Glycoconjugate vaccines are based on chemical conjugation of pathogen‐associated carbohydrates with immunogenic carrier proteins and are considered a very cost‐effective way to prevent infections. ...Most of the licensed glycoconjugate vaccines are composed of saccharide antigens extracted from bacterial sources. However, synthetic oligosaccharide antigens have become a promising alternative to natural polysaccharides with the advantage of being well‐defined structures providing homogeneous conjugates. Haemophilus influenzae (Hi) is responsible for a number of severe diseases. In recent years, an increasing rate of invasive infections caused by Hi serotype a (Hia) raised some concern, because no vaccine targeting Hia is currently available. The capsular polysaccharide (CPS) of Hia is constituted by phosphodiester‐linked 4‐β‐d‐glucose‐(1→4)‐d‐ribitol‐5‐(PO4→) repeating units and is the antigen for protein‐conjugated polysaccharide vaccines. To investigate the antigenic potential of the CPS from Hia, we synthesized related saccharide fragments containing up to five repeating units. Following the synthetic optimization of the needed disaccharide building blocks, they were assembled using the phosphoramidite approach for the installation of the phosphodiester linkages. The resulting CPS‐based Hia oligomers were conjugated to CRM197 carrier protein and evaluated in vivo for their immunogenic potential, showing that all glycoconjugates were capable of raising antibodies recognizing Hia synthetic fragments.
The synthesis of the protein conjugates of Haemophilus influenzae type a (Hia) capsular polysaccharide oligomers is reported. The obtained neoglycoconjugates, comprising from one to five well‐defined disaccharide repeating units, were employed in immunization studies, showing their ability to induce a specific immune response.
Climate is changing at a fast pace, causing widespread, profound consequences for living organisms. Failure to adjust the timing of life-cycle events to climate may jeopardize populations by causing ...ecological mismatches to the life cycle of other species and abiotic factors. Population declines of some migratory birds breeding in Europe have been suggested to depend on their inability to adjust migration phenology so as to keep track of advancement of spring events at their breeding grounds. In fact, several migrants have advanced their spring arrival date, but whether such advancement has been sufficient to compensate for temporal shift in spring phenophases or, conversely, birds have become ecologically mismatched, is still an unanswered question, with very few exceptions. We used a novel approach based on accumulated winter and spring temperatures (degree-days) as a proxy for timing of spring biological events to test if the progress of spring at arrival to the breeding areas by 117 European migratory bird species has changed over the past five decades. Migrants, and particularly those wintering in sub-Saharan Africa, now arrive at higher degree-days and may have therefore accumulated a ‘thermal delay’, thus possibly becoming increasingly mismatched to spring phenology. Species with greater ‘thermal delay’ have shown larger population decline, and this evidence was not confounded by concomitant ecological factors or by phylogenetic effects. These findings provide general support to the largely untested hypotheses that migratory birds are becoming ecologically mismatched and that failure to respond to climate change can have severe negative impacts on their populations. The novel approach we adopted can be extended to the analysis of ecological consequences of phenological response to climate change by other taxa.
Telemedicine, the remote delivery of healthcare services, represents a great opportunity for cancer pain management. A care model of telemedicine that combines remote visits and hospital access could ...be an effective and safe strategy for pain management of cancer patients.
A retrospective study was conducted using the dataset of the telemedicine program at the Istituto Nazionale Tumori of Naples, Italy for assessing the efficacy of a telehealth-based model of care. Demographic, clinical, and process variables were investigated.
A total of 226 cases and 489 visits were included in the analysis. The mean age of patients was 63.4 years (SD=12.4 years), and no sex differences were observed. Approximately 55% of patients were ECOG-PS ≤2 and 87% suffered from metastatic disease. More than half of the patients were treated with high doses of opioids. Each patient had a mean of 2 remote visits and half of the patients had more than 1 telehealth consultation. The dropout ratio was 5.3%. Most visits (n=472) were conducted on patients in the Campania Region, Italy. The maximum covered distance from the Cancer Center and the patients' location was 555.22 Km. A significant difference in the overall number of visits (p=0.006) and the number of pro-capita remote visits (p=0.010) was found, in favor of the group of patients treated before the end of the Covid-19 emergency in Italy, compared to those treated after the pandemic.
Despite various positive outcomes, the analysis highlights several weaknesses, such as the need to assist patients with advanced and non-advanced disease located outside the regional territory. Overall, the telehealth processes should be adapted to post-pandemic scenarios towards their implementation in routine clinical practice.
The aim of this study was to determine a gait pattern, i.e., a subset of spatial and temporal parameters, through a supervised machine learning (ML) approach, which could be used to reliably ...distinguish Parkinson's Disease (PD) patients with and without mild cognitive impairment (MCI). Thus, 80 PD patients underwent gait analysis and spatial-temporal parameters were acquired in three different conditions (normal gait, motor dual task and cognitive dual task). Statistical analysis was performed to investigate the data and, then, five ML algorithms and the wrapper method were implemented: Decision Tree (DT), Random Forest (RF), Naïve Bayes (NB), Support Vector Machine (SVM) and K-Nearest Neighbour (KNN). First, the algorithms for classifying PD patients with MCI were trained and validated on an internal dataset (sixty patients) and, then, the performance was tested by using an external dataset (twenty patients). Specificity, sensitivity, precision, accuracy and area under the receiver operating characteristic curve were calculated. SVM and RF showed the best performance and detected MCI with an accuracy of over 80.0%. The key features emerging from this study are stance phase, mean velocity, step length and cycle length; moreover, the major number of features selected by the wrapper belonged to the cognitive dual task, thus, supporting the close relationship between gait dysfunction and MCI in PD.
FKBP51 immunophilin is abundantly expressed by immune cells. Co-inhibitory immune receptor signalling generates the splicing isoform FKBP51s. Tregs stained by FKBP51s are increased in melanoma ...patients and their counts are associated with anti-CTLA-4 response. An expansion of FKBP51s
PD-L1
monocytes was measured in a group of non-responding patients to anti-CTLA-4. The aim of this work was to confirm the predictive value of response of FKBP51s
Tregs in a cohort of patients undergoing anti-PD1 treatment and shed light on a monocyte subset co-expressing PD-L1/FKBP51s.
Co-cultures of organoids and autologous lymphocytes were used to confirm that tumour T-cell interaction can induce FKBP51s. PBMC immunophenotype and flow cytometry served to assess and monitor FKBP51s
Treg and FKBP51s
PD-L1
monocytes in 22 advanced melanoma patients treated with anti-PD1. Silencing and overexpression of FKBP51s in human macrophages served to address the protein role in the tolerant macrophages' behaviour.
FKBP51s
Tregs count was increased in responders and had a prognostic value. Non-responders showed an early increase in FKBP51s
PD-L1
monocytes during anti-PD1 treatment. Manipulation of FKBP51s modulated the macrophage-phenotype, with forced protein expression promoting aspects associated with tolerance.
FKBP51s may guide in the selection and monitoring of melanoma patient candidates to immune-checkpoint-targeted therapy. Manipulation of FKBP51s may overcome resistance.
While in the literature there is much interest in investigating lower limbs gait of patients affected by neurological diseases, such as Parkinson's Disease (PD), fewer publications involving upper ...limbs movements are available. In previous studies, 24 motion signals (the so-called reaching tasks) of the upper limbs of PD patients and Healthy Controls (HCs) were used to extract several kinematic features through a custom-made software; conversely, the aim of our paper is to investigate the possibility to build models-using these features-for distinguishing PD patients from HCs. First, a binary logistic regression and, then, a Machine Learning (ML) analysis was performed by implementing five algorithms through the Knime Analytics Platform. The ML analysis was performed twice: first, a leave-one out-cross validation was applied; then, a wrapper feature selection method was implemented to identify the best subset of features that could maximize the accuracy. The binary logistic regression achieved an accuracy of 90.5%, demonstrating the importance of the maximum jerk during subjects upper limb motion; the Hosmer-Lemeshow test supported the validity of this model (p-value=0.408). The first ML analysis achieved high evaluation metrics by overcoming 95% of accuracy; the second ML analysis achieved a perfect classification with 100% of both accuracy and area under the curve receiver operating characteristics. The top-five features in terms of importance were the maximum acceleration, smoothness, duration, maximum jerk and kurtosis. The investigation carried out in our work has proved the predictive power of the features, extracted from the reaching tasks involving the upper limbs, to distinguish HCs and PD patients.
Selective inhibition of FKBP51 has emerged as possible novel treatment for diseases like major depressive disorder, obesity, chronic pain, and certain cancers. The current FKBP51 inhibitors are ...rather large, flexible, and have to be further optimized. By using a structure-based rigidification strategy, we hereby report the design and synthesis of a novel promising bicyclic scaffold for FKBP51 ligands. The structure–activity analysis revealed the decalin scaffold as the best moiety for the selectivity-enabling subpocket of FBKP51. The resulting compounds retain high potency for FKBP51 and excellent selectivity over the close homologue FKBP52. With the cocrystal structure of an advanced ligand in this novel series, we show how the decalin locks the key selectivity-inducing cyclohexyl moiety of the ligand in a conformation typical for FKBP51-selective binding. The best compound 29 produces cell death in a HeLa-derived KB cell line, a cellular model of cervical adenocarcinoma, where FKBP51 is highly overexpressed. Our results show how FKBP51 inhibitors can be rigidified and extended while preserving FKBP51 selectivity. Such inhibitors might be novel tools in the treatment of human cancers with deregulated FKBP51.
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5-Lipoxygenase (LO) catalyzes the first steps in the formation of pro-inflammatory leukotrienes (LT) that are pivotal lipid mediators contributing to allergic reactions and ...inflammatory disorders. Based on its key role in LT biosynthesis, 5-LO is an attractive drug target, demanding for effective and selective inhibitors with efficacy in vivo, which however, are still rare. Encouraged by the recent identification of the catechol 4-(3,4-dihydroxyphenyl)dibenzofuran 1 as 5-LO inhibitor, simple structural modifications were made to yield even more effective and selective catechol derivatives. Within this new series, the two most potent compounds 3,4-dihydroxy-3′-phenoxybiphenyl (6b) and 2-(3,4-dihydroxyphenyl)benzobthiophene (6d) potently inhibited human 5-LO in cell-free (IC506b and 6d = 20 nM) and cell-based assays (IC506b = 70 nM, 6d = 60 nM). Inhibition of 5-LO was reversible, unaffected by exogenously added substrate arachidonic acid, and not primarily mediated via radical scavenging and antioxidant activities. Functional 5-LO mutants expressed in HEK293 cells were still prone to inhibition by 6b and 6d, and docking simulations revealed distinct binding of the catechol moiety to 5-LO at an allosteric site. Analysis of 5-LO nuclear membrane translocation and intracellular Ca2+ mobilization revealed that these 5-LO-activating events are hardly affected by the catechols. Importantly, the high inhibitory potency of 6b and 6d was confirmed in human blood and in a murine zymosan-induced peritonitis model in vivo. Our results enclose these novel catechol derivatives as highly potent, novel type inhibitors of 5-LO with high selectivity and with marked effectiveness under pathophysiological conditions.
The rapid growth in the complexity of services and stringent quality requirements present a challenge to all healthcare facilities, especially from an economic perspective. The goal is to implement ...different strategies that allows to enhance and obtain health processes closer to standards. The Length Of Stay (LOS) is a very useful parameter for the management of services within the hospital and is an index evaluated for the management of costs. In fact, a patient's LOS can be affected by a number of factors, including their particular condition, medical history, or medical needs. To reduce and better manage the LOS it is necessary to be able to predict this value.
In this study, a predictive model was built for the total LOS of patients undergoing laparoscopic appendectomy, one of the most common emergency procedures. Demographic and clinical data of the 357 patients admitted at "San Giovanni di Dio e Ruggi d'Aragona" University Hospital of Salerno (Italy) had used as independent variable of the multiple linear regression model.
The obtained model had an R
value of 0.570 and, among the independent variables, the significant variables that most influence the total LOS were Age, Pre-operative LOS, Presence of Complication and Complicated diagnosis.
This work designed an effective and automated strategy for improving the prediction of LOS, that can be useful for enhancing the preoperative pathways. In this way it is possible to characterize the demand and to be able to estimate a priori the occupation of the beds and other related hospital resources.
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