Interactive effects of pain and arousal state on heart rate and cortical activity in the mouse anterior cingulate and somatosensory cortices.

Sensory disconnection is a hallmark of sleep, yet the cortex retains some ability to process sensory information. Acute noxious stimulation during sleep increases the heart rate and the likelihood of awakening, indicating that certain mechanisms for pain sensing and processing remain active. However, processing of somatosensory information, including pain, during sleep remains underexplored. To assess somatosensation in natural sleep, we simultaneously recorded heart rate and local field potentials in the anterior cingulate (ACC) and somatosensory (S1) cortices of naïve, adult male mice, while applying noxious and non-noxious stimuli to their hind paws throughout their sleep-wake cycle. Noxious stimuli evoked stronger heart rate increases in both wake and non-rapid eye movement sleep (NREMS), and resulted in larger awakening probability in NREMS, as compared to non-noxious stimulation, suggesting differential processing of noxious and non-noxious information during sleep. Somatosensory information differentially reached S1 and ACC in sleep, eliciting complex transient and sustained responses in the delta, alpha, and gamma frequency bands as well as somatosensory evoked potentials. These dynamics depended on sleep state, the behavioral response to the stimulation and stimulation intensity (non-noxious vs. noxious). Furthermore, we found a correlation of the heart rate with the gamma band in S1 in the absence of a reaction in wake and sleep for noxious stimulation. These findings confirm that somatosensory information, including nociception, is sensed and processed during sleep even in the absence of a behavioral response.

Mimicking opioid analgesia in cortical pain circuits.

The anterior cingulate cortex plays a pivotal role in the cognitive and affective aspects of pain perception. Both endogenous and exogenous opioid signaling within the cingulate mitigate cortical nociception, reducing pain unpleasantness. However, the specific functional and molecular identities of cells mediating opioid analgesia in the cingulate remain elusive. Given the complexity of pain as a sensory and emotional experience, and the richness of ethological pain-related behaviors, we developed a standardized, deep-learning platform for deconstructing the behavior dynamics associated with the affective component of pain in mice-LUPE (Light aUtomated Pain Evaluator). LUPE removes human bias in behavior quantification and accelerated analysis from weeks to hours, which we leveraged to discover that morphine altered attentional and motivational pain behaviors akin to affective analgesia in humans. Through activity-dependent genetics and single-nuclei RNA sequencing, we identified specific ensembles of nociceptive cingulate neuron-types expressing mu-opioid receptors. Tuning receptor expression in these cells bidirectionally modulated morphine analgesia. Moreover, we employed a synthetic opioid receptor promoter-driven approach for cell-type specific optical and chemical genetic viral therapies to mimic morphine's pain-relieving effects in the cingulate, without reinforcement. This approach offers a novel strategy for precision pain management by targeting a key nociceptive cortical circuit with on-demand, non-addictive, and effective analgesia.

Combining EHMT and PARP Inhibition: A Strategy to Diminish Therapy-Resistant Ovarian Cancer Tumor Growth while Stimulating Immune Activation.

Despite the success of Poly-ADP-ribose polymerase inhibitors (PARPi) in the clinic, high rates of resistance to PARPi presents a challenge in the treatment of ovarian cancer, thus it is imperative to find therapeutic strategies to combat PARPi resistance. Here, we demonstrate that inhibition of epigenetic modifiers Euchromatic histone lysine methyltransferases 1/2 (EHMT1/2) reduces the growth of multiple PARPi-resistant ovarian cancer cell lines and tumor growth in a PARPi-resistant mouse model of ovarian cancer. We found that combinatory EHMT and PARP inhibition increases immunostimulatory dsRNA formation and elicits several immune signaling pathways in vitro. Using epigenomic profiling and transcriptomics, we found that EHMT2 is bound to transposable elements, and that EHMT inhibition leads to genome-wide epigenetic and transcriptional derepression of transposable elements. We validated EHMT-mediated activation of immune signaling and upregulation of transposable element transcripts in patient-derived, therapy-naïve, primary ovarian tumors, suggesting potential efficacy in PARPi-sensitive disease as well. Importantly, using multispectral immunohistochemistry, we discovered that combinatory therapy increased CD8 T cell activity in the tumor microenvironment of the same patient-derived tissues. In a PARPi-resistant syngeneic murine model, EHMT and PARP inhibition combination inhibited tumor progression and increased Granzyme B+ cells in the tumor. Together, our results provide evidence that combinatory EHMT and PARP inhibition stimulates a cell autologous immune response in vitro, is an effective therapy to reduce PARPi resistant ovarian tumor growth in vivo, and promotes anti-tumor immunity activity in the tumor microenvironment of patient-derived ex vivo tissues of ovarian cancer.

NP3 MS Workflow: An Open-Source Software System to Empower Natural Product-Based Drug Discovery Using Untargeted Metabolomics.

Natural products (or specialized metabolites) are historically the main source of new drugs. However, the current drug discovery pipelines require miniaturization and speeds that are incompatible with traditional natural product research methods, especially in the early stages of the research. This article introduces the NP3 MS Workflow, a robust open-source software system for liquid chromatography-tandem mass spectrometry (LC-MS/MS) untargeted metabolomic data processing and analysis, designed to rank bioactive natural products directly from complex mixtures of compounds, such as bioactive biota samples. NP3 MS Workflow allows minimal user intervention as well as customization of each step of LC-MS/MS data processing, with diagnostic statistics to allow interpretation and optimization of LC-MS/MS data processing by the user. NP3 MS Workflow adds improved computing of the MS2 spectra in an LC-MS/MS data set and provides tools for automatic [M + H]+ ion deconvolution using fragmentation rules; chemical structural annotation against MS2 databases; and relative quantification of the precursor ions for bioactivity correlation scoring. The software will be presented with case studies and comparisons with equivalent tools currently available. NP3 MS Workflow shows a robust and useful approach to select bioactive natural products from complex mixtures, improving the set of tools available for untargeted metabolomics. It can be easily integrated into natural product-based drug-discovery pipelines and to other fields of research at the interface of chemistry and biology.

Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity.

Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-b]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea 8z exhibited excellent potency against FGFR4WT, FGFR4V550L, and FGFR4V550M with IC50 values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4WT, FGFR4V550L, and FGFR4V550M, and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC50 values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, 8z displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.

Causas anatómicas inusuales de malposición de catéteres venosos centrales / Unusual anatomical causes of malposition of central venous catheters

Resumen: La malposición de los catéteres venosos centrales se asocia a importantes riesgos, a menudo infraestimados. Aunque se han descrito algunos factores que pueden favorecer la malposición, generalmente su causa no llega a diagnosticarse y parece ser de origen multifactorial. Presentamos dos casos de malposición de catéteres venosos centrales motivadas por causas anatómicas inusuales, diagnosticadas en el perioperatorio. En el primer caso, se diagnostica una agenesia de vena cava superior en el transcurso de una sustitución mitral por esternotomía, que lógicamente se asocia con una malposición de la vía central insertada. La utilización de catéteres y dispositivos a través de venas yugulares y subclavias en pacientes con esta infrecuente patología implica importantes limitaciones y complicaciones potenciales graves. En el segundo caso, la existencia de un bocio no diagnosticado provoca la malposición bilateral y simultánea de dos catéteres venosos canalizados, en el contexto de una situación de emergencia, en ambas venas yugulares internas.

Abstract: Malposition of central venous catheters is associated with important and underestimated risks. Although some factors have been related with malposition, its cause is generally not diagnosed, and it seems to have multifactorial origin. We present two cases of central venous catheter malposition due to unusual anatomical causes, diagnosed in the perioperative period. In the first case, superior vena cava agenesis was diagnosed during mitral replacement by sternotomy, which was logically associated with malposition of the inserted central line. The use of catheters and devices through jugular and subclavian veins in patients with this infrequent pathology is associated with important limitations and serious potential complications. In the second case, an undiagnosed goiter causes bilateral and simultaneous malpositioning of two inserted central venous catheters, in the context of an emergency situation, in both internal jugular veins.

Inhibitory to non-inhibitory evolution of the ζ subunit of the F1FO-ATPase of Paracoccus denitrificans and α-proteobacteria as related to mitochondrial endosymbiosis.

Introduction: The ζ subunit is a potent inhibitor of the F1FO-ATPase of Paracoccus denitrificans (PdF1FO-ATPase) and related α-proteobacteria different from the other two canonical inhibitors of bacterial (ε) and mitochondrial (IF1) F1FO-ATPases. ζ mimics mitochondrial IF1 in its inhibitory N-terminus, blocking the PdF1FO-ATPase activity as a unidirectional pawl-ratchet and allowing the PdF1FO-ATP synthase turnover. ζ is essential for the respiratory growth of P. denitrificans, as we showed by a Δζ knockout. Given the vital role of ζ in the physiology of P. denitrificans, here, we assessed the evolution of ζ across the α-proteobacteria class. Methods: Through bioinformatic, biochemical, molecular biology, functional, and structural analyses of several ζ subunits, we confirmed the conservation of the inhibitory N-terminus of ζ and its divergence toward its C-terminus. We reconstituted homologously or heterologously the recombinant ζ subunits from several α-proteobacteria into the respective F-ATPases, including free-living photosynthetic, facultative symbiont, and intracellular facultative or obligate parasitic α-proteobacteria. Results and discussion: The results show that ζ evolved, preserving its inhibitory function in free-living α-proteobacteria exposed to broad environmental changes that could compromise the cellular ATP pools. However, the ζ inhibitory function was diminished or lost in some symbiotic α-proteobacteria where ζ is non-essential given the possible exchange of nutrients and ATP from hosts. Accordingly, the ζ gene is absent in some strictly parasitic pathogenic Rickettsiales, which may obtain ATP from the parasitized hosts. We also resolved the NMR structure of the ζ subunit of Sinorhizobium meliloti (Sm-ζ) and compared it with its structure modeled in AlphaFold. We found a transition from a compact ordered non-inhibitory conformation into an extended α-helical inhibitory N-terminus conformation, thus explaining why the Sm-ζ cannot exert homologous inhibition. However, it is still able to inhibit the PdF1FO-ATPase heterologously. Together with the loss of the inhibitory function of α-proteobacterial ε, the data confirm that the primary inhibitory function of the α-proteobacterial F1FO-ATPase was transferred from ε to ζ and that ζ, ε, and IF1 evolved by convergent evolution. Some key evolutionary implications on the endosymbiotic origin of mitochondria, as most likely derived from α-proteobacteria, are also discussed.

The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining.

Microhomology-mediated end joining (MMEJ) is an intrinsically mutagenic pathway of DNA double-strand break (DSB) repair essential for proliferation of homologous recombination (HR)-deficient tumors. Although targeting MMEJ has emerged as a powerful strategy to eliminate HR-deficient (HRD) cancers, this is limited by an incomplete understanding of the mechanism and factors required for MMEJ repair. Here, we identify the APE2 nuclease as an MMEJ effector. We show that loss of APE2 inhibits MMEJ at deprotected telomeres and at intra-chromosomal DSBs and is epistatic with Pol Theta for MMEJ activity. Mechanistically, we demonstrate that APE2 possesses intrinsic flap-cleaving activity, that its MMEJ function in cells depends on its nuclease activity, and further identify an uncharacterized domain required for its recruitment to DSBs. We conclude that this previously unappreciated role of APE2 in MMEJ contributes to the addiction of HRD cells to APE2, which could be exploited in the treatment of cancer.

Combinatory EHMT and PARP inhibition induces an interferon response and a CD8 T cell-dependent tumor regression in PARP inhibitor-resistant models.

Euchromatic histone lysine methyltransferases 1 and 2 (EHMT1/2), which catalyze demethylation of histone H3 lysine 9 (H3K9me2), contribute to tumorigenesis and therapy resistance through unknown mechanisms of action. In ovarian cancer, EHMT1/2 and H3K9me2 are directly linked to acquired resistance to poly-ADP-ribose polymerase (PARP) inhibitors and are correlated with poor clinical outcomes. Using a combination of experimental and bioinformatic analyses in several PARP inhibitor resistant ovarian cancer models, we demonstrate that combinatory inhibition of EHMT and PARP is effective in treating PARP inhibitor resistant ovarian cancers. Our in vitro studies show that combinatory therapy reactivates transposable elements, increases immunostimulatory dsRNA formation, and elicits several immune signaling pathways. Our in vivo studies show that both single inhibition of EHMT and combinatory inhibition of EHMT and PARP reduces tumor burden, and that this reduction is dependent on CD8 T cells. Together, our results uncover a direct mechanism by which EHMT inhibition helps to overcome PARP inhibitor resistance and shows how an epigenetic therapy can be used to enhance anti-tumor immunity and address therapy resistance.

Measuring direct and indirect tendon parameters to characterize the proximal tendinous complex of the rectus femoris in football and futsal players.

Objective: To present unprecedented radiological parameters that characterize the angle between the direct and indirect tendons of the proximal rectus femoris (RF) and its inclinations and to evaluate the population variability according to demographic variables. Materials and methods: From September 2019 to July 2021, using MRI multiplanar reconstructions of the proximal thigh/hip, two blinded radiologists measured the direct and indirect tendon angle and the inclination of each tendon in different planes. The intra- and inter-observer agreements were assessed with Bland-Altman analysis and intraclass correlation coefficient (ICC). The correlations between radiological parameters and demographic variables were evaluated using linear regression, Student's t-test, and analysis of variance. Results: We performed 112 thigh/hip MRI scans on 91 football players of different age, gender, and disciplines (football and futsal). For observer 1 (the reference), the mean direct and indirect tendon angle was 56.74° ± 9.37, the mean indirect tendon slope was -7.90° ± 7.49, and the mean direct tendon slope was 22.16° ± 5.88. The three measurements showed inter- and intra-observer agreement (mean differences ∼0). No correlation was observed between age and the parameters. Likewise, no statistically significant differences were found for gender, dominant limb, examined limb, and sport. Conclusion: There is an inter- and intra-observer agreement in the measurements of the direct and indirect tendon angle and the inclination of each tendon. There is population variability in the proximal tendinous complex unrelated to demographic factors. These results allow further detection of morphological patterns that represent a risk factor for lesions in the RF in professional football and futsal players and other sports.

Knowledge and expectations about miRNAs as biomarkers in head and neck squamous cell cancers.

Head and neck squamous cell cancer patients suffer from a high postoperative recurrence rate and poor prognosis. Thus, it is essential to better understand the underlying molecular mechanisms and identify the role of new biomarkers. Recent research has shown that the dysregulation of microRNAs is a potential biomarker as a screening or prognostic tool. Moreover, the literature reveals its promising usefulness to select the best treatment strategy and monitor tumour response. The purpose of this review is to identify and synthesize the available literature on microRNAs as biomarkers that could help manage patients with head and neck squamous cell cancer. A search in scientific databases was completed, including all relevant articles related to circulating microRNAs in head and neck squamous cell cancer published in English or Spanish. We focused on articles whose main findings were related to their usefulness in diagnosis and prognosis. Conclusion: Knowledge of microRNAs opens the possibilities that these molecules offer in terms of monitoring cancer disease in a less-invasive, simple manner, allowing for serial sampling to assess the response to treatment and minimal residual disease. It is yet to be determined whether liquid biopsy will replace the traditional biopsy in the future but it represents a change in the paradigm of management of head and neck squamous cell cancer.

Design, Synthesis, and Biological Evaluation of 5-Formyl-pyrrolo[3,2-b]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors.

The FGF19-FGFR4 signaling pathway has been extensively studied as a promising target for the treatment of hepatocellular carcinoma (HCC). Several FGFR4-selective inhibitors have been developed, but none of them receives approval. Additionally, acquired resistance caused by FGFR4 gatekeeper mutations is emerging as a serious limitation for these targeted therapies. Herein, we report a novel series of 5-formyl-pyrrolo[3,2-b]pyridine derivatives as new reversible-covalent inhibitors targeting wild-type and gatekeeper mutant variants of FGFR4 kinase. The representative compound 10z exhibited single-digit nanomolar activity against wild-type FGFR4 and the FGFR4V550L/M mutant variants in biochemical and Ba/F3 cellular assays, while sparing FGFR1/2/3. Furthermore, 10z showed significant antiproliferative activity against Hep3B, JHH-7, and HuH-7 HCC cells with IC50 values of 37, 32, and 94 nM, respectively. MALDI-TOF-MS and X-ray protein crystallography studies were consistent with 10z acting as a reversible-covalent inhibitor of FGFR4, serving as a promising lead compound for further anticancer drug development.

Evolution of the Inhibitory and Non-Inhibitory ε, ζ, and IF1 Subunits of the F1FO-ATPase as Related to the Endosymbiotic Origin of Mitochondria.

The F1FO-ATP synthase nanomotor synthesizes >90% of the cellular ATP of almost all living beings by rotating in the "forward" direction, but it can also consume the same ATP pools by rotating in "reverse." To prevent futile F1FO-ATPase activity, several different inhibitory proteins or domains in bacteria (ε and ζ subunits), mitochondria (IF1), and chloroplasts (ε and γ disulfide) emerged to block the F1FO-ATPase activity selectively. In this study, we analyze how these F1FO-ATPase inhibitory proteins have evolved. The phylogeny of the α-proteobacterial ε showed that it diverged in its C-terminal side, thus losing both the inhibitory function and the ATP-binding/sensor motif that controls this inhibition. The losses of inhibitory function and the ATP-binding site correlate with an evolutionary divergence of non-inhibitory α-proteobacterial ε and mitochondrial δ subunits from inhibitory bacterial and chloroplastidic ε subunits. Here, we confirm the lack of inhibitory function of wild-type and C-terminal truncated ε subunits of P. denitrificans. Taken together, the data show that ζ evolved to replace ε as the primary inhibitor of the F1FO-ATPase of free-living α-proteobacteria. However, the ζ inhibitory function was also partially lost in some symbiotic α-proteobacteria and totally lost in some strictly parasitic α-proteobacteria such as the Rickettsiales order. Finally, we found that ζ and IF1 likely evolved independently via convergent evolution before and after the endosymbiotic origin mitochondria, respectively. This led us to propose the ε and ζ subunits as tracer genes of the pre-endosymbiont that evolved into the actual mitochondria.

Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.

Aberrant FGF19/FGFR4 signaling has been shown to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC) with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently being evaluated in the clinic. However, FGFR4 gatekeeper mutation induced acquired resistance remains an unmet clinical challenge for HCC treatment. Thus, a series of aminoindazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. One representative compound (7v) exhibited excellent potency against FGFR4, FGFR4V550L, and FGFR4V550M with nanomolar activity in both the biochemical and cellular assays while sparing FGFR1/2/3. While compound 7v demonstrated modest in vivo antitumor efficacy in nude mice bearing the Huh-7 xenograft model consistent with its unfavorable pharmacokinetic properties, it provides a promising new starting point for future drug discovery combating FGFR4 gatekeeper mediated resistance in HCC patients.

The place of scientific knowledge in the teaching of technical skills in initial nursing training: a descriptive qualitative study / Place des savoirs scientifiques dans l'enseignement des gestes techniques en formation infirmière initiale : une étude qualitative descriptive

Context: Universitarization and the nursing education reference system encourage the use of scientific knowledge and the integration of evidence into clinical practice. Students in initial training are trained in technical gestures. On what knowledge are they based? Objective: The main objective of this study is to identify the knowledge utilised by nurses and trainers to teach technical nursing procedures. Method: A descriptive qualitative study was carried out using semi-directed interviews with 16 participants. Results: The teaching of nursing skills is mainly based on local or authoritative knowledge. Trainers and nurses who display scientific knowledge update their practices and education more easily. As in health care services, the lack of knowledge and training in evidence-based medicine and the use databases, as well as the lack of English language skills, are the major obstacles to teaching technical procedures based on scientific knowledge. Discussion: The use of scientific data in the learning of technical procedures during initial training could legitimate the knowledge taught, develop the students’ critical thinking and encourage their autonomy in the face of protocol injunctions and service habits.

Contexte: L'universitarisation et le référentiel de la formation infirmière favorisent l'utilisation de savoirs scientifiques et l'intégration des données probantes dans la pratique clinique. Les étudiants en formation initiale sont formés aux gestes techniques. Sur quels savoirs se basent-ils ? Objectif: L'objectif principal de cette étude est d'identifier les savoirs mobilisés par les infirmiers et les formateurs pour enseigner les gestes techniques infirmiers. Méthode: Une étude qualitative descriptive a été menée à l'aide d'entretiens semi-dirigés auprès de 16 participants. Résultats: Les enseignements des gestes techniques se basent principalement sur des savoirs locaux ou issus de l'autorité. Les formateurs et les infirmières qui mobilisent les savoirs scientifiques réactualisent plus facilement leurs pratiques et leurs enseignements. Comme dans les services de soins, le manque de connaissance et de formation concernant les données probantes et l'utilisation des bases de données ainsi que la maîtrise de l'anglais sont les freins majeurs à l'enseignement des gestes techniques à partir de savoirs scientifiques. Discussion: La mobilisation de données scientifiques dans l'apprentissage des gestes techniques en formation initiale pourrait légitimer les savoirs enseignés, développer la pensée critique des étudiants, et favoriser leur autonomie face aux injonctions protocolaires et aux habitudes de service.

Antibiotic Resistance and Virulence Profiles of Klebsiella pneumoniae Strains Isolated From Different Clinical Sources.

Klebsiella pneumoniae is a Gram-negative bacterium capable of colonizing, invading, and causing infections in different anatomical sites of the human body. Its ability to evade the immune system, its increasing antimicrobial resistance and the emergence of hypervirulent pathotypes have become a major challenge in the medical field. In this study, 127 strains from different clinical sources (urine, respiratory tract or blood) were characterized for antimicrobial resistance, the presence of virulence factor genes, serum resistance, hypermucoviscosity and the ability to form biofilms. Specific characteristics of the uropathogenic strains were examined and compared with the other clinical groups. Differences were found between urine and the other groups of strains. Urine strains showed the highest antibiotic resistance (64.91%) compared to blood (63.64%) or respiratory strains (51.35%) as well as the highest extended-spectrum beta-lactamases (ESBL) production. These strains also showed statistically significant high resistance to fosfomycin (24.56%) compared to the other groups (p = 0.008). Regarding virulence, 84.21% of the urine strains presented the uge gene, showing a statistically significant difference (p = 0.03) compared to the other clinical sources, indicating a possible role of this gene in the development of urinary tract infection. In addition, 46% of biofilm-forming strains belonged to the urine sample group (p = 0.043). In conclusion, K. pneumoniae strains isolated from urine samples showed higher antimicrobial resistance, ESBL production, and biofilm-forming ability compared to those isolated from respiratory or blood samples. The rapid spread of clinical strains with these characteristics is of concern, and new therapeutic alternatives are essential to mitigate their harmful effects.

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients.

Lamivudine, also widely known as 3TC belongs to a family of nucleotide/nucleoside analogues of cytidine or cytosine that inhibits the Reverse Transcriptase (RT) of retroviruses such as HIV. Lamivudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection or for chronic Hepatitis B (HBV) virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. HBV reactivation in patients with HBV infections who receive anticancer chemotherapy can be a life-threatening complication during and after the completion of chemotherapy. Lamivudine is used, as well as other antiretrovirals, to prevent the reactivation of the Hepatitis B virus during and after chemotherapy. In addition, Lamivudine has been shown to sensitize cancer cells to chemotherapy. Lamivudine and other similar analogues also have direct positive effects in the prevention of cancer in hepatitis B or HIV positive patients, independently of chemotherapy or radiotherapy. Recently, it has been proposed that Lamivudine might be also repurposed against SARS-CoV-2 in the context of the COVID-19 pandemic. In this review we first examine recent reports on the re-usage of Lamivudine or 3TC against the SARS-CoV-2, and we present docking evidence carried out in silico suggesting that Lamivudine may bind and possibly work as an inhibitor of the SARS-CoV-2 RdRp RNA polymerase. We also evaluate and propose assessment of repurposing Lamivudine as anti-SARS-CoV-2 and anti-COVID-19 antiviral. Secondly, we summarize the published literature on the use of Lamivudine or (3TC) before or during chemotherapy to prevent reactivation of HBV, and examine reports of enhanced effectiveness of radiotherapy in combination with Lamivudine treatment against the cancerous cells or tissues. We show that the anti-cancer properties of Lamivudine are well established, whereas its putative anti-COVID effect is under investigation. The side effects of lamivudine and the appearance of resistance to 3TC are also discussed.

Impact of an intervention program with reinforcement on nursing students' stress and anxiety levels in their clinical practices.

BACKGROUND AND OBJECTIVE: Several interventions have resulted in effectively reducing stress and anxiety in nursing students, however the efficacy of these interventions has only been investigated in the short term. This study had to objectives 1) to determine the effect of an intervention program to manage stress and anxiety in nursing students during clinical practices with two phases, phase I composed by cognitive behavioral therapy and progressive muscle relaxation and phase II or reinforcement phase with progressive muscle relaxation and 2) to determine the effect of phase I of the intervention program to manage stress and anxiety in nursing students during clinical practices. DESIGN: An experimental, analytical, longitudinal and prospective study. METHODS: Data were collected between April 2018 to June 2019 with 4 measurements of KEZKAK questionnaire and State-Trait Anxiety Inventory. An intervention program composed of cognitive behavioral therapy and progressive muscle relaxation was developed. The intervention program was divided in two phases, phase I and phase II or reinforcement phase. Fifty-nine nursing students from a Spanish university participated. A control group (n = 29), an intervention group one (n = 15) that received phase I and an intervention group 2 (n = 15) that received phase I and phase II or reinforcement phase were formed. RESULTS: After completing phase I, significant differences were found in the state of stress and anxiety between nursing students who received this phase and those who did not and after 3 months they continued to show differences. After phase II or reinforcement phase, the inter-groups did not present significant differences between them. The inter-group comparison of the stress and anxiety values at the end of the intervention program minus the initial values indicated that the CG presented significant differences with both intervention groups in the total of the KEZKAK and also with the IG1 in factors 3 (p = 0.030) and 4 (p = 0.027) and with the IG2 in factors 1 (p = 0.006) and 7 (p = 0.018). On the other hand, no differences were found between both intervention groups, IG1-IG2, in levels of stress and anxiety (p > 0.05) CONCLUSIONS: The intervention program contributes to provide evidence on the effectiveness of cognitive behavioral therapy and progressive muscle relaxation for stress and anxiety management in nursing students during clinical practices. This study suggests that we should continue in this line of research to improve the available evidence.

Investigation of Covalent Warheads in the Design of 2-Aminopyrimidine-based FGFR4 Inhibitors.

Covalent kinase inhibitors are rapidly emerging as a class of therapeutics with clinical benefits. Herein we report a series of selective 2-aminopyrimidine-based fibroblast growth factor receptor 4 (FGFR4) inhibitors exploring different types of cysteine-targeting warheads. The structure-activity relationship study revealed that the chemically tuned warheads α-fluoro acrylamide, vinylsulfonamide, and acetaldehyde amine were suitable as covalent warheads for the design of selective FGFR4 inhibitors. Compounds 6a, 6h, and 6i selectively suppressed FGFR4 enzymatic activity with IC50 values of 53 ± 18, 45 ± 11, and 16 ± 4 nM, respectively, while sparing FGFR1/2/3. X-ray crystal structure and MALDI-TOF studies demonstrated that compound 6h bearing the α-fluoro acrylamide binds to FGFR4 with an irreversible binding mode, whereas compound 6i with an acetaldehyde amine binds to FGFR4 with a reversible covalent mode. 6h and 6i might provide some fundamental structural information for the rational design of new selective FGFR4 inhibitors.

Estrés y ansiedad al comienzo de las prácticas clínicas en estudiantes de Enfermería / Stress and anxiety in Nursing students at the start of their clinical practice

OBJETIVO: describir la percepción del estrés, los factores potencialmente estresantes y la ansiedad de los estudiantes de la Facultad de Enfermería de Soria al comienzo de sus prácticas clínicas, y determinar la influencia de factores sociodemográficos, académicos, situación familiar y estilos de vida sobre la percepción de estos. MÉTODO: estudio descriptivo transversal con 61 estudiantes de la Facultad de Enfermería de Soria (curso). Se estudiaron variables sociodemográficas (sexo, edad, actividad laboral), académicas (año de ingreso, cursar solo Prácticum I, beca, otros estudios), de situación familiar (residencia, pareja, personas a cargo, familiar sanitario, pérdida de familiar), estilos de vida (fumador/a, bebedor/a, ejercicio físico), estrés y factores potencialmente estresores (Cuestionario KEZKAK -mín. 0 a máx. 3 puntos-) y ansiedad estado-rasgo (Cuestionario STAI -mín. 0 a máx. 60 puntos-). Se realizaron análisis descriptivo y bivariantes para las variables psicológicas. RESULTADOS: participaron 60 estudiantes (edad mediana (Me) = 21 años). La puntuación global de estrés presentó una mediana de 1,89 (RIQ = 0,48). Los factores percibidos como más estresantes fueron "falta de competencia" (Me = 2,09; RIQ = 0,43) e "impotencia e incertidumbre" (Me = 2,05; RIQ = 0,54). La ansiedad estado-rasgo presentó una mediana de 17 (IQR = 8) y 17,5 (IQR = 10), respectivamente. El nivel de estrés, los factores potencialmente estresantes y la ansiedad estado se asociaron con el sexo (p < 0,05). CONCLUSIONES: los estudiantes de Enfermería en sus primeras prácticas clínicas percibieron niveles de estrés moderadamente altos y una ansiedad moderada, siendo los principales estresores "falta de competencia" e "impotencia e incertidumbre". El sexo está altamente asociado con el estrés y la ansiedad, siendo mayor en las mujeres

OBJECTIVE: to describe the perception of stress, the potentially stressful factors, and the anxiety among students from the School of Nursing of Soria at the start of their clinical practice; and to determine the impact on their perception of sociodemographical and academic factors, their family situation and lifestyles. METHOD: a descriptive cross-sectional study with 61 students from the School of Nursing of Soria (course). The study included sociodemographical variables (gender, age, occupation), academic (year of admission, practicum I only, scholarship, other studies), family situation (place of residence, partner, dependent persons, health professional relatives, loss of relatives), lifestyles (smoking, drinking, physical exercise), stress and potential stressors (KEZKAK Questionnaire -min. 0 to max. 3 scores-) and State-Trait anxiety (STAI Questionnaire -min. 0 to max. 60 scores). Descriptive and bivariate analyses were conducted for the psychological variables. RESULTS: the study included 60 students (median age (Me= 21-year-old). The overall stress score presented a median score of 1.89 (IQR = 0.48). The factors perceived as more stressful were "lack of competence" (Me = 2.09; IQR = 0.43) and "impotence and uncertainty" (Me = 2.05; IQR = 0.54). The State-Trait anxiety presented a median score of 17 (IQR = 8) and 17.5 (IQR = 10), respectively. The level of stress, potential stressors and state anxiety were associated with gender (p< 0.05). CONCLUSIONS: nursing students in their first clinical practice perceived moderately high levels of stress and moderate anxiety; the main stressors were "lack of competence" and "anxiety and uncertainty". Gender is highly associated with stress and anxiety, and it is higher in women