Unveiling the Antiviral Capabilities of Targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2.

The urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase (HsDHODH), one of the main enzymes responsible for pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated naphthoquinone fragments, discovering potent HsDHODH inhibition with IC50 ranging from 48 to 684 nM, and promising in vitro anti-SARS-CoV-2 activity with EC50 ranging from 1.2 to 2.3 µM. These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools such as molecular docking and quantitative structure-activity relationship (QSAR) models to analyze protein-ligand interactions, revealing that these naphthoquinones exhibit a protein binding pattern similar to brequinar, a potent HsDHODH inhibitor. These findings represent a significant step forward in the search for effective antiviral treatments and have great potential to impact the development of new broad-spectrum antiviral drugs.

How do microplastics alter molluscicidal activity? Effects of weathered microplastics and niclosamide in developing freshwater snails.

Despite the wide distribution and persistence of microplastics (MPs), their interactive effects with molluscicides are unknown. Schistosomiasis, a neglected tropical disease, affects 236.6 million people worldwide. Niclosamide (NCL) is the only molluscicide recommended by the World Health Organization (WHO) and it is used to control the population of Schistosoma spp.'s intermediate host. Thus, this study aimed to evaluate of the interaction between polyethylene (PE) MPs and NCL, and their associated toxicity in the freshwater snail Biomphalaria glabrata (Say 1818). Weathered PE MPs were characterized and theoretical analysis of NCL-MP adsorption nature was made using quantum mechanical calculations. The toxicity of NCL isolated (0.0265 to 0.0809 mg L-1) and under interaction with PE MPs (3400 µg L-1) in B. glabrata embryos and newly hatched snails was analyzed. In silico analysis confirmed the adsorption mechanisms of NCL into PE MPs. PE MPs decreased the NCL toxicity to both B. glabrata developmental stages, increasing their survival and NCL lethal concentrations, indicating concerns regarding NCL use as molluscicide in aquatic environments polluted by MPs. In conclusion, MPs may change the efficiency of chemicals used in snail control programs.

Eu3+ doped ZnAl layered double hydroxides as calibrationless, fluorescent sensors for carbonate.

The photoluminescence properties (PL) of Eu3+ hosted in the hydroxide layers of layered double hydroxides (LDHs) enables calibrationless quantification of anions in the interlayers. The concept is demonstrated during the nitrate-to-carbonate ion exchange in Zn2+/Al3+/Eu3+ LDHs and can be implemented as a remote optical sensor to detect intrusion of anions such as Cl- or CO32-.

Greenhouse Gas Emissions and Crossbred Cow Milk Production in a Silvopastoral System in Tropical Mexico.

In Mexico, pasture degradation is associated with extensive pastures; additionally, under these conditions, livestock activities contribute considerably to greenhouse gas (GHG) emissions. Among the options to improve grazing systems and reduce GHG emissions, silvopastoral systems (SPS) have been recommended. The objectives of this work were to quantify the N outflow in a soil-plant-animal interface, as well as the CH4 emissions and milk production in an SPS with woody legumes (Leucaena leucocephala) that is associated with stargrass (Cynodon nlemfuensis). This was then compared with stargrass in a monoculture system (MS) in the seasons (dry and rainy period) over a two-year period. Dung was collected from the animals of each of the grazing systems and applied fresh to the land plots. Fresh dung and urine were collected from the cows of each grazing system and were applied to the experimental plots. In addition, the soil CH4 and N2O contents were measured to quantify the emissions. Average milk yield by seasons was similar: MS (7.1 kg per animal unit (AU)/day-1) and SPS (6.31 kg per AU/day-1). Cows in the MS had a mean N intake of 171.9 g/UA day-1 without seasonal variation, while the SPS animals' mean N intake was 215.7 g/UA day-1 for both seasons. For the urine applied to soil, the N2O outflow was higher in the MS (peak value = 1623.9 µg N-N2O m-2 h-1). The peak value for the SPS was 755.9 µg of N-N2O m-2 h-1. The N2O emissions were higher in the rainy season (which promotes denitrification). The values for the feces treatment were 0.05% (MS) and 0.01% (SPS). The urine treatment values were 0.52% (MS) and 0.17% (SPS). The emissions of CH4 showed that the feces of the SPS systems resulted in a higher accumulation of gas in the rainy season (29.8 g C ha-1), followed by the feces of the MS system in the dry season (26.0 g C ha-1). Legumes in the SPS helped to maintain milk production, and the N2O emissions were lower than those produced by the MS (where the pastures were fertilized with N).

Diversity of Microbiomes Across a 13,000-Year-Old Amazon Sediment.

The microbiome is fundamental for understanding bacterial activities in sediments. However, only a limited number of studies have addressed the microbial diversity of Amazonian sediments. Here, we studied the microbiome of sediments from a 13,000-year BP core retrieved in a floodplain lake in Amazonia using metagenomics and biogeochemistry. Our aim was to evaluate the possible environmental influence over a river to a lake transition using a core sample. To this end, we sampled a core in the Airo Lake, a floodplain lake in the Negro River basin. The Negro River is the largest tributary of the Amazon River. The obtained core was divided into three strata: (i) surface, almost complete separation of the Airo Lake from the Negro River when the environment becomes more lentic with greater deposition of organic matter (black-colored sediment); (ii) transitional environment (reddish brown); and (iii) deep, environment with a tendency for greater past influence of the Negro River (brown color). The deepest sample possibly had the greatest influence of the Negro River as it represented the bottom of this river in the past, while the surface sample is the current Airo Lake bottom. In total, six metagenomes were obtained from the three different depth strata (total number of reads: 10.560.701; sequence length: 538 ± 24, mean ± standard deviation). The older (deeper) sediment strata contained a higher abundance of Burkholderia, Chitinophaga, Mucilaginibacter, and Geobacter, which represented ~ 25% of the metagenomic sequences. On the other hand, the more recent sediment strata had mainly Thermococcus, Termophilum, Sulfolobus, Archaeoglobus, and Methanosarcina (in total 11% of the metagenomic sequences). The sequence data were binned into metagenome-assembled genomes (MAGs). The majority of the obtained MAGs (n = 16) corresponded to unknown taxa, suggesting they may belong to new species. The older strata sediment microbiome was enriched with sulfur cycle genes, TCA cycle, YgfZ, and ATP-dependent proteolysis in bacteria. Meanwhile, serine-glyoxylate cycle, stress response genes, bacterial cell division, cell division-ribosomal stress protein cluster, and oxidative stress increased in the younger strata. Metal resistance and antimicrobial resistance genes were found across the entire core, including genes coding for fluoroquinolones, polymyxin, vancomycin, and multidrug resistance transporters. These findings depict the possible microbial diversity during the depositional past events and provided clues of the past microbial metabolism throughout time.

Photocatalytic degradation of bisphenol-A (BPA) over titanium dioxide, and determination of its by-products by HF-LPME/GC-MS.

In this work, analytical strategies were developed based on the technique of hollow fiber liquid-phase microextraction and chromatographic methods (LC-UV and GC/MS). These methods allowed the identification of the main Bisphenol-A by-products applying heterogeneous photocatalysis in water samples. BPA degradation in this study was in the order of 90%, and the conditions used in the HF-LPME were optimized through 23 factorial design (6 cm fiber length, stirring speed of 750 rpm, and an extraction time of 30 min). Using a HF-LPME/GC-MS analytical strategy, it was possible to identify six by-products of BPA photodegradation, two of which have not been reported in the literature so far. This knowledge was quite important since the degradation can lead to the formation of more toxic and persistent by-products than the BPA. With the Toxtree software, three degradation products were found to be persistent to the environment, in addition to BPA; however, in 360 minutes of reaction, chromatographic peaks of the precursors were not identified, suggesting that there may have been a total degradation of these compounds. The results showed a great application potential of a miniaturized extraction technique to extract and pre-concentrate the degradation products of emerging contaminants.

Bradyrhizobium occurrence in nodules of perennial horsegram.

The introduction of a forage legume into a tropical pasture should decrease the need for N fertilizer, provided biological N2 fixation (BNF) contributes enough to compensate for exported N. Macrotyloma axillare (perennial horsegram) is a suitable legume for composing mixed pastures, and our hypothesis is that the isolation of indigenous rhizobia from roots and rhizosphere is the way of achieving an efficient inoculant to maximize BNF to the legume. Nodules and rhizosphere soil taken from M. axillare grown in a mixed pasture with palisade grass were sampled and used in a trap host assay using Leonard jars containing a mixture of vermiculite and sand. A total of ten bacteria were initially isolated using this technique. The isolates were then used in two experiments to evaluate the inoculation responses on the perennial horsegram in greenhouse conditions to which nodulation, plant growth, and shoot N accumulation were measured. Phylogenetic analyses based on 16S rRNA and recA placed all strains within genus Bradyrhizobium, some of them not previously described. The best strain provided more than 120 nodules and more than 65 mg of nodules per plant. Strain BR14182 was considered the most promising given the high dry matter and N accumulation in plant shoots. This study provides the first analysis of Bradyrhizobium diversity nodulating M. axillare in Brazil and provided evidence of the role of inoculation in incrementing the plant-rhizobium symbiosis in a forage legume.

Alginate-based hydrogel fiber as a restricted access material for microextraction of drugs in biological samples.

A novel lab-made alginate-based hydrogel device was successfully prepared and applied as a sorption material for the solid-phase microextraction of drugs (fluoxetine and its metabolite, norfluoxetine) in human plasma, with subsequent determination by high performance liquid chromatography-fluorescence detection (HPLC-FD). When supported in a polypropylene hollow fiber, the alginate was able to extract the analytes and functioned as a restricted access material, excluding >95 % of proteins from the biological matrix. The results indicate the potential use of this phase/device for quantitative drugs extraction from biological matrices at concentrations compatible with those typical in the literature (0.5 µg mL-1), and with satisfactory precision (13.4 % for fluoxetine and 6.2 % for norfluoxetine). Such outcomes, promoted by a simple and inexpensive material, open a new perspective of exploration of hydrogels as the sorption phase in biological matrices, a concept previously unexplored in the literature.

Molecular Characterization of a First-in-Human Clinical Response to Nimesulide in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a hematologic malignancy associated with high morbidity and mortality. Here we describe a case of a patient with AML who presented a partial response after utilization of the non-steroidal anti-inflammatory drug nimesulide. The response was characterized by complete clearance of peripheral blood blasts and an 82% decrease of bone marrow blasts associated with myeloblast differentiation. We have then shown that nimesulide induces in vitro cell death and cell cycle arrest in all AML cell lines (HL-60, THP-1, OCI-AML2, and OCI-AML3). Weighted Correlation Network Analysis (WGCNA) of serial whole-transcriptome data of cell lines treated with nimesulide revealed that the sets of genes upregulated after treatment with nimesulide were enriched for genes associated with autophagy and apoptosis, and on the other hand, the sets of downregulated genes were associated with cell cycle and RNA splicing. Serial transcriptome of bone marrow patient sample confirmed the upregulation of genes associated with autophagy after the response to nimesulide. Lastly, we demonstrated that nimesulide potentiates the cytotoxic in vitro effect of several Food and Drug Administration (FDA)-approved chemotherapy drugs used in AML, including cytarabine.

Acetaminophen treatment evokes anticontractile effects in rat aorta by blocking L-type calcium channels.

BACKGROUND: Acetaminophen (APAP) is the most widely used analgesic and antipyretic in the world. However, in high or continuous doses, it can cause serious side effects including blood pressure variability and cardiovascular injuries, which are barely explored. This study aimed to evaluate the acute effect of APAP treatment on vascular tone focused on the blocking of Ca2+ channels. METHODS: Rats were treated with APAP orally by gavage (500 mg/kg/single dose). After 12 h, the aorta was isolated for vascular reactivity studies in an isolated organ bath. Vascular contraction and relaxation were measured after different stimuli. Moreover, molecular docking studies were performed to evaluate the action of NAPQI (APAP metabolite) on L-type calcium channels. RESULTS: Phenylephrine-induced maximal vascular contraction was reduced in the APAP group (138.4 ± 9.2%) compared to the control group (172.2 ± 11.1%). APAP treatment significantly reduced contraction induced by Ca2+ influx stimulated with phenylephrine or KCl and reduced contraction mediated by Ca2+ released from the sarcoplasmic reticulum induced by caffeine. There was no difference in vascular relaxation induced by acetylcholine or sodium nitroprusside. Computational molecular docking demonstrated that NAPQI is capable of blocking L-type Ca2+ channels (Cav1.2), which would limit the influx of Ca2+. CONCLUSION: These results suggest that APAP treatment causes an anticontractile effect in rat aorta, possibly by blocking the influx of Ca2+ through L-type channels (Cav1.2).

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence.

Schistosomiasis is a parasitic disease caused by trematode worms of the genus Schistosoma and affects over 200 million people worldwide. The control and treatment of this neglected tropical disease is based on a single drug, praziquantel, which raises concerns about the development of drug resistance. This, and the lack of efficacy of praziquantel against juvenile worms, highlights the urgency for new antischistosomal therapies. In this review we focus on innovative approaches to the identification of antischistosomal drug candidates, including the use of automated assays, fragment-based screening, computer-aided and artificial intelligence-based computational methods. We highlight the current developments that may contribute to optimizing research outputs and lead to more effective drugs for this highly prevalent disease, in a more cost-effective drug discovery endeavor.

Constitutive nitric oxide synthase-like enzyme in two species involved in cutaneous and mucocutaneous leishmaniasis.

Leishmania is an obligate intracellular parasite that primarily inhabits macrophages. The destruction of the parasite in the host cell is a fundamental mechanism for infection control. In addition, inhibition of the leishmanicidal activity of macrophages seems to be related to the ability of some species to inhibit the production of nitric oxide (NO) by depleting arginine. Some species of Leishmania have the ability to produce NO from a constitutive nitric oxide synthase-like enzyme (cNOS-like). However, the localization of cNOS-like in Leishmania has not been described before. As such, this study was designed to locate cNOS-like enzyme and NO production in promastigotes of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis. NO production was initially quantified by flow cytometry, which indicated a significant difference in NO production between L. (L.) amazonensis (GMFC = 92.17 +/- 4.6) and L. (V.) braziliensis (GMFC = 18.89 +/- 2.29) (P < 0.05). Analysis of cNOS expression by immunoblotting showed more expression in L. (L.) amazonensis versus L. (V.) braziliensis. Subsequently, cNOS-like immunolabeling was observed in promastigotes in regions near vesicles, the flagellar pocket and mitochondria, and small clusters of particles appeared to be fusing with vesicles suggestive of glycosomes, peroxisome-like-organelles that compartmentalize the glycolytic pathway in trypanosomatid parasites. In addition, confocal microscopy analysis demonstrated colocalization of cNOS-like and GAPDH, a specific marker for glycosomes. Thus, L. (L.) amazonensis produces greater amounts of NO than L. (V.) braziliensis, and both species present the cNOS-like enzyme inside glycosomes.

Multi-Sensor Wearable Health Device Framework for Real-Time Monitoring of Elderly Patients Using a Mobile Application and High-Resolution Parameter Estimation.

Automatized scalable healthcare support solutions allow real-time 24/7 health monitoring of patients, prioritizing medical treatment according to health conditions, reducing medical appointments in clinics and hospitals, and enabling easy exchange of information among healthcare professionals. With recent health safety guidelines due to the COVID-19 pandemic, protecting the elderly has become imperative. However, state-of-the-art health wearable device platforms present limitations in hardware, parameter estimation algorithms, and software architecture. This paper proposes a complete framework for health systems composed of multi-sensor wearable health devices (MWHD), high-resolution parameter estimation, and real-time monitoring applications. The framework is appropriate for real-time monitoring of elderly patients' health without physical contact with healthcare professionals, maintaining safety standards. The hardware includes sensors for monitoring steps, pulse oximetry, heart rate (HR), and temperature using low-power wireless communication. In terms of parameter estimation, the embedded circuit uses high-resolution signal processing algorithms that result in an improved measure of the HR. The proposed high-resolution signal processing-based approach outperforms state-of-the-art HR estimation measurements using the photoplethysmography (PPG) sensor.

Pain impairs consolidation, but not acquisition or retrieval of a declarative memory.

Among the physical conditions that impair memory performance, pain is one of the most prevalent. However, the mechanisms by which pain impairs memory are largely unknown. In this study, we asked whether pain affects memory acquisition, consolidation and retrieval as well as whether memory impairment depends on pain intensity. Wistar rats received a hind paw injection of formalin (1%) at different phases of object recognition test. The injection of formalin after training but not before training or testing impaired object recognition memory. We concluded that pain impairs the consolidation but not acquisition or retrieval of object recognition memory, which is a subtype of declarative memory. Morphine, at a dose that did not affect object recognition memory in control rats, drastically reduced formalin-induced nociceptive behavior without reversing memory impairment. A lower dose of formalin (0.25%) induced less nociceptive behavior, but similar memory impairment. There is no statistical correlation between the intensity of nociceptive response and the performance in object recognition test. However, when formalin-induced nociceptive response was blocked by a local anesthetic, memory impairment was prevented. These findings suggest that pain-induced impairment in the consolidation of object recognition memory does not directly depend on the intensity of nociceptive activity.

Should the Vancomycin Minimal Inhibitory Concentration be used as an Infant Critical Care Regular Criteria?

BACKGROUND: Vancomycin is the first-line antibiotic used for the treatment of staphylococcal infections. Because of its narrow therapeutic window and the pharmacokinetics variability, vancomycin trough serum concentration should be monitored. However, due to the increased cases of staphylococcus' commensal species infections and the case of vancomycin resistance, the minimal inhibitory concentration should be considered on antimicrobial therapy. OBJECTIVE: This article aimed to show the importance of the minimal inhibitory concentration to infants on vancomycin therapy as regular criteria. MATERIALS AND METHODS: Three infants in the use of vancomycin, hospitalized in the same maternity hospital, and that had at least one blood culture performed during the intensive-care-unit hospitalization were included in the study. Vancomycin serum concentrations were determined by particleenhanced- turbidimetric inhibition-immunoassay. The vancomycin minimal inhibitory concentration data were interpreted by following the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). The trough serum concentration range of 10 to 20 mg.L-1 was considered therapeutic. RESULTS: All three patients had at least one infection by S. epidermidis, being one patient exhibit vancomycin- resistant S. epidermidis infection. All patients had stoppages in the vancomycin treatment, and the minimal inhibitory concentration was performed for only one patient. CONCLUSION: The data obtained from these patients also showed the need to perform therapeutic monitoring by using minimal inhibitory concentration values, because, although the serum concentrations were within the reference range, they are insufficient to guarantee patient therapeutic success.

Setting New Routes for Antifungal Drug Discovery Against Pathogenic Fungi.

Fungal diseases are life-threatening to human health and responsible for millions of deaths around the world. Fungal pathogens lead to a high number of morbidity and mortality. Current antifungal treatment comprises drugs, such as azoles, echinocandins, and polyenes and the cure is not guaranteed. In addition, such drugs are related to severe side effects and the treatment lasts for an extended period. Thus, setting new routes for the discovery of effective and safe antifungal drugs should be a priority within the health care system. The discovery of alternative and efficient antifungal drugs showing fewer side effects is time-consuming and remains a challenge. Natural products can be a source of antifungals and used in combinatorial therapy. The most important natural products are antifungal peptides, antifungal lectins, antifungal plants, and fungi secondary metabolites. Several proteins, enzymes, and metabolic pathways could be targets for the discovery of efficient inhibitor compounds and recently, heat shock proteins, calcineurin, salinomycin, the trehalose biosynthetic pathway, and the glyoxylate cycle have been investigated in several fungal species. HSP protein inhibitors and echinocandins have been shown to have a fungicidal effect against azole-resistant fungi strains. Transcriptomic and proteomic approaches have advanced antifungal drug discovery and pointed to new important specific-pathogen targets. Certain enzymes, such as those from the glyoxylate cycle, have been a target of antifungal compounds in several fungi species. Natural and synthetic compounds inhibited the activity of such enzymes and reduced the ability of fungal cells to transit from mycelium to yeast, proving to be promisor antifungal agents. Finally, computational biology has developed effective approaches, setting new routes for early antifungal drug discovery since normal approaches take several years from discovery to clinical use. Thus, the development of new antifungal strategies might reduce the therapeutic time and increase the quality of life of patients.

Deep Learning-driven research for drug discovery: Tackling Malaria.

Malaria is an infectious disease that affects over 216 million people worldwide, killing over 445,000 patients annually. Due to the constant emergence of parasitic resistance to the current antimalarial drugs, the discovery of new drug candidates is a major global health priority. Aiming to make the drug discovery processes faster and less expensive, we developed binary and continuous Quantitative Structure-Activity Relationships (QSAR) models implementing deep learning for predicting antiplasmodial activity and cytotoxicity of untested compounds. Then, we applied the best models for a virtual screening of a large database of chemical compounds. The top computational predictions were evaluated experimentally against asexual blood stages of both sensitive and multi-drug-resistant Plasmodium falciparum strains. Among them, two compounds, LabMol-149 and LabMol-152, showed potent antiplasmodial activity at low nanomolar concentrations (EC50 <500 nM) and low cytotoxicity in mammalian cells. Therefore, the computational approach employing deep learning developed here allowed us to discover two new families of potential next generation antimalarial agents, which are in compliance with the guidelines and criteria for antimalarial target candidates.

Involvement of the gabaergic, serotonergic and glucocorticoid mechanism in the anxiolytic-like effect of mastoparan-L.

Mastoparan-L (mast-L) is a cell-penetrating tetradecapeptide and stimulator of monoamine exocytosis. In the present study, we evaluated the anxiolytic-like effect of mast-L. Preliminary pharmacological tests were conducted to determine the most appropriate route of administration, extrapolate dose and detect potential toxic effects of this peptide. Oral and intracerebroventricular administration of mast-L (0.1, 0.3 or 0.9 mg.kg-1), diazepam (1 or 5 mg.kg-1), buspirone (10 mg.kg-1) or vehicle 10 mL.kg-1 was carried out prior to the exposure of mice to the anxiety models: open field, light-dark box and elevated plus-maze. To characterize the mechanism underlying the antianxiety-like effect of mast-L, pharmacological antagonism, blood plasma analysis, molecular docking, and receptor binding assays were performed. The absence of a neurotoxic sign, animal's death as well as lack of significant changes in the relative organ weight, hematological and biochemical parameters suggest that mast-L is relatively safe. The anxiolytic-like effect of mast-L was attenuated by flumazenil (antagonist of benzodiazepine binding site) and WAY100635 (selective antagonist of 5-HT1A receptors) pretreatments. Mast-L reduced plasma corticosterone and lowered the scoring function at GABAA -18.48 kcal/mol (Ki = 155 nM), 5-HT1A -22.39 kcal/mol (Ki = 130 nM), corticotropin-releasing factor receptor subtype 1 (CRF1) -11.95 kcal/mol (Ki = 299 nM) and glucocorticoid receptors (GR) -14.69 kcal/mol (Ki = 3552 nM). These data fit the binding affinity (Ki) and demonstrate the involvement of gabaergic, serotonergic and glucocorticoid mechanisms in the anxiolytic-like property of mast-L.

Guidelines of the Brazilian Society of Oncologic Surgery for pelvic exenteration in the treatment of cervical cancer.

BACKGROUND AND OBJECTIVES: The primary treatment for locally advanced cases of cervical cancer is chemoradiation followed by high-dose brachytherapy. When this treatment fails, pelvic exenteration (PE) is an option in some cases. This study aimed to develop recommendations for the best management of patients with cervical cancer undergoing salvage PE. METHODS: A questionnaire was administered to all members of the Brazilian Society of Surgical Oncology. Of them, 68 surgeons participated in the study and were divided into 10 working groups. A literature review of studies retrieved from the National Library of Medicine database was carried out on topics chosen by the participants. These topics were indications for curative and palliative PE, preoperative and intraoperative evaluation of tumor resectability, access routes and surgical techniques, PE classification, urinary, vaginal, intestinal, and pelvic floor reconstructions, and postoperative follow-up. To define the level of evidence and strength of each recommendation, an adapted version of the Infectious Diseases Society of America Health Service rating system was used. RESULTS: Most conducts and management strategies reviewed were strongly recommended by the participants. CONCLUSIONS: Guidelines outlining strategies for PE in the treatment of persistent or relapsed cervical cancer were developed and are based on the best evidence available in the literature.

Integrative Multi-Kinase Approach for the Identification of Potent Antiplasmodial Hits.

Malaria is a tropical infectious disease that affects over 219 million people worldwide. Due to the constant emergence of parasitic resistance to the current antimalarial drugs, the discovery of new antimalarial drugs is a global health priority. Multi-target drug discovery is a promising and innovative strategy for drug discovery and it is currently regarded as one of the best strategies to face drug resistance. Aiming to identify new multi-target antimalarial drug candidates, we developed an integrative computational approach to select multi-kinase inhibitors for Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4) and protein kinase 6 (PK6). For this purpose, we developed and validated shape-based and machine learning models to prioritize compounds for experimental evaluation. Then, we applied the best models for virtual screening of a large commercial database of drug-like molecules. Ten computational hits were experimentally evaluated against asexual blood stages of both sensitive and multi-drug resistant P. falciparum strains. Among them, LabMol-171, LabMol-172, and LabMol-181 showed potent antiplasmodial activity at nanomolar concentrations (EC50 ≤ 700 nM) and selectivity indices >15 folds. In addition, LabMol-171 and LabMol-181 showed good in vitro inhibition of P. berghei ookinete formation and therefore represent promising transmission-blocking scaffolds. Finally, docking studies with protein kinases CDPK1, CDPK4, and PK6 showed structural insights for further hit-to-lead optimization studies.