Public support for and concerns regarding pediatric dose optimization for seizures in emergency medical services: An exception from informed consent (EFIC) trial.

BACKGROUND: Federal regulations allow exception from informed consent (EFIC) to study emergent conditions when obtaining prospective consent is not feasible. Little is known about public views on including children in EFIC studies. The Pediatric Dose Optimization for Seizures in EMS (PediDOSE) trial implements age-based, standardized midazolam dosing for pediatric seizures. The primary objective of this study was to determine public support for and concerns about the PediDOSE EFIC trial. The secondary objective was to assess how support for PediDOSE varied by demographics. METHODS: We conducted a mixed-methods study in 20 U.S. communities. Participants reviewed information about PediDOSE before completing an online survey. Descriptive data were generated. Univariable and multivariable logistic regression analysis identified factors associated with support for PediDOSE. Reviewers identified themes from free-text response data regarding participant concerns. RESULTS: Of 2450 respondents, 79% were parents/guardians, and 20% had a child with previous seizures. A total of 96% of respondents supported PediDOSE being conducted, and 70% approved of children being enrolled without prior consent. Non-Hispanic Black respondents were less likely than non-Hispanic White respondents to support PediDOSE with an adjusted odds ratio (aOR) of 0.57 (95% CI 0.42-0.75). Health care providers were more likely to support PediDOSE, with strongest support among prehospital emergency medicine clinicians (aOR 5.82, 95% CI 3.19-10.62). Age, gender, parental status, and level of education were not associated with support of PediDOSE. Common concerns about PediDOSE included adverse effects, legal and ethical concerns about enrolling without consent, and potential racial bias. CONCLUSIONS: In communities where this study will occur, most respondents supported PediDOSE being conducted with EFIC and most approved of children being enrolled without prior consent. Support was lowest among non-Hispanic Black respondents and highest among health care providers. Further research is needed to determine optimal ways to address the concerns of specific racial and ethnic groups when conducting EFIC trials.

Neuropeptide expression and action in the reproductive system of the starfish Asterias rubens.

Reproductive processes are regulated by a variety of neuropeptides in vertebrates and invertebrates. In starfish (phylum Echinodermata), relaxin-like gonad-stimulating peptide triggers oocyte maturation and spawning. However, little is known about other neuropeptides as potential regulators of reproduction in starfish. To address this issue, here, we used histology and immunohistochemistry to analyze the reproductive system of the starfish Asterias rubens at four stages of the seasonal reproductive cycle in male and female animals, investigating the expression of eight neuropeptides: the corticotropin-releasing hormone-type neuropeptide ArCRH, the calcitonin-type neuropeptide ArCT, the pedal peptide-type neuropeptides ArPPLN1b and ArPPLN2h, the vasopressin/ocytocin-type neuropeptide asterotocin, the gonadotropin-releasing hormone-type neuropeptide ArGnRH, and the somatostatin/allatostatin-C-type neuropeptides ArSS1 and ArSS2. The expression of five neuropeptides, ArCRH, ArCT, ArPPLN1b, ArPPLN2h, and asterotocin, was detected in the gonoducts and/or gonads. For example, extensive ArPPLN2h expression was revealed in the coelomic epithelial layer of the gonads throughout the seasonal reproductive cycle in both males and females. However, seasonal and/or sexual differences in the patterns of neuropeptide expression were also observed. Informed by these findings, the in vitro pharmacological effects of neuropeptides on gonad preparations from male and female starfish were investigated. This revealed that ArSS1 causes gonadal contraction and that ArPPLN2h causes gonadal relaxation, with both neuropeptides being more effective on ovaries than testes. Collectively, these findings indicate that multiple neuropeptide signaling systems are involved in the regulation of reproductive function in starfish, with some neuropeptides exerting excitatory or inhibitory effects on gonad contractility that may be physiologically relevant when gametes are expelled during spawning.

Chemical conjugation of aptamer-sphingomyelin nanosystems and their potential as inhibitors of tumour cell proliferation in breast cancer cells.

Breast cancer is a complex and heterogeneous disease with a high mortality rate due to non-specific cytotoxicity, low intratumoral accumulation and drug resistance associated with the ineffectiveness of chemotherapy. In recent years, all efforts have been focused on finding new markers and therapeutic targets, protein kinase MNK1b being a promising candidate. Recently, an aptamer known as apMNK2F showed a highly specific interaction with this protein kinase, leading to a significant reduction in tumour cell proliferation, migration and colony formation. However, as aptamers are unable to penetrate the cell membrane and reach the target, these small biomolecules need to be conjugated to suitable vectors that can transport and protect them inside the cells. In this work, covalent conjugation between biocompatible and non-harmful nanoemulsions of vitamin E and sphingomyelin and the aptamer was performed to facilitate intracellular delivery of the therapeutic aptamer apMNK2F. All strategies employed were based on 2-step bioconjugation and optimized to get the simplest and most reproducible vehicle with the highest association efficiency (about 70% in all cases). The ability of the nanosystems to successfully deliver the conjugated therapeutic aptamer was demonstrated and compared to other commercial transfection agents such as Lipofectamine 2000, leading to an effective decrease of breast cancer cell proliferation in the MDA-MB-231 cell line. The proliferation inhibition of the aptamer nanoconjugates compared to the non-conjugated aptamer provides evidence that the antitumoral capacity derived from kinase interaction is improved in a dose-dependent manner. Furthermore, various experiments including cell migration and colony formation assays, along with apoptosis induction experiments, emphasize the significant antitumoral potential. Overall, the obtained results indicate that the developed formulation could be a promising therapy for the treatment of breast cancer.

Gonadotropic activity of a second relaxin-type peptide in starfish.

In starfish, a relaxin-like gonad-stimulating peptide (RGP) acts as a gonadotropin that triggers gamete maturation and spawning. In common with other relaxin/insulin superfamily peptides, RGP consists of an A- and a B-chain, with cross-linkages mediated by one intra- and two inter-chain disulfide bonds. In this study, a second relaxin-like peptide (RLP2) was identified in starfish species belonging to the orders Valvatida, Paxillosida, and Forcipulatida. Like RGP, RLP2 precursors comprise a signal peptide and a C-peptide in addition to the A- and B-chains. However, a unique cysteine motif [CC-(3X)-C-(10X)-C] is present in the A-chain of RLP2, which contrasts with the cysteine motif in other members of the relaxin/insulin superfamily [CC-(3X)-C-(8X)-C]. Importantly, in vitro pharmacological tests revealed that Patiria pectinifera RLP2 (Ppe-RLP2) and Asterias rubens RLP2 (Aru-RLP2) trigger shedding of mature eggs from ovaries of P. pectinifera and A. rubens, respectively. Furthermore, the potencies of Ppe-RLP2 and Aru-RLP2 as gonadotropic peptides were similar to those of Ppe-RGP and Aru-RGP, respectively, and the effect of RLP2 exhibited partial species-specificity. These findings indicate that two relaxin-type peptides regulate spawning in starfish and therefore we propose that RGP and RLP2 are renamed RGP1 and RGP2, respectively.

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas Disease.

In 2020, the WHO established the road map for neglected tropical diseases 2021-2030, which aims to control and eradicate 20 diseases, including leishmaniosis and Chagas disease. In addition, since 2015, the WHO has been developing a Global Action Plan on Antimicrobial Resistance. In this context, the achievement of innovative strategies as an alternative to replace conventional therapies is a first-order socio-sanitary priority, especially regarding endemic zoonoses in poor regions, such as those caused by Trypanosoma cruzi and Leishmania spp. infections. In this scenario, it is worth highlighting a group of natural peptide molecules (AMPs and CPPs) that are promising strategies for improving therapeutic efficacy against these neglected zoonoses, as they avoid the development of toxicity and resistance of conventional treatments. This review presents the novelties of these peptide molecules and their ability to cross a whole system of cell membranes as well as stimulate host immune defenses or even serve as vectors of molecules. The efforts of the biotechnological sector will make it possible to overcome the limitations of antimicrobial peptides through encapsulation and functionalization methods to obtain approval for these treatments to be used in clinical programs for the eradication of leishmaniosis and Chagas disease.

Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment: A Phase 1/2 Randomized Clinical Trial.

Importance: ApTOLL is a TLR4 antagonist with proven preclinical neuroprotective effect and a safe profile in healthy volunteers. Objective: To assess the safety and efficacy of ApTOLL in combination with endovascular treatment (EVT) for patients with ischemic stroke. Design, Setting, and Participants: This phase 1b/2a, double-blind, randomized, placebo-controlled study was conducted at 15 sites in Spain and France from 2020 to 2022. Participants included patients aged 18 to 90 years who had ischemic stroke due to large vessel occlusion and were seen within 6 hours after stroke onset; other criteria were an Alberta Stroke Program Early CT Score of 6 to 10, estimated infarct core volume on baseline computed tomography perfusion of 5 to 70 mL, and the intention to undergo EVT. During the study period, 4174 patients underwent EVT. Interventions: In phase 1b, 0.025, 0.05, 0.1, or 0.2 mg/kg of ApTOLL or placebo; in phase 2a, 0.05 or 0.2 mg/kg of ApTOLL or placebo; and in both phases, treatment with EVT and intravenous thrombolysis if indicated. Main Outcomes and Measures: The primary end point was the safety of ApTOLL based on death, symptomatic intracranial hemorrhage (sICH), malignant stroke, and recurrent stroke. Secondary efficacy end points included final infarct volume (via MRI at 72 hours), NIHSS score at 72 hours, and disability at 90 days (modified Rankin Scale [mRS] score). Results: In phase Ib, 32 patients were allocated evenly to the 4 dose groups. After phase 1b was completed with no safety concerns, 2 doses were selected for phase 2a; these 119 patients were randomized to receive ApTOLL, 0.05 mg/kg (n = 36); ApTOLL, 0.2 mg/kg (n = 36), or placebo (n = 47) in a 1:1:√2 ratio. The pooled population of 139 patients had a mean (SD) age of 70 (12) years, 81 patients (58%) were male, and 58 (42%) were female. The primary end point occurred in 16 of 55 patients (29%) receiving placebo (10 deaths [18.2%], 4 sICH [7.3%], 4 malignant strokes [7.3%], and 2 recurrent strokes [3.6%]); in 15 of 42 patients (36%) receiving ApTOLL, 0.05 mg/kg (11 deaths [26.2%], 3 sICH [7.2%], 2 malignant strokes [4.8%], and 2 recurrent strokes [4.8%]); and in 6 of 42 patients (14%) receiving ApTOLL, 0.2 mg/kg (2 deaths [4.8%], 2 sICH [4.8%], and 3 recurrent strokes [7.1%]). ApTOLL, 0.2 mg/kg, was associated with lower NIHSS score at 72 hours (mean difference log-transformed vs placebo, -45%; 95% CI, -67% to -10%), smaller final infarct volume (mean difference log-transformed vs placebo, -42%; 95% CI, -66% to 1%), and lower degrees of disability at 90 days (common odds ratio for a better outcome vs placebo, 2.44; 95% CI, 1.76 to 5.00). Conclusions and Relevance: In acute ischemic stroke, 0.2 mg/kg of ApTOLL administered within 6 hours of onset in combination with EVT was safe and associated with a potential meaningful clinical effect, reducing mortality and disability at 90 days compared with placebo. These preliminary findings await confirmation from larger pivotal trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04734548.

Localization of relaxin-like gonad-stimulating peptide expression in starfish reveals the gonoducts as a source for its role as a regulator of spawning.

Oocyte maturation and gamete release (spawning) in starfish are triggered by relaxin-like gonad-stimulating peptide (RGP), a neuropeptide that was first isolated from the radial nerve cords of these animals. Hitherto, it has generally been assumed that the radial nerve cords are the source of RGP that triggers spawning physiologically. To investigate other sources of RGP, here we report the first comprehensive anatomical analysis of its expression, using both in situ hybridization and immunohistochemistry to map RGP precursor transcripts and RGP, respectively, in the starfish Asterias rubens. Cells expressing RGP precursor transcripts were revealed in the ectoneural epithelium of the radial nerve cords and circumoral nerve ring, arm tips, tube feet, cardiac stomach, pyloric stomach, and, most notably, gonoducts. Using specific antibodies to A. rubens RGP, immunostaining was revealed in cells and/or fibers in the ectoneural region of the radial nerve cords and circumoral nerve ring, tube feet, terminal tentacle and other arm tip-associated structures, body wall, peristomial membrane, esophagus, cardiac stomach, pyloric stomach, pyloric caeca, and gonoducts. Our discovery that RGP is expressed in the gonoducts of A. rubens proximal to its gonadotropic site of action in the gonads is important because it provides a new perspective on how RGP may act as a gonadotropin in starfish. Thus, we hypothesize that it is the release of RGP from the gonoducts that triggers gamete maturation and spawning in starfish, while RGP produced in other parts of the body may regulate other physiological/behavioral processes.

An Aptamer against MNK1 for Non-Small Cell Lung Cancer Treatment.

Lung cancer is the leading cause of cancer-related death worldwide. Its late diagnosis and consequently poor survival make necessary the search for new therapeutic targets. The mitogen-activated protein kinase (MAPK)-interacting kinase 1 (MNK1) is overexpressed in lung cancer and correlates with poor overall survival in non-small cell lung cancer (NSCLC) patients. The previously identified and optimized aptamer from our laboratory against MNK1, apMNKQ2, showed promising results as an antitumor drug in breast cancer in vitro and in vivo. Thus, the present study shows the antitumor potential of apMNKQ2 in another type of cancer where MNK1 plays a significant role, such as NSCLC. The effect of apMNKQ2 in lung cancer was studied with viability, toxicity, clonogenic, migration, invasion, and in vivo efficacy assays. Our results show that apMNKQ2 arrests the cell cycle and reduces viability, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT) processes in NSCLC cells. In addition, apMNKQ2 reduces tumor growth in an A549-cell line NSCLC xenograft model. In summary, targeting MNK1 with a specific aptamer may provide an innovative strategy for lung cancer treatment.

Enzyme-Linked Oligonucleotide Assay (ELONA).

Aptamers are single-stranded oligonucleotides able to recognize a target with high affinity and specificity. Aptamers are used in different diagnostics applications, highlighting, among all, variations of the traditional enzyme-linked immunosorbent assay (ELISA). In this chapter, we show the procedures for the development of two types of indirect ELONA: a sandwich ELONA and a direct ELONA coupled to either real-time quantitative PCR as a direct and sensitive readout.

First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers.

ApTOLL is an aptamer that antagonizes Toll-like receptor 4 and improves functional outcomes in models of ischemic stroke and myocardial infarction. The aim of this study was to characterize the safety and pharmacokinetics of ApTOLL in healthy volunteers. A first-in-human dose-ascending, randomized, placebo-controlled phase I clinical trial to assess safety and pharmacokinetics of ApTOLL (30-min infusion intravenously) was performed in 46 healthy adult male volunteers. The study was divided into two parts: part A included seven single ascending dose levels, and part B had one multiple dose cohort. Safety and pharmacokinetic parameters were evaluated. No serious adverse events or biochemistry alterations were detected at any dose nor at any administration pattern studied. Maximum concentration was detected at the end of the infusion and mean half-life was 9.3 h. Interestingly, exposure increased in the first four levels receiving doses from 0.7 mg to 14 mg (AUC of 2,441.26 h∗ng/mL to 23,371.11 h∗ng/mL) but remained stable thereafter (mean of 23,184.61 h∗ng/mL after 70 mg). Consequently, the multiple dose study did not show any accumulation of ApTOLL. These results show an excellent safety and adequate pharmacokinetic profile that, together with the efficacy demonstrated in nonclinical studies, provide the basis to start clinical trials in patients.

Association of Physical Activity, Sports, and Screen Time With Adolescent Behaviors in Youth Who Visit the Pediatric Emergency Department.

Moderate to vigorous physical activity (MVPA), sports, and reduced screen time are associated with favorable youth risk profiles. We evaluated the association of MVPA, sports, and screen time with adolescent behaviors among pediatric emergency department youth. Adolescents were assessed for alcohol/drug use, risky behavior, conduct disorder, and depressive mood. MVPA was activity for ≥5 days/week and ≥60 minutes/day. Increased screen time was ≥3 hours/day computer/TV use for non-schoolwork. Multivariable regression studied association between MVPA, sports, and increased screen time and outcomes adjusting for demographics and academic achievement. Older age and lower academic achievement were significantly associated with risky behaviors, conduct disorder, and depression. Youth who endorsed MVPA and sports participation had less depression (odds ratio [OR] = 0.76; confidence interval [CI] = 0.66-0.87). Increased screen time was associated with conduct disorder (OR = 1.6; CI = 1.3-2.1), depression (OR = 1.2; CI = 1.0-1.4), and drug use (OR = 1.8; CI = 1.1-2.8). In pediatric emergency department youth, MVPA and sports participation is associated with less depression. Increased screen time is associated with conduct disorders, depression, and drug use.

Selection and characterization of DNA aptamers for highly selective recognition of the major allergen of olive pollen Ole e 1.

In this study, single-stranded DNA aptamers with binding affinity to Ole e 1, the major allergen of olive pollen, were selected using systematic evolution of ligands by exponential enrichment (SELEX) method. Binding of the aptamers was firstly established by enzyme-linked oligonucleotide assay (ELONA) and aptaprecipitation assays. Additionally, aptamer-modified monolithic capillary chromatography was used in order to evaluate the recognition of this allergenic protein against other non-target proteins. The results indicated that AptOle1#6 was the aptamer that provided the highest affinity for Ole e 1. The selected aptamer showed good selective recognition of this protein, being not able to retain other non-target proteins (HSA, cyt c, and other pollen protein such as Ole e 9). The feasibility of the affinity monolithic column was demonstrated by selective recognition of Ole e 1 in an allergy skin test. The stability and reproducibility of this monolithic column was suitable, with relative standard deviations (RSDs) in retention times and peak area values of 7.8 and 9.3%, respectively (column-to-column reproducibility). This is the first study that describes the design of an efficient DNA aptamer for this relevant allergen.

FPR2 DNA Aptamers for Targeted Therapy of Wound Repair.

Chronic wounds represent a major health problem worldwide. Some of the available therapies based on recombinant proteins usually fail owing to the hostile environment found at the wound bed. Aptamers appear as an attractive alternative to recombinant factors owing in part to their stability, sensitivity, specificity, and low-cost production. In this study, the Cell-Systematic Evolution of Ligands by EXponential Enrichment technology was employed to generate aptamers that specifically recognize and modulate the function of the FPR2, a receptor expressed in a variety of cells involved in wound repair. Three aptamers were obtained that specifically bound to FPR2 stable transfectants generated in HaCaT cells. The targeted aptamers were shown to act as FPR2 agonists in different in vitro functional assays, including wound healing assays, and elicited a similar pattern of response to that obtained with other known FPR2 peptide agonists, such as the human LL37 cathelicidin. We have also obtained in vivo evidence for the prohealing activities of one of these FPR2 aptamers in a skin-humanized mouse model developed by us, previously shown to accurately recreate the main phases of physiological human wound repair process. In conclusion, we provide evidence of the potential therapeutic value of FPR2 aptamers for cutaneous repair.

Potential Therapeutic Use of Aptamers against HAT1 in Lung Cancer.

Lung cancer is one of the leading causes of death worldwide and the most common of all cancer types. Histone acetyltransferase 1 (HAT1) has attracted increasing interest as a potential therapeutic target due to its involvement in multiple pathologies, including cancer. Aptamers are single-stranded RNA or DNA molecules whose three-dimensional structure allows them to bind to a target molecule with high specificity and affinity, thus making them exceptional candidates for use as diagnostic or therapeutic tools. In this work, aptamers against HAT1 were obtained, subsequently characterized, and optimized, showing high affinity and specificity for HAT1 and the ability to inhibit acetyltransferase activity in vitro. Of those tested, the apHAT610 aptamer reduced cell viability, induced apoptosis and cell cycle arrest, and inhibited colony formation in lung cancer cell lines. All these results indicate that the apHAT610 aptamer is a potential drug for the treatment of lung cancer.

Anti-HIV Aptamers: Challenges and Prospects.

Human Immunodeficiency Virus (HIV) infection continues to be a significant health burden in many countries around the world. Current HIV treatment through a combination of different antiretroviral drugs (cART) effectively suppresses viral replication, but drug resistance and crossresistance are significant challenges. This has prompted the search for novel targets and agents, such as nucleic acid aptamers. Nucleic acid aptamers are oligonucleotides that attach to the target sites with high affinity and specificity. This review provides a target-by-target account of research into anti-HIV aptamers and summarises the challenges and prospects of this therapeutic strategy, specifically in the unique context of HIV infection.

DNA Aptamers against Vaccinia-Related Kinase (VRK) 1 Block Proliferation in MCF7 Breast Cancer Cells.

Vaccinia-related kinase (VRK) 1 is a serin/threonine kinase that plays an important role in DNA damage response (DDR), phosphorylating some proteins involved in this process such as 53BP1, NBS1 or H2AX, and in the cell cycle progression. In addition, VRK1 is overexpressed in many cancer types and its correlation with poor prognosis has been determined, showing VRK1 as a new therapeutic target in oncology. Using in vitro selection, high-affinity DNA aptamers to VRK1 were selected from a library of ssDNA. Selection was monitored using the enzyme-linked oligonucleotide assay (ELONA), and the selected aptamer population was cloned and sequenced. Three aptamers were selected and characterized. These aptamers recognized the protein kinase VRK1 with an affinity in the nanomolar range and showed a high sensibility. Moreover, the treatment of the MCF7 breast cell line with these aptamers resulted in a decrease in cyclin D1 levels, and an inhibition of cell cycle progression by G1 phase arrest, which induced apoptosis in cells. These results suggest that these aptamers are specific inhibitors of VRK1 that might be developed as potential drugs for the treatment of cancer.

Research environment and resources to support pediatric emergency medicine fellow research.

BACKGROUND: There is a need for pediatric emergency medicine (PEM) researchers, but the current state of PEM fellow research training is not well described. We sought to (1) describe resources and gaps in PEM fellowship research training and (2) assess agreement between fellow and program director (PD) perceptions of these in fellow research experience. METHODS: Surveys were distributed electronically to U.S. PEM fellows and PDs from March to April 2020. Fellows and PDs were queried on program research infrastructure and current gaps in fellow research experience. For programs that had at least one fellow and PD response, each fellow response was compared to their PD's corresponding response (reference standard). For each binary survey item, we determined the percent of responses with agreement between the fellow and PD. RESULTS: Of 79 fellowship programs, 70 (89%) were represented with at least one response, including responses from 59 PDs (75%) and 218 fellows (39% of all fellows, representing 80% of programs). Fellows and PDs identified mentorship and faculty engagement as the most important needs for successful fellowship research; for every one fellow there was a median of 0.8 potential faculty mentors in the division. Twenty percent of fellows were not satisfied with mentorship opportunities. There was no association between fellow career research intent (high, defined as ≥20% dedicated time, or low) with current year of training (p = 0.88), program size (p = 0.67), and area of research focus (p = 0.40). Fellows were often unaware of research being performed by division faculty. CONCLUSION: PEM fellows were not consistently aware of resources available to support research training. To better support PEM fellows' research training, many programs may need to expand mentorship and increase fellows' awareness of local and external resources and opportunities.

The Relevance of the SH2 Domain for c-Src Functionality in Triple-Negative Breast Cancer Cells.

The role of Src family kinases (SFKs) in human tumors has been always associated with tyrosine kinase activity and much less attention has been given to the SH2 and SH3 adapter domains. Here, we studied the role of the c-Src-SH2 domain in triple-negative breast cancer (TNBC). To this end, SUM159PT and MDA-MB-231 human cell lines were employed as model systems. These cells conditionally expressed, under tetracycline control (Tet-On system), a c-Src variant with point-inactivating mutation of the SH2 adapter domain (R175L). The expression of this mutant reduced the self-renewal capability of the enriched population of breast cancer stem cells (BCSCs), demonstrating the importance of the SH2 adapter domain of c-Src in the mammary gland carcinogenesis. In addition, the analysis of anchorage-independent growth, proliferation, migration, and invasiveness, all processes associated with tumorigenesis, showed that the SH2 domain of c-Src plays a very relevant role in their regulation. Furthermore, the transfection of two different aptamers directed to SH2-c-Src in both SUM159PT and MDA-MB-231 cells induced inhibition of their proliferation, migration, and invasiveness, strengthening the hypothesis that this domain is highly involved in TNBC tumorigenesis. Therefore, the SH2 domain of c-Src could be a promising therapeutic target and combined treatments with inhibitors of c-Src kinase enzymatic activity may represent a new therapeutic strategy for patients with TNBC, whose prognosis is currently very negative.

Diagnostic accuracy of infrared thermal imaging for detecting COVID-19 infection in minimally symptomatic patients.

INTRODUCTION: Despite being widely used as a screening tool, a rigorous scientific evaluation of infrared thermography for the diagnosis of minimally symptomatic patients suspected of having COVID-19 infection has not been performed. METHODS: A consecutive sample of 60 adult individuals with a history of close contact with COVID-19 infected individuals and mild respiratory symptoms for less than 7 days and 20 confirmed COVID-19 negative healthy volunteers were enrolled in the study. Infrared thermograms of the face were obtained with a mobile camera, and RT-PCR was used as the reference standard test to diagnose COVID-19 infection. Temperature values and distribution of the face of healthy volunteers and patients with and without COVID-19 infection were then compared. RESULTS: Thirty-four patients had an RT-PCR confirmed diagnosis of COVID-19 and 26 had negative test results. The temperature asymmetry between the lacrimal caruncles and the forehead was significantly higher in COVID-19 positive individuals. Through a random forest analysis, a cut-off value of 0.55°C was found to discriminate with an 82% accuracy between patients with and without COVID-19 confirmed infection. CONCLUSIONS: Among adults with a history of COVID-19 exposure and mild respiratory symptoms, a temperature asymmetry of ≥ 0.55°C between the lacrimal caruncle and the forehead is highly suggestive of COVID-19 infection. This finding questions the widespread use of the measurement of absolute temperature values of the forehead as a COVID-19 screening tool.

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer.

The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are involved in oncogenic transformation and can promote metastasis and tumor progression. In human cells, there are four MNKs isoforms (MNK1a/b and MNK2a/b), derived from two genes by alternative splicing. These kinases play an important role controlling the expression of specific proteins involved in cell cycle, cell survival and cell motility via eukaryotic initiation factor 4E (eIF4E) regulation, but also through other substrates such as heterogeneous nuclear ribonucleoprotein A1, polypyrimidine tract-binding protein-associated splicing factor and Sprouty 2. In this review, we provide an overview of the role of MNK in human cancers, describing the studies conducted to date to elucidate the mechanism involved in the action of MNKs, as well as the development of MNK inhibitors in different hematological cancers and solid tumors.