5 research outputs found
The analysis of PIK3CA mutations in gastric carcinoma and metanalysis of literature suggest that exon-selectivity is a signature of cancer type
BACKGROUND: PIK3CA is one of the genes most frequently mutated in human cancers and it is a potential target for personalized therapy. The aim of this study was to assess the frequency and type of PIK3CA mutations in gastric carcinoma and compare them with their clinical pathological correlates. METHODS: We analysed 264 gastric cancers, including 39 with microsatellite instability (MSI), for mutations in the two PIK3CA hotspots in exons 9 and 20 by direct sequencing of DNA obtained from microdissected cancer cells. RESULTS: The cases harbouring mutations were 42 (16%). All were heterozygous missense single base substitutions; the most common was H1047R (26/42; 62%) in exon 20 and the second was Q546K (4/42; 9.5%) in exon 9. All the mutated MSI cases (8/39) carried the H1047R mutation. No other association between PI3KCA mutations and clinical pathological covariates was found. A metanalysis of the mutations occurring in the same regions in 27 publications showed that ratio between exon 20 and exon 9 prevalences was 0.6 (95% CI: 0.5 -0.8) for colon, 1.6 (95% CI: 1.1 -2.3) for breast, 2.7 (95% CI: 1.6 -4.9) for gastric and 4.1 (95% CI: 1.9 -10.3) for endometrial cancer. CONCLUSIONS: The overall prevalence of PIK3CA mutations implies an important role for PIK3CA in gastric cancer. The lack of association with any clinical-pathological condition suggests that mutations in PIK3CA occur early in the development of cancer. The metanalysis showed that exon-selectivity is an important signature of cancer type reflecting different contexts in which tumours arise
Association between preoperative evaluation with lung ultrasound and outcome in frail elderly patients undergoing orthopedic surgery for hip fractures: study protocol for an Italian multicenter observational prospective study (LUSHIP)
Hip fracture is one of the most common orthopedic causes of hospital admission in frail elderly patients. Hip fracture fixation in this class of patients is considered a high-risk procedure. Preoperative physical examination, plasma natriuretic peptide levels (BNP, Pro-BNP), and cardiovascular scoring systems (ASA-PS, RCRI, NSQIP-MICA) have all been demonstrated to underestimate the risk of postoperative complications. We designed a prospective multicenter observational study to assess whether preoperative lung ultrasound examination can predict better postoperative events thanks to the additional information they provide in the form of "indirect" and "direct" cardiac and pulmonary lung ultrasound signs
Analysis of single nucleotide polymorphisms (SNPs) to assess the genetic risk of disease
L’analisi dei polimorfismi a singolo nucleotide (SNPs) in popolazioni di pazienti e
soggetti sani può contribuire a chiarire le basi genetiche delle malattie complesse mediante
l’identificazione di possibili fattori di rischio genetico. In questo lavoro di tesi sono
riportati quattro studi di associazione genetica che tentano di assegnare ad alcune varianti
genetiche un ruolo nello sviluppo e progressione di malattie complesse quali il cancro
gastrico, il linfoma e una rara malattia autoimmune: la sclerosi sistemica.
Nel primo studio, due polimorfismi del gene ADP-ribosylation factor-like tumorsuppressor
gene 1 (ARLTS1), precedentemente associati ad una maggiore predisposizione
a vari tipi di cancro familiare, sono risultati associati al rischio di cancro gastrico. Le
frequenze dei polimorfismi G446A e T442C, determinate mediante sequenziamento
diretto in una casistica di 297 pazienti e in 340 soggetti sani, hanno presentato differenze
statisticamente significative tra le due popolazioni. Questi risultati suggeriscono che
ARLTS1 possa avere un ruolo nella patogenesi del cancro gastrico.
Alcuni polimorfismi di geni coinvolti nella risposta infiammatoria sono stati
associati al rischio di sviluppo di cancro gastrico. In questo studio, sono state analizzate le
frequenze genotipiche di 10 SNP contenuti nei geni IL1A, IL1B, IL1RN, IL2, IL6, IL10,
TNF e LTA in 453 pazienti con cancro gastrico (328 con istotipo intestinale, 99 diffuso e
26 misto) e 1174 controlli. Rispetto ai dati riportati in letteratura, non è stata trovata
alcuna correlazione tra i polimorfismi IL1B-31 e IL1B-511 e il rischio di cancro gastrico.
Per quanto riguarda i restanti SNP analizzati, solo per il polimorfismo IL10-3575 è stata
trovata una differenza statisticamente significativa tra le distribuzioni genotipiche dei casi
e controlli. E’ probabile che alla base dei risultati discrepanti ci siano differenze
geografiche legate alla dieta, agli stili di vita o al background genetico. I nostri dati non
supportano un’associazione tra i polimorfismi di IL1B e l’aumento del rischio di cancro
gastrico, ma piuttosto suggeriscono un ruolo delle varianti di IL10 nello sviluppo del
cancro gastrico.
Varianti comuni di geni della risposta immunitaria ed infiammatoria possono
influenzare il rischio di sviluppare il linfoma non Hodgkin. Questa ipotesi è stata vagliata
in un terzo studio in cui sono stati analizzati i dati non pubblicati provenienti da un
consorzio multicentrico, l’International Lymphoma Epidemiology Consortium
(InterLymph). Sulla base dei dati d’associazione e funzionali riportati in letteratura, sono
stati selezionati 12 SNP contenuti in 9 geni importanti per lo sviluppo dei linfonodi,
l’equilibrio Th1/Th2 e per la risposta pro/anti infiammatoria (IL1A, IL1RN, IL1B, IL2, IL6,
IL10, TNF, LTA, and CARD15). Sono stati analizzati 3586 casi di linfoma non Hodgkin e
4018 controlli. I polimorfismi TNF G-308A e IL10 T−3575A sono risultati associati al
rischio di linfoma non Hodgkin, in particolare al linfoma diffuso a grandi cellule B, il
principale sottotipo istologico, ma non al linfoma follicolare. Gli individui omozigoti per
l’allele TNF −308 A e portatori di almeno un’allele IL10 −3575 A possiedono un rischio
doppio di linfoma diffuso a grandi cellule B. Questi risultati suggeriscono che
polimorfismi di TNF and IL10, citochine chiave nella risposta infiammatoria e nel
bilanciamento Th1/Th2, potrebbero essere loci di suscettibilità per il linfoma non
Hodgkin.
Nell’ultimo studio sono state analizzate le possibili associazioni di 9 SNP nei geni
IL10, IL1B, IL1A, IL1RN, IL2, LTA e IL6 con la suscettibilità ad una rara malattia
autoimmune, la sclerosi sistemica (SSc). E’ stato determinato il genotipo di 78 pazienti
con SSc (31 con SSc diffusa (dcSSc), 47 con SSc di tipo limitato (lcSSc)) e di 692
donatori di sangue sani. Le frequenze dei polimorfismi IL1B-31 e IL1B-511 sono risultate
differenti nelle due popolazioni. I portatori di almeno una copia dell’allele IL1B-31 C
possiedono un rischio più alto di SSc e una simile associazione è stata osservata per i
portatori dell’allele IL1B-511 T. Inoltre, i portatori dell’allele IL2-384 G sono
significativamente più frequenti tra i pazienti con lcSSc, rispetto ai pazienti con il
sottotipo diffuso. Infine, le distribuzioni genotipiche di IL2-384 nei controlli e nei pazienti
affetti da lcSSc sono risultate differenti, mentre non sono state riscontrate differenze
statisticamente significative tra controlli e pazienti dcSSc. In conclusione, i polimorfismi
dei geni IL1B e IL2 possono essere coinvolti nella suscettibilità a SSc e l’allele IL2-384 G
potrebbe essere un marcatore per la forma limitata di SSc.An approach to elucidate the genetic basis of human complex diseases and to
identify the possible genetic risk factors, is to analyze the distribution of single nucleotide
polymorphisms (SNPs) in affected and control populations and assess the genetic risk of
disease. Four genetic association studies were reported in this work that attempt to
determine clinical significance of several genetic variants in the development and
progression of complex human diseases, such as gastric cancer, lymphoma and systemic
sclerosis.
In the first study, two polymorphisms in the ADP-ribosylation factor-like tumorsuppressor
gene 1 (ARLTS1) gene, already reported to be predisposing for various types of
familial cancers, were associated with risk of gastric cancer. We analyzed the frequency of
G446A and T442C polymorphisms in a series of 297 patients and 340 controls, by means
of direct sequencing, and we found significant differences in the frequencies between the
two groups. These results suggest that ARLTS1 may be related to the pathogenesis of
gastric cancer.
Polymorphisms in several genes involved in an inflammatory response have been
variably associated with increased risk for development of gastric cancer. We have
examined the genotypic frequencies of 10 polymorphisms in the inflammatory genes
IL1A, IL1B, IL1RN, IL2, IL6, IL10, TNF, and LTA in 453 patients with gastric cancer and
1174 controls. Cancers included 328 intestinal, 99 diffuse and 26 mixed histotype. We
found no statistically significant correlations between the risk of gastric cancer and the
IL1B-31 and IL1B-511 alleles. Of the remainder of the polymorphisms, only the IL10-
3575 SNP showed a significantly different distribution between cases and controls.
Geographical differences attributable to diet, lifestyles or genetic background may be
potential sources of discrepant results among previous reports. Our data do not support an
association between polymorphisms in IL1B and an increased risk for gastric cancer, but
instead, suggest that variants in the IL10 gene may confer increased risk.
Common genetic variants in immune and inflammatory response genes can affect
the risk of developing non-Hodgkin lymphoma. We aimed to test this hypothesis using
previously unpublished data from eight European, Canadian, and US case-control studies
of the International Lymphoma Epidemiology Consortium (InterLymph). We selected 12
single-nucleotide polymorphisms for analysis, on the basis of previous functional or
association data, in nine genes that have important roles in lymphoid development,
Th1/Th2 balance, and proinflammatory or anti-inflammatory pathways (IL1A, IL1RN,
IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15). Genotype data for one or more SNPs were
available for 3586 cases of non-Hodgkin lymphoma and for 4018 controls. The TNF G-
308A and IL10 T−3575A polymorphisms were associated with increased risk of non-
Hodgkin lymphoma, particularly for diffuse large B-cell lymphoma, the main histological
subtype, but not for follicular lymphoma. For individuals homozygous for the TNF −308A
allele and carrying at least one IL10 −3575A allele, risk of diffuse large B-cell lymphoma
doubled. These results suggest that common polymorphisms in TNF and IL10, which are
key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility
loci for non-Hodgkin lymphoma.
The last genetic association study reported in this work aims to investigate possible
associations of 9 single nucleotide polymorphisms in the IL10, IL1B, IL1A, IL1RN, IL2,
LTA and IL6 genes with susceptibility to rare autoimmune disease, systemic sclerosis
(SSc). A total of 78 patients with SSc [diffuse SSc (dcSSc), n=31; limited SSc, (lcSSc),
n=47] and 692 healthy blood donors were genotyped. Alleles in IL1B-31 and IL1B-511
showed a significantly different distribution between cases and controls. Carriers of at
least one copy of the IL1B-31-C allele had an increased risk of SSc, while a similar strong
association was also evident for IL1B-511-T carriers. Interestingly, carriers of the IL2-
384-G allele were significantly more frequent in lcSSc patients, compared to patients with
the diffuse subtype. Lastly, the distribution of the IL2-384 genotype showed statistically
significant differences between controls and lcSSc patients. There were no differences
between dcSSc patients and controls. We concluded that IL1B and IL2 gene
polymorphisms may be involved in susceptibility to SSc. Moreover, the IL2-384-G allele
may be a marker for the limited phenotype of SSc
Can Lung Ultrasound Be the Ideal Monitoring Tool to Predict the Clinical Outcome of Mechanically Ventilated COVID-19 Patients? An Observational Study
Background: During the COVID-19 pandemic, lung ultrasound (LUS) has been widely used since it can be performed at the patient’s bedside, does not produce ionizing radiation, and is sufficiently accurate. The LUS score allows for quantifying lung involvement; however, its clinical prognostic role is still controversial. Methods: A retrospective observational study on 103 COVID-19 patients with respiratory failure that were assessed with an LUS score at intensive care unit (ICU) admission and discharge in a tertiary university COVID-19 referral center. Results: The deceased patients had a higher LUS score at admission than the survivors (25.7 vs. 23.5; p-value = 0.02; cut-off value of 25; Odds Ratio (OR) 1.1; Interquartile Range (IQR) 1.0−1.2). The predictive regression model shows that the value of LUSt0 (OR 1.1; IQR 1.0–1.3), age (OR 1.1; IQR 1.0−1.2), sex (OR 0.7; IQR 0.2−3.6), and days in spontaneous breathing (OR 0.2; IQR 0.1–0.5) predict the risk of death for COVID-19 patients (Area under the Curve (AUC) 0.92). Furthermore, the surviving patients showed a significantly lower difference between LUS scores at admission and discharge (mean difference of 1.75, p-value = 0.03). Conclusion: Upon entry into the ICU, the LUS score may play a prognostic role in COVID-19 patients with ARDS. Furthermore, employing the LUS score as a monitoring tool allows for evaluating the patients with a higher probability of survival