Adolescent reproductive health and awareness of HIV among rural high school students, North Western Ethiopia.

Ethiopia is faced with an increasing problem from HIV infection, and the vulnerability of adolescents is a key concern. There is little information on the knowledge, attitudes and practices of this age group with respect to HIV, sexually transmitted diseases and preventive measures. We conducted a cross-sectional study among 260 students from two rural high schools in North Western Ethiopia. We found that although the general awareness of HIV was high, correct knowledge of the virus and its modes of transmission was shown in only 44% of adolescent boys and 41% of adolescent girls. Knowledge of HIV and condoms was lower among students whose parents were farmers, significant so among girls (p=0.02). Use of condoms among sexually active single male students (49%) was insufficient but was higher than among adolescents in many other African settings. Knowledge of STDs was generally low: 82% of adolescent males and 37% of adolescent females had some awareness of STDs. Almost 20% of sexually active males in the study had previously experienced an STD, almost all of whom had visited a commercial sex worker. Targeted interventions are warranted among adolescents and sex workers in Ethiopia complemented by STD treatment services

Surfactants: physicochemical interactions with biological macromolecules

Macromolecules are essential cellular components in biological systems responsible for performing a large number of functions that are necessary for growth and perseverance of living organisms. Proteins, lipids and carbohydrates are three major classes of biological macromolecules. To predict the structure, function, and behaviour of any cluster of macromolecules, it is necessary to understand the interaction between them and other components through basic principles of chemistry and physics. An important number of macromolecules are present in mixtures with surfactants, where a combi- nation of hydrophobic and electrostatic interactions is responsible for the specific properties of any solution. It has been demonstrated that surfactants can help the formation of helices in some proteins thereby promot- ing protein structure formation. On the other hand, there is extensive research towards the use of surfac- tants to solubilize drugs and pharmaceuticals; there- fore, it is evident that the interaction between surfactants with macromolecules is important for many applications which includes environmental processes and the pharmaceutical industry. In this review, we describe the properties of different types of surfactants that are relevant for their physicochemical interactions with biological macromolecules, from macromolecules–surfactant complexes to hydrophobic and electrostatic interactions

Exploring a potential palonosetron allosteric binding site in the 5-HT 3 receptor

Palonosetron (Aloxi) is a potent second generation 5-HT3 receptor antagonist whose mechanism of action is not yet fully understood. Palonosetron acts at the 5-HT3 receptor binding site but recent computational studies indicated other possible sites of action in the extracellular domain. To test this hypothesis we mutated a series of residues in the 5-HT3A receptor subunit (Tyr73, Phe130, Ser 163, and Asp165) and in the 5-HT3B receptor subunit (His73, Phe130, Glu170, and Tyr143) that were previously predicted by in silico docking studies to interact with palonosetron. Homomeric (5-HT3A) and heteromeric (5-HT3AB) receptors were then expressed in HEK293 cells to determine the potency of palonosetron using both fluorimetric and radioligand methods to test function and ligand binding, respectively. The data show that the substitutions have little or no effect on palonosetron inhibition of 5-HT-evoked responses or binding. In contrast, substitutions in the orthosteric binding site abolish palonosetron binding. Overall, the data support a binding site for palonosetron at the classic orthosteric binding pocket between two 5-HT3A receptor subunits but not at allosteric sites previously identified by in silico modelling and docking

Diffusive Release of Photosensitizing Agents (PS) from Novel PVA-Borate Semi-Solid Drug Carriers Through In Vitro Oral Streptococcus mutans Biofilm

Background: Streptococcus mutans, one of the agent of human dental caries, is particularly effective at forming biofilms on the hard tissues of the human oral cavity; the purpose of this study was to investigate and quantify the diffusional release of photosentising agents (PS): methylene blue (MB), toludine blue (TB), rose bengal (RB) and methyl orange (MO) from Polyvinyl alcohol (PVA)-borate semi-solid gels in the presence of in vitro oral Streptococcus mutans biofilm. Methods: S. mutans biofilm growths were ascertained to ensure proper dental plaque formation and were characterized using confocal microscopy. Release profiles for MB, TB, RB and MO-loaded PVA-borate semi-solids in the absence of biofilms were directly compared to their counterparts in the presence of S. mutans biofilms. In addition, their diffusion coefficients and resistances were determined. Results: The confocal imaging results showed that biofilms grown over a 5-day period had a generally uninterrupted film of colonies occupying the entire surface area of growth surface of a nylon mesh support with approximately 60 µm biofilm size. The overall diffusion resistance of all PVA-borate semi-solids in the presence of S. mutans biofilms was about 1.2 times lower than the diffusion resistance for PVAborate semi-solids in the absence of biofilms. The diffusion resistances for all studied PS, indicate that electrostatic forces and molecular size play an important part in controlled and sustained drug release from PVA-borate semi-solids. Conclusions: PVA-borate semi-solids as novel PSs carriers might offer an innovative delivery system in the treatment against Streptococcus mutans

Effect of Mono and Di-rhamnolipids on Biofilms Pre-formed by Bacillus subtilis BBK006.

Different microbial inhibition strategies based on the planktonic bacterial physiology have been known to have limited efficacy on the growth of biofilms communities. This problem can be exacerbated by the emergence of increasingly resistant clinical strains. Biosurfactants have merited renewed interest in both clinical and hygienic sectors due to their potential to disperse microbial biofilms. In this work, we explore the aspects of Bacillus subtilis BBK006 biofilms and examine the contribution of biologically derived surface-active agents (rhamnolipids) to the disruption or inhibition of microbial biofilms produced by Bacillus subtilis BBK006. The ability of mono-rhamnolipids (Rha-C10-C10) produced by Pseudomonas aeruginosa ATCC 9027 and the di-rhamnolipids (Rha-Rha-C14-C14) produced by Burkholderia thailandensis E264, and phosphate-buffered saline to disrupt biofilm of Bacillus subtilis BBK006 was evaluated. The biofilm produced by Bacillus subtilis BBK006 was more sensitive to the di-rhamnolipids (0.4 g/L) produced by Burkholderia thailandensis than the mono-rhamnolipids (0.4 g/L) produced by Pseudomonas aeruginosa ATCC 9027. Rhamnolipids are biologically produced compounds safe for human use. This makes them ideal candidates for use in new generations of bacterial dispersal agents and useful for use as adjuvants for existing microbial suppression or eradication strategies

Dietary Changes During COVID-19 Lockdown in Adults With Type 1 Diabetes on a Hybrid Artificial Pancreas

In this retrospective analysis, we examine the impact of the lockdown of the coronavirus pandemic (COVID-19) on eating habits in individuals with type 1 diabetes (T1D) on a hybrid artificial pancreas (HAP). Dietary composition before and during lockdown was assessed by 7-day food records of 12 participants with T1D on HAP (three men and nine women, ages 38 ± 13 years, HbA1c 6.8 ± 0.3%, M ± SD). Continuous glucose monitoring (CGM) metrics and lifestyle changes (online questionnaire) were also assessed. Compared to prelockdown, reported body weight tended to increase during lockdown with no changes in total energy intake. Participants significantly decreased animal protein intake (−2.1 ± 3.7% of total energy intake, p = 0.048), but tended to increase carbohydrate intake (+17 ± 28 g/day, p = 0.052). These changes were induced by modifications of eating habits at breakfast and lunch during weekdays. Patients consumed more cereals (+21 ± 33 g/day, p = 0.038), whole grain (+22 ± 32 g/day, p = 0.044), and sweets (+13 ± 17 g/day, p = 0.021), and less animal protein sources (−42 ± 67 g/day, p = 0.054). Participants showed a more regular meal timing and decreased physical activity. Blood glucose control remained optimal (time-in-range 76 ± 8 vs. 75 ± 7% before lockdown), and daily total insulin infusion increased (42 ± 10 vs. 39 ± 12 I.U., p = 0.045). During the lockdown, patients with T1D on HAP modified dietary habits by decreasing animal protein and increasing carbohydrate intake. This increase, mainly concerning whole grain and low-glycemic-index products, did not influence blood glucose control

The evolving therapeutic landscape of trastuzumab-drug conjugates: Future perspectives beyond HER2-positive breast cancer

A novel class of drugs, antibody-drug conjugates (ADCs), are now rapidly emerging as highly effective treatments for solid tumours. ADCs conjugate conventional chemotherapeutics with highly selective targeted monoclonal antibodies. Anti-HER2 therapies selectively target cancer cells expressing human epidermal growth factor receptor 2 (HER2), among them trastuzumab has been the first HER2-targeting monoclonal antibody to achieve successful results that made it the backbone of anti-HER2 therapies. Trastuzumab drug conjugates (T-DCs), use trastuzumab as a selective antibody to lead cytotoxic drugs inside cancer cells. Trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-Dxd) are the two approved T-DCs. T-Dxd along with other five T-DCs represents “second generation ADCs” that has been firstly tested in HER2 positive breast cancer (BC) and then in HER2-low BC and other cancers showing promising results thanks to extraordinary and innovative pharmacokinetic and pharmacodynamic characteristics. The evidence generated so far are establishing them as a completely new class of agents effective in solid cancer treatments but also warrants physicians against unconventional toxicity profiles. The role of T-DCs in HER2-positive BC has been largely reviewed, while in this review, we provided for the first time in literature an overview of trastuzumab drug conjugates (T-DCs) approved and/or in clinical development with a specific focus on their efficacy and safety profile in HER2-low BC and other solid tumours different from BC. We started by analysing T-DCs biological characteristics that underly the differences in T-DCs pharmacodynamics and safety profile, then presented the main evidence on the activity and efficacy of these emerging T-DCs in HER2-low BC and other HER2 overexpressing and/or mutated solid tumours and lastly, we provided an overview of the complex and still evolving scenario in which these compounds should be allocated. A specific focus on possible combination strategies with other drugs such as immunotherapy, chemotherapy and target therapy, to increase T-DCs activity and eventually overcome future upcoming resistance mechanisms, are here also critically reviewed

A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells

A minor population of glioblastoma stem-like cells (GSCs) has been implicated in the relapse and resistance of glioblastoma to therapeutic treatments. Based on knowledge of the involvement of multiple microRNAs in GSC propagation, we designed a combinational approach to target the GSC population with multiple miRNA-based therapeutics. As carriers for the targeted delivery we took advantage of two aptamers that bind to, and inhibit, the receptor tyrosine kinases, Axl and PDGFRβ. We showed that the aptamer conjugates are transported through an in vitro blood-brain barrier (BBB) model. Furthermore, combining miR-137 and antimiR-10b synergizes with the receptor inhibitory function of aptamer carriers and prevents GSC expansion. Results highlighted the potential of combining multifunctional RNA-based therapeutics for selective targeting of GSCs and offer a proof of principle strategy to potentially fulfill the still unmet need for effective and safe treatment of glioma

webPIPSA: a web server for the comparison of protein interaction properties

Protein molecular interaction fields are key determinants of protein functionality. PIPSA (Protein Interaction Property Similarity Analysis) is a procedure to compare and analyze protein molecular interaction fields, such as the electrostatic potential. PIPSA may assist in protein functional assignment, classification of proteins, the comparison of binding properties and the estimation of enzyme kinetic parameters. webPIPSA is a web server that enables the use of PIPSA to compare and analyze protein electrostatic potentials. While PIPSA can be run with downloadable software (see http://projects.eml.org/mcm/software/pipsa), webPIPSA extends and simplifies a PIPSA run. This allows non-expert users to perform PIPSA for their protein datasets. With input protein coordinates, the superposition of protein structures, as well as the computation and analysis of electrostatic potentials, is automated. The results are provided as electrostatic similarity matrices from an all-pairwise comparison of the proteins which can be subjected to clustering and visualized as epograms (tree-like diagrams showing electrostatic potential differences) or heat maps. webPIPSA is freely available at: http://pipsa.eml.org

Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting CSCs compartment via YAP inhibition

Background: Despite the introduction of several novel therapeutic approaches that improved survival, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease. Herein we report the synergistic antitumor interaction between two well-known drugs used for years in clinical practice, the antiepileptic agent with histone deacetylase inhibitory activity valproic acid and the cholesterol lowering agent simvastatin, in mCRPC models. Methods: Synergistic anti-tumor effect was assessed on PC3, 22Rv1, DU145, DU145R80, LNCaP prostate cancer cell lines and EPN normal prostate epithelial cells, by calculating combination index (CI), caspase 3/7 activation and colony formation assays as well as on tumor spheroids and microtissues scored with luminescence 3D-cell viability assay. Cancer stem cells (CSC) compartment was studied evaluating specific markers by RT-PCR, western blotting and flow cytometry as well as by limiting dilution assay. Cholesterol content was evaluated by 1H-NMR. Overexpression of wild-type YAP and constitutively active YAP5SA were obtained by lipofectamine-based transfection and evaluated by immunofluorescence, western blotting and RT-PCR. 22Rv1 R_39 docetaxel resistant cells were selected by stepwise exposure to increasing drug concentrations. In vivo experiments were performed on xenograft models of DU145R80, 22Rv1 parental and docetaxel resistant cells, in athymic mice. Results: We demonstrated the capacity of the combined approach to target CSC compartment by a novel molecular mechanism based on the inhibition of YAP oncogene via concurrent modulation of mevalonate pathway and AMPK. Because both CSCs and YAP activation have been associated with chemo-resistance, we tested if the combined approach can potentiate docetaxel, a standard of care in mCRCP treatment. Indeed, we demonstrated, both in vitro and in vivo models, the ability of valproic acid/simvastatin combination to sensitize mCRPC cells to docetaxel and to revert docetaxel-resistance, by mevalonate pathway/YAP axis modulation. Conclusion: Overall, mCRPC progression and therapeutic resistance driven by CSCs via YAP, can be tackled by the combined repurposing of two generic and safe drugs, an approach that warrants further clinical development in this disease