RESUMEN
Candida auris is a multidrug-resistant fungus known to be a global public health problem. The skin-based transmission, together with the marked resistance to drugs, resulted in its rapid spread to all continents. The aim of this study was to identify an essential oil (EO) active in the fight against C. auris. A total of 15 EOs were tested against 10 clinical strains of C. auris. Cinnamomum zeylanicum EO (CZ-EO) was the most effective (MIC90 and MFC90 equal to 0.06% vol/vol). Three fractions obtained from CZ-EO, and the cinnamaldehyde (CIN), the major chemical compound, were tested to identify the principal compound effectives against C. auris. All CIN-containing samples showed anti-fungal activity. To study the synergy with fluconazole, CZ-EO, its active fraction (FR2), and CIN were tested in checkerboard tests. Results show that CZ-EO and FR2, but not CIN, synergize with fluconazole. Furthermore, only the copresence of CZ-EO or FR2 synergize with fluconazole at therapeutic concentrations of the drug (0.45 ± 0.32 µg/mL and 0.64 ± 0.67 µg/mL, respectively), while CIN only shows additive activity. In vivo studies conducted on Galleria mellonella larvae show the absence of toxicity of CZ-EO up to concentrations of 16% vol/vol, and the ability of CZ-EO to reactivate the efficacy of fluconazole when formulated at synergic concentrations. Finally, biochemical tests were made to study the mechanism of action of CZ-EO. These studies show that in the presence of both fluconazole and CZ-EO, the activity of fungal ATPases decreases and, at the same time, the amount of intracellular drug increases. IMPORTANCE This study highlights how small doses of CZ-EO are able to inhibit the secretion of fluconazole and promote its accumulation in the fungal cell. In this manner, the drug is able to exert its pharmacological effects bypassing the resistance of the yeast. If further studies will confirm this synergy, it will be possible to develop new therapeutic formulations active in the fight against C. auris resistances.
RESUMEN
In our institution, a prospective observational trial testing micro-RNA (miRNA) and ARV7 mutational status in metastatic, castration resistant prostate cancer (mCRPC), is currently recruiting (PRIMERA trial, NCT04188275). A pre-planned interim analysis was performed when 50% of the planned accrual was reached. In this report, we explored the predictive value of Circulating Tumor Cell (CTC) detection in mCRPC patients undergoing 1st line therapy. Moreover, ARV7, ARFL, PSMA and PSA expression on CTC was reported to explore potential correlation with patient prognosis and response to therapy. PRIMERA is a prospective observational trial enrolling mCRPC patients undergoing standard treatment (ARTA + ADT) after I line ADT failure. Clinical and pathological features were collected. Outcomes selected for this preliminary analysis were time to castration resistance (TTCR), PSA at 8 weeks after ARTA therapy start, PSA drop at 8 weeks, Overall PSA drop, PSA nadir. Correlation between these outcomes and CTC detection was tested. Expression of ARV7, ARFL, PSA and PSMA was explored in CTC+ patients to assess their prevalence in this cohort and their impact on selected outcomes. Median TTCR was significantly shorter in CTC+ vs CTC- patients (32.3 vs 75 months, respectively, p = 0.03) and in ARFL+ vs ARFL- patients (30.2 vs 51.1 months, respectively, p = 0.02). ARV7, PSMA and PSA expression on CTC had no impact on median TTCR, nor on biochemical response to therapy. Patients in whom CTC and ARFL expression were detected had significant reduced TTCR. However, PSA response was not influenced by CTCs detection and specific biomarkers expression.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Antígenos de Superficie/análisis , Glutamato Carboxipeptidasa II/análisis , Células Neoplásicas Circulantes/química , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética , Humanos , Calicreínas/sangre , Masculino , Estudios Prospectivos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/mortalidadRESUMEN
Penile metastasization is an uncommon condition, mostly derived from primitive advanced abdominal cancers, with disabling symptoms. Palliative treatment, in reason of poor prognosis patients, is frequently surgical with destructive management. We report two cases of penile metastasis, from primitive prostatic adenocarcinoma and primitive urothelial carcinoma, effectively managed with radiation treatment at our institution. A three-dimensional conformal radiation therapy with 42Gy to the planning target volume in 14 fractions was delivered. Radiation treatment was safely delivered, with low toxicity profile and achieved adequate symptoms control without compromising genitourinary functions. Radiation therapy should be considered in management of rare penile metastases.
Asunto(s)
Adenocarcinoma/radioterapia , Carcinoma de Células Transicionales/radioterapia , Neoplasias del Pene/radioterapia , Radioterapia Conformacional , Adenocarcinoma/patología , Adenocarcinoma/secundario , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/secundario , Humanos , Masculino , Neoplasias del Pene/secundario , Neoplasias de la Próstata/patología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
AIMS: 68Ga-Prostate-specific membrane antigen (PSMA) PET/CT is widely used in patients with biochemical recurrence (BCR) after radical prostatectomy. We collected data about patients staged with PSMA PET/CT after BCR (PSA < 1 ng/ml) in four different institutes. Impact of baseline features (Gleason score, risk classification, PSA at recurrence, PSA doubling time and time to recurrence) was explored to understand predictive factors of (PSMA) PET/CT positivity. Impact of restaging on following treatment approaches was reported. RESULTS: 92 patients were included. PSMA PET/CT detection rate was 56.5% and low-volume disease (≤ 3 non-visceral lesions) was detected in 52.2% of patients. After positive scan, 13.5% of patients still lies on observation, ADT alone was administered in 30.8% of cases, Stereotactic body RT (SBRT) alone was delivered to 44.2% of patients and 11.5% of patients underwent concomitant SBRT and ADT. Seven patients underwent conventional salvage prostate bed RT. Chi-squared test showed a higher rate of positive PSMA PET/CT for patients with Gleason score > 7 (p = 0.004) and TTR < 29.5 months (p = 0.003). CONCLUSIONS: PSMA PET/CT showed a high detection rate. This influenced clinical management in a significant percentage of patients, allowing treatment tailoring on the basis of imaging.
Asunto(s)
Isótopos de Galio , Radioisótopos de Galio , Recurrencia Local de Neoplasia/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Radiofármacos , Anciano , Antagonistas de Andrógenos/uso terapéutico , Antígenos de Superficie , Glutamato Carboxipeptidasa II , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias/métodos , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Radiocirugia/estadística & datos numéricos , Radioterapia/estadística & datos numéricos , Radioterapia de Intensidad Modulada/estadística & datos numéricos , Estudios Retrospectivos , Terapia Recuperativa/métodos , Terapia Recuperativa/estadística & datos numéricos , Factores de TiempoRESUMEN
PURPOSE: Nonalcoholic fatty liver disease (NAFLD) is defined by excessive lipid accumulation in the liver and involves an ample spectrum of liver diseases, ranging from simple uncomplicated steatosis to cirrhosis and hepatocellular carcinoma. Accumulating evidence demonstrates that high fructose intake enhances NAFLD development and progression promoting inhibition of mitochondrial ß-oxidation of long-chain fatty acids and oxidative damages. L-Carnitine (LC), involved in ß-oxidation, has been used to reduce obesity caused by high-fat diet, which is beneficial to ameliorating fatty liver diseases. Moreover, in the recent years, various studies have established LC anti-oxidative proprieties. The objective of this study was to elucidate primarily the underlying anti-oxidative mechanisms of LC in an in vitro model of fructose-induced liver steatosis. METHODS: Human hepatoma HepG2 cells were maintained in medium supplemented with LC (5 mM LC) with or without 5 mM fructose (F) for 48 h and 72 h. In control cells, LC or F was not added to medium. Fat deposition, anti-oxidative, and mitochondrial homeostasis were investigated. RESULTS: LC supplementation decreased the intracellular lipid deposition enhancing AMPK activation. However, compound C (AMPK inhibitor-10 µM), significantly abolished LC benefits in F condition. Moreover, LC, increasing PGC1 α expression, ameliorates mitochondrial damage-F induced. Above all, LC reduced ROS production and simultaneously increased protein content of antioxidant factors, SOD2 and Nrf2. CONCLUSION: Our data seemed to show that LC attenuate fructose-mediated lipid accumulation through AMPK activation. Moreover, LC counteracts mitochondrial damages and reactive oxygen species production restoring antioxidant cellular machine. These findings provide new insights into LC role as an AMPK activator and anti-oxidative molecule in NAFLD.
Asunto(s)
Carnitina/uso terapéutico , Hígado Graso/tratamiento farmacológico , Hepatocitos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Biomarcadores/metabolismo , Carnitina/administración & dosificación , Hígado Graso/inducido químicamente , Hígado Graso/metabolismo , Fructosa , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The novel HLA-C*04:288 differs from HLA-C*04:01:01:06 by a single nucleotide substitution in exon 2.
RESUMEN
A novel HLA-DPB1 allele, named HLA-DPB1*647:01, identified in a leukemia patient.
Asunto(s)
Alelos , Cadenas beta de HLA-DP/genética , Leucemia/genética , Secuencia de Aminoácidos , Secuencia de Bases , Codón/genética , Cadenas beta de HLA-DP/química , Humanos , ItaliaRESUMEN
Two novel alleles, HLA-A*31:125 and HLA-B*44:269, are described in Italian bone marrow donors.
Asunto(s)
Alelos , Médula Ósea/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Donantes de Tejidos , Secuencia de Bases , Exones/genética , Humanos , ItaliaRESUMEN
In the last decade, several examples have been produced by scientific literature about zebrafish as a model to study human bone diseases. In fish, bone turnover, reparation and remodeling of the adult bone tissue cannot be studied in embryonic or juvenile stages. In addition, fins and scales represent unique anatomical features useful to study adult bone metabolism and diseases. For these reasons, the adult zebrafish represents an innovative and readily available resource for studying the bone metabolism at cellular and molecular level. Although the adult fish is less used than the embryo, several applications have been found in the last years with the production of innovative pathological models in adult zebrafish, helpful to understand the mechanisms of bone physiopathology. The use of mutants, regenerating organs, transgenic fish and scales have increased the power of this model in the last years.
Asunto(s)
Enfermedades Óseas/fisiopatología , Huesos/metabolismo , Modelos Animales , Pez Cebra/fisiología , Factores de Edad , Animales , Animales Modificados Genéticamente , Humanos , Regeneración , Pez Cebra/genética , Pez Cebra/crecimiento & desarrolloRESUMEN
One nucleotide substitution at residue 142 of the HLA-DRB1*13:01:01 results in a new allele, HLA-DRB1*13:215.
Asunto(s)
Alelos , Exones , Cadenas HLA-DRB1/genética , Polimorfismo de Nucleótido Simple , Donantes de Tejidos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Secuencia de Bases , Codón/química , Cadenas HLA-DRB1/inmunología , Trasplante de Células Madre Hematopoyéticas , Prueba de Histocompatibilidad , Humanos , Italia , Reacción en Cadena de la Polimerasa , Alineación de Secuencia , Análisis de Secuencia de ADNRESUMEN
Endocannabinoids are a class of lipid mediators involved in a wide range of physiological pathways including pain perception, and immunological defences. In particular, the involvement of endocannabinoids in bone metabolism and bone resorption has recently been studied. Moreover, one study on total knee arthroplasty describes the probable role of endocannabinoids in pain perception after surgery. The aim of the present study was to evaluate variations of endocannabinoid concentrations in patients undergoing total hip or total knee arthroplasty before and after surgery. Sera from 23 patients were collected at three different times: before surgery and at two different times during rehabilitation, and endocannabinoids were quantified by HPLC-MS/MS analysis. Mean values of endocannabinoids in presurgical serum samples were: 6.11±0.5 ng/ml for N-palmitoylethanolamide, 1.39±0.08ng/ml for N-stearoylethanolamide, 4.84±0.04 ng/ml for N-oleoylethanolamide, 0.44±0.03ng/ml for N-arachidonoylethanolamide, 0.84±0.05ng/ml for N-linoleoylethanolamide, 0.17±0.01ng/ml for N-α-linolenoylethanolamide. Statistical analysis showed a significant decrease of all the endocannabinoids after surgery, while there were no remarkable differences between total hip and total knee arthroplasties or between genders. Moreover, the results show no significant correlation between endocannabinoid concentrations and C-reactive protein and Erythrocyte sedimentation rate. The present study shows for the first time a specific and univocal behaviour of six endocannabinoids and N-acylethanolamides in orthopaedic surgery, suggesting the endocannabinoid system as a possible pharmacological target for presurgical therapeutics.
Asunto(s)
Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Endocannabinoides/sangre , Anciano , Anciano de 80 o más Años , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor Postoperatorio/sangre , Dolor Postoperatorio/etiología , Espectrometría de Masas en TándemRESUMEN
The endocannabinoid system (which includes fatty acid derivatives, receptors, and metabolizing enzymes) is involved in a variety of physiological processes, including bone metabolism in which it regulates the function of osteoblasts and osteoclasts, as well as differentiation of their precursors. The zebrafish (Danio rerio) provides a useful animal model for bone research since zebrafish bones develop rapidly and are anatomically similar to mammalian bones. Putative orthologues and paralogs of endocannabinoid genes have recently been identified in zebrafish, demonstrating the presence of cannabinoid type 1 (CB1) and type 2 (CB2) receptors with affinity to endocannabinoid ligands. To identify therapeutic molecules potentially useful in bone-related diseases, we evaluated the in vivo effects of exposure to long-chain fatty acid amides in adult zebrafish. Using a well-established zebrafish scale model, we found that anandamide and N-linoleoylethanolamine are able to stimulate bone formation by increasing alkaline phosphatase activity in physiological conditions. In addition, they prevent the alteration of bone markers in a prednisolone-induced osteoporosis model in adult zebrafish scales, whereas their esterified forms do not. These data suggest that long-chain fatty acid amides are involved in regulating bone metabolism in zebrafish scales and that the CB2 receptor is a key mediator in this process.
Asunto(s)
Huesos/efectos de los fármacos , Alcamidas Poliinsaturadas/farmacología , Fosfatasa Ácida/metabolismo , Fosfatasa Alcalina/metabolismo , Animales , Huesos/metabolismo , Endocannabinoides/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Glucocorticoides , Masculino , Osteoporosis/inducido químicamente , Osteoporosis/metabolismo , Prednisolona , Receptor Cannabinoide CB2/metabolismo , Pez CebraRESUMEN
UNLABELLED: The aim of this study was the setting up of a gluten-free sourdough from selected lactobacilli and yeasts isolated from a traditional wheat-based Type I sourdough. A gluten-free matrix was inoculated with Lactobacillus sanfranciscensis and Candida humilis, fermented to pH 4·0, and constantly propagated for ten times. A stable association between micro-organisms was observed from the second refreshment with mean values of 9·08 ± 0·25 log CFU g(-1) for lactobacilli and 7·81 ± 0·07 log CFU g(-1) for yeasts. In order to have a good workability of the dough, a 230 BU consistency was considered. Rheofermentographic indices remained constant over the ten refreshments, showing an average value of 23·2 mm dough height in about 7·5 h. The CO2 production and retention volumes reached average values of 1430 and 1238 ml respectively. The microbiological and technological data obtained highlighted that a GF sourdough was effectively developed. SIGNIFICANCE AND IMPACT OF THE STUDY: Type I sourdough has a long tradition as a leavening agent of baked goods as its use results in an improved texture, flavour, taste and extended shelf-life of the final products. In this study a Type I gluten-free sourdough was obtained. After few refreshments in controlled conditions, the sourdough presented a stable association between Lactobacillus sanfranciscensis and Candida humilis, constant fermentation times and technological properties (in terms of dough consistency, dough maximum height, CO2 production and retention). The results showed that the gluten-free sourdough developed in this study can improve the overall quality of gluten-free baked products.
Asunto(s)
Pan/microbiología , Candida/metabolismo , Glútenes/metabolismo , Lactobacillus/metabolismo , Triticum/metabolismo , Candida/crecimiento & desarrollo , Candida/aislamiento & purificación , Enfermedad Celíaca , Dieta Sin Gluten , Fermentación , Humanos , Lactobacillus/crecimiento & desarrollo , Lactobacillus/aislamiento & purificaciónRESUMEN
We retrieved 34 medieval ovicaprine remains, from three archaeological sites of central Italy dating to about 1000 years old, and analyzed them using mitochondrial DNA. We compared the reconstructed haplogroups with modern sheep samples from Europe and the Middle East and sequences from the literature. In modern sheep, haplogroup HA is present in countries with access to the Mediterranean and close to the domestication center, whereas it is very rare or absent in the rest of Europe. The haplogroup HB was predominant in ancient samples (90%), whereas haplogroup HA was found at 10%. Ancient haplogroups match the present distribution in modern sheep in Italy, indicating that the current proportion of HA/HB was already established in the Middle Ages and is not the result of subsequent events such as selective breeding practices.
Asunto(s)
ADN Mitocondrial/genética , Evolución Molecular , Haplotipos , Oveja Doméstica/genética , Animales , Europa (Continente) , Italia , Medio Oriente , Análisis de Secuencia de ADNRESUMEN
A novel HLA-DPB1 allele, named DPB1*296:01, was identified in the Thai mother of a hematologic patient.
Asunto(s)
Alelos , Cadenas beta de HLA-DP/genética , Secuencia de Bases , Médula Ósea , Femenino , Prueba de Histocompatibilidad , Humanos , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Tailandia , Donantes de TejidosRESUMEN
A novel HLA-A allele, HLA-A*68:105, was detected by sequence-based typing (SBT) in an Italian bone marrow donor. It differs from HLA-A*68:01:02 at five nucleotides, three intronic, nt 699 T->G (intron 2), nt 705 T->C (intron 2) and nt 2770 G->A (intron 7), and two located in exon 3, at positions 726 A-G (codon 94 Ile->Val) and 733 T-G (codon 97 Arg->Met), respectively.
Asunto(s)
Alelos , Genoma Humano/genética , Antígenos HLA-A/genética , Análisis de Secuencia de ADN , Secuencia de Bases , Exones/genética , Humanos , Datos de Secuencia Molecular , Alineación de SecuenciaRESUMEN
A newly identified allele, named HLA B*15:276, differs from B*15:01:01:01 by the single nucleotide substitution 511T-C at codon 147 (Trp â Arg) in exon 3.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-B/genética , Secuencia de Bases , Exones/genética , Humanos , Recién Nacido , Italia , Donadores Vivos , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Alineación de Secuencia , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido NucleicoRESUMEN
The killer cell immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA) interaction represents an example of genetic epistasis, where the concomitant presence of specific genes or alleles encoding receptor-ligand units is necessary for the activity of natural killer (NK) cells. Although KIR and HLA genes segregate independently, they co-evolved under environmental pressures to maintain particular KIR-HLA functional blocks for species survival. We investigated, in 270 Italian healthy individuals, the distribution of KIR and HLA polymorphisms in three climatic areas (from cold north to warm south), to verify their possible geographical stratification. We analyzed the presence of 13 KIR genes and genotyped KIR ligands belonging to HLA class I: HLA-C, HLA-B and HLA-A. We did not observe any genetic stratification for KIR genes and HLA-C ligands in Italy. By contrast, in a north-to-south direction, we found a decreasing trend for the HLA-A3 and HLA-A11 ligands (P = 0.012) and an increasing trend for the HLA-B ligands carrying the Bw4 epitope (P = 0.0003) and the Bw4 Ile80 epitope (P = 0.0005). The HLA-A and HLA-B KIR ligands were in negative linkage disequilibrium (correlation coefficient -0.1211), possibly as a consequence of their similar function in inhibiting NK cells. The distribution of the KIR-HLA functional blocks was different along Italy, as we observed a north-to-south ascending trend for KIR3DL1, when coupled with HLA-B Bw4 ligands (P = 0.0067) and with HLA-B Bw4 Ile80 (P = 0.0027), and a descending trend for KIR3DL2 when coupled with HLA-A3 and HLA-A11 ligands (P = 0.0044). Overall, people from South Italy preferentially use the KIR3DL1-HLA-B Bw4 functional unit, while those from the North Italy equally use both the KIR3DL2-HLA-A3/A11 and the KIR3DL1-HLA-B Bw4 functional units to fight infections. Thus, only KIR3DL receptors, which exert the unique role of microbial sensors through the specific D0 domain, and their cognate HLA-A and HLA-B ligands are selectively pressured in Italy according to geographical north-to-south distribution.
Asunto(s)
Genética de Población , Antígenos HLA/genética , Receptores KIR/genética , Adulto , Alelos , Femenino , Frecuencia de los Genes/genética , Geografía , Humanos , Italia , Ligandos , Desequilibrio de Ligamiento/genética , MasculinoRESUMEN
The new HLA DRB1*01:54 differs from DRB1*01:02:01 by one nucleotide at exon 2.
Asunto(s)
Alelos , Cadenas HLA-DRB1/genética , Prueba de Histocompatibilidad , Análisis de Secuencia de ADN , Secuencia de Bases , Exones/genética , Humanos , Datos de Secuencia Molecular , Alineación de SecuenciaRESUMEN
Bone mass is the net product of formation and resorption, which are closely regulated by the equilibrium between endogenous/exogenous factors. Sclerostin inhibits the Wnt canonical signaling and is considered an anti-anabolic factor. We compared sclerostin serum concentrations between genders in athletes belonging to different sport disciplines, characterized by a different weight-bearing, and in their sedentary counterparts in order to study the possible link between bone metabolism in athletes and its peripheral concentration. We also compared sclerostin levels with bone alkaline phosphatase activity, a marker of bone formation. Sixty-one elite athletes, belonging to weight-bearing (15 male rugby players, 11 male enduro racers, 8 female basketball players), high-impact (6 male tennis players, 8 female ice skaters), non weight-bearing sports (13 male cyclists) and 16 sedentary controls were enrolled. Higher levels of sclerostin were found in females. Sclerostin was higher in weight-bearing than in non-weight-bearing disciplines in males. Significant inverse age-related correlation was found. Higher bone alkaline phosphatase activity was observed in females. The young adult elite athlete represents a peculiar physiologic model for studying sclerostin behavior: the applied load increased the marker concentrations, testifying a high bone turnover rate; however, a gender effect is evident.