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Background: In the currently ongoing coronavirus pandemic, coinfections with unrelated life-threatening febrile conditions may pose a particular challenge to clinicians. Leishmaniasis is a zoonosis that may present general symptoms, including fever, malaise, and arthralgia, rendering it indistinguishable from COVID-19. Methods: In this paper, we aim to draw attention to this issue and analyze the clinical characteristics of the coinfection SARS-CoV-2/Leishmania through a systematic review of the literature. We were motivated by the observation of the first case of visceral leishmaniasis and COVID-19 in a paediatric patient. Conclusion: Our case is a reminder for healthcare providers to consider the diagnosis of visceral leishmaniasis in patients presenting with febrile syndrome in endemic regions during the COVID-19 pandemic.

The current guidelines recommend the sentinel lymph node biopsy to evaluate the lymph node involvement for breast cancer patients with clinically negative lymph nodes on clinical or radiological examination. Machine learning (ML) models have significantly improved the prediction of lymph nodes status based on clinical features, thus avoiding expensive, time-consuming and invasive procedures. However, the classification of sentinel lymph node status represents a typical example of an unbalanced classification problem. In this work, we developed a ML framework to explore the effects of unbalanced populations on the performance and stability of feature ranking for sentinel lymph node status classification in breast cancer. Our results indicate state-of-the-art AUC (Area under the Receiver Operating Characteristic curve) values on a hold-out set (67%) while providing particularly stable features related to tumor size, histological subtype and estrogen receptor expression, which should therefore be considered as potential biomarkers.

Gaucher disease is a disorder of lysosomes caused by a functional defect of the glucocerebrosidase enzyme. The disease is mainly due to mutations in the GBA1 gene, which determines the gradual storage of glucosylceramide substrate in the patient’s macrophages. In this paper, we describe the case of a 38-year-old man who clinically presented with hyperferritinemia, thrombocytopenia, leukopenia, anemia and mild splenomegaly; a diagnosis of hemochromatosis was made 10 years earlier. Re-evaluation of the clinical case led to a suspicion of Gaucher disease, which was confirmed by enzymatic analysis, which was found to be below the normal range, and genetic evaluation, which identified compound heterozygosity N370S/RecNciI. We know that patients suffering from Gaucher disease can also have high ferritin levels. Even if the mechanism underlying the changes in iron metabolism is not yet elucidated, the chronic mild inflammatory state present in these patients probably causes the storage of ferritin in macrophages, resulting in hyperferritinemia. Therefore, in the presence of few typical signs and symptoms of the disease should raise an alarm bell in the clinicians, inducing clinical suspicion of Gaucher disease. Misdiagnosis and diagnostic delay in metabolic diseases could cause irreversible organ damage and delay the start of specific therapy for these patients.

Immune checkpoint inhibitors (ICIs) have made a breakthrough in the systemic treatment for metastatic triple-negative breast cancer (TNBC) patients. However, results of phase II and III clinical trials assessing ICIs plus chemotherapy as neoadjuvant treatment were controversial and conflicting. We performed a meta-analysis aimed at assessing the Odds Ratio (OR) of the pathological complete response (pCR) rate in trials assessing neoadjuvant chemoimmunotherapy in TNBC. According to our results, the use of neoadjuvant chemoimmunotherapy was associated with higher pCR (OR 1.95; 95% Confidence Intervals, 1.27–2.99). In addition, we highlighted that this benefit was observed regardless of PD-L1 status since the analysis reported a statistically significant and clinically meaningful benefit in both PD-L1 positive and PD-L1 negative patients. These findings further support the exploration of the role of ICIs plus chemotherapy in early-stage TNBC, given the potentially meaningful clinical impact of these agents. Further studies aimed at more deeply investigating this emerging topic in breast cancer immunotherapy are warranted.

Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) — or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling — induced T cell–dependent tumor growth retardation of aggressive tumor models. In conditions in which anti–PD-1 alone or in combination with anti–CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade–linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell–mediated cancer immunosurveillance.

ObjectiveTo report the clinical profile associated with G60 and I60 over a 4-year prospective observational period in 2 large cohorts of adult patients with CF.Methods319 patients were included (210 Canadian and 119 French) and classified according to their inclusion G60 (≥ or < 11.1 mmol/L) and the median inclusion I60 (≥ or < 24 mU/I). Forced expiratory volume in 1 second (FEV1), body mass index (BMI) were collected on OGTT days. Linear mixed regression models were used to assess the effect of G60 and I60.ResultsHigh G60 was not associated to a lower FEV1 at inclusion and the follow-up decline was not higher in the high G60 group (Coefficient [95% CI]: -3.4 [-7.4;0.6], p = 0.0995.). There was no significant association between BMI and G60. Patients with high I60 tended to have a higher mean BMI (+0.5 kg/m2 [0.0 to 1.1], p = 0.05) but no interaction over time was observed.ConclusionsHigh G60 is not associated with a lower lung function at inclusion nor its decline over a 4-year follow-up. High I60 is slightly associated to a higher weight at inclusion, but not with BMI evolution over time in adult patients.

Until recently, continuing androgen deprivation therapy (ADT) and closely monitoring patients until evolution towards metastatic castration-resistant prostate cancer (CRPC) were recommended in men with non-metastatic CRPC (nmCRPC). Because delaying the development of metastases and symptoms in these patients is a major issue, several trials have investigated next-generation androgen receptor (AR) axis inhibitors such as apalutamide, darolutamide, and enzalutamide in this setting. This review summarizes the recent advances in the management of nmCRPC, highlighting the favourable impact of next-generation AR inhibitors on metastases-free survival, overall survival and other clinically meaningful endpoints.

Cell motility varies according to intrinsic features and microenvironmental stimuli, being a signature of underlying biological phenomena. The heterogeneity in cell response, due to multilevel cell diversity especially relevant in cancer, poses a challenge in identifying the biological scenario from cell trajectories. We propose here a novel peer prediction strategy among cell trajectories, deciphering cell state (tumor vs. nontumor), tumor stage, and response to the anticancer drug etoposide, based on morphology and motility features, solving the strong heterogeneity of individual cell properties. The proposed approach first barcodes cell trajectories, then automatically selects the good ones for optimal model construction (good teacher and test sample selection), and finally extracts a collective response from the heterogeneous populations via cooperative learning approaches, discriminating with high accuracy prostate noncancer vs. cancer cells of high vs. low malignancy. Comparison with standard classification methods validates our approach, which therefore represents a promising tool for addressing clinically relevant issues in cancer diagnosis and therapy, e.g., detection of potentially metastatic cells and anticancer drug screening.

We report the case of a 56-year-old Caucasian male affected by thymoma and myasthenia gravis that developed recurrent visceral leishmaniasis 11 years after thymectomy. After treatment of each relapse with liposomal amphotericin B the PCR-Leishmania was negative and the patient showed clinical improvement. An immunologic work-up was performed showing lymphopenia with an important decrease in CD4+ T cells (52 cells/μ) and CD4/CD8 ratio (0.2). HIV test was negative. On the basis of previous thymoma and myasthenia gravis and on the basis of the immunological profile a diagnosis of Good's syndrome was made. Since IFNγ plays a main role in the control of Leishmania infection the production of IFNγ was evaluated. After mitogen stimulation of peripheral blood mononuclear cells the production of IFNγ was lower than normal. This is the second reported case of Good's syndrome with recurrent leishmaniasis and indicates that a definitive cure for leishmaniasis in patients with Good's syndrome is not possible. Immunologic work-up in our patient strongly suggests that relapses could be correlated with the low CD4+ T cell number and with the low IFNγ production. Immunotherapy with IFNγ or with compounds able to block the Th2 interleukin production could be a therapeutic option in these patients.

Abstract Background Soluble Receptor for Advanced Glycation End Products (sRAGE) may be considered a marker inversely related to inflammation and its participation has been established in patients with advanced atherosclerotic vascular diseases. However, it is still unknown whether sRAGE reduction could be early metabolic change in the first stage of hypertension and initial hypertension-associated cardiac damage. We sought to determine the sRAGE values in otherwise healthy, untreated and recently diagnosed mild hypertensives and evaluate their association with blood pressure (BP) values, metabolic parameters, and with subclinical initial signs of cardiac target organ damage (TOD). Methods sRAGE were measured in 100 hypertensive and 100 normotensive subjects matched for age, gender and body mass index (BMI), submitted to a clinic visit and both ambulatory BP monitoring and echocardiography to determine the presence of initial cardiac TOD (presence of signs of left ventricular hypertrophy: left ventricular mass indexed for height2.7 (LVMi) > 48 g/m2.7 for men and > 44 g/m2.7 for women and/or increased left atrial volume 4-chamber indexed for body surface area (LAVi) > 34 ml/m2). Results sRAGE levels were similar between hypertensive and normotensive subjects and were not significantly correlated with office and 24-h BPs values. However, when subgrouping the hypertensive patients in Hyp-TOD and Hyp-withoutTOD, sRAGE was found to be different among the three groups (p = 0.030), being lower in the Hyp-TOD group than the values of both Hyp-withoutTOD (p = 0.038) and normotensives (p = 0.038). In hypertensive patients sRAGE was negatively related with both LVMi (r = − 0.239, p = 0.034) and LAVi (r = − 0.315, p = 0.005) and was independently related to cardiac TOD also in multivariable analysis. Conclusions In this population of mild hypertensives, low circulating sRAGE may be a very early marker of initial TOD, suggesting the possible participation of oxidative stress in initial cardiac changes in human hypertension.

Chloris gayana is a warm-season grass, often cultivated in areas where soil salinity is a major constraint for forage production. Five cultivars (2 unselected populations and 3 synthetic varieties) were evaluated through agronomic traits as well as Inter Simple Sequence Repeats (ISSRs) and Sequence-related Amplified Polymorphism (SRAP) molecular markers. The consensus between both agronomic and molecular data sets was high (>99%) suggesting that both systems provided similar estimates of genetic relationships. The analysis revealed that synthetic varieties, Finecut, Topcut and Santana, were the most genetically different cultivars, whereas the unselected populations, Pioneer and Katambora, were closely related. Responses to salinity stress during germination and early vegetative growth stages were evaluated in only the synthetic varieties. The results showed that Finecut and Santana were able to germinate in the same proportion as controls even at concentrations of 200 mM NaCl. Under hydroponic conditions, Santana attained approximately 20% higher total dry weight than the other 2 varieties and the longest roots. Finecut presented the highest root dry weight. These results suggested that Santana and Finecut showed high salinity tolerance at germination and early vegetative growth stages, both crucial phases when seeking a successful pasture establishment, particularly in saline environments. Further studies in the field are needed to determine if these hydroponic results are reproduced under field conditions.

Prunus spinosa L. (from Italy) fruit ethanol extract (40 µg/mL) was assessed by evaluating the antioxidant, anti-inflammatory and antimicrobial activities against five bacterial and two fungi ATCC strains. Moreover, the phenolic profile was also investigated and results are indicative of an intense anthocyanin accumulation which may be responsible for the antioxidant properties revealed by the DPPH assay. MIC and MBC/MFC values (4.36–8.72 mg/mL; 8.72–17.44 mg/mL, respectively) revealed a wide antibacterial activity and yeast inhibition. No specific inhibitory action was observed against the tested Gram-negative or Gram-positive bacteria. Preliminary data on the effect on both miR-126 and miR-146a expression levels suggested a very interesting anti-inflammatory activity of the extract. A possible mechanism underpinning the observed effects was hypothesized and discussed. Finally, P. spinosa fruit extract could be used as supplementary source of functional additives and might be a promising antimicrobial compound of natural origin to be employed to fight microbial resistance.

Human ageing can be characterized by a profile of circulating microRNAs (miRNAs), which are potentially predictors of biological age. They can be used as a biomarker of risk for age-related inflammatory outcomes, and senescent endothelial cells (ECs) have emerged as a possible source of circulating miRNAs. In this paper, a panel of four circulating miRNAs including miR-146a-5p, miR-126-3p, miR-21-5p, and miR-181a-5p, involved in several pathways related to inflammation, and ECs senescence that seem to be characteristic of the healthy ageing phenotype. The circulating levels of these miRNAs were determined in 78 healthy subjects aged between 22 to 111 years. Contextually, extracellular miR-146a-5p, miR-126-3p, miR-21-5p, and miR-181a-5p levels were measured in human ECs in vitro model, undergoing senescence. We found that the levels of the four miRNAs, using ex vivo and in vitro models, progressively increase with age, apart from ultra-centenarians that showed levels comparable to those measured in young individuals. Our results contribute to the development of knowledge regarding the identification of miRNAs as biomarkers of successful and unsuccessful ageing. Indeed, they might have diagnostic/prognostic relevance for age-related diseases.

Abstract Background Intestinal-type sinonasal adenocarcinomas (ITACs) are aggressive malignancies related to wood dust and leather exposure. ITACs are generally associated with advanced stage at presentation due to the insidious growth pattern and non-specific symptoms. Therefore, biomarkers that can detect the switch from the benign disease to malignancy are needed. Essential for tumour growth, angiogenesis is an important step in tumour development and progression. This process is strictly regulated, and MiR-126 considered its master modulator. Methods We have investigated MiR-126 levels in ITACs and compared them to benign sinonasal lesions, such as sinonasal-inverted papillomas (SIPs) and inflammatory polyps (NIPs). The tumour-suppressive functions of MiR-126 were also evaluated. Results We found that MiR-126 can significantly distinguish malignancy from benign nasal forms. The low levels of MiR-126 in ITACs point to its role in tumour progression. In this context, restoration of MiR-126 induced metabolic changes, and inhibited cell growth and the tumorigenic potential of MNSC cells. Conclusions We report that MiR-126 delivered via exosomes from endothelial cells promotes anti-tumour responses. This paracrine transfer of MiRs may represent a new approach towards MiR-based therapy.

Background/Aims: Fabry disease (FD) is a lysosomal storage disorder characterized by pervasive renal involvement. However, this disease is underdiagnosed in patient with chronic kidney disease (CKD), including those with end stage renal disease (ESRD), so their investigation represents an unexploited opportunity for early diagnosis of the disease and for its identification in relatives of affected patients. Methods: We investigated Fabry disease in a clinical and biological database including ESRD patients of unknown cause in a geographical area with 2 million residents. The study was based on state of art GLA gene sequencing and was extended to relatives of affected ESRD patients. Results: Among ESRD patients qualified for enrollment into this study, a previously undiagnosed young man harboring the mutation p.I91T was identified. The study of the proband's family led to the identification of 8 additional cases. In another ESRD male patient, we identified the functional polymorphism p.D313Y. Furthermore, in 55 ESRD patients (24.2%) we found intronic polymorphisms of uncertain functional relevance in the non-coding regions of the GLA gene. Conclusion: A comprehensive survey of ESRD patients in a geographical area of 2 million residents identified one undiagnosed case of Fabry disease and led to the identification of 8 additional cases among his relatives. Screening protocols starting from the dialysis population and upstream extended to families of affected individuals may be an effective strategy to maximize the early identification of subjects with Fabry disease.

Review of: Raimundi Lulli Opera Latina 44: Ars inventiva veritatis, ed. Jorge Uscatescu Barrón, Turnhout: Brepols, 2014 (Corpus Christianorum. Continuatio Mediaevalis, 265; Raimundi Lulli Opera Latina, 37), CXXII + 513 pp., ISBN 9782503552569

Influenza A and B viruses are responsible for respiratory infections, representing globally seasonal threats to human health. The 2 viral types often co-circulate and influenza B plays an important role in the spread of infection. A 6-year retrospective surveillance study was conducted between 2010 and 2016 in 2 large administrative regions of Italy, located in the north (Liguria) and in the south (Sicily) of the country, to describe the burden and epidemiology of both B/Victoria and B/Yamagata lineages in different healthcare settings. Influenza B viruses were detected in 5 of 6 seasonal outbreaks, exceeding influenza A during the season 2012–2013. Most of influenza B infections were found in children aged ≤ 14 y and significant differences were observed in the age-groups infected by the different lineages. B/Victoria strains prevailed in younger population than B/Yamagata, but also were more frequently found in the community setting. Conversely, B/Yamagata viruses were prevalent among hospitalized cases suggesting their potential role in the development of more severe disease. The relative proportions of viral lineages varied from year to year, resulting in different lineage-level mismatch for the B component of trivalent influenza vaccine. Our findings confirmed the need for continuous virological surveillance of seasonal epidemics and bring attention to the adoption of universal influenza immunization program in the childhood. The use of tetravalent vaccine formulations may be useful to improve the prevention and control of the influenza burden in general population.

Abstract Background Visceral leishmaniasis is a vector-borne parasitic disease caused by protozoa belonging to the genus Leishmania. The clinical presentation of visceral leishmaniasis strictly depends on the host immunocompetency, whereas depressive conditions of the immune system impair the capability to resolve the infection and allow reactivation from sites of latency of the parasite. Case presentation We describe a case of visceral leishmaniasis (VL) that occurred in a patient with chronic hepatitis C treated with direct-acting antiviral drugs (DAA). The hypothesized mechanism is the alteration of protective inflammation mechanisms secondary to DAA therapy. Downregulation of type II and III IFNs, their receptors, which accompany HCV clearance achieved during treatment with sofosbuvir and ribavirin might have a negative impact on a risk for reactivation of a previous Leishmania infection. We know indeed that IFN-γ is important to enhance killing mechanisms in macrophages, which are the primary target cells of Leishmania. Conclusion Since VL is endemic in Sicily as well as in other countries of the Mediterranean basin, physicians should be aware of the possible unmasking of cryptic Leishmania infection by DAAs.