Discoveries (Craiova, Romania)最新文献

Recent studies indicate that the composition of gut bacteria can influence the effectiveness of certain cancer immunotherapy drugs and that modulating the gut microbiome may expand the pool of patients benefiting from cancer immunotherapies. Checkpoint blockade therapy has been effective on several types of malignancies (e.g. melanoma, lung cancer, kidney cancer). However, the number of patients that do not respond, or only partially respond, to cancer immunotherapy is high. Recently, several human and mouse studies have shown that gut microbiome may be a significant determinant of the response to cancer immunotherapy. This review focuses on the recent advances in our understanding of the interaction between human gut microbiome and response to immunotherapy in cancer. The gut microbiome may serve as a theranostic biomarker, by acting both as a useful prognostic biomarker and a target in cancer therapy.

Growth hormone deficiency (GHD) is an endocrine disorder, which may be either isolated or associated with other pituitary hormone deficiencies. In children, short stature is a useful clinical marker for GHD. In contrast, symptomatology is not always so obvious in adults, and the existing methods of testing might be inaccurate and imprecise, especially in the lack of a suggestive clinical profile. Since the quality of life of patients diagnosed with GHD could also be significantly affected, in both children and adults, a correct and accurate diagnosis is therefore tremendously important to select those patients that can benefit from the GH treatment. In general, the endocrine diseases are challenging in terms of diagnosis, the simple measurement of the basal level of hormones is not sufficient for distinguishing between the physiological and pathological conditions. Traditionally, several stimulation tests have been considered by professional clinical guidelines, such as insulin tolerance test (ITT), GHRH-arginine stimulation test and the glucagon stimulation test, and all of them have both advantages and limitations. More recently (December 2017), FDA approved a growth hormone secretagogue receptor agonist, macimorelin, for the diagnosis of adults with GHD. The obvious advantage for macimorelin is the simple oral administration and the high level of agreement with the insulin tolerance test for those patients with organic disease and low levels of insulin-like growth factor (IGF-I). However, the safety profile and the diagnostic value was not yet established for the pediatric population and for those adults with extreme or morbid obesity. In addition, administration of macimorelin with drugs that prolong QT interval and CYP3A4 inducers should be avoided. Genetic screening could obviously bring a great insight in the GHD pathology. However, it remains an open question if it would be also cost effective to include it in the routine evaluation of the patients with GHD. Although major progresses have been made in this area, genetic testing continues to be difficult to access, mostly because of its high costs, especially in the low-income and middle-income countries.

Increasing bacterial resistance to antibiotics is a worldwide ongoing issue. Urgent need for new antibacterial agents has resulted in significant research efforts, with new molecules proposed for use in clinical practice. However, as highlighted by many groups this process does not have an optimal rhythm and efficacy, to fully combat highly adaptive germs, particularly in the intensive care units. This review focuses on the last three years of novel FDA approved antibacterial agents (2015-2017): ceftazidime/avibactam, obiltoxaximab, bezlotoxu-mab, delafloxacin, meropenem/vaborbactam, ozenoxacin. Ceftazidime/avibactam and meropenem/ vaborbactam are new players in the field of resistant bacteria treatment. Ceftazidime/avibactam is validated in selected patients with complicated urinary or intra-abdominal infections, hospital and ventilator-associated pneumonia. Meropenem/ vaborbactam gained approval for the cases of complicated urinary tract infections. Other potential indications are under investigation, widened and validated by future studies. Obiltoxaximab is a monoclonal antibody that can be used in the prevention and treatment of inhalational anthrax. Bezlotoxumab monoclonal antibody is an useful and specific tool for the management of recurrent Clostridium difficile infection. Delafloxacin is approved for patients with acute skin or skin structure infections. Despite recent progress, it is imperative to continue the development of new antibiotic drugs and new strategies to counteract resistance to antibiotics.

Background: Gold-induced autologous cytokine (GOLDIC) treatment is usually used in the therapy of the inflammatory musculoskeletal disorders (e.g. osteoarthritis in humans) and is able to modulate the inflammatory reaction. Moreover, governed by chemokines and cytokines, the complex inflammatory response after an acute myocardial infarction (MI), the main cause of death worldwide, plays an important role in the preservation of heart function. Therefore, we hypothesized that GOLDIC could also have an important role in ventricular remodeling after MI.

Methods: Myocardial infarction was induced in mice and GOLDIC-enriched serum was directly injected directly in the infarcted tissue. Four weeks later, the function of the heart, as well as the infarction size and the scar composition were analyzed. Statistical analysis was performed with Prism 6.1 software (GraphPad), using 1-way ANOVA, followed by Newman-Keuls post-hoc-test, as indicated. Data are represented as mean ± SEM.

Results: Four weeks after MI, GOLDIC-treated mice show significantly decreased heart function and higher infarction size compared to the control group. Immunohistochemistry reveals a significantly increased number of myofibroblasts, correlating with higher collagen content in the infarcted area. Despite impaired heart function, angiogenesis in the GOLDIC-treated group is improved compared with the control, due to the increased vascular endothelial growth factor (VEGF) in the GOLDIC serum.

Conclusions: In conclusion, GOLDIC treatment impairs the ventricular remodeling, worsening the heart function. Therefore, these systemic effects should be taken into account when new therapies are designed for the musculoskeletal disorders.

Amyloids play critical roles in human diseases but have increasingly been recognized to also exist naturally. Shared physicochemical characteristics of amyloids and of their smaller oligomeric building blocks offer the prospect of molecular interactions and crosstalk amongst these assemblies, including the propensity to mutually influence aggregation. A case in point might be the recent discovery of an interaction between the amyloid β peptide (Aβ) and somatostatin (SST). Whereas Aβ is best known for its role in Alzheimer disease (AD) as the main constituent of amyloid plaques, SST is intermittently stored in amyloid-form in dense core granules before its regulated release into the synaptic cleft. This review was written to introduce to readers a large body of literature that surrounds these two peptides. After introducing general concepts and recent progress related to our understanding of amyloids and their aggregation, the review focuses separately on the biogenesis and interactions of Aβ and SST, before attempting to assess the likelihood of encounters of the two peptides in the brain, and summarizing key observations linking SST to the pathobiology of AD. While the review focuses on Aβ and SST, it is to be anticipated that crosstalk amongst functional and disease-associated amyloids will emerge as a general theme with much broader significance in the etiology of dementias and other amyloidosis.

Computational machine learning, especially self-enhancing algorithms, prove remarkable effectiveness in applications, including cardiovascular medicine. This review summarizes and cross-compares the current machine learning algorithms applied to electrocardiogram interpretation. In practice, continuous real-time monitoring of electrocardiograms is still difficult to realize. Furthermore, automated ECG interpretation by implementing specific artificial intelligence algorithms is even more challenging. By collecting large datasets from one individual, computational approaches can assure an efficient personalized treatment strategy, such as a correct prediction on patient-specific disease progression, therapeutic success rate and limitations of certain interventions, thus reducing the hospitalization costs and physicians' workload. Clearly such aims can be achieved by a perfect symbiosis of a multidisciplinary team involving clinicians, researchers and computer scientists. Summarizing, continuous cross-examination between machine intelligence and human intelligence is a combination of precision, rationale and high-throughput scientific engine integrated into a challenging framework of big data science.

The presence of protein aggregates in the brain is a hallmark of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Considerable evidence has revealed that the pathological protein aggregates in many neurodegenerative diseases are able to self-propagate, which may enable pathology to spread from cell-to-cell within the brain. This property is reminiscent of what occurs in prion diseases such as Creutzfeldt-Jakob disease. A widely recognized feature of prion disorders is the existence of distinct strains of prions, which are thought to represent unique protein aggregate structures. A number of recent studies have pointed to the existence of strains of protein aggregates in other, more common neurodegenerative illnesses such as AD, PD, and related disorders. In this review, we outline the pathobiology of prion strains and discuss how the concept of protein aggregate strains may help to explain the heterogeneity inherent to many human neurodegenerative disorders.

Neuronal porosomes are 15 nm cup-shaped lipoprotein secretory machines composed of nearly 30 proteins present at the presynaptic membrane, that have been investigated using multiple imaging modalities, such as electron microscopy, atomic force microscopy, and solution X-ray. Synaptic vesicles transiently dock and fuse at the base of the porosome cup facing the cytosol, by establishing a fusion pore for neurotransmitter release. Studies on the morphology, dynamics, isolation, composition, and reconstitution of the neuronal porosome complex provide a molecular understanding of its structure and function. In the past twenty years, a large body of evidence has accumulated on the involvement of the neuronal porosome proteins in neurotransmission and various neurological disorders. In light of these findings, this review briefly summarizes our current understanding of the neuronal porosome complex, the secretory nanomachine at the nerve terminal.

Increasing need for novel drugs and their application for treating diseases are the main reasons for the development of bioinformatics platforms for drug repositioning. The use of existing approved drugs for treating other diseases reduces cost and time needed for a drug to come to clinical use. Different strategies for drug repositioning have been reported. The use of several omics types is becoming increasingly important in drug repositioning. Although there are several public databases intended for drug repositioning, not many successful cases of novel use of drugs have been reported in the literature and transferred to clinical use. Additionally, the study approaches in published literature are very heterogeneous. A classification scheme - Drug Repositioning Evidence Level (DREL) - for drug repositioning projects, according to the level of scientific evidence has been proposed previously. In the present study, we have reviewed main databases and bioinformatics approaches enabling drug repositioning studies. We also reviewed six published studies and evaluated them according to the DREL classification. The evaluated cases used drug repositioning approach for therapy of rheumatoid arthritis, cancer, coronary artery disease, diabetes, and gulf war illness. The drug repositioning study field could benefit from clearer definition in published articles therefore including drug repositioning DREL classification scheme could be included in published original and review studies. Novel bioinformatics approaches to improve prediction of drug-target interactions, continuous updating of the databases, and development of novel validation techniques are needed to facilitate the development of the drug repositioning field. Although there are still many challenges in drug repositioning and personalized medicine, stratification of patients based on their molecular signatures and testing of signature-targeting drugs should improve drug efficacy in clinical trials.