Publications by authors named "Massimiliano Copetti"

222 Publications

Involvement of Gut Microbiota in Schizophrenia and Treatment Resistance to Antipsychotics.

Biomedicines 2021 Jul 23;9(8). Epub 2021 Jul 23.

Unit of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, 09127 Cagliari, Italy.

The gut microbiota is constituted by more than 40,000 bacterial species involved in key processes including high order brain functions. Altered composition of gut microbiota has been implicated in psychiatric disorders and in modulating the efficacy and safety of psychotropic medications. In this work we characterized the composition of the gut microbiota in 38 patients with schizophrenia (SCZ) and 20 healthy controls (HC), and tested if SCZ patients with different response to antipsychotics (18 patients with treatment resistant schizophrenia (TRS), and 20 responders (R)) had specific patterns of gut microbiota composition associated with different response to antipsychotics. Moreover, we also tested if patients treated with typical antipsychotics (n = 20) presented significant differences when compared to patients treated with atypical antipsychotics (n = 31). Our findings showed the presence of distinct composition of gut microbiota in SCZ versus HC, with several bacteria at the different taxonomic levels only present in either one group or the other. Similar findings were observed also depending on treatment response and exposure to diverse classes of antipsychotics. Our results suggest that composition of gut microbiota could constitute a biosignatures of SCZ and TRS.
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http://dx.doi.org/10.3390/biomedicines9080875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389684PMC
July 2021

Transthoracic ultrasound shear wave elastography for the study of subpleural lung lesions.

Ultrasonography 2021 Apr 15. Epub 2021 Apr 15.

Unit of Interventional and Diagnostic Ultrasound, Department of Internal Medicine, IRCCS Fondazione Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.

Purpose: The aim of this study was to assess whether new-generation shear wave elastography (SWE) is suitable for the characterization of lung subpleural lesions.

Methods: In total, 190 consecutive patients with subpleural lung lesions received ultrasonography and SWE. Patients with suspected malignancy underwent ultrasound-guided transthoracic needle biopsy. Final diagnoses were made on the basis of patients' clinical course, microbiological studies, and histological results. SWE was also performed in 25 healthy volunteers.

Results: We found no statistically significant differences in stiffness between lung carcinomas, lung metastases, and pneumonia (P=0.296) or between different histological types of lung cancer (P=0.393). Necrosis was associated with reduced stiffness in pneumonia. Excluding necrotic lesions, pneumonia showed higher stiffness than lung carcinomas (2.95±0.68 m/s vs. 2.60±0.54 m/s, P=0.006). Chronic pneumonia showed increased stiffness (3.03±0.63 m/s), probably due to the presence of fibrotic tissue on histology. Pleural effusion was associated with a statistically significant reduction in stiffness, both in lung carcinomas (P=0.004) and lung metastases (P=0.002). The presence of air in healthy lung tissue may lead to incorrect speed estimates due to shear wave reflection (very high values, 14.64±2.19 m/s).

Conclusion: Transthoracic SWE could not distinguish lung malignancy from pneumonia, or between different histological types of lung carcinomas. In particular, SWE seems unable to resolve the clinical dilemma of chronic subpleural consolidations.
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http://dx.doi.org/10.14366/usg.21021DOI Listing
April 2021

A serum resistin and multi-cytokine inflammatory pathway is linked with and helps predict all-cause death in diabetes.

J Clin Endocrinol Metab 2021 Jun 30. Epub 2021 Jun 30.

Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.

Context: Type 2 diabetes shows high mortality rate, partly mediated by atherosclerotic plaque instability. Discovering novel biomarkers may help identify high-risk patients to expose to more aggressive and specific managements. We recently described a serum REsistin and multiMulti-cytokine inflammAatory Pathway (REMAP), including resistin, IL-1β, IL-6, IL-8 and TNF-α) which associates with cardiovascular disease.

Objective: We investigated whether REMAP associates with and improves the prediction of mortality in type 2 diabetes.

Design: A REMAP score was investigated in three cohorts comprising 1,528 patients with T2D (409 incident deaths) and in 59 patients who underwent carotid endoarterectomy (CEA; 24 deaths). Plaques were classified as unstable/stable according to the modified American Heart Association atherosclerosis classification.

Results: REMAP was associated to all-cause mortality in each cohort and in all 1,528 individuals (fully-adjusted HR for one SD increase =1.34, p<0.001). In CEA patients, REMAP was associated with mortality (HR =1.64, p = 0.04) and a modest change was observed when plaque stability was taken into account [HR =1.58; P = 0.07]. REMAP improved discrimination and reclassification measures of both ENFORCE and RECODe, well-established prediction models of mortality in type 2 diabetes (P<0.05-<0.001).

Conclusions: REMAP is independently associated with and improves predict all-cause mortality in type 2 diabetes; it can therefore be used to identify high-risk individuals to be targeted with more aggressive managements. Whether REMAP can also identify those patients who are more responsive to IL-6 and IL-1β monoclonal antibodies which reduce cardiovascular burden and total mortality is an intriguing possibility to be tested.
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http://dx.doi.org/10.1210/clinem/dgab472DOI Listing
June 2021

Which are the limiting factors in lung tissue sampling and diagnostic accuracy for a new Interventional Pulmonology Unit? From expert consensus-based evidence to results of a new-born Unit.

J Thorac Dis 2021 May;13(5):2942-2951

Pathology Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, (FG), Italy.

Background: There is a gap of knowledge about the factors that may determine the quality and the accuracy of diagnostic bronchoscopic procedures when setting up a new Interventional Pulmonology Unit. As little evidence-based medicine is available on this matter, an online consensus opinion of experts was gathered and compared with real-life data coming from a new Interventional Pulmonology (IP) Unit.

Methods: A survey was emailed to the heads of all Italian IP Units to investigate the factors influencing the success of the diagnostic yield of a new IP Unit. The survey consisted of 24 items grouped by topic; the level of agreement ranged from 1 (no influence) to 7 (strong influence). After responses were collected, we submitted the data on the accuracy of the endoscopic procedures performed during the first two years of our new IP Unit to the attention of the participants for a second round of survey; the level of consistency between the first and second round of responses was assessed.

Results: After having been shown the results of the first two years of activity of our Unit, in the second round of the survey the responders indicated the personal skills of the Interventional Pulmonologist, the availability of echoendoscopic technology and the expertise in evaluating cytological samples as the factors able to positively influence the performance of a newly established IP Unit. Neither the role of dedicated nursing assistance, the availability of a rapid on-site evaluation, nor the presence of anesthesiology assistance were considered to be limiting factors for the final accuracy results.

Conclusions: A consensus of opinion of a group of expert interventional pulmonologists highlighted the factors that may be responsible for the diagnostic success of a newly established Italian IP Unit. These factors are mainly three: personal skills of the interventional pulmonologist, the availability of echoendoscopic technology, and the expertise in reading cytological samples.
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http://dx.doi.org/10.21037/jtd-20-2990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182518PMC
May 2021

All-cause mortality prediction models in type 2 diabetes: applicability in the early stage of disease.

Acta Diabetol 2021 Oct 29;58(10):1425-1428. Epub 2021 May 29.

Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy.

Aims: The rate of all-cause mortality is twofold higher in type 2 diabetes than in the general population. Being able to identify patients with the highest risk from the very beginning of the disease would help tackle this burden.

Methods: We tested whether ENFORCE, an established prediction model of all-cause mortality in type 2 diabetes, performs well also in two independent samples of patients with early-stage disease prospectively followed up.

Results: ENFORCE's survival C-statistic was 0.81 (95%CI: 0.72-0.89) and 0.78 (95%CI: 0.68-0.87) in both samples. Calibration was also good. Very similar results were obtained with RECODe, an alternative prediction model of all-cause mortality in type 2 diabetes.

Conclusions: In conclusion, our data show that two well-established prediction models of all-cause mortality in type 2 diabetes can also be successfully applied in the early stage of the disease, thus becoming powerful tools for educated and timely prevention strategies for high-risk patients.
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http://dx.doi.org/10.1007/s00592-021-01746-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164049PMC
October 2021

The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Amyotrophic Lateral Sclerosis Progression: A Cross-Sectional Study.

Life (Basel) 2021 Apr 17;11(4). Epub 2021 Apr 17.

Neurology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Background-Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease; smoking and alcohol drinking may impact its progression rate. Objective-To ascertain the influence of smoking and alcohol consumption on ALS progression rates. Methods-Cross-sectional multicenter study, including 241 consecutive patients (145 males); mean age at onset was 59.9 ± 11.8 years. Cigarette smoking and alcohol consumption data were collected at recruitment through a validated questionnaire. Patients were categorized into three groups according to ΔFS (derived from the ALS Functional Rating Scale-Revised and disease duration from onset): slow ( = 81), intermediate (80), and fast progressors (80). Results-Current smokers accounted for 44 (18.3%) of the participants, former smokers accounted for 10 (4.1%), and non-smokers accounted for 187 (77.6%). The age of ALS onset was lower in current smokers than non-smokers, and the ΔFS was slightly, although not significantly, higher for smokers of >14 cigarettes/day. Current alcohol drinkers accounted for 147 (61.0%) of the participants, former drinkers accounted for 5 (2.1%), and non-drinkers accounted for 89 (36.9%). The log(ΔFS) was weakly correlated only with the duration of alcohol consumption ( = 0.028), but not with the mean number of drinks/day or the drink-years. Conclusions: This cross-sectional multicenter study suggested a possible minor role for smoking in worsening disease progression. A possible interaction with alcohol drinking was suggested.
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http://dx.doi.org/10.3390/life11040352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072690PMC
April 2021

Investigation of Nasal/Oropharyngeal Microbial Community of COVID-19 Patients by 16S rDNA Sequencing.

Int J Environ Res Public Health 2021 02 23;18(4). Epub 2021 Feb 23.

Gastroenterology Unit Fondazione-IRCCS "Casa Sollievo della Sofferenza" Hospital, 71013 San Giovanni Rotondo, Italy.

Since December 2019, SARS-CoV-2 infection has been still rapidly spreading, resulting in a pandemic, followed by an increasing number of cases in countries throughout the world. The severity of the disease depends on the patient's overall medical condition but no appropriate markers are available to establish the prognosis of the patients. We performed a 16S rRNA gene sequencing, revealing an altered composition of the nasal/oropharyngeal (NOP) microbiota in 21 patients affected by COVID-19, paucisymptomatic or in an Intensive Care Unit (ICU), as compared to 10 controls negative for COVID-19 or eight affected by a different Human Coronavirus (HKU, NL63 and OC43). A significant decrease in Chao1 index was observed when patients affected by COVID-19 (in ICU) were compared to paucisymptomatic. Furthermore, patients who were in ICU, paucisymptomatic or affected by other Coronaviruses all displayed a decrease in the Chao1 index when compared to controls, while Shannon index significantly decreased only in patients under ICU as compared to controls and paucisymptomatic patients. At the phylum level, Deinococcus-Thermus was present only in controls as compared to SARS-CoV-2 patients admitted to ICU, paucisymptomatic or affected by other coronaviruses. Candidatus Saccharibacteria (formerly known as TM7) was strongly increased in negative controls and SARS-CoV-2 paucisymptomatic patients as compared to SARS-CoV-2 ICU patients. Other modifications were observed at a lower taxonomy level. Complete depletion of Bifidobacterium and Clostridium was exclusively observed in ICU SARS-CoV-2 patients, which was the only group characterized by the presence of Salmonella, Scardovia, Serratia and Pectobacteriaceae. In conclusion, our preliminary results showed that nasal/oropharyngeal microbiota profiles of patients affected with SARS-CoV-2 may provide valuable information in order to facilitate the stratification of patients and may open the way to new interventional strategies in order to ameliorate the outcome of the patients.
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http://dx.doi.org/10.3390/ijerph18042174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926517PMC
February 2021

Diagnosis of COVID-19 in Patients with Negative Nasopharyngeal Swabs: Reliability of Radiological and Clinical Diagnosis and Accuracy Versus Serology.

Diagnostics (Basel) 2021 Feb 25;11(3). Epub 2021 Feb 25.

Unit of Internal Medicine, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Background: The diagnosis of Coronavirus disease 2019 (COVID-19) relies on the positivity of nasopharyngeal swab. However, a significant percentage of symptomatic patients may test negative. We evaluated the reliability of COVID-19 diagnosis made by radiologists and clinicians and its accuracy versus serology in a sample of patients hospitalized for suspected COVID-19 with multiple negative swabs.

Methods: Admission chest CT-scans and clinical records of swab-negative patients, treated according to the COVID-19 protocol or deceased during hospitalization, were retrospectively evaluated by two radiologists and two clinicians, respectively.

Results: Of 254 patients, 169 swab-confirmed cases and one patient without chest CT-scan were excluded. A total of 84 patients were eligible for the reliability study. Of these, 21 patients died during hospitalization; the remaining 63 underwent serological testing and were eligible for the accuracy evaluation. Of the 63, 26 patients showed anti-Sars-Cov-2 antibodies, while 37 did not. The inter-rater agreement was "substantial" (kappa 0.683) between radiologists, "moderate" (kappa 0.454) between clinicians, and only "fair" (kappa 0.341) between radiologists and clinicians. Both radiologic and clinical evaluations showed good accuracy compared to serology.

Conclusions: The radiologic and clinical diagnosis of COVID-19 for swab-negative patients proved to be sufficiently reliable and accurate to allow a diagnosis of COVID-19, which needs to be confirmed by serology and follow-up.
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http://dx.doi.org/10.3390/diagnostics11030386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996330PMC
February 2021

Interobserver agreement of the Paris and simplified classifications of superficial colonic lesions: a Western study.

Endosc Int Open 2021 Mar 19;9(3):E388-E394. Epub 2021 Feb 19.

Fondazione "Casa Sollievo della Sofferenza", IRCCS, Gastroenterology and Endoscopy Units, San Giovanni Rotondo, Foggia, Italy.

The Paris classification of superficial colonic lesions has been widely adopted, but a simplified description that subgroups the shape into pedunculated, sessile/flat and depressed lesions has been proposed recently. The aim of this study was to evaluate the accuracy and inter-rater agreement among 13 Western endoscopists for the two classification systems. Seventy video clips of superficial colonic lesions were classified according to the two classifications, and their size estimated. The interobserver agreement for each classification was assessed using both Cohen k and AC1 statistics. Accuracy was taken as the concordance between the standard morphology definition and that made by participants. Sensitivity analyses investigated agreement between trainees (T) and staff members (SM), simple or mixed lesions, distinct lesion phenotypes, and for laterally spreading tumors (LSTs). Overall, the interobserver agreement for the Paris classification was substantial (κ = 0.61; AC1 = 0.66), with 79.3 % accuracy. Between SM and T, the values were superimposable. For size estimation, the agreement was 0.48 by the κ-value, and 0.50 by AC1. For single or mixed lesions, κ-values were 0.60 and 0.43, respectively; corresponding AC1 values were 0.68 and 0.57. Evaluating the several different polyp subtypes separately, agreement differed significantly when analyzed by the k-statistics (0.08-0.12) or the AC1 statistics (0.59-0.71). Analyses of LSTs provided a κ-value of 0.50 and an AC1 score of 0.62, with 77.6 % accuracy. The simplified classification outperformed the Paris classification: κ = 0.68, AC1 = 0.82, accuracy = 91.6 %. Agreement is often measured with Cohen's κ, but we documented higher levels of agreement when analyzed with the AC1 statistic. The level of agreement was substantial for the Paris classification, and almost perfect for the simplified system.
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http://dx.doi.org/10.1055/a-1352-3437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895665PMC
March 2021

Accuracy and inter-observer agreement of the nice and kudo classifications of superficial colonic lesions: a comparative study.

Int J Colorectal Dis 2021 Jul 1;36(7):1561-1568. Epub 2021 Mar 1.

Gastroenterology and Endoscopy Units, Fondazione "Casa Sollievo della Sofferenza", IRCCS, San Giovanni Rotondo, Italy.

Purpose: For superficial colonic lesions, the NICE and Kudo classifications are used in the in vivo prediction of histology and as guide to therapy. The NICE system derives information from unmagnified NBI endoscopic images. The Kudo one necessitates a magnification, but, as this tool is not commonly available, it is applied also to characterize unmagnified pictures to compare their diagnostic performances.

Methods: We conducted a prospective comparison of the NICE versus the Kudo classification for the differential diagnosis of colonic polyps taking histology as the gold standard. The inter-observer agreement for both classifications among 11 colonoscopists was also evaluated. Short unmagnified NBI videoclips of 64 colonic polyps were sent twice to the participants. In the first round, they classified the lesions according to the NICE classification; 4 months later, the same videos were assessed with the Kudo system. The diagnosis provided by the participants was grouped in non-neoplastic, non-invasive neoplasia, invasive neoplasia.

Results: Overall, the diagnostic accuracy was 82% (95%CI: 79-85) with the NICE system and 81% (95%CI: 78-84) with the Kudo one (ρ = 0.78). The accuracy of the NICE classification for non-neoplastic lesions was greater compared with the Kudo's (ρ = 0.03). Sensitivity sub-analyses revealed a higher ability of the NICE in distinguishing between neoplastic vs. non-neoplastic lesions (ρ = 0.01). The overall inter-rater agreement did not differ when the classifications were compared.

Conclusion: The NICE and the Kudo classifications might be considered comparable. Our data could allow the use of the NBI Kudo classification even in those centers where magnification is not available.
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http://dx.doi.org/10.1007/s00384-021-03897-8DOI Listing
July 2021

Machine and deep learning in multiple sclerosis research are just powerful statistics - Commentary.

Mult Scler 2021 04 24;27(5):664-666. Epub 2021 Feb 24.

Medical Data Science & Analytics, Personalized Health Research Analytics & Solution, World Wide Medical, Biogen, Cambridge, MA, USA.

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http://dx.doi.org/10.1177/1352458521996699DOI Listing
April 2021

Combined analysis of miR-200 family and its significance for breast cancer.

Sci Rep 2021 Feb 3;11(1):2980. Epub 2021 Feb 3.

Laboratorio Di Oncologia, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale Padre Pio, 71013, San Giovanni Rotondo, FG, Italy.

While the molecular functions of miR-200 family have been deeply investigated, a role for these miRNAs as breast cancer biomarkers remains largely unexplored. In the attempt to clarify this, we profiled the miR-200 family members expression in a large cohort of breast cancer cases with a long follow-up (H-CSS cohort) and in TCGA-BRCA cohort. Overall, miR-200 family was found upregulated in breast tumors with respect to normal breast tissues while downregulated in more aggressive breast cancer molecular subtypes (i.e. Luminal B, HER2 and triple negative), consistently with their function as repressors of the epithelial-to-mesenchymal transition (EMT). In particular miR-141-3p was found differentially expressed in breast cancer molecular subtypes in both H-CSS and TCGA-BRCA cohorts, and the combined analysis of all miR-200 family members demonstrated a slight predictive accuracy on H-CSS cancer specific survival at 12 years (survival c-statistic: 0.646; 95%CI 0.538-0.754).
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http://dx.doi.org/10.1038/s41598-021-82286-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859396PMC
February 2021

Review of clinical and molecular variability in autosomal recessive cutis laxa 2A.

Am J Med Genet A 2021 03 27;185(3):955-965. Epub 2020 Dec 27.

Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, Foggia, Italy.

ATP6V0A2-related cutis laxa, also known as autosomal recessive cutis laxa type 2A (ARCL2A), is a subtype of hereditary cutis laxa originally characterized by skin, skeletal, and neurological involvement, and a combined defect of N-glycosylation and O-glycosylation. The associated clinical spectrum subsequently expanded to a less severe phenotype dominated by cutaneous involvement. At the moment, ARCL2A was described in a few case reports and series only. An Italian adult woman ARCL2A with a phenotype restricted to skin and the two novel c.3G>C and c.1101dup ATP6V0A2 variants has been reported. A systematic literature review allowed us to identify 69 additional individuals from 64 families. Available data were scrutinized in order to describe the clinical and molecular variability of ARCL2A. About 78.3% of known variants were predicted null alleles, while 11 were missense and 2 affected noncanonical splice sites. Age at ascertainment appeared as the unique phenotypic discriminator with earlier age more commonly associated with facial dysmorphism (p .02), high/cleft palate (p .005), intellectual disability/global developmental delay (p .013), and seizures (p .024). No specific genotype-phenotype correlations were identified. This work confirmed the existence of an attenuated phenotype associated with ATP6V0A2 biallelic variants and offers an updated critique to the clinical and molecular variability of ARCL2A.
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http://dx.doi.org/10.1002/ajmg.a.62047DOI Listing
March 2021

Is positivity for hepatitis C virus antibody predictive of lower risk of death in COVID-19 patients with cirrhosis?

World J Clin Cases 2020 Nov;8(22):5831-5834

Department of Biostatistics, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo 71013, Italy.

Liver injury has been reported in coronavirus disease 2019 (COVID-19) cases but the impact of pre-existing liver damage and related etiology have not been completely elucidated. Our research interests include the potential reciprocal influence of COVID-19 and pre-existing liver damage related to hepatitis C virus (HCV) infection, in particular. To this end, we have evaluated three cohorts of patients admitted at three Italian hospitals during the coronavirus pandemic; these included 332 patients with COVID-19 and 1527 patients with HCV who were from established real-world antiviral treatment study cohorts (sofosbuvir/velpatasvir), with either liver disease (various severities; = 1319) or cirrhosis ( = 208). Among the COVID-19 patients, 10 had cirrhosis (3%), including 7 of metabolic origin and 3 of viral origin. Mortality among the COVID-19 patients was 27.1%, with 70% of those with cirrhosis of metabolic etiology having died. Cirrhosis, older age, low white blood cell count and lymphocyte count being identified as risk predictors of death [odds ratio (OR) = 13.7, 95% confidence interval (CI): 2.59-83.01, = 0.006; OR = 1.05, 95%CI: 1.03-1.08, = 0.0001; OR = 1.09, 95%CI: 1.36-1.16, = 0.001; OR = 0.61, 95%CI: 0.39-0.93, = 0.023, respectively]. In the two cohorts of HCV patients, COVID-19 diagnosis was made in 0.07% of those with liver disease and 1% of those with cirrhosis. Thus, the prevalence of HCV antibodies among COVID-19-infected patients was comparable to that currently reported for the general population in Italy. Amongst the COVID-19 patients, pre-existing metabolic cirrhosis appears to be associated with higher mortality, while HCV antibodies may be suggestive of "protection" against COVID-19.
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http://dx.doi.org/10.12998/wjcc.v8.i22.5831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716316PMC
November 2020

The presenting symptoms of Lafora Disease: An electroclinical and genetic study in five Apulian (Southern Italy) families.

Seizure 2020 Dec 27;83:145-153. Epub 2020 Oct 27.

Epilepsy Centre-S.C. Neurologia Universitaria, Policlinico Riuniti, Foggia, Italy.

Purpose: To elucidate the presenting symptoms of Lafora Disease (LD) to differentiate it from Juvenile Myoclonic Epilepsy (JME).

Methods: We collected and evaluated the early electroclinical data of 5 unrelated Apulian (Southern Italy) LD families, 30 LD patients selected from the literature, and 30 Apulian JME patients.

Results: The Apulian LD patients presented with generalised tonic-clonic and focal visual seizures, followed by myoclonic seizures and action-postural myoclonus. In these patients, EEG background slowing and occipital epileptiform abnormalities were significantly more evident than in the other groups. Genetic analysis revealed the presence of mutations in the EPM2A gene in 4 families, and in the NHLRC1 gene in the remaining family. In detail, we identified 2 different point mutations in EPM2A and only 1 in NHLRC1, and expanded the molecular spectrum of the EPM2A gene mutations reporting for the first time a patient carrier of the c.243_246del genetic variant. In the previously reported LD cases, generalised tonic-clonic and focal visual seizures and myoclonus were the most frequent symptoms, as confirmed by the first EEGs showing occipital or diffuse epileptiform abnormalities with photosensitivity in the background activity slowing. In the Apulian JME patients, myoclonus appeared earlier, usually at awakening, with diffuse epileptiform abnormalities during sleep and photosensitivity in the normal background activity. The diagnosis of JME was established much earlier than the LD one. During evolution, unlike JME patients, LD patients showed a significant resistance to drugs.

Conclusions: Tonic-clonic and focal visual seizures followed by myoclonic seizures and action-postural myoclonus together with EEG background slowing with diffuse and occipital epileptiform abnormalities suggest a diagnosis of LD. An early molecular confirmation allows a better diagnosis, counselling and management of affected patients and their families, and it may be useful to improve the patients' quality of life using, when possible, emerging personalized treatments that may slow the evolution of the disease.
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http://dx.doi.org/10.1016/j.seizure.2020.10.022DOI Listing
December 2020

Brain structural alterations in patients with mutations associated DOPA-responsive dystonia.

J Neurol Neurosurg Psychiatry 2021 03 21;92(3):332-333. Epub 2020 Oct 21.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy

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http://dx.doi.org/10.1136/jnnp-2020-324535DOI Listing
March 2021

Hsa-miR-155-5p Up-Regulation in Breast Cancer and Its Relevance for Treatment With Poly[ADP-Ribose] Polymerase 1 (PARP-1) Inhibitors.

Front Oncol 2020 12;10:1415. Epub 2020 Aug 12.

Fondazione IRCCS Casa Sollievo Della Sofferenza, Laboratorio di Oncologia, San Giovanni Rotondo, Italy.

miR-155-5p is a well-known oncogenic microRNA, showing frequent overexpression in human malignancies, including breast cancer. Here, we show that high miR-155-5p levels are associated with unfavorable prognostic factors in two independent breast cancer cohorts (CSS cohort, = 283; and TCGA-BRCA dataset, = 1,095). Consistently, miR-155-5p results as differentially expressed in the breast cancer subgroups identified by the surrogate molecular classification in the CSS cohort and the PAM50 classifier in TCGA-BRCA dataset, with the TNBC and -amplified tumors carrying the highest levels. Since the analysis of TCGA-BC dataset also demonstrated a significant association between miR-155-5p levels and the presence of mutations in homologous recombination (HR) genes, we hypothesized that miR-155-5p might affect cell response to the PARP-1 inhibitor Olaparib. As expected, miR-155-5p ectopic overexpression followed by Olaparib administration resulted in a greater reduction of cell viability as compared to Olaparib administration alone, suggesting that miR-155-5p might induce a synthetic lethal effect in cancer cells when coupled with PARP-1-inhibition. Overall, our data point to a role of miR-155-5p in homologous recombination deficiency and suggest miR-155-5p might be useful in predicting response to PARP1 inhibitors in the clinical setting.
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http://dx.doi.org/10.3389/fonc.2020.01415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435065PMC
August 2020

Exploring the Role of Gut Microbiota in Major Depressive Disorder and in Treatment Resistance to Antidepressants.

Biomedicines 2020 Aug 27;8(9). Epub 2020 Aug 27.

Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.

Major depressive disorder (MDD) is a common severe psychiatric illness, exhibiting sub-optimal response to existing pharmacological treatments. Although its etiopathogenesis is still not completely understood, recent findings suggest that an altered composition of the gut microbiota might play a role. Here we aimed to explore potential differences in the composition of the gut microbiota between patients with MDD and healthy controls (HC) and to identify possible signatures of treatment response by analyzing two groups of MDD patients characterized as treatment-resistant (TR) or responders (R) to antidepressants. Stool samples were collected from 34 MDD patients (8 TR, 19 R and 7 untreated) and 20 HC. Microbiota was characterized using the 16S metagenomic approach. A penalized logistic regression analysis algorithm was applied to identify bacterial populations that best discriminate the diagnostic groups. Statistically significant differences were identified for the families of and , for the genus , and the species , , and among others. The phyla and the family were more abundant in TR, whereas the phylum was enriched in R patients. Moreover, a number of bacteria only characterized the microbiota of TR patients, and many others were only detected in R. Our results confirm that dysbiosis is a hallmark of MDD and suggest that microbiota of TR patients significantly differs from responders to antidepressants. This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD, suggesting a role in response to antidepressants.
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http://dx.doi.org/10.3390/biomedicines8090311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554953PMC
August 2020

Long-term blood pressure variability, incidence of hypertension and changes in renal function in type 2 diabetes.

J Hypertens 2020 11;38(11):2279-2286

University of Genoa and IRCCS Ospedale Policlinico San Martino, Genova.

Objectives: Long-term visit-to-visit SBP variability (VVV) predicts cerebro-cardiovascular and renal events in patients with hypertension. Whether VVV predicts hypertension and/or chronic kidney disease is currently unknown. We assessed the role of VVV on the development of hypertension and changes in renal function in patients with type 2 diabetes and normal blood pressure (NBP) in a real-life clinical setting.

Methods: Clinical records from 8998 patients with type 2 diabetes, NBP, and normal estimated glomerular filtration rate (eGFR) were analyzed. VVV was measured by SD of the mean SBP recorded in at least four visits during 2 consecutive years before follow-up. Hypertension was defined as SBP at least 140 mmHg and DBP at least 90 mmHg or the presence of antihypertensive treatment. Renal function was defined as worsening of albuminuria status and/or a reduction in eGFR at least 30% from baseline.

Results: After a mean follow-up time of 3.5 ± 2.8 years, 3795 patients developed hypertension (12.1 per 100 person-years). An increase of 5 mmHg VVV was associated with a 19% (P < 0.0001) and a 5% (P = 0.008) independent increased risk of developing hypertension and worsening of albuminuria, respectively. We found no association between VVV and eGFR decrease from baseline. Patients with VVV in the upper quartile (>12.8 mmHg) showed a 50% increased risk of developing hypertension (P < 0.0001) and an almost 20% increased risk of worsening albuminuria (P = 0.004) as compared with those in the lower one (<6.9 mmHg).

Conclusion: Increased VVV independently predicts incident hypertension and albuminuria worsening in type 2 diabetes and NBP.
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http://dx.doi.org/10.1097/HJH.0000000000002543DOI Listing
November 2020

EAN Guideline on Palliative Care of People with Severe, Progressive Multiple Sclerosis.

J Palliat Med 2020 11 29;23(11):1426-1443. Epub 2020 May 29.

The Tizard Centre, University of Kent, Canterbury, United Kingdom.

Patients with severe, progressive multiple sclerosis (MS) have complex physical and psychosocial needs, typically over several years. Few treatment options are available to prevent or delay further clinical worsening in this population. The objective was to develop an evidence-based clinical practice guideline for the palliative care of patients with severe, progressive MS. This guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Formulation of the clinical questions was performed in the Patients-Intervention-Comparator-Outcome format, involving patients, carers and healthcare professionals (HPs). No uniform definition of severe MS exists: in this guideline, constant bilateral support required to walk 20 m without resting (Expanded Disability Status Scale score >6.0) or higher disability is referred to. When evidence was lacking for this population, recommendations were formulated using indirect evidence or good practice statements were devised. Ten clinical questions were formulated. They encompassed general and specialist palliative care, advance care planning, discussing with HPs the patient's wish to hasten death, symptom management, multidisciplinary rehabilitation, interventions for caregivers and interventions for HPs. A total of 34 recommendations (33 weak, 1 strong) and seven good practice statements were devised. The provision of home-based palliative care (either general or specialist) is recommended with weak strength for patients with severe, progressive MS. Further research on the integration of palliative care and MS care is needed. Areas that currently lack evidence of efficacy in this population include advance care planning, the management of symptoms such as fatigue and mood problems, and interventions for caregivers and HPs.
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http://dx.doi.org/10.1089/jpm.2020.0220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583337PMC
November 2020

Moving Toward the Implementation of Precision Medicine Needs Highly Discriminatory, Validated, Inexpensive, and Easy-to-Use Prediction Models.

Diabetes Care 2020 04;43(4):701-703

Unit of Biostatistics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

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http://dx.doi.org/10.2337/dci19-0079DOI Listing
April 2020

The Synergic Association of hs-CRP and Serum Amyloid P Component in Predicting All-Cause Mortality in Patients With Type 2 Diabetes.

Diabetes Care 2020 05 6;43(5):1025-1032. Epub 2020 Mar 6.

Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo, Italy

Objective: Type 2 diabetes is characterized by increased death rate. In order to tackle this dramatic event, it becomes essential to discover novel biomarkers capable of identifying high-risk patients to be exposed to more aggressive preventive and treatment strategies. hs-CRP and serum amyloid P component (SAP) are two acute-phase inflammation proteins, which interact physically and share structural and functional features. We investigated their combined role in associating with and improving prediction of mortality in type 2 diabetes.

Research Design And Methods: Four cohorts comprising 2,499 patients with diabetes (643 all-cause deaths) were analyzed. The improvement of mortality prediction was addressed using two well-established prediction models, namely, EstimatioN oF mORtality risk in type 2 diabetiC patiEnts (ENFORCE) and Risk Equations for Complications of Type 2 Diabetes (RECODe).

Results: Both hs-CRP and SAP were independently associated with all-cause mortality (hazard ratios [HRs] [95% CIs]: 1.46 [1.34-1.58] [ < 0.001] and 0.82 [0.76-0.89] [ < 0.001], respectively). Patients with SAP ≤33 mg/L were at increased risk of death versus those with SAP >33 mg/L only if hs-CRP was relatively high (>2 mg/L) (HR 1.96 [95% CI 1.52-2.54] [ < 0.001] and 1.20 [0.91-1.57] [ = 0.20] in hs-CRP >2 and ≤2 mg/L subgroups, respectively; hs-CRP-by-SAP strata interaction < 0.001). The addition of hs-CRP and SAP significantly (all < 0.05) improved several discrimination and reclassification measures of both ENFORCE and RECODe all-cause mortality prediction models.

Conclusions: In type 2 diabetes, hs-CRP and SAP show opposite and synergic associations with all-cause mortality. The use of both markers, possibly in combination with others yet to be unraveled, might improve the ability to predict the risk of death in the real-life setting.
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http://dx.doi.org/10.2337/dc19-2489DOI Listing
May 2020

Vitamin D serum level in subjects with critical illness polyneuropathy and myopathy.

J Musculoskelet Neuronal Interact 2020 03;20(1):18-26

Unit of Neuro-rehabilitation, and Rehabilitation Medicine, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.

Background: Critical illness polyneuropathy and myopathy (CIPNM) is a disabling neuropathy that occurs in intensive care unit (ICU) subjects. It was hypothesized that a low serum level or deficiency of 25(OH)D might be associated with CIPNM. The aim of the present study was to ascertain the 25(OH)D serum level in subjects with CIPNM.

Method: Consecutive ICU patients admitted to neuro-rehabilitation were prospectively enrolled. At admission, vitamin D serum levels were measured and EMG examination was performed to ascertain those with CIPNM. 25(OH)D was stratified as sufficient (≥30 ng/mL) insufficient (20-29.9 ng/mL), and deficient (<20 ng/mL).

Results: Eighty-four patients (31 F, 53 M; mean age 51.7±12.6) were identified and 63 (21 F, 42 M) enrolled. CIPNM was detected in 38 (9 F, 29 M) patients. A deficient mean serum level of vitamin D was observed in the whole population: 18.1 ± 9.2 ng/mL. No difference of vitamin D serum levels was detected in subjects with and without CIPNM: 17.5 ± 8.4 and 19.0 ± 10.5 ng/mL (p=0.58), respectively.

Conclusion: Almost all subjects showed Vitamin D deficiency. No difference was detected between those with and without CIPNM. The condition might represent a secondary phenomenon resulting from the inflammatory process as well as from conditions that could interfere with vitamin D metabolism.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104589PMC
March 2020

Chronic migraine long-term regular treatment with onabotulinumtoxinA: a retrospective real-life observational study up to 4 years of therapy.

Neurol Sci 2020 Jul 12;41(7):1809-1820. Epub 2020 Feb 12.

Unit of Neurology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.

Introduction: OnabotulinumtoxinA (BoNT-A) was proved effective and safe in chronic migraine (CM) prevention by the Phase III Research Evaluating Migraine Prophylaxis (PREEMPT) and Phase IV Chronic migraine OnabotulinuMtoxinA Prolonged Efficacy open-Label (COMPEL) trials over 1 and 2 years of treatment, respectively. Real-life studies highlighted BoNT-A sustained benefits up to 3 years of administration. Aim of this retrospective real-life study was observing within a 4-year timeframe the progress of a consecutive series of CM patients treated with BoNT-A and evaluating whether long-term quarterly treatment (up to 16 cycles) confirms the outcomes of previous studies over shorter periods of therapy.

Methods: One hundred nine chronic migraineurs were quarterly treated with BoNT-A according to the PREEMPT paradigm. Headache days and hours, analgesics intake and latency time together with disability were analysed at baseline, thereafter bi-annually up to 48 months. Patient responsiveness (improvement in monthly headache days and hours versus baseline) was computed at each study timepoint.

Results: A significant overall decrease from baseline to the 48-month assessment (p < 0.001) was evidenced for the mean number of monthly headache days and hours, analgesics intake and latency time. Severe disability cases significantly decreased at 6 months (p < 0.001), and a progressive shift towards lower degrees of disability was observed at each subsequent timepoint. A gradual percentage increase of responsive cases was observed as treatment was repeated over time. Transitory neck pain was reported in 6 cases.

Conclusions: This study appears to reconfirm the benefits of long-lasting CM prevention with BoNT-A, thus supporting quarterly treatment with BoNT-A over several year.
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http://dx.doi.org/10.1007/s10072-020-04283-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359167PMC
July 2020

How Have Intravitreal Anti-VEGF and Dexamethasone Implant Been Used in Italy? A Multiregional, Population-Based Study in the Years 2010-2016.

Biomed Res Int 2020 11;2020:7582763. Epub 2020 Jan 11.

Unit of Clinical Pharmacology, A.O.U. "G. Martino", Messina, Italy.

Purpose: To describe intravitreal anti-VEGF drug and dexamethasone use in four Italian regions.

Methods: Four regional claims databases were used to measure drug prevalence, compare dosing intervals to those recommended in the summary of product characteristics (SPC), and identify switchers. Bilateral treatment and diabetic macular edema (DME) coding algorithms were validated, linking claims with a sample of prospectively collected ophthalmological data.

Results: Overall, 41,836 patients received ≥1 study drug in 2010-2016 (4.8 per 10,000 persons). In 2016, anti-VEGF drug use ranged from 0.8 (Basilicata) to 5.7 (Lombardy) per 10,000 persons while intravitreal dexamethasone use ranged from 0.2 (Basilicata) to 1.4 (Lombardy) per 10,000 persons. Overall, 40,815 persons were incident users of study drugs. Among incident users with ≥1 year of follow-up ( = 30,745), 16.0% ( = 30,745), 16.0% ( = 30,745), 16.0% (.

Conclusion: Study drug use increased over time in Lombardy, Basilicata, Calabria, and Sicily, despite a large heterogeneity in prevalence of use across regions. Drug treatment appeared to be partly in line with SPC, suggesting that improvement in clinical practice may be needed to maximize drug benefits.
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http://dx.doi.org/10.1155/2020/7582763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977336PMC
September 2020

Cerebral Infarcts After Coronary Angiography and Percutaneous Coronary Intervention: A Prospective Propensity-Score-Adjusted Comparison of Right Radial, Left Radial, and Femoral Approaches.

Cardiovasc Revasc Med 2020 07 12;21(7):882-887. Epub 2019 Nov 12.

Unit of Cardiology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

Background: New cerebral infarcts (CIs) detected at magnetic resonance imaging (MRI) are reported after cardiac procedures. Clinical and procedural aspects are implicated as potential causal factors. The aim of this study was to evaluate the incidence of new CIs after coronary angiography and percutaneous coronary intervention according to the arterial access site.

Methods: 180 patients undergoing elective coronary angiography were studied with cerebral MRI the day before and the day after the procedure. Unadjusted and propensity score (PS) analyses were performed comparing the occurrence of CIs in right radial (RR), left radial (LR) and transfemoral (TF) access groups.

Results: New CIs were observed in 14 patients (7.8% of the total sample, one with neurological sequelae). CIs were detected in 15.5% vs 4.9% vs 3.3% of RR, LR and TF groups, respectively (p = .026). In PS adjusted analyses, the RR approach was associated with more CIs compared with the TF approach (odds ratio [OR] estimate from logistic regression adjusted by PS quartiles: 0.158; 95% confidence interval: 0.031 to 0.814; p = .027) and the LR approach (OR: 0.266; 95% confidence interval: 0.066 to 1.080; p = .064). In a secondary analysis, a comparison of RR vs non-RR approach (TF + LR) was performed, showing that post-procedural CIs were more frequent in the RR group (OR: 0.170; 95% confidence interval: 0.050 to 0.574; p = .004).

Conclusions: Our study suggests that the RR approach may be associated with a higher rate of new CIs after coronary angiography compared with LR and TF approaches.
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http://dx.doi.org/10.1016/j.carrev.2019.11.010DOI Listing
July 2020

Predicting disability progression in multiple sclerosis: Insights from advanced statistical modeling.

Mult Scler 2020 12 5;26(14):1828-1836. Epub 2019 Nov 5.

Biogen, Cambridge, MA, USA/Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Background: There is an unmet need for precise methods estimating disease prognosis in multiple sclerosis (MS).

Objective: Using advanced statistical modeling, we assessed the prognostic value of various clinical measures for disability progression.

Methods: Advanced models to assess baseline prognostic factors for disability progression over 2 years were applied to a pooled sample of patients from placebo arms in four different phase III clinical trials. least absolute shrinkage and selection operator (LASSO) and ridge regression, elastic nets, support vector machines, and unconditional and conditional random forests were applied to model time to clinical disability progression confirmed at 24 weeks. Sensitivity analyses for different definitions of a combined endpoint were carried out, and bootstrap was used to assess prediction model performance.

Results: A total of 1582 patients were included, of which 434 (27.4%) had disability progression in a combined endpoint over 2 years. Overall model discrimination performance was relatively poor (all -indices ⩽ 0.65) across all models and across different definitions of progression.

Conclusion: Inconsistency of prognostic factor importance ranking confirmed the relatively poor prediction ability of baseline factors in modeling disease progression in MS. Our findings underline the importance to explore alternative predictors as well as alternative definitions of commonly used endpoints.
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http://dx.doi.org/10.1177/1352458519887343DOI Listing
December 2020

Gut Microbiota Profiles Differ among Individuals Depending on Their Region of Origin: An Italian Pilot Study.

Int J Environ Res Public Health 2019 10 23;16(21). Epub 2019 Oct 23.

Division of Gastroenterology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Background And Aims: Microbiota heterogeneity among humans is mainly due to genetic background, age, dietary habits, lifestyle and local environments. In this study we investigated whether the gut microbiota profile of Italian healthy volunteers could differ based on their geographical origin.

Materials And Methods: 16S rRNA gene sequencing was employed to analyze the gut microbiota of 31 healthy volunteers from three different Italian regions: Apulia (South), Lazio (Center) and Lombardy (North).

Results: Differences in microbiota composition were detected when the study participants were grouped by their region of origin and when they were classified based on age classes (-values < 0.05). Also species richness was significantly different both according to Italian Regions (median richness: 177.8 vs. 140.7 vs. 168.0 in Apulia, Lazio and Lombardy; < 0.001) and according to age classes (median richness: 140.1 vs. 177.8 vs. 160.0 in subjects < 32, 32-41 and > 41 years; < 0.001), whereas the Shannon index and beta diversity did not change.

Conclusions: This study identified differences in the gut microbiota composition and richness among individuals with the same ethnicity coming from three different Italian regions. Our results underline the importance of studies on population-specific variations in human microbiota composition leading to geographically tailored approaches to microbiota engineering.
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http://dx.doi.org/10.3390/ijerph16214065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862301PMC
October 2019

Hsa-miR-210-3p expression in breast cancer and its putative association with worse outcome in patients treated with Docetaxel.

Sci Rep 2019 10 17;9(1):14913. Epub 2019 Oct 17.

Fondazione IRCCS Casa Sollievo della Sofferenza Laboratorio di Oncologia, San Giovanni Rotondo, FG, Italy.

MicroRNA-210-3p is the most prominent hypoxia regulated microRNA, and it has been found significantly overexpressed in different human cancers. We performed the expression analysis of miR-210-3p in a retrospective cohort of breast cancer patients with a median follow-up of 76 months (n = 283). An association between higher levels of miR-210-3p and risk of disease progression (HR: 2.13, 95%CI: 1.33-3.39, P = 0.002) was found in the subgroup of patients treated with Epirubicin and Cyclophosphamide followed by Docetaxel. Moreover, a cut off value of 20.966 established by ROC curve analyses allowed to discriminate patients who developed distant metastases with an accuracy of 85% at 3- (AUC: 0.870, 95%CI: 0.690-1.000) and 83% at 5-years follow up (AUC: 0.832, 95%CI: 0.656-1.000). Whereas the accuracy in discriminating patients who died for the disease was of 79.6% at both 5- (AUC: 0.804, 95%CI: 0.517-1.000) and 10-years (AUC: 0.804. 95%CI: 0.517-1.000) follow-up. In silico analysis of miR-210-3p and Docetaxel targets provided evidence for a putative molecular cross-talk involving microtubule regulation, drug efflux metabolism and oxidative stress response. Overall, our data point to the miR-210-3p involvement in the response to therapeutic regimens including Docetaxel in sequential therapy with anthracyclines, suggesting it may represent a predictive biomarker in breast cancer patients.
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http://dx.doi.org/10.1038/s41598-019-51581-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797767PMC
October 2019
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