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BACKGROUND: Monoclonal antibodies (mAbs) and antivirals have been approved for early therapy of coronavirus disease (COVID-19), however, in the real-life setting, there are difficulties to prescribe these therapies within few days from symptom onset as recommended, and effectiveness of combined use of these drugs have been hypothesised in most-at-risk patients (such as those immunocompromised) but data supporting this strategy are limited. METHODS: We describe the real-life experience of SARS-CoV-2 antivirals and/or monoclonal antibodies (mAbs) and focus on the hospitalisation rate due to the progression of COVID-19. Clinical results obtained through our risk-stratification algorithm and benefits achieved through a strategic proximity territorial centre are provided. We also report a case series with an in-depth evaluation of SARS-CoV-2 genome in relationship with treatment strategy and clinical evolution of patients. RESULTS: Two hundred eighty-eight patients were analysed; 94/288 (32.6%) patients were treated with mAb monotherapy, 171/288 (59.4%) patients were treated with antivirals, and 23/288 (8%) patients received both mAbs and one antiviral drug. Haematological malignancies were more frequent in patients treated with combination therapy than in the other groups (p = 0.0003). There was a substantial increase in the number of treated patients since the opening of the centre dedicated to early therapies for COVID-19. The provided disease-management and treatment appeared to be effective since 98.6% patients recovered without hospital admission. Moreover, combination therapy with mAbs and antivirals seemed successful because all patients admitted to the hospital for COVID-19 did not receive such therapies, while none of the most-at-risk patients treated with combination therapy were hospitalized or reported adverse events. CONCLUSIONS: A low rate of COVID-19 progression requiring hospital admission was observed in patients included in this study. The dedicated COVID-19 proximity territorial service appeared to strengthen the regional sanitary system, avoiding the overwhelming of other services. Importantly, our results also support early combination therapy: it is possible that this strategy reduces the emergence of escape mutants of SARS-CoV-2, thereby increasing efficacy of early treatment, especially in immunocompromised individuals.
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Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Humanos , Prevención Secundaria , Estudios Retrospectivos , Antivirales/uso terapéutico , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
BACKGROUND: Most studies focused on the benefits of lycopene on serum lipids but no studies have been specifically designed to assess the role of a tomato sauce from vine-ripened tomatoes on patients affected by polygenic hypercholesterolemia. The aim of this study was to compare the lipid-lowering effect of a novel functional tomato sauce with a well-known functional food with a lipid-lowering effect, i.e. a sterol-enriched yogurt. METHODS: In this cross-over study, we evaluated a population of 108 ambulatory patients affected by polygenic hypercholesterolemia of both gender, who were allocated to a tomato sauce (namely OsteoCol) 150 ml/day or a sterol-enriched yogurt (containing sterols 1.6 g/die) treatment, for 6 weeks. Carotenoids content was 3.5 mg per gram of product. We measured serum lipids and creatinine and transaminases at basal and follow-up visit. RESULTS: A total of 91 subjects completed the protocol. A significant difference in LDL-cholesterol change was found between participants taking yogurt, tomato sauce (high adherence) and tomato sauce (low adherence) (- 16; - 12; + 8 mg/dl respectively; p < 0.001). We found a greater LDL-cholesterol reduction in the participants with a basal LDL-cholesterol more than 152 mg/dl (15% for sterol-enriched yogurt and 12% for tomato sauce at high adherence). CONCLUSION: A novel functional tomato sauce from vine-ripened tomatoes compares favourably with a commercialised sterol-enriched yogurt in term of absolute LDL-cholesterol change. Intake of a tomato sauce with a high carotenoid content may support treatment of patients affected by common hypercholesterolemia. The present study has various limitations. The presence of other dietary components, which may have influenced the results, cannot be ruled out. Of course, these results cannot be extrapolated to other populations. Furthermore, there was a low adherence rate in the tomato sauce group. Moreover, we did not report serum carotenoids data. TRIAL REGISTRATION: ID: 13244115 on the ISRCTN registry, retrospectively registered in 2019-5-14. URL: http://www.isrctn.com/ISRCTN13244115.
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Hipercolesterolemia , Fitosteroles , Solanum lycopersicum , Estudios Cruzados , Humanos , Hipercolesterolemia/tratamiento farmacológico , LípidosRESUMEN
OBJECTIVES: Autofluorescence is considered a useful technique in the early detection of oral mucosal alterations. However, its efficacy to discriminate tumor margins is still under debate. The purpose of this pilot study was to confirm the existence of molecular divergence from the center of a lesion compared to white light and autofluorescence (VELscopeTM ) visualized margins in leukoplakia and oral carcinoma. MATERIALS AND METHODS: Molecular divergence from the center of the lesion to white light and VELscopeTM defined margins was compared in patients with leukoplakia (n = 3) and oral carcinoma (n = 4). Expression profiling of 45 selected genes was performed through custom-made TaqMan arrays. Gene Ontology was used for biological pathway analysis. RESULTS: Irrespective of pathology, the greatest molecular divergence existed between the center of the lesion and both white light and VELscopeTM margins. VELscopeTM and white light margins were also molecularly distinct in oral carcinoma samples. Indeed, the white light margin retained molecular abnormalities observed in the center of the lesion thus suggesting the existence of a "partially transformed" cell population. CONCLUSION: Despite the limited low number of patients, our data confirm the benefit of combining autofluorescence with conventional oral examination in identifying surgical margins during biopsy procedures for leukoplakia and oral carcinoma.
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Carcinoma , Márgenes de Escisión , Expresión Génica , Humanos , Leucoplasia , Leucoplasia Bucal/genética , Proyectos PilotoRESUMEN
BACKGROUND: Despite an apparent effective vaccination, some patients are admitted to the hospital after SARS-CoV-2 infection. The role of adaptive immunity in COVID-19 is growing; nonetheless, differences in the spike-specific immune responses between patients requiring or not hospitalization for SARS-CoV-2 infection remains to be evaluated. In this study, we aim to evaluate the spike-specific immune response in patients with mild-moderate or severeSARS-CoV-2 infection, after breakthrough infection following two doses of BNT162b2 mRNA vaccine. METHODS: We included three cohorts of 15 cases which received the two BNT162b2 vaccine doses in previous 4 to 7 months: 1) patients with severe COVID-19; 2) patients with mild-moderate COVID-19 and 3) vaccinated individuals with a negative SARS-CoV-2 molecular pharyngeal swab (healthy subjects). Anti-S1 and anti-S2 specific SARS-CoV-2 IgM and IgG titers were measured through a chemiluminescence immunoassay technology. In addition, the frequencies of IFNγ-releasing cells were measured by ELISpot. RESULTS: The spike-specific IFNγ-releasing cells were significantly lower in severe patients (8 [0; 26] s.f.c.×106), as compared to mild-moderate patients (135 [64; 159] s.f.c.×106; p<0.001) and healthy subjects (103 [50; 188] s.f.c.×106; p<0.001). The anti-Spike protein IgG levels were similar among the three cohorts of cases (p = 0.098). All cases had an IgM titer below the analytic sensitivity of the test. The Receiver Operating Curve analysis indicated the rate of spike-specific IFNγ-releasing cells can discriminate correctly severe COVID-19 and mild-moderate patients (AUC: 0.9289; 95%CI: 0.8376-1.000; p< 0.0001), with a diagnostic specificity of 100% for s.f.c. > 81.2 x 106. CONCLUSIONS: 2-doses vaccinated patients requiring hospitalization for severe COVID-19 show a cellular-mediated immune response lower than mild-moderate or healthy subjects, despite similar antibody titers.
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COVID-19 , SARS-CoV-2 , Humanos , Vacuna BNT162 , Interferón gamma , Anticuerpos Antivirales , Inmunoglobulina M , Inmunoglobulina G , VacunaciónRESUMEN
We investigated the evolution of SARS-CoV-2 spread in Calabria, Southern Italy, in 2022. A total of 272 RNA isolates from nasopharyngeal swabs of individuals infected with SARS-CoV-2 were sequenced by whole genome sequencing (N = 172) and/or Sanger sequencing (N = 100). Analysis of diffusion of Omicron variants in Calabria revealed the prevalence of 10 different sub-lineages (recombinant BA.1/BA.2, BA.1, BA.1.1, BA.2, BA.2.9, BA.2.10, BA.2.12.1, BA.4, BA.5, BE.1). We observed that Omicron spread in Calabria presented a similar trend as in Italy, with some notable exceptions: BA.1 disappeared in April in Calabria but not in the rest of Italy; recombinant BA.1/BA.2 showed higher frequency in Calabria (13%) than in the rest of Italy (0.02%); BA.2.9, BA.4 and BA.5 emerged in Calabria later than in other Italian regions. In addition, Calabria Omicron presented 16 non-canonical mutations in the S protein and 151 non-canonical mutations in non-structural proteins. Most non-canonical mutations in the S protein occurred mainly in BA.5 whereas non-canonical mutations in non-structural or accessory proteins (ORF1ab, ORF3a, ORF8 and N) were identified in BA.2 and BA.5 sub-lineages. In conclusion, the data reported here underscore the importance of monitoring the entire SARS-CoV-2 genome.
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COVID-19 , Humanos , COVID-19/epidemiología , Evolución Molecular , Genoma Viral , SARS-CoV-2/genética , Italia/epidemiologíaRESUMEN
In a convenience sample of 93 patients treated with monoclonal antibodies (moAbs) against SARS-CoV-2, the interleukin-62/lymphocyte count ratio (IL-62/LC) was able to predict clinical worsening both in early stages of COVID-19 and in oxygen-requiring patients. Moreover, we analysed 18 most at-risk patients with asymptomatic or mild disease treated with both moAbs and antiviral treatment and found that only 2 had clinical progression, while patients with a similar risk were reported to have an unfavourable outcome in most cases from recent data. In only one of our 18 patients, clinical progression was attributable to COVID-19, and in the other cases, clinical progression was observed despite IL-62/LC being above the risk cut-off. In conclusion, IL-62/LC may be a valuable method to identify patients requiring more aggressive treatments both in earlier and later stages of the disease; however, most at-risk patients can be protected from clinical worsening by combining moAbs and antivirals, even if levels of the IL-62/LC biomarker are lower than the risk cut-off.
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COVID-19 , Humanos , Interleucina-6 , SARS-CoV-2 , Anticuerpos Monoclonales/uso terapéutico , Linfocitos , Progresión de la EnfermedadRESUMEN
Ménière's disease (MD) is a disorder of the inner ear characterized by an insidious onset and aspecific symptoms, such as dizziness, vertigo, tinnitus, and hearing loss, that may become very debilitating. The presence of endolymphatic hydrops is a common feature in MD patients, but the pathophysiology is still largely unknown. In this study, we have used a proteomics-driven approach to identify potential biomarkers of MD. To this end, plasma was obtained from whole blood of 16 individuals previously diagnosed as suffering from MD and compared to plasma from healthy donors. A depletion of the highly abundant proteins (i.e., albumin, IgG, transferrin, etc.) was performed in order to enhance the chance of detection of the less represented ones, therefore reducing the noise-background. Two-dimensional gel electrophoresis, followed by in-gel tryptic digestion of the selected spots and LC-MS/MS analysis, allowed us to identify a set of proteins whose expression appears to be differentially modulated in patients versus controls. In particular: complement factor H and B, fibrinogen alpha and gamma chains, beta-actin and pigment epithelium derived factor are over expressed; on the other hand, the levels of beta-2 glycoprotein-1, vitamin D binding protein and apolipoprotein-1 are significantly decreased in the plasma of MD-affected individuals. Even though preliminary and not necessarily linked directly to the molecular pathogenesis of the disease, our original findings suggest that a molecular signature, represented by the plasma protein profile previously described, might represent a potentially powerful, innovative and not invasive tool for early diagnosis and clinical management of MD patients. J. Cell. Physiol. 227: 308-312, 2012. © 2011 Wiley Periodicals, Inc.
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Enfermedad de Meniere/sangre , Proteómica , Biomarcadores/análisis , Biomarcadores/sangre , Cromatografía Liquida , Electroforesis en Gel Bidimensional , Femenino , Humanos , Masculino , Espectrometría de Masas , Enfermedad de Meniere/genética , Enfermedad de Meniere/fisiopatología , Persona de Mediana EdadRESUMEN
OBJECTIVES: Neutralizing monoclonal antibodies (moAbs) improves clinical outcomes in patients with COVID-19 when administered during the initial days of infection. The action of moAbs may impair the generation or maintenance of effective immune memory, similar to that demonstrated in other viral diseases. We aimed to evaluate short-term memory T-cell responses in patients effectively treated with bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab (SOT). METHODS: Spike (S)-specific T-cell responses were analyzed in 23 patients with COVID-19 (vaccinated or unvaccinated) before and after a median of 50 (range: 28-93) days from moAb treatment, compared with 11 vaccinated healthy controls. T-cell responses were measured by interferon-γ-enzyme-linked immunospot and flow cytometric activation-induced marker assay. RESULTS: No statistically significant difference in S-specific T-cell responses was observed between patients treated with moAb and vaccinated healthy controls. Bamlanivimab/etesevimab and casirivimab/imdevimab groups showed significant increases in cellular responses in paired baseline/postrecovery series, as well as vaccinated patients receiving SOT. In contrast, unvaccinated patients prescribed SOT presented no statistically significant increases in T-cell-responses, suggesting diverse impacts of different moAbs on the evolution of S-specific T-cell responses in vaccinated and unvaccinated patients. CONCLUSION: The moAbs did not hinder short-term memory S-specific T-cell responses in the overall group of patients; however, differences among moAbs must be further investigated both in vaccinated and unvaccinated individuals.
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Antineoplásicos Inmunológicos , Tratamiento Farmacológico de COVID-19 , Humanos , SARS-CoV-2 , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos AntiviralesRESUMEN
BACKGROUND: Nursing homes have represented important hotspots of viral spread during the initial wave of COVID-19 pandemics. The proximity of patients inside nursing homes allows investigate the dynamics of viral transmission, which may help understand SARS-Cov2 biology and spread. METHODS: SARS-CoV-2 viral genomes obtained from 46 patients infected in an outbreak inside a nursing home in Calabria region (South Italy) were analyzed by Next Generation Sequencing. We also investigated the evolution of viral genomes in 8 patients for which multiple swabs were available. Phylogenetic analysis and haplotype reconstruction were carried out with IQ-TREE software and RegressHaplo tool, respectively. RESULTS: All viral strains isolated from patients infected in the nursing home were classified as B.1 lineage, clade G. Overall, 14 major single nucleotide variations (SNVs) (frequency > 80%) and 12 minor SNVs (frequency comprised between 20% and 80%) were identified with reference to the Wuhan-H-1 sequence (NC_045512.2). All patients presented the same 6 major SNVs: D614G in the S gene; P4715L, ntC3037T (F924F) and S5398P in Orf1ab gene; ntC26681T (F53F) in the M gene; and ntC241T in the non-coding UTR region. However, haplotype reconstruction identified a founder haplotype (Hap A) in 36 patients carrying only the 6 common SNVs indicated above, and 10 other haplotypes (Hap BK) derived from Hap A in the remaining 10 patients. Notably, no significant association between a specific viral haplotype and clinical parameters was found. CONCLUSION: The predominant viral strain responsible for the infection in a nursing home in Calabria was the B.1 lineage (clade G). Viral genomes were classified into 11 haplotypes (Hap A in 36 patients, Hap BK in the remaining patients).
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COVID-19 , SARS-CoV-2 , COVID-19/epidemiología , Genoma Viral , Humanos , Casas de Salud , Filogenia , ARN Viral/genética , SARS-CoV-2/genéticaRESUMEN
In this study, we report on the results of SARS-CoV-2 surveillance performed in an area of Southern Italy for 12 months (from March 2021 to February 2022). To this study, we have sequenced RNA from 609 isolates. We have identified circulating VOCs by Sanger sequencing of the S gene and defined their genotypes by whole-genome NGS sequencing of 157 representative isolates. Our results indicated that B.1 and Alpha were the only circulating lineages in Calabria in March 2021; while Alpha remained the most common variant between April 2021 and May 2021 (90 and 73%, respectively), we observed a concomitant decrease in B.1 cases and appearance of Gamma cases (6 and 21%, respectively); C.36.3 and Delta appeared in June 2021 (6 and 3%, respectively); Delta became dominant in July 2021 while Alpha continued to reduce (46 and 48%, respectively). In August 2021, Delta became the only circulating variant until the end of December 2021. As of January 2022, Omicron emerged and took over Delta (72 and 28%, respectively). No patient carrying Beta, Iota, Mu, or Eta variants was identified in this survey. Among the genomes identified in this study, some were distributed all over Europe (B1_S477N, Alpha_L5F, Delta_T95, Delta_G181V, and Delta_A222V), some were distributed in the majority of Italian regions (B1_S477N, B1_Q675H, Delta_T95I and Delta_A222V), and some were present mainly in Calabria (B1_S477N_T29I, B1_S477N_T29I_E484Q, Alpha_A67S, Alpha_A701S, and Alpha_T724I). Prediction analysis of the effects of mutations on the immune response (i.e., binding to class I MHC and/or recognition of T cells) indicated that T29I in B.1 variant; A701S in Alpha variant; and T19R in Delta variant were predicted to impair binding to class I MHC whereas the mutations A67S identified in Alpha; E484K identified in Gamma; and E156G and ΔF157/R158 identified in Delta were predicted to impair recognition by T cells. In conclusion, we report on the results of SARS-CoV-2 surveillance in Regione Calabria in the period between March 2021 and February 2022, identified variants that were enriched mainly in Calabria, and predicted the effects of identified mutations on host immune response.
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Embryonic stem cells (ESCs) are pluripotent cells with indefinite self-renewal ability and differentiation properties. To function properly and maintain genomic stability, ESCs need to be endowed with an efficient repair system as well as effective redox homeostasis. In this study, we investigated different aspects involved in ESCs' response to iron accumulation following stable knockdown of the ferritin heavy chain (FTH1) gene, which encodes for a major iron storage protein with ferroxidase activity. Experimental findings highlight unexpected and, to a certain extent, paradoxical results. If on one hand FTH1 silencing does not correlate with increased ROS production nor with changes in the redox status, strengthening the concept that hESCs are extremely resistant and, to a certain extent, even refractory to intracellular iron imbalance, on the other, the differentiation potential of hESCs seems to be affected and apoptosis is observed. Interestingly, we found that FTH1 silencing is accompanied by a significant activation of the nuclear factor (erythroid-derived-2)-like 2 (Nrf2) signaling pathway and pentose phosphate pathway (PPP), which crosstalk in driving hESCs antioxidant cascade events. These findings shed new light on how hESCs perform under oxidative stress, dissecting the molecular mechanisms through which Nrf2, in combination with PPP, counteracts oxidative injury triggered by FTH1 knockdown.
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Ferritinas/genética , Células Madre Embrionarias Humanas/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Oxidorreductasas/genética , Elementos de Respuesta Antioxidante , Apoptosis , Diferenciación Celular , Células Cultivadas , Ferritinas/farmacología , Silenciador del Gen , Humanos , Oxidación-Reducción , Oxidorreductasas/metabolismo , Vía de Pentosa Fosfato , Transducción de SeñalRESUMEN
Although much progress has been made in cancer treatment, the molecular mechanisms underlying cancer radioresistance (RR) as well as the biological signatures of radioresistant cancer cells still need to be clarified. In this regard, we discovered that breast, bladder, lung, neuroglioma, and prostate 6 Gy X-ray resistant cancer cells were characterized by an increase of lipid droplet (LD) number and that the cells containing highest LDs showed the highest clonogenic potential after irradiation. Moreover, we observed that LD content was tightly connected with the iron metabolism and in particular with the presence of the ferritin heavy chain (FTH1). In fact, breast and lung cancer cells silenced for the FTH1 gene showed a reduction in the LD numbers and, by consequence, became radiosensitive. FTH1 overexpression as well as iron-chelating treatment by Deferoxamine were able to restore the LD amount and RR. Overall, these results provide evidence of a novel mechanism behind RR in which LDs and FTH1 are tightly connected to each other, a synergistic effect that might be worth deeply investigating in order to make cancer cells more radiosensitive and improve the efficacy of radiation treatments.
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Ferritinas/metabolismo , Gotas Lipídicas/efectos de la radiación , Neoplasias/metabolismo , Neoplasias/radioterapia , Oxidorreductasas/metabolismo , Línea Celular Tumoral , Ferritinas/genética , Humanos , Gotas Lipídicas/metabolismo , Neoplasias/genética , Oxidorreductasas/genética , Tolerancia a Radiación , Rayos XRESUMEN
Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients' outcome. Indeed, currently available therapeutic-strategies to overcome CRS, should be urgently evaluated for their capability of reducing COVID-19 mortality. Notably, COVID-19 shares different pathogenic aspects with acute graft-versus-host-disease (aGVHD), hemophagocytic-lymphohistiocytosis (HLH), myelofibrosis, and CAR-T-associated CRS. Specifically, similarly to aGVHD, an induced tissue damage (caused by the virus) leads to increased cytokine release (TNFα and IL-6) which in turn leads to exaggerated dendritic cells, macrophages (like in HLH) and lymphocytes (as in CAR-T) activation, immune-cells migration, and tissue-damage (including late-stage fibrosis, similar to myelofibrosis). Janus Kinase (JAK) signaling represents a molecular hub linking all these events, rendering JAK-inhibitors suitable to limit deleterious effects of an overwhelming inflammatory-response. Accordingly, ruxolitinib is the only selective JAK1 and JAK2-inhibitor approved for the treatment of myelofibrosis and aGVHD. Here, we discuss, from a molecular and hematological point of view, the rationale for targeting JAK signaling in the management of COVID-19 patients and report the clinical results of a patient admitted to ICU among the firsts to be treated with ruxolitinib in Italy.
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Enhanced glycolysis is a hallmark of breast cancer. In cancer cells, the high glycolytic flux induces carbonyl stress, a damaging condition in which the increase of reactive carbonyl species makes DNA, proteins, and lipids more susceptible to glycation. Together with glucose, methylglyoxal (MGO), a byproduct of glycolysis, is considered the main glycating agent. MGO is highly diffusible, enters the nucleus, and can react with easily accessible lysine- and arginine-rich tails of histones. Glycation adducts on histones undergo oxidization and further rearrange to form stable species known as advanced glycation end-products (AGEs). This modification alters nucleosomes stability and chromatin architecture deconstructing the histone code. Formation of AGEs has been associated with cancer, diabetes, and several age-related diseases. Recently, DJ-1, a cancer-associated protein that protects cells from oxidative stress, has been described as a deglycase enzyme. Although its role in cell survival results still controversial, in several human tumors, its expression, localization, oxidation, and phosphorylation were found altered. This work aimed to explore the molecular mechanism that triggers the peculiar cellular compartmentalization and the specific post-translational modifications (PTM) that, occurring in breast cancer cells, influences the DJ-1 dual role. Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. Notably, this threonine is in addition to histidine 126, a key residue involved in the formation of catalytic triade (glu18-Cys106-His126) inside the glioxalase active site of DJ. Interestingly, we found that pharmacological modulation of Akt pathway induces a functional tuning of DJ-1 proteoforms, as well as their shuttle from cytosol to nucleus, pointing out that pathway as critical in the development of DJ-1 pro-tumorigenic abilities. Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation. In normal conditions, DJ-1 acts as a redox-sensitive chaperone and as an oxidative stress sensor. In cancer cells, glycolytic rewiring, inducing increased reactive oxygen species (ROS) levels, enhances AGEs products. Alongside, the moderate increase of ROS enhances Akt signaling that induces DJ-1-phosphorylation. When phosphorylated DJ-1 increases its glyoxalase activity, the level of AGEs on histones decreases. Therefore, phospho-DJ-1 prevents glycation-induced histones misregulation and its Akt-related hyperactivity represents a way to preserve the epigenome landscape sustaining proliferation of cancer cells. Together, these results shed light on an interesting mechanism that cancer cells might execute to escape the metabolic induced epigenetic misregulation that otherwise could impair their malignant proliferative potential.
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Neoplasias de la Mama/genética , Cromatografía Liquida/métodos , Epigénesis Genética/genética , Proteína Desglicasa DJ-1/metabolismo , Espectrometría de Masas en Tándem/métodos , Femenino , Humanos , Modelos MolecularesRESUMEN
Since December 2019, coronavirus disease 2019 (COVID-19) pandemic has spread from China all over the world and many COVID-19 outbreaks have been reported in long-term care facilities (LCTF). However, data on clinical characteristics and prognostic factors in such settings are scarce. We conducted a retrospective, observational cohort study to assess clinical characteristics and baseline predictors of mortality of COVID-19 patients hospitalized after an outbreak of SARS-CoV-2 infection in a LTCF. A total of 50 patients were included. Mean age was 80 years (SD, 12 years), and 24/50 (57.1%) patients were males. The overall in-hospital mortality rate was 32%. At Cox regression analysis, significant predictors of in-hospital mortality were: hypernatremia (HR 9.12), lymphocyte count < 1000 cells/µL (HR 7.45), cardiovascular diseases other than hypertension (HR 6.41), and higher levels of serum interleukin-6 (IL-6, pg/mL) (HR 1.005). Our study shows a high in-hospital mortality rate in a cohort of elderly patients with COVID-19 and hypernatremia, lymphopenia, CVD other than hypertension, and higher IL-6 serum levels were identified as independent predictors of in-hospital mortality. Given the small population size as major limitation of our study, further investigations are necessary to better understand and confirm our findings in elderly patients.
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COVID-19/diagnóstico , COVID-19/mortalidad , Mortalidad Hospitalaria , Cuidados a Largo Plazo/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/complicaciones , China/epidemiología , Síndrome de Liberación de Citoquinas/patología , Femenino , Hospitalización , Humanos , Hipernatremia/complicaciones , Interleucina-6/sangre , Linfopenia/complicaciones , Masculino , Casas de Salud , Factores de Riesgo , SARS-CoV-2RESUMEN
OBJECTIVE: The growing life expectancy has led the elderly to be increasingly referred to coronary artery bypass grafting. Preexisting comorbidities may benefit from theoretical advantages of pulsatile perfusion during cardiopulmonary bypass (CPB). DESIGN: Prospective randomized trial. SETTING: Cardiac surgery unit in a university hospital. PATIENTS: Eighty consecutive patients older than 70 years. INTERVENTIONS: Elective coronary artery bypass grafting on CPB, randomizing to conventional linear CPB (40 patients, group A) or intra-aortic balloon pump (IABP)-induced pulsatile CPB (40 patients, group B). MEASUREMENTS AND MAIN RESULTS: We evaluated hemodynamic response by pulmonary artery flotation catheter, metabolic/splanchnic response by lactate and transaminase, bilirubin, amylase, and renal function (creatinine clearance, creatinine, incidence of renal insufficiency and failure), respiratory response by Pao2/Fio2, respiratory compliance, scoring of chest radiograph, intubation time, and need for noninvasive positive-pressure ventilation, hematologic response by chest drainage, hemocoagulative and fibrinolytic cascades, and transfusions. IABP-related complications were recorded. Two minor IABP-related complications (2.5%) were registered. Hemodynamics was comparable, except for a slightly better cardiac index and indexed systemic vascular resistances at the end of CPB and at intensive therapy unit (ITU) admission (p < 0.05). Transaminases, bilirubin, amylase, proved lower in group B (p < 0.05 from ITU admission to 48 hours). Creatinine clearance, serum creatinine, and lactate were better in group B (p < 0.05), and acute renal insufficiency was accordingly lower (p = 0.02). Respiratory response demonstrated better Pao2/Fio2 and respiratory compliance from aortic declamping to 48 hours, with better scoring of chest radiograph (p < 0.05 from ITU admission to 48 hours), lower noninvasive positive-pressure ventilation (p = 0.002) and intubation time (p = 0.031) in group B. Lower chest drainage (p < 0.05 at first and second day), transfusions (p < 0.05), activated partial thromboplastin time, international normalized ratio, white blood cells, and D-dimer (p < 0.05 from ITU admission to 48 hours), together with higher platelets, fibrinogen, and antithrombin III (p < 0.05 from ITU admission to 48 hours) were demonstrated in the pulsated group. CONCLUSIONS: IABP-induced pulsatile flow significantly improves whole body perfusion in the elderly undergoing CPB.
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Puente Cardiopulmonar , Enfermedad de la Arteria Coronaria/cirugía , Contrapulsador Intraaórtico , Flujo Pulsátil , Anciano , Terapia Combinada , Femenino , Humanos , Masculino , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Acute cardiogenic shock or cardiac arrest (CS/CA) before cardiopulmonary bypass (CPB) installation are life-threatening events in acute coronary syndromes. We evaluated whether continuous retrograde warm-blood perfusion(CRWBP) before aortic cross-clamping (ACC),with immediate CPB installation may improve hospital results in these dreadful events. Hospital outcome of 18 coronary artery bypass grafting (CABG) (Group A) with CS/CA before CPB, with immediate CPB installation and CRWBP,has been compared with 24 CABG (Group B) with CS/CA undergoing only immediate CPB installation. No differences have been detected in the mean time to establish CPB(P = 0.655). Electrocardiography normalized in a significantly higher number of CRWBP (P = 0.0001). Group B showed longer CPB (116.2 +/- 21.2 min vs. 157.8 +/- 32.4;P = 0.0001) and postoperative intra-aortic balloon pumping time course (36.2 +/- 5.9 h vs. 77.8 +/-13.2; P = 0.0001).CRWBP reduced postoperative acute myocardial infarction (P = 0.004) and damage (P = 0.033), death (P = 0.026),and need for high inotropic support (0% vs. 37.5%; P =0.003). Troponin I was significantly lower in Group A(P = 0.013 from coronary sinus; P = 0.0001 at 12, 24, and 48 h postoperatively; P = 0.008 at 72 h), never reaching values suggestive of acute myocardial infarction. Group A had also lower lactate release from aortic declamping to 48 h postoperatively (P = 0.0001).CRWBP improved post operative left ventricular ejection fraction (EF) (P = 0.017)and wall motion score index (P = 0.041), whereas Group B showed a significant worsening of EF (P = 0.0001) and wall motion score index (P = 0.002). Patients in Group A had shorter intubation time (P = 0.0001), intensive therapy unit(ITU) stay (P = 0.001), and hospital stay (P = 0.0001).CRWBP reverses myocardial damage in patients with CS/CA during acute coronary syndromes, adding a straightforward benefit to hospital survival.
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Vasos Coronarios , Infarto del Miocardio/prevención & control , Isquemia Miocárdica/terapia , Reperfusión Miocárdica , Miocardio/patología , Síndrome Coronario Agudo/terapia , Anciano , Biomarcadores/sangre , Puente Cardiopulmonar , Cardiotónicos/administración & dosificación , Puente de Arteria Coronaria , Creatinina/sangre , Muerte Súbita Cardíaca/prevención & control , Ecocardiografía , Electrocardiografía , Femenino , Corazón/fisiopatología , Paro Cardíaco/terapia , Hemodinámica , Humanos , Unidades de Cuidados Intensivos , Contrapulsador Intraaórtico , Ácido Láctico/sangre , Tiempo de Internación , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Isquemia Miocárdica/prevención & control , Proyectos de Investigación , Estudios Retrospectivos , Choque Cardiogénico/terapia , Factores de Tiempo , Resultado del Tratamiento , Troponina I/sangreRESUMEN
Immune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T-cell subpopulations from melanoma patients. The patients' immune profiles suggested that melanoma progression leads to changes in peripheral blood NK and T-cell subsets. Stage IV melanoma was characterized by an increased frequency of CCR7+CD56bright NK cells as well as high serum concentrations of the CCR7 ligand CCL19. CCR7 expression and CCL19 secretion were also observed in melanoma cell lines. The CCR7+ melanoma cell subpopulation coexpressed PD-L1 and Galectin-9 and had stemness properties. Analysis of melanoma-derived cancer stem cells (CSC) showed high CCR7 expression; these CSCs were efficiently recognized and killed by NK cells. An accumulation of CCR7+, PD-L1+, and Galectin-9+ melanoma cells in melanoma metastases was demonstrated ex vivo Altogether, our data identify biomarkers that may mark a CCR7-driven metastatic melanoma pathway.