Design and synthesis of wm5 analogues as HIV-1 TAR RNA binders

The 6-aminoquinolone WM5, previously identified by us, is among the most selective small molecules known as TAR RNA binders to show anti-HIV activity. Methods: Starting from WM5, a series of analogues modified at N-1, C-6 or C-7 position was prepared by inserting guanidine or amidine groups as well as other protonable moieties intended to electrostatically bind the phosphate backbone of TAR. All the compounds were tested for their ability to inhibit HIV-1 replication in MT-4 cells and in parallel for their cytotoxicity. The active compounds were also evaluated for their ability to interfere with the formation of the Tat-TAR complex using a Fluorescence Quenching Assay (FQA). Results: Some of the synthesized compounds showed an anti-HIV-1 activity in the sub-micromolar range with the naphthyridone derivatives being the most potent. Three of the synthesized derivatives were able to interact with the Tat-TAR complex formation presenting Ki values improved as compared to the values obtained with WM5. Conclusion: The addition of a pyridine-based protonable side chain at the N-1 position of the quinolone/naphthyridone core imparted to the compounds the ability to interfere with Tat-TAR complex formation and HIV-1 replicatio

Nirmatrelvir treatment of SARS-CoV-2-infected mice blunts antiviral adaptive immune responses

Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS-CoV-2 pandemic. Nirmatrelvir-an orally available inhibitor of the 3-chymotrypsin-like cysteine protease-has been shown to reduce the risk of progression to severe COVID-19. However, the impact of nirmatrelvir treatment on the development of SARS-CoV-2-specific adaptive immune responses is unknown. Here, by using mouse models of SARS-CoV-2 infection, we show that nirmatrelvir administration blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals

Prostaglandin E2 stimulates the expansion of regulatory hematopoietic stem and progenitor cells in type 1 diabetes

Hematopoietic stem and progenitor cells (HSPCs) are multipotent stem cells that have been harnessed as a curative therapy for patients with hematological malignancies. Notably, the discovery that HSPCs are endowed with immunoregulatory properties suggests that HSPC-based therapeutic approaches may be used to treat autoimmune diseases. Indeed, infusion with HSPCs has shown promising results in the treatment of type 1 diabetes (T1D) and remains the only "experimental therapy" that has achieved a satisfactory rate of remission (nearly 60%) in T1D. Patients with newly diagnosed T1D have been successfully reverted to normoglycemia by administration of autologous HSPCs in association with a non-myeloablative immunosuppressive regimen. However, this approach is hampered by a high incidence of adverse effects linked to immunosuppression. Herein, we report that while the use of autologous HSPCs is capable of improving C-peptide production in patients with T1D, ex vivo modulation of HSPCs with prostaglandins (PGs) increases their immunoregulatory properties by upregulating expression of the immune checkpoint-signaling molecule PD-L1. Surprisingly, CXCR4 was upregulated as well, which could enhance HSPC trafficking toward the inflamed pancreatic zone. When tested in murine and human in vitro autoimmune assays, PG-modulated HSPCs were shown to abrogate the autoreactive T cell response. The use of PG-modulated HSPCs may thus provide an attractive and novel treatment of autoimmune diabetes

The importance of knowing growth and pubertal development in Down Syndrome

Knowing growth and pubertal development in Down Syndrome (DS) is very important to early detect catch down growth/weight or pubertal delay that can be suggetsive of disorders such as autoimmune diseases, endocrinopathies or oncological pathologie

Influence of Periodontal Biotype on Root Surface Exposure During Orthodontic Treatment : a Preliminary Study

The aim of this study was to investigate the role of periodontal biotype in the development of gingival recession in patients who have undergone orthodontic treatment. A total of 60 mandibular incisors were analyzed. The qualitative assessment of periodontal biotype was performed with the use of a new biotype probe. A strong correlation was found between thin biotype and proinclination in terms of recession depth and keratinized tissue width. Patients with thin periodontal biotype are more prone to gingival margin instability, irrespective of the type of orthodontic movements. Thin periodontal biotype and proinclination orthodontic movement were related to loss of keratinized tissue width

Trasposizione dentale e trattamento ortodontico : revisione della letteratura

OBJECTIVES. The purpose of this study is to provide a review of the literature concerning dental transposition, by investigating its prevalence, any possibly associated dental abnormalities, its peculiar characteristics and its classification system. MATERIALS AND METHODS. The review was conducted using PubMed databases. The words entered in the search box were "tooth transposition orthodontics" and "orthodontic transposition". RESULTS. The overall prevalence of transposition is less than 1% and the etiology involves genetic and environmental factors. Different types have been identified and classified according to the teeth involved. The main goal of treatment is to correct their position. CONCLUSIONS. The management of this orthodontic problem may be improved with a deeper scientific understanding of such dental anomaly

The impact of new continuous glucose monitoring (CGM) devices versus self-management of blood glucose (SMBG) on the daily life of parents and children affected by type 1 diabetes mellitus

Background: Type 1 diabetes mellitus is a chronic autoimmune endocrine and metabolic disease which frequently occurs during infancy and childhood. Self-monitoring of blood glucose (SMBG) is of utmost importance to achieve good glycemic control. Common side effects of SMBG in children are pain, discomfort, skin induration, and reduced tactile sensitivity; moreover, SMBG does not allow continuous glycemic monitoring. The more recent introduction of much less invasive devices for continuous glucose monitoring (CGM) has indeed reduced procedure-related pain and discomfort, and allowed real-time glycemic monitoring. Methods: From the beginning of May to the end of September 2019, we conducted a survey by means of a two-section (children/parents) questionnaire, aimed at assessing the impact of CGM on children affected by type 1 diabetes mellitus and their families, referring to the Pediatric Diabetes outpatient clinic at Guglielmo da Saliceto Hospital in Piacenza, Italy. Results: The vast majority (80%) of children reported that the placement of the glycemic sensor is much less painful than fingertip multiple capillary punctures, as with traditional SMBG. Likewise, 90% of parents think that the use of CGM devices allowed a remarkable improvement of glycemic control, with regard either to the reduction of hypo- and/or hyper-glycemic episodes or to glycated hemoglobin (HbA1c) level. Moreover, 89% of parents believe that the use of glycemic sensors has led to a sharp improvement in children’s quality of life. According to children, school and sport are the two areas with the most evident improvement of their quality of life; less anxiety, high comfort and better glycemic control, particularly when not at home, have been indicated as major benefits.Conclusions: According to our data, the use of CGM devices can significantly improve the quality of life of type 1 diabetic children and their families

Cleft lip and/or palate : Review

Aim. Aim of the review was to provide a literature overview of the birth defects of cleft lip and/or cleft palate (CL/P). Methods. Through the use of the PubMed database items were collected that would provide information about the condition, leading to the discussion of the following topics: epidemiology, anatomical features, genetics, environmental factors, diagnosis and treatment. Results. According to these data, the CL/P are the most common congenital malformations of the craniofacial region. There are different phenotypes and clinical features of this malformation, which differ according to the anatomical structures involved: cleft lip, cleft lip and cleft palate. The etiology is multifactorial and includes both genetic factors and environmental factors. For proper diagnosis and treatment it is important to complete a multidisciplinary approach to guide the patient from birth to the end of growth. Among the outstanding figures for the care of the anomaly are: the gynecologist, the pediatrician, the maxillofacial surgeon and orthodontist. Individuals with a cleft lip and/or cleft palate may experience problems in feeding, pronunciation, hearing and social integration, which can be corrected to a different extent by surgery, dental treatment, speech therapy and psychosocial interventions. Conclusion. Today the optimal treatment is difficult to find, because of the large variability of malformations and the subjective response of each patient to therapy

Visible-Light Photocatalytic Functionalization of Isocyanides for the Synthesis of Secondary Amides and Ketene Aminals

A new visible light-induced photocatalytic protocol enabling the formation of secondary amides from electron-poor organic bromides and isocyanides was developed. In addition, the in situ interception of ketenimine intermediates with nitrogen nucleophiles such as amines, hydrazines, and TMSN3 afforded, in a one-pot two-step procedure, valuable scaffolds such as ketene aminals, pyrazolones, and tetrazoles. Mechanistic evidence confirmed a radical pathway where isocyanides acted as radical geminal acceptors generating key imidoyl radical species

Visible light photocatalysis in the late-stage functionalization of pharmaceutically relevant compounds

The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-Activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them