239 research outputs found
Therapies currently in phase II trials for malignant pleural mesothelioma
No full textIntroduction: Malignant pleural mesothelioma (MPM) is an aggressive cancer
associated with asbestos exposure, whose incidence will peak within the next
years. Despite an overall low response rate, the current first-line therapy is
represented by combined chemotherapy with cisplatin and antifolate. Moreover,
there are no currently approved regimens for relapsed or refractory
MPM. Therefore, it is clear how both preclinical and clinical researches aimed
at identifying new therapeutic targets and testing them in early clinical
settings are badly needed.
Areas covered: The aim of this review is to summarize and critically comment
the ongoing Phase II trials for MPM.
Expert opinion: Over the past few years, there has been a significant endeavor
of addressing the clinical research for MPM beyond the very modest results of
chemotherapy. Nonetheless, our understanding is that the treatment of MPM
should not be merely ‘copied’ from that of other much better studied tumors.
In the light of recent results, studies toward the metabolic characteristics of
this tumor are being progressively addressed. These evidences are disclosing
a rather unusual model of malignancy, very likely to be more sensitive to
novel ‘MPM cells- and microenvironment-tailored’ therapy addressing these
characteristics rather than the sole cancer proliferatio
ETF dehydrogenase advances in molecular genetics and impact on treatment
No full textElectron transfer flavoprotein dehydrogenase, also called ETF-ubiquinone oxidoreductase (ETF-QO), is a protein localized in the inner membrane of mitochondria, playing a central role in the electron-transfer system. Indeed, ETF-QO mediates electron transport from flavoprotein dehydrogenases to the ubiquinone pool. ETF-QO mutations are often associated with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD, OMIM#231680), a multisystem genetic disease characterized by various clinical manifestations with different degrees of severity. In this review, we outline the clinical features correlated with ETF-QO deficiency and the benefits obtained from different treatments, such as riboflavin, L-carnitine and/or coenzyme Q10 supplementation, and a diet poor in fat and protein. Moreover, we provide a detailed summary of molecular and bioinformatic investigations, describing the mutations identified in ETFDH gene and highlighting their predicted impact on enzymatic structure and activity. In addition, we report biochemical and functional analysis, performed in HEK293 cells and patient fibroblasts and muscle cells, to show the relationship between the nature of ETFDH mutations, the variable impairment of enzyme function, and the different degrees of RR-MADD severity. Finally, we describe in detail 5 RR-MADD patients carrying different ETFDH mutations and presenting variable degrees of clinical symptom severity
Characterization of two ETFDH mutations in a novel case of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency
No full textBackground: Deficiency of electron transfer flavoprotein dehydrogenase (ETFDH) is associated with multiple acylCoA dehydrogenase deficiency (MADD). This disorder is an autosomal recessive lipid storage myopathy (LSM) that exhibits a wide range of clinical features, including myopathy, weakness and multisystem dysfunctions. Many patients with late onset of MADD improve when treated with riboflavin and are also referred to as RR-MADD (riboflavin-responsive multiple Acyl-CoA dehydrogenase disorder). Methods: In this study, we report the clinical and genetic characterization of a novel RR-MADD patient. Biochemical data were obtained from analysis of muscle and plasma samples. DNA and RNA were extracted from peripheral blood, and sequence analysis and expression study of ETFDH gene were performed. Finally, the impact of mutations on ETFDH folding was evaluated using bioinformatic tools. Results: Patient initially presented with vomiting, muscle weakness, and acidosis. Muscle biopsy revealed typical myopathological patterns of lipid storage myopathy and blood acylcarnitine profiles showed a combined elevation of long and medium chain acylcarnitines, supporting the diagnosis of RR-MADD. Molecular analysis of ETFDH gene revealed two heterozygous mutations, a novel splice variation in intron 10, c.1285+1G>A, and the previously reported c.560C>T missense mutation. RT-PCR analysis showed an alteration of ETFDH RNA splicing which in turn should lead to the production of a truncated protein. The in silico prediction analysis of ETFDH tridimensional structure demonstrated that the missense mutation resulted in instability and loss of protein activation, while the splice site variation induced a dramatic conformational change of the truncated protein. After MCT diet supplemented with carnitine and riboflavin, the patient showed significant biochemical and clinical improvement, in spite of severe molecular defect. Conclusion: This case report extends the spectrum of ETFDH mutations in MADD, providing further evidence that patients presenting at least one missense mutation in the FAD-binding domain may respond to either carnitine or riboflavin treatment, due to the recovery of some enzymatic activity
Clinical and genetic characterization of a Chanarin Dorfman Syndrome patient born to diseased parents
No full textBACKGROUND:
Chanarin Dorfman Syndrome (CDS) is a rare autosomal recessive disorder characterized by ichthyosiform non-bullous erythroderma and variable involvement of the liver and the neuromuscular system. In CDS patients, the accumulation of neutral lipids inside cytoplasmic lipid droplets has been demonstrated in different tissues. To date, ninety families with this disease have been described worldwide; most of them are from Mediterranean countries.
CASE PRESENTATION:
In this report, we describe a consanguineous Turkish family with typical features of CDS. The parents are first cousins and are both diseased. At the age of eight, their child presented CDS with non-bullous congenital ichthyosiform erythroderma, hepatosteatosis, hepatomegaly and ectropion. Electromyographic examination is compatible with myopathy. A five-year-old cousin of the child is also affected by CDS. She was born to non-affected consanguineous parents. Mutation analysis of the ABHD5 gene revealed the previously reported mutation, N209X, which is the most frequent in Turkish patients. Lipid vacuoles, also known as Jordan's anomaly, are detectable in their leucocytes.
CONCLUSIONS:
To the best of our knowledge, this is the first report of a CDS family in which both parents and their child are affected by CDS. To date, the child does not present a more severe clinical phenotype compared with those of his relatives or other CDS patients of the same age. These findings suggest that high levels of triacylglycerol accumulation, that may be supposed to be present in high amount inside the ooplasm, did not affect embryo development and foetal growth
Plasma and Salivary Irisin Response to Resistance Training: A Comparative Study
No full textIrisin is a myokine released in response to physical exercise that enhances energy expenditure, the browning of white adipose tissue, bone homeostasis, muscle hypertrophy, and the regulation of glucose and lipid metabolism1. Existing literature clearly indicates that aerobic exercise leads to increased plasma irisin levels2; instead, the effects of resistance exercise remain unclear. Some studies suggest that resistance exercise increases plasma irisin levels, while others report no change or a decrease3-4. Furthermore, irisin is typically analysed in blood samples, which is invasive and poses potential risks. The substitution of saliva samples for blood would represent a less invasive method for irisin detection; however, only a limited number of studies have evaluated irisin levels in saliva5. This preliminary study aimed to investigate the acute release of plasma and saliva irisin in response to resistance exercise. A total of seven healthy, trained men (age: 23.5 ± 2.5 years; training experience: 5 ± 3 years) were recruited. The protocol included three test sessions (10RM, TUT, 1RM) and one experimental training session (TS). TS sets (n.30) were carried out to muscular failure, with a time under tension (TUT) of 5-1-2-1, emphasising the eccentric phase of the movements. Blood and saliva samples were collected at baseline (T0), 15 minutes (T1), 24 hours (T2), and 48 hours (T4) post-exercise. Plasma samples were used to evaluate irisin and CK levels, while salivary samples were only used for irisin detection, assessed using an ELISA Assay Kit (#EK-067-29). Both plasma and salivary irisin levels demonstrated a significant increase in response to TS between T0 vs T1 (plasma 10.44 ± 0.9 to 11,38 ± 1,4 ng/mg, p:0.02*; saliva 0.051 ± 0.006 to 0.053 ± 0.008 ng/ml, 0.021, p:0.02*). CK values revealed significant differences between T0 Vs T1 (130.2 ± 27.9 to 295.4 ± 111.9 U/L, p:<0.001***), T0 vs T2 (406.4 ± 160.8 U/L, p:<0.001***), T0 vs T3 (248.4 ± 93.2 U/L, p:<0.001***); T1 vs T3 p:0.01**; and T2 vs T3 p:0.006**. A significant correlation was found between percentage changes in plasma vs saliva irisin increase between T0 and T1 (plasma 9.6 ± 15.2%, saliva 3.9 ± 4.4%; rho: 0.86, p:0.02*). This preliminary study is the first to explore irisin production following resistance training sessions in both saliva and plasma. The results show a moderate but significant increase for both plasma and saliva irisin. Correlation analysis, although preliminary, suggests that saliva sampling might be a sensitive method for detecting changes in irisin levels in response to resistance training exercises. Further studies with larger sample sizes and additional sampling points are required to comprehensively understand irisin's role in resistance training
Novel missense mutations in PNPLA2 causing late onset and clinical heterogeneity of neutral lipid storage disease with myopathy in three siblings
No full textNeutral lipid storage disease with myopathy (NLSD-M) is a rare autosomal recessive disorder characterised by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). NLSD-M patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. Mutations in the PNPLA2 gene cause variable phenotypes of NLSD-M. PNPLA2 codes for adipose triglyceride lipase (ATGL), an enzyme that hydrolyses fatty acids from triacylglycerol. This report outlines the clinical and genetic findings in a NLSD-M Italian family with three affected members. In our patients, we identified two novel PNPLA2 missense mutations (p.L56R and p.I193F). Functional data analysis demonstrated that these mutations caused the production of ATGL proteins able to bind to LDs, but with decreased lipase activity. The oldest brother, at the age of 38, had weakness and atrophy of the right upper arm and kyphosis. Now he is 61. years old and is unable to raise arms in the horizontal position. The second brother, from the age of 44, had exercise intolerance, cramps and pain in lower limbs. He is currently 50. years old and has an asymmetric distal amyotrophy. One of the two sisters, 58. years old, presents the same PNPLA2 mutations, but she is still oligo-symptomatic on neuromuscular examination with slight triceps muscle involvement. She suffered from diabetes and liver steatosis. This NLSD-M family shows a wide range of intra-familial phenotypic variability in subjects carrying the same mutations, both in terms of target-organs and in terms of rate of disease progression
A novel mutation of ABHD5 gene in a Chanarin Dorfman patient with unusual dermatological findings
No full textBackground: Chanarin Dorfman Syndrome (CDS) is a rare autosomal recessive disorder characterized by the multisytemic accumulation of neutral lipids inside the cytoplasmic lipid droplets. This condition is caused by mutations in the abhydrolase domain containing 5 gene (ABHD5). In CDS the skin involvement is the prevalent and always observed clinical feature, consisting of a non-bullous congenital ichthyosiform erythroderma (NCIE). Moreover, a variable involvement of the liver and neuromuscular system can be also observed. In this report, we aimed to perform the clinical and genetic characterization of a patient affected by CDS with atypical dermatological findings, considering this rare inborn error of neutral lipid metabolism.
Methods: Genomic DNA samples obtained from patient and his parents were used to perform the sequencing of the ABHD5 exons and their intron/exon boundaries. Bioinformatic analyses were performed to investigate the possible effect of the identified mutation on protein structure.
Results: Here we present the case of a 29-year-old male patient with CDS, who, for long time, has been misdiagnosed as pityriasis rubra pilaris (PRP). He has a history of increasing hyperlipidemia; hepatomegaly associated with hepatosteatosis was also detected. ABHD5 molecular analysis revealed a novel missense mutation, the c.811G > A (p.G271R). Bioinformatic investigations showed that the variant has a deleterious effect on ABHD5 function, probably causing an incorrect folding of the mutant protein.
Conclusions: These results highlihts the importance of genetic testing for ABHD5 in unresolved cases of patients presenting unusual skin lesions, that resemble PRP, associated with a history of hyperlipidemia and nonalcoholic fatty live
A novel PNPLA2 mutation causing total loss of RNA and protein expression in two NLSDM siblings with early onset but slowly progressive severe myopathy
No full textNeutral lipid storage disease with myopathy (NLSDM) is a rare autosomal recessive disorder, due to an enzymatic error of lipid metabolism. Patients present always with skeletal muscle myopathy and variable cardiac and hepatic involvement. NLSDM is caused by mutations in the PNPLA2 gene, which encodes the adipose triglyceride lipase (ATGL). Here we report the molecular characterization and clinical findings of two NLSDM siblings carrying the novel c.187+1G > C homozygous PNPLA2 mutation, localized in the splice site of intron 2. Molecular analyses revealed that neither aberrant PNPLA2 mRNA isoforms, nor ATGL mutated protein were detectable in patient's cells.
Clinically, both patients presented early onset muscle weakness, in particular of proximal upper limb muscles. In almost 15 years, muscle damage affected also distal upper limbs.
This is a NLSDM family, displaying a severe PNPLA2 mutation in two siblings with clinical presentation characterized by an early onset, but a slowly evolution of severe myopathy
Severe cardiomyopathy in a young patient with complete deficiency of adipose triglyceride lipase due to a novel mutation in PNPLA2 gene
No full textWe report the case of a 26 year-old male patient affected by neutral lipid storage myopathy with severe cardiac involvement. Patient parents were first cousins; a brother died at 3 years of age, during surgery. They referred that the child had always walked on toes, but he never presented weakness or difficulties in physical activity, compared to peers. The patient was first evaluated when he was 11 years-old and was reported to walk on toes, with difficulty to walk on heels, and to have mild calves hypertrophy and reduced tendon reflexes. Blood test revealed high values of CK (1657 U/L), while total and free carnitine levels were normal. Electromyography was normal; an effort test revealed excessive increase in lactic acid levels. He underwent a muscle biopsy that showed abnormal lipid storage. He was diagnosed to suffer from a lipid storage myopathy and therapy with riboflavin was started with some benefit to the patient. A neutral lipid storage myopathy was hypothesized and molecular analysis of the PNPLA2 gene revealed a homozygous novel deletion of seven nucleotides in exon 2 (c.41_47delGCTGCGG)
The BDNFval66met polymorphism and individual differences in temperament in 4-month-old infants: A pilot study
No full textIndividual differences in infants’ temperament are under genetic control. We investigated the association between brain-derived-neurotrophic-factor (BDNFval66met) polymorphism and temperament in 63 full-term infants. Met-carriers (N = 25) had lower Regulatory capacities compared to val-homozygotes (N = 38). These findings suggest that the BDNF polymorphism affects early temperament individual differences
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