Automatic attention to sexual stimuli: exploring the role of neuroticism and sexual excitation/inhibition through event-related potentials.

BACKGROUND: Previous findings have shown that neuroticism is a higher-order vulnerability factor in the development and maintenance of sexual dysfunctions and can have an impact on the attentional processing of sexual stimuli; however, the influence of psychosexual dimensions on the early automatic phases of such cognitive processes has not been established yet. AIM: To examine the mediating role of sexual inhibition/excitation propensity in the relationship between neuroticism and automatic attention to visual erotica and to identify the neuroelectric correlates of such a process. METHODS: We analyzed the answers provided by 58 individuals on the Neuroticism subscale of the NEO Personality Inventory-Revised and the Sexual Inhibition/Excitation Scales. Event-related potentials (ERPs) were recorded during a modified oddball paradigm containing romantic and sexually explicit pictures. Parallel mediations were performed to simultaneously test the mediating role of sexual inhibition/excitation in the relationship between neuroticism and each ERP. OUTCOMES: Three early attention ERP components (P1, P2, and N2) were assessed. RESULTS: Findings revealed an indirect effect of neuroticism on automatic attention, via sexual inhibition due to threat of performance failure (SIS1), for romantic and sexually explicit stimuli. This effect was significant only for component N2, which showed increased amplitudes and earlier latencies in participants with high SIS1. CLINICAL IMPLICATIONS: Sexual stimuli, due to their emotional valence and arousal potential, might be perceived as virtually threatening by individuals with neuroticism, who may benefit from strategies that decrease hyperarousal and sympathetic activation. STRENGTHS AND LIMITATIONS: This was one of the first studies to analyze neuroelectric activity associated with automatic attention toward sexual stimuli in relation to personality and sexual excitation/inhibition propensity. Nevertheless, the limited number of participants demands caution in generalizing the results. CONCLUSION: These results provide a better understanding of the relationship between personality and sexual cognition and open new avenues of research in relation to other automatic cognitive phenomena related to human sexual behavior.

Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy.

Chemokines are a large family of small chemotactic cytokines that coordinates immune cell trafficking. In cancer, they have a pivotal role in the migration pattern of immune cells into the tumor, thereby shaping the tumor microenvironment immune profile, often towards a pro-tumorigenic state. Furthermore, chemokines can directly target non-immune cells in the tumor microenvironment, including cancer, stromal and vascular endothelial cells. As such, chemokines participate in several cancer development processes such as angiogenesis, metastasis, cancer cell proliferation, stemness and invasiveness, and are therefore key determinants of disease progression, with a strong influence in patient prognosis and response to therapy. Due to their multifaceted role in the tumor immune response and tumor biology, the chemokine network has emerged as a potential immunotherapy target. Under the present review, we provide a general overview of chemokine effects on several tumoral processes, as well as a description of the currently available chemokine-directed therapies, highlighting their potential both as monotherapy or in combination with standard chemotherapy or other immunotherapies. Finally, we discuss the most critical challenges and prospects of developing targeted chemokines as therapeutic options.

Liposomes as Antibiotic Delivery Systems: A Promising Nanotechnological Strategy against Antimicrobial Resistance.

Antimicrobial drugs are key tools to prevent and treat bacterial infections. Despite the early success of antibiotics, the current treatment of bacterial infections faces serious challenges due to the emergence and spread of resistant bacteria. Moreover, the decline of research and private investment in new antibiotics further aggravates this antibiotic crisis era. Overcoming the complexity of antimicrobial resistance must go beyond the search of new classes of antibiotics and include the development of alternative solutions. The evolution of nanomedicine has allowed the design of new drug delivery systems with improved therapeutic index for the incorporated compounds. One of the most promising strategies is their association to lipid-based delivery (nano)systems. A drug's encapsulation in liposomes has been demonstrated to increase its accumulation at the infection site, minimizing drug toxicity and protecting the antibiotic from peripheral degradation. In addition, liposomes may be designed to fuse with bacterial cells, holding the potential to overcome antimicrobial resistance and biofilm formation and constituting a promising solution for the treatment of potential fatal multidrug-resistant bacterial infections, such as methicillin resistant Staphylococcus aureus. In this review, we aim to address the applicability of antibiotic encapsulated liposomes as an effective therapeutic strategy for bacterial infections.

Diazaborines Are a Versatile Platform to Develop ROS-Responsive Antibody Drug Conjugates*.

Antibody-drug conjugates (ADCs) are a new class of therapeutics that combine the lethality of potent cytotoxic drugs with the targeting ability of antibodies to selectively deliver drugs to cancer cells. In this study we show for the first time the synthesis of a reactive-oxygen-species (ROS)-responsive ADC (VL-DAB31-SN-38) that is highly selective and cytotoxic to B-cell lymphoma (CLBL-1 cell line, IC50 value of 54.1 nM). The synthesis of this ADC was possible due to the discovery that diazaborines (DABs) are a very effective ROS-responsive unit that are also very stable in buffer and in plasma. DFT calculations performed on this system revealed a favorable energetic profile (ΔGR=-74.3 kcal mol-1 ) similar to the oxidation mechanism of aromatic boronic acids. DABs' very fast formation rate and modularity enabled the construction of different ROS-responsive linkers featuring self-immolative modules, bioorthogonal functions, and bioconjugation handles. These structures were used in the site-selective functionalization of a VL antibody domain and in the construction of the homogeneous ADC.

Pediatric Complicated Pneumonia Caused by Streptococcus pneumoniae Serotype 3 in 13-Valent Pneumococcal Conjugate Vaccinees, Portugal, 2010-2015.

Despite use of 7-valent pneumococcal conjugate vaccine, incidence of pleural effusion and empyema (pediatric complicated pneumococcal pneumonia [PCPP]) is reportedly increasing globally. We cultured and performed PCR on 152 pleural fluid samples recovered from pediatric patients in Portugal during 2010-2015 to identify and serotype Streptococcus pneumoniae. We identified only 17 cases by culture, but molecular methods identified S. pneumoniae in 68% (92/135) of culture-negative samples. The most frequent serotypes were 3, 1, and 19A, together accounting for 62% (68/109) of cases. Nineteen cases attributable to 13-valent pneumococcal conjugate vaccine (PCV13) serotypes (mostly serotype 3) were detected among 22 children age-appropriately vaccinated with PCV13. The dominance of the additional serotypes included in PCV13 among PCPP cases in Portugal continues, even with PCV13 available on the private market (without reimbursement) since 2010 and with average annual coverage of 61% among age-eligible children. Our data suggest reduced effectiveness of PCV13 against serotype 3 PCPP.

Liposomal Rifabutin-A Promising Antibiotic Repurposing Strategy against Methicillin-Resistant Staphylococcus aureus Infections.

Methicillin-resistant Staphylococcus aureus (M RSA) infections, in particular biofilm-organized bacteria, remain a clinical challenge and a serious health problem. Rifabutin (RFB), an antibiotic of the rifamycins class, has shown in previous work excellent anti-staphylococcal activity. Here, we proposed to load RFB in liposomes aiming to promote the accumulation of RFB at infected sites and consequently enhance the therapeutic potency. Two clinical isolates of MRSA, MRSA-C1 and MRSA-C2, were used to test the developed formulations, as well as the positive control, vancomycin (VCM). RFB in free and liposomal forms displayed high antibacterial activity, with similar potency between tested formulations. In MRSA-C1, minimal inhibitory concentrations (MIC) for Free RFB and liposomal RFB were 0.009 and 0.013 µg/mL, respectively. Minimum biofilm inhibitory concentrations able to inhibit 50% biofilm growth (MBIC50) for Free RFB and liposomal RFB against MRSA-C1 were 0.012 and 0.008 µg/mL, respectively. Confocal microscopy studies demonstrated the rapid internalization of unloaded and RFB-loaded liposomes in the bacterial biofilm matrix. In murine models of systemic MRSA-C1 infection, Balb/c mice were treated with RFB formulations and VCM at 20 and 40 mg/kg of body weight, respectively. The in vivo results demonstrated a significant reduction in bacterial burden and growth index in major organs of mice treated with RFB formulations, as compared to Control and VCM (positive control) groups. Furthermore, the VCM therapeutic dose was two fold higher than the one used for RFB formulations, reinforcing the therapeutic potency of the proposed strategy. In addition, RFB formulations were the only formulations associated with 100% survival. Globally, this study emphasizes the potential of RFB nanoformulations as an effective and safe approach against MRSA infections.

Rifabutin: a repurposed antibiotic with high potential against planktonic and biofilm staphylococcal clinical isolates.

Staphylococcus aureus poses a significant threat as an opportunistic pathogen in humans, and animal medicine, particularly in the context of hospital-acquired infections (HAIs). Effective treatment is a significant challenge, contributing substantially to the global health burden. While antibiotic therapy remains the primary approach for staphylococcal infections, its efficacy is often compromised by the emergence of resistant strains and biofilm formation. The anticipated solution is the discovery and development of new antibacterial agents. However, this is a time consuming and expensive process with limited success rates. One potential alternative for addressing this challenge is the repurposing of existing antibiotics. This study investigated the potential of rifabutin (RFB) as a repurposed antibiotic for treating S. aureus infections. The minimum inhibitory concentration (MIC) of rifabutin was assessed by the broth microdilution method, in parallel to vancomycin, against 114 clinical isolates in planktonic form. The minimum biofilm inhibitory concentration (MBIC50) was determined by an adaptation of the broth microdilution method, followed by MTT assay, against a subset of selected 40 clinical isolates organized in biofilms. The study demonstrated that RFB MIC ranged from 0.002 to 6.250 µg/mL with a MIC50 of 0.013 µg/mL. RFB also demonstrated high anti-biofilm activity in the subset of 40 clinical isolates, with confirmed biofilm formation, with no significant MBIC50 differences observed between the MSSA and MRSA strains, in contrast to that observed for the VAN. These results highlight the promising efficacy of RFB against staphylococcal clinical isolates with different resistance patterns, whether in planktonic and biofilm forms.

Malignant melanoma in Portuguese adult population: a scoping review of the real-world evidence.

PURPOSE: Malignant melanoma is an aggressive cancer, and there is a notable dearth on epidemiology, clinical and treatment characterization within the Portuguese population. We performed a scoping review to identify real-world evidence studies focused in Portuguese adult patients with malignant melanoma. METHODS: A comprehensive search was conducted. After screening, we described the studies by design, sample size, geographics, setting, population, and outcomes reported. RESULTS: The search yielded 54 studies, mainly retrospective (79.6%). The population assessed was heterogeneous varying from patients with melanoma in general to specific types of melanoma, or even more restricted to patients with specific conditions. The evidence found was mostly concerning clinical outcomes (n=46), patients' clinical profile (n=44) and demographic characterization (n=48). Treatment information was described in 30 studies whereas only 18 reported epidemiological parameters. Studies were mainly performed by the major oncology centers in Lisbon, Oporto and Coimbra, and only two evaluated the entire Portuguese population. To allow comparability, only studies including patients with cutaneous malignant melanoma were considered (13 of the 54) for outcomes evaluation analysis. Median OS varied from 18 to 36 months, assessed after melanoma treatment. Incidence was the most reported epidemiological parameter, confirming the increasing number of cutaneous malignant melanoma patients over the years. Only one study reported prevalence and four reported mortality rates. CONCLUSIONS: The evidence found confirms the lack of information about malignant melanoma in Portugal, highlighting the need of real-world studies to assess melanoma prevalence and incidence rates, current treatment approaches, and clinical characterization of these patients.

A systematic review on the efficacy of CBT interventions for the mental and sexual health of survivors of prostate cancer.

INTRODUCTION: Prostate cancer (PCa) is the second-most frequently diagnosed oncologic condition among biological men, affecting physical and psychological well-being, as well as sexual health and quality of life. Prior research has shown that cognitive-behavioral therapy (CBT) can be effective in addressing a range of psychological and sexual problems but also in improving the sexual and mental health of survivors of PCa. OBJECTIVES: This systematic review aimed to methodically research and summarize results concerning the efficacy of CBT in the mental and sexual health of survivors of PCa. METHODS: A systematic search was carried out via electronic databases until August 2022 (EBSCO, MEDLINE, Cochrane Library, and Web of Science). By combining specific search words and following the PRISMA checklist, we identified 15 eligible articles among 8616 initial records. RESULTS: Four studies showed evidence of intervention efficacy for the improvement of sexual health, specifically for overall sexual function, erectile function, sexual desire, and sexual satisfaction. Eight studies found intervention efficacy for the improvement of mental health dimensions, such as psychological distress, depressive symptoms, anxiety, and quality of life. CONCLUSION: There is evidence that CBT interventions have the potential to effectively promote mental and sexual health in survivors of PCa, but further research comprising larger and more diverse populations is needed. Future studies should focus on understanding mechanisms of change through CBT interventions to ensure the mental and sexual health of survivors of PCa.

Short-term Clinical and Microbiological Performance of Resin-modified Glass Ionomer Cement Containing Chlorhexidine for Atraumatic Restorative Treatment.

Aim: This study evaluated the short-term clinical and microbiological performance of resin-modified glass ionomer cement (RM-GIC) cement containing chlorhexidine (CHX) for atraumatic restorative treatment (ART) in primary teeth. Materials and methods: The clinical trial was conducted in 36 children that received ART in primary molars either with GIC (group I, n = 18) or GIC containing 1.25% CHX (group II, n = 18). The survival rate of restorations was checked 7 days, 3, and 6 months after their application when saliva and biofilm were collected for microbiological assessment of mutans streptococci (MS) counts. Data were analyzed using the Kruskal-Wallis/Mann-Whitney U tests for clinical analysis and microbiological evaluations (p < 0.05). Results: The survival rate of restorations was similar comparing groups I with II. Microbiological analysis showed a significant reduction in MS levels 7 days after the treatment in both saliva and biofilm of children treated with RM-GIC containing CHX (group II); however, MS counts at 3 and 6 months did not differ from the initial counts. Conclusion: A total of 1.25% CHX improved the microbiological properties of GIC in the short term without impairing the clinical performance of ART restorations. Clinical significance: Glass ionomer cement (GIC) containing CHX could be an alternative in ART procedures with the objective of promoting an additional antimicrobial effect, which is interesting for children with high counts of MS during the initial phase of adaptation to dental treatment. How to cite this article: da Silva ME, de Sena MD, Colombo NH, et al. Short-term Clinical and Microbiological Performance of Resin-modified Glass Ionomer Cement Containing Chlorhexidine for Atraumatic Restorative Treatment. Int J Clin Pediatr Dent 2023;16(S-1):S27-S32.

Mapping the contributions of dyadic approaches to couples' psychosocial adaptation to prostate cancer: a scoping review.

INTRODUCTION: Prostate cancer is the second-most prevalent cancer diagnosis worldwide among males. Although prostate cancer affects the physical, sexual, and mental health of patients, the impact of prostate cancer on partners has also been increasingly recognized. Hence, taking a dyadic approach is of relevance. Moreover, there is evidence of the utility of dyadic approaches to the study of relational stress that chronic diseases such as prostate cancer can bring to couples, even though knowledge is sparse about prostate cancer. OBJECTIVES: This scoping review aimed to map existing dyadic studies on the psychosocial adaptation of couples to prostate cancer. METHODS: A systematic search of studies published from 2005 to November 2022 was conducted on electronic databases (PubMed, Cochrane Library, EBSCOHost, Scopus, and Web of Science) following PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-analyses-Extension for Scoping Reviews). RESULTS: The review included 25 eligible studies from the initial 2514 articles retrieved. Overall, the results emphasized the interdependency between couple members and suggested how partners' adaptation influences patients' adaptation to prostate cancer and vice versa, regarding several psychosocial dimensions (eg, intimacy, quality of life). CONCLUSIONS: This work can bring awareness to health care professionals to adopt a couples approach when managing prostate cancer whenever there is a partner, due to these interdependent influences. For researchers and future studies, this work can strengthen the relevance of dyadic approaches on how couples adapt to prostate cancer and explore which other dimensions influence these complex dynamics.

Panobinostat-loaded folate targeted liposomes as a promising drug delivery system for treatment of canine B-cell lymphoma.

Introduction: Cancer is a major public health problem with over 19 million cases reported in 2020. Similarly to humans, dogs are also largely affected by cancer, with non-Hodgkin's lymphoma (NHL) among the most common cancers in both species. Comparative medicine has the potential to accelerate the development of new therapeutic options in oncology by leveraging commonalities between diseases affecting both humans and animals. Within this context, in the present study, we investigated the potential of panobinostat (Pan)-loaded folate-targeted PEGylated liposomes (FA-PEG-Pan-Lip) for the treatment of canine B-cell lymphoma, while contributing to new perspectives in comparative oncology. Methods and results: Two formulations were developed, namely: PEG-Pan-Lip and FA-PEG-Pan-Lip. Firstly, folate receptor expression in the CLBL-1 canine B-cell lymphoma cell line was assessed. After confirming receptor expression, both Pan-loaded formulations (PEG-Pan-Lip, FA-PEG-Pan-Lip) demonstrated dose-dependent inhibitory effects on CLBL-1 cell proliferation. The FA-PEG-Pan-Lip formulation (IC50 = 10.9 ± 0.03 nM) showed higher cytotoxicity than the non-targeted PEG-Pan-Lip formulation (IC50 = 12.9 ± 0.03 nM) and the free panobinostat (Pan) compound (IC50 = 18.32±0.03 nM). Moreover, mechanistically, both Pan-containing formulations induced acetylation of H3 histone and apoptosis. Flow cytometry and immunofluorescence analysis of intracellular uptake of rhodamine-labeled liposome formulations in CLBL-1 cells confirmed cellular internalization of PEG-Lip and FA-PEG-Lip formulations and higher uptake profile for the latter. Biodistribution studies of both radiolabeled formulations in CD1 and SCID mice revealed a rapid clearance from the major organs and a 1.6-fold enhancement of tumor uptake at 24 h for 111In-FA-PEG-Pan-Lip (2.2 ± 0.1 %ID/g of tumor) compared to 111In-PEG-Pan-Lip formulation (1.2±0.2 %ID/g of tumor). Discussion: In summary, our results provide new data validating Pan-loaded folate liposomes as a promising targeted drug delivery system for the treatment of canine B-cell lymphoma and open innovative perspectives for comparative oncology.

Rabbit derived VL single-domains as promising scaffolds to generate antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are among the fastest-growing classes of therapeutics in oncology. Although ADCs are in the spotlight, they still present significant engineering challenges. Therefore, there is an urgent need to develop more stable and effective ADCs. Most rabbit light chains have an extra disulfide bridge, that links the variable and constant domains, between Cys80 and Cys171, which is not found in the human or mouse. Thus, to develop a new generation of ADCs, we explored the potential of rabbit-derived VL-single-domain antibody scaffolds (sdAbs) to selectively conjugate a payload to Cys80. Hence, a rabbit sdAb library directed towards canine non-Hodgkin lymphoma (cNHL) was subjected to in vitro and in vivo phage display. This allowed the identification of several highly specific VL-sdAbs, including C5, which specifically target cNHL cells in vitro and present promising in vivo tumor uptake. C5 was selected for SN-38 site-selective payload conjugation through its exposed free Cys80 to generate a stable and homogenous C5-DAB-SN-38. C5-DAB-SN-38 exhibited potent cytotoxicity activity against cNHL cells while inhibiting DNA-TopoI activity. Overall, our strategy validates a platform to develop a novel class of ADCs that combines the benefits of rabbit VL-sdAb scaffolds and the canine lymphoma model as a powerful framework for clinically translation of novel therapeutics for cancer.

Occurrence of MDR1 1-delta mutation in herding dog breeds in Portugal.

The impact of drug transporters in veterinary medicine has been recognized in recent years. One of the most well-characterized is the product of the MDR1 gene, P-gp. A 4-bp deletion in the MDR1 gene known since 2001 has been described to affect herding dog breeds. Since many used drugs in veterinary medicine are substrates for P-gp, including the macrocyclic lactones, such as avermectins, this 4-bp deletion causes a pathological condition known as "ivermectin toxicosis." For this reason, it is important to determine the animal status concerning this mutation. In Portugal, the information of the occurrence of this mutation in our breeds is limited. The aim of the present study was to determine the occurrence of this mutation and evaluate its association with Portuguese and non-Portuguese dog breeds in Portugal. To achieve this, a total of 105 animals were studied for the presence of the MDR1 4-bp deletion, 23 of which were from Barbado da Terceira, 10 from Cão da Serra d'Aires, 55 belonging to breeds known to carry the mutation (Australian Shepperd, Border Collie and others) and 17 to other breeds (Labrador Retriever, Jack Russel, and others). Despite the small sample size, we observed the presence of the MDR1 1-delta mutation in previously described breeds and identified this mutation in Barbado da Terceira breed for the first time.

Characterization of the canine CD20 as a therapeutic target for comparative passive immunotherapy.

Anti-CD20 therapies have revolutionized the treatment of B-cell malignancies. Despite these advances, relapsed and refractory disease remains a major treatment challenge. The optimization of CD20-targeted immunotherapies is considered a promising strategy to improve current therapies. However, research has been limited by the scarcity of preclinical models that recapitulate the complex interaction between the immune system and cancers. The addition of the canine lymphoma (cNHL) model in the development of anti-CD20 therapies may provide a clinically relevant approach for the translation of improved immunotherapies. Still, an anti-CD20 therapy for cNHL has not been established stressing the need of a comprehensive target characterization. Herein, we performed an in-depth characterization on canine CD20 mRNA transcript and protein expression in a cNHL biobank and demonstrated a canine CD20 overexpression in B-cell lymphoma samples. Moreover, CD20 gene sequencing analysis identified six amino acid differences in patient samples (C77Y, L147F, I159M, L198V, A201T and G273E). Finally, we reported the use of a novel strategy for the generation of anti-CD20 mAbs, with human and canine cross-reactivity, by exploring our rabbit derived single-domain antibody platform. Overall, these results support the rationale of using CD20 as a target for veterinary settings and the development of novel therapeutics and immunodiagnostics.

Analysis of invasiveness of pneumococcal serotypes and clones circulating in Portugal before widespread use of conjugate vaccines reveals heterogeneous behavior of clones expressing the same serotype.

To estimate the invasive disease potential of serotypes and clones circulating in Portugal before extensive use of the seven-valent pneumococcal conjugate vaccine, we analyzed 475 invasive isolates recovered from children and adults and 769 carriage isolates recovered from children between 2001 and 2003. Isolates were serotyped and genotyped by pulsed-field gel electrophoresis, and a selection of isolates were also characterized by multilocus sequence typing. We found that the diversities of serotypes and genotypes of pneumococci responsible for invasive infections and carriage were identical and that most carried clones could also be detected as causes of invasive disease. Their ability to do so, however, varied substantially. Serotypes 1, 3, 4, 5, 7F, 8, 9N, 9L, 12B, 14, 18C, and 20 were found to have an enhanced propensity to cause invasive disease, while serotypes 6A, 6B, 11A, 15B/C, 16F, 19F, 23F, 34, 35F, and 37 were associated with carriage. In addition, significant differences in invasive disease potential between clones sharing the same serotype were found among several serotypes, namely, 3, 6A, 6B, 11A, 14, 19A, 19F, 22F, 23F, 34, and NT. This heterogeneous behavior of the clones was found irrespective of the serotype's overall invasive disease potential. Our results highlight the importance of the genetic background when analyzing the invasive disease potential of certain serotypes and provide an important baseline for its monitoring following conjugate vaccine use. Continuous surveillance should be maintained, and current research should focus on uncovering the genetic determinants that contribute to the heterogeneity of invasive disease potential of clones sharing the same serotype.

Biocompatibility evaluation of 3 facial silicone elastomers.

The failure of facial prostheses is caused by limitations in the properties of existing materials, especially the biocompatibility. This study aimed to evaluate the biocompatibility of maxillofacial silicones in subcutaneous tissue of rats. Thirty Wistar rats received subcutaneous implants of 3 maxillofacial silicone elastomers (LIM 6050, MDX 4-4210, and industrial Silastic 732 RTV). A histomorphometric evaluation was conducted to analyze the biocompatibility of the implants. Eight areas of 60.11 mm(2) from the surgical pieces were analyzed. Mesenchymal cells, eosinophils, and foreign-body giant cells were counted. Data were submitted to analysis of variance and Tukey test. Initially, all implanted materials exhibited an acceptable tissue inflammatory response, with tissue reactions varying from light to moderate. Afterward, a fibrous capsule around the silicone was observed. The silicones used in the current study presented biocompatibility and can be used for implantation in both medical and dental areas. Their prosthetic indication is conditioned to their physical properties. Solid silicone is easier to adapt and does not suffer apparent modifications inside the tissues.

Lipid-based nanosystems for targeting bone implant-associated infections: current approaches and future endeavors.

Bone infections caused by Staphylococcus aureus are a major concern in medical care, particularly when associated with orthopedic-implant devices. The ability of the bacteria to form biofilms and their capacity to invade and persist within osteoblasts turn the infection eradication into a huge challenge. The reduction of antibiotic penetration through bacterial biofilms associated with the presence of persistent cells, ability to survive in the host, and high tolerance to antibiotics are some of the reasons for the difficult treatment of these infections. Effective therapeutic approaches are urgently needed. In this sense, lipid-based nanosystems, such as liposomes, have been investigated as an innovative and alternative strategy for the treatment of implant-associated S. aureus infections, due to their preferential accumulation at infected sites and interaction with S. aureus. This review highlights the recent advances on antibiotic-loaded liposome formulations both in vitro and in vivo and how the interaction with S. aureus biofilms may be improved by modulating the liposomal external surface. Graphical Abstract.

Liposomes as a Nanoplatform to Improve the Delivery of Antibiotics into Staphylococcus aureus Biofilms.

Staphylococcus aureus biofilm-associated infections are a major public health concern. Current therapies are hampered by reduced penetration of antibiotics through biofilm and low accumulation levels at infected sites, requiring prolonged usage. To overcome these, repurposing antibiotics in combination with nanotechnological platforms is one of the most appealing fast-track and cost-effective approaches. In the present work, we assessed the potential therapeutic benefit of three antibiotics, vancomycin, levofloxacin and rifabutin (RFB), through their incorporation in liposomes. Free RFB displayed the utmost antibacterial effect with MIC and MBIC50 below 0.006 µg/mL towards a methicillin susceptible S. aureus (MSSA). RFB was selected for further in vitro studies and the influence of different lipid compositions on bacterial biofilm interactions was evaluated. Although positively charged RFB liposomes displayed the highest interaction with MSSA biofilms, RFB incorporated in negatively charged liposomes displayed lower MBIC50 values in comparison to the antibiotic in the free form. Preliminary safety assessment on all RFB formulations towards osteoblast and fibroblast cell lines demonstrated that a reduction on cell viability was only observed for the positively charged liposomes. Overall, negatively charged RFB liposomes are a promising approach against biofilm S. aureus infections and further in vivo studies should be performed.

Immunotherapeutic Strategies for Canine Lymphoma: Changing the Odds Against Non-Hodgkin Lymphoma.

The new era of immune-oncology has brought complexities and challenges that emphasize the need to identify new strategies and models to develop successful and cost-effective therapies. The inclusion of a canine model in the drug development of cancer immunotherapies is being widely recognized as a valid solution to overcome several hurdles associated with conventional preclinical models. Driven by the success of immunotherapies in the treatment of human non-Hodgkin lymphoma (NHL) and by the remarkable similarities of canine NHL to its human counterpart, canine NHL has been one of the main focus of comparative research. Under the present review, we summarize a general overview of the challenges and prospects of today's cancer immunotherapies and the role that comparative medicine might play in solving the limitations brought by this rapidly expanding field. The state of art of both human and canine NHL and the rationale behind the use of the canine model to bridge the translational gap between murine preclinical studies and human clinical trials are addressed. Finally, a review of currently available immunotherapies for canine NHL is described, highlighting the potential of these therapeutic options.