence.
The patient achieved virilization and spermatogenesis with gonadotrophin administration. Two years after discontinuing
hormonal therapy, he maintained moderate oligozoospermia and normal testosterone levels. Prok2 and Prok-
R2 gene sequence analyses were performed. The proband had a homozygous mutation in Prok-R2 exon 2 that harbours
the c.T820>A base substitution, causing the introduction of an aspartic acid in place of valine at position 274
(Val274Asp). His mother had the same mutation in heterozygous state. This report describes a novel homozygous
mutation of Prok-R2 gene in a man with variant KS, underlying the role of Prok-R2 gene in the olfactory and reproductive
system development in humans. Present findings indicate that markedly delayed activation of gonadotrophin
secretion may occur in some KS cases with definite gene defects, and that oligozoospermia might result from a variant
form of reversible hypogonadotrophic hypogonadism
In silico clinical trials through AI and statistical model checking
A Virtual Patient (VP) is a computational model accounting for individualised (patho-) physiology and Pharmaco-Kinetics/Dynamics of relevant drugs. Availability of VPs is among the enabling technology for In Silico Clinical Trials. Here we shortly outline the state of the art as for VP generation and summarise our recent work on Artificial Intelligence (AI) and Statistical Model Checking based generation of VPs
Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells.
Triple-negative breast cancer is a heterogeneous disease that still lacks specific
therapeutic approaches. The identification of new biomarkers, predictive of the disease’s
aggressiveness and pharmacological response, is a challenge for a more tailored
approach in the clinical management of patients. Nerve growth factor, initially identified
as a key factor for neuronal survival and differentiation, turned out to be a multifaceted
molecule with pleiotropic effects in quite divergent cell types, including cancer cells.
Many solid tumors exhibit derangements of the nerve growth factor and its receptors,
including the tropomyosin receptor kinase A. This receptor is expressed in triple-negative
breast cancer, although its role in the pathogenesis and aggressiveness of this disease is
still under investigation. We now report that triple-negative breast cancer-derived MDAMB-
231 and MDA-MB-453 cells express appreciable levels of tropomyosin receptor
kinase A and release a biologically active nerve growth factor. Activation of tropomyosin
receptor kinase by nerve growth factor treatment positively affects the migration,
invasion, and proliferation of triple-negative breast cancer cells. An increase in the size
of triple-negative breast cancer cell spheroids is also detected. This latter effect might
occur through the nerve growth factor-induced release of matrix metalloproteinase 9,
which contributes to the reorganization of the extracellular matrix and cell invasiveness.
The tropomyosin receptor kinase A inhibitor GW441756 reverses all these responses.
Co-immunoprecipitation experiments in both cell lines show that nerve growth factor
triggers the assembly of the TrkA/b1-integrin/FAK/Src complex, thereby activating
several downstream effectors. GW441756 prevents the complex assembly induced by
nerve growth factor as well as the activation of its dependent signaling. Pharmacological
inhibition of the tyrosine kinases Src and FAK (focal adhesion kinase), together with the
silencing of b1-integrin, shows that the tyrosine kinases impinge on both proliferation
and motility, while b1-integrin is needed for motility induced by nerve growth factor in
triple-negative breast cancer cells. The present data support the key role of the nerve
growth factor/tropomyosin receptor kinase A pathway in triple-negative breast cancer
and offer new hints in the diagnostic and therapeutic management of patients
Irrational beliefs about COVID-19: A scoping review
Since the emergence of the recent Coronavirus Disease of 2019 (COVID-19) and its spread as a pandemic, there has been a parallel spread of false and misleading information, known as an infodemic. The COVID-19 infodemic has induced distrust in scientific communities, governments, institutions and the population, and a confidence crisis that has led to harmful health behaviours, also impacting on mental health. The aim of this study is to provide a scoping review of the scientific literature about COVID-19-related misinformation and conspiracy theories, focusing on the construction of a conceptual framework which is useful for the interpretation of the conspiracy theory phenomenon surrounding COVID-19, and its consequences. Particular socio-environmental conditions (i.e., low educational level, younger age), psychological processes and attitudes (such as low levels of epistemic trust, the avoidance of uncertainty, extraversion, collective narcissism, and a conspiracy-prone mindset), and contextual factors (e.g., high levels of self-perceived risk and anxiety) seem to underpin the adherence to beliefs that are not solely the domain of paranoids and extremists but a widespread phenomenon that has caused important health, social and political consequences
Mechanisms underlying clinical efficacy of Angiotensin II type 2 receptor (AT(2)R) antagonist EMA401 in neuropathic pain: clinical tissue and in vitro studies
BACKGROUND: The clinical efficacy of the Angiotensin II (AngII) receptor AT(2)R antagonist EMA401, a novel peripherally-restricted analgesic, was reported recently in post-herpetic neuralgia. While previous studies have shown that AT(2)R is expressed by nociceptors in human DRG (hDRG), and that EMA401 inhibits capsaicin responses in cultured hDRG neurons, the expression and levels of its endogenous ligands AngII and AngIII in clinical neuropathic pain tissues, and their signalling pathways, require investigation. We have immunostained AngII, AT(2)R and the capsaicin receptor TRPV1 in control post-mortem and avulsion injured hDRG, control and injured human nerves, and in cultured hDRG neurons. AngII, AngIII, and Ang-(1-7) levels were quantified by ELISA. The in vitro effects of AngII, AT(2)R agonist C21, and Nerve growth factor (NGF) were measured on neurite lengths; AngII, NGF and EMA401 effects on expression of p38 and p42/44 MAPK were measured using quantitative immunofluorescence, and on capsaicin responses using calcium imaging. RESULTS: AngII immunostaining was observed in approximately 75% of small/medium diameter neurons in control (n = 5) and avulsion injured (n = 8) hDRG, but not large neurons i.e. similar to TRPV1. AngII was co-localised with AT(2)R and TRPV1 in hDRG and in vitro. AngII staining by image analysis showed no significant difference between control (n = 12) and injured (n = 13) human nerves. AngII levels by ELISA were also similar in control human nerves (4.09 ± 0.36 pmol/g, n = 31), injured nerves (3.99 ± 0.79 pmol/g, n = 7), and painful neuromas (3.43 ± 0.73 pmol/g, n = 12); AngIII and Ang-(1-7) levels were undetectable (<0.03 and 0.05 pmol/g respectively). Neurite lengths were significantly increased in the presence of NGF, AngII and C21 in cultured DRG neurons. AngII and, as expected, NGF significantly increased signal intensity of p38 and p42/44 MAPK, which was reversed by EMA401. AngII mediated sensitization of capsaicin responses was not observed in the presence of MAP kinase inhibitor PD98059, and the kinase inhibitor staurosporine. CONCLUSION: The major AT(2)R ligand in human peripheral nerves is AngII, and its levels are maintained in injured nerves. EMA401 may act on paracrine/autocrine mechanisms at peripheral nerve terminals, or intracrine mechanisms, to reduce neuropathic pain signalling in AngII/NGF/TRPV1-convergent pathways
Levulinic acid-based bioplasticizers: a facile approach to enhance the thermal and mechanical properties of polyhydroxyalkanoates
PHB has been engineered by incorporating different levulinic acid-based bioplasticizers, which enhance flexibility and thermal processability of the neat biopolymer, while retaining excellent biocompatibility and biodegradability
Nociceptin/Orphanin FQ receptor expression in clinical pain disorders and functional effects in cultured neurons
The Nociceptin/Orphanin FQ peptide receptor (NOP), activated by its endogenous peptide ligand Nociceptin/Orphanin FQ (N/OFQ), exerts several effects including modulation of pain signalling. We have examined, for the first time, the tissue distribution of the NOP receptor in clinical visceral and somatic pain disorders by immunohistochemistry, and assessed functional effects of NOP and [micro] opioid receptor activation in cultured human and rat dorsal root ganglion (DRG) neurons. Quantification of NOP-positive nerve fibres within the bladder sub-urothelium revealed a remarkable several-fold increase in Detrusor Overactivity (p<0.0001) and Painful Bladder Syndrome patient specimens (p=0.0014), compared to controls. In post-mortem control human DRGs, 75-80% of small/medium neurons (<=50 [micro]m diameter) in the lumbar (somatic) and sacral (visceral) DRG were positive for NOP, and fewer large neurons; avulsion-injured cervical human DRG neurons showed similar numbers. NOP-immunoreactivity was significantly decreased in injured peripheral nerves (p=0.0004), and also in painful neuromas (p=0.025). Calcium imaging studies in cultured rat DRG neurons demonstrated dose-dependent inhibition of capsaicin responses in the presence of N/OFQ, with an IC50 of 8.6 pM. In cultured human DRG neurons, 32% inhibition of capsaicin responses was observed in the presence of 1 pM N/OFQ (p<0.001). The maximum inhibition of capsaicin responses was greater with N/OFQ than [mu]-opioid receptor agonist DAMGO. Our findings highlight the potential of NOP agonists, particularly in urinary bladder overactivity and pain syndromes. The regulation of NOP expression in visceral and somatic sensory neurons by target-derived neurotrophic factors deserves further study, and the efficacy of NOP selective agonists in clinical trials
Involvement of hypothalamus autoimmunity in patients with autoimmune hypopituitarism: role of antibodies to hypothalamic cells.
Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS
Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known pan-ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. In particular, compound 2u is a brain penetrant ASIC2 inhibitor endowed with an optimal pharmacokinetic profile. This compound may represent a useful tool to validate in animal models in vivo the role of ASIC2 in different neurodegenerative central nervous system pathologies
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