SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells.

BACKGROUND: Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute and post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA COVID-19 vaccines. We investigated whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells. METHODS: In human umbilical vein endothelial cells (HUVEC) and monocytes, the components of NF-κB and the NLRP3 inflammasome system, as well as coagulation regulators, were assessed by qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence. RESULTS: S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1ß formation in both cell types. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor, that was mediated, at least in part, by IL-1ß. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Monocytes and HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches and gene silencing showed that TLR4 receptors mediated the effects of S protein in monocytes, but not in HUVEC. CONCLUSION: S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Interfering with the receptors or signaling pathways evoked by the S protein may help preventing immune and vascular complications driven by such an isolated viral element. Video Abstract.

Gold-Catalyzed Synthesis of Small Rings.

Three- and four-membered rings, widespread motifs in nature and medicinal chemistry, have fascinated chemists ever since their discovery. However, due to energetic considerations, small rings are often difficult to assemble. In this regard, homogeneous gold catalysis has emerged as a powerful tool to construct these highly strained carbocycles. This review aims to provide a comprehensive summary of all the major advances and discoveries made in the gold-catalyzed synthesis of cyclopropanes, cyclopropenes, cyclobutanes, cyclobutenes, and their corresponding heterocyclic or heterosubstituted analogs.

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer.

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted. Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CB2R. We show that HER2 physically interacts with CB2R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ9-tetrahydrocannabinol (THC) disrupts HER2-CB2R complexes by selectively binding to CB2R, which leads to (i) the inactivation of HER2 through disruption of HER2-HER2 homodimers, and (ii) the subsequent degradation of HER2 by the proteasome via the E3 ligase c-CBL. This in turn triggers antitumor responses in vitro and in vivo. Selective targeting of CB2R transmembrane region 5 mimicked THC effects. Together, these findings define HER2-CB2R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.

Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy.

HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR-mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2-amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2, termed miR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription of NOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR-mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes.

Traditional and complementary medicine in a nephrology department: practitioner knowledge and advice.

BACKGROUND: Knowledge of traditional and complementary medicine (TCM) and its use by patients are essential for patient safety. AIMS: To examine knowledge of TCM among practitioners in a nephrology unit and their advice to patients. METHODS: This was a descriptive, observational, cross-sectional study. Sociodemographic data were collected and an ad hoc closed response survey was used. FINDINGS: This study included 62 practitioners, of whom: 32.26% had been trained in TCM, with no significant differences between professional groups; 41.93% used TCM and 67.74% recommended TCM to patients, with no significant difference between personal use and training received. The majority (62.90%) approved of TCM being included in clinical practice, 77.42% were in favour of it being included in formal health teaching programmes, 27.42% said patients had requested information on TCM and 50% knew it could interact with conventional treatment. CONCLUSION: Although the majority of practitioners had not been trained in TCM, they were interested in including such treatments in clinical practice. They recommended TCM to patients, but neither training nor personal experience were significant factors in relation to these recommendations. Training in TCM is required to ensure advice is safe.

Gold(I)-Catalyzed Intramolecular C(sp3 )-H Insertion by Decarbenation of Cycloheptatrienes.

A novel synthesis of indanes and dihydronaphtalenes based on the intramolecular insertion into C(sp3 )-H bonds of gold(I) carbenes generated by retro-Buchner reaction (decarbenation) has been developed. Deuterium-labeling and kinetic isotope effect experiments, DFT calculations, and generation of the proposed carbene intermediate from a well-characterized gold(I) carbenoid support the involvement of a three-center concerted mechanism for the C(sp3 )-H functionalization process.

Patient preference for oral chemotherapy in the treatment of metastatic breast and lung cancer.

OBJECTIVES: Although new therapies against metastatic cancer have been developed in recent decades, chemotherapy is still an important treatment option. Prolonged treatment and side-effects are often discouraging for patients, and in many cases, therapy is only palliative, not curative. This study explores patient preference for oral or intravenous (IV) chemotherapy in the treatment of metastatic breast or lung cancer. METHODS: It is a descriptive, open label, multicentre, nation-wide study, in which a 16-item questionnaire consisting of single-choice questions scored on a 5-point Likert scale was administered to patients in a single visit, and another 11-item questionnaire was self-administered by the patient's oncologist. RESULTS: A total of 131 breast and lung cancer specialists at 64 hospitals enrolled 412 patients (lung cancer = 161; breast cancer = 251). To be eligible, patients must have already received IV therapy and at least 2 cycles of oral chemotherapy. Most (77%) patients expressed preference for oral therapy. Most considered their daily life was less disrupted with tablets (70.4%), had no trouble swallowing them (86.9%), and were not concerned about forgetting to take them (56.8%). Half (56.3%) were worried about problems related to drug infusion with IV therapy, 61.7% were concerned about nurses failing to find a suitable vein, and 63.1% were dissatisfied with hospital waiting times. A uniform response was obtained from both samples of patients. CONCLUSION: Convenience, ease of administration, fewer side effects and better quality of life tilt the balance towards oral drug administration.

Dental malocclusions are not just about small and weak bones: assessing the morphology of the mandible with cross-section analysis and geometric morphometrics.

OBJECTIVES: Dental malocclusions in modern populations would be the result of small and weak jaws developing under low masticatory loads. We assess the validity of this by characterising the external and internal morphology of mandibles affected by class II and III malocclusions and comparing them with those from individuals with different masticatory load patterns. MATERIALS AND METHODS: CTs from up to 118 individuals exerting intensive, medium and low masticatory loads with harmonic occlusion, and from class II and III individuals, were used to compare their external shape using geometric morphometrics, as well as their internal amount and distribution of cortical bone. RESULTS: The low-load groups (harmonic, class II and III occlusion) are externally more gracile than the intense and medium load groups. But more relevant in shape variation is a marked allometric pattern, which differentiates class II (small) and III (large) mandibles. Despite gracility, the relative amount of cortical bone in the low-load groups is larger than in the remaining groups. CONCLUSIONS: There is no evidence that the modern mandible, including class II and III individuals, is intrinsically small and weak. Instead, there is a rather large degree of morphological variation, which could be linked to a lack of constraints derived from low masticatory loads. Thus, the effect of other factors such as genetics, but also basal metabolism, should be looked in more depth. CLINICAL RELEVANCE: Dental malocclusions are a common disorder whose aetiology has not been unravelled, and several to be considered in the prevention and therapy of malocclusion.

A Platform Integrating Acquisition, Reconstruction, Visualization, and Manipulator Control Modules for MRI-Guided Interventions.

This work presents a platform that integrates a customized MRI data acquisition scheme with reconstruction and three-dimensional (3D) visualization modules along with a module for controlling an MRI-compatible robotic device to facilitate the performance of robot-assisted, MRI-guided interventional procedures. Using dynamically-acquired MRI data, the computational framework of the platform generates and updates a 3D model representing the area of the procedure (AoP). To image structures of interest in the AoP that do not reside inside the same or parallel slices, the MRI acquisition scheme was modified to collect a multi-slice set of intraoblique to each other slices; which are termed composing slices. Moreover, this approach interleaves the collection of the composing slices so the same k-space segments of all slices are collected during similar time instances. This time matching of the k-space segments results in spatial matching of the imaged objects in the individual composing slices. The composing slices were used to generate and update the 3D model of the AoP. The MRI acquisition scheme was evaluated with computer simulations and experimental studies. Computer simulations demonstrated that k-space segmentation and time-matched interleaved acquisition of these segments provide spatial matching of the structures imaged with composing slices. Experimental studies used the platform to image the maneuvering of an MRI-compatible manipulator that carried tubing filled with MRI contrast agent. In vivo experimental studies to image the abdomen and contrast enhanced heart on free-breathing subjects without cardiac triggering demonstrated spatial matching of imaged anatomies in the composing planes. The described interventional MRI framework could assist in performing real-time MRI-guided interventions.

Direct Observation of Aryl Gold(I) Carbenes that Undergo Cyclopropanation, C-H Insertion, and Dimerization Reactions.

Mesityl gold(I) carbenes lacking heteroatom stabilization or shielding ancillary ligands have been generated and spectroscopically characterized from chloro(mesityl)methylgold(I) carbenoids bearing JohnPhos-type ligands by chloride abstraction with GaCl3 . The aryl carbenes react with PPh3 and alkenes to give stable phosphonium ylides and cyclopropanes, respectively. Oxidation with pyridine N-oxide and intermolecular C-H insertion to cyclohexane have also been observed. In the absence of nucleophiles, a bimolecular reaction, similar to that observed for other metal carbenes, leads to a symmetrical alkene.

Using Creative Activities to Improve Treatment Perceptions of Patients on Hemodialysis.

Hemodialysis (HD) has a significant impact on health-related quality of life (HRQoL). We performed an observational study to assess the mental and physical status of 41 patients on chronic HD treatment. We planned and launched a program of recreational and therapeutic intradialysis activities to reduce patients' boredom due to inactivity. Patients' mental and physical status was reassessed at 12 months. Our initial attempt to introduce these recreational activities as intradialysis therapy has been rated positively by all patients. After one year, anxiety decreased (without statistical significance) and willingness to participate in activities increased from 50.00% to 85.71% (p=0.019). No improvement was observed on the remaining studied variables. This preliminary initiative is promising. We plan to maintain these successful therapies and include others to help consolidate this program.

Enantioselective Synthesis of Cyclobutenes by Intermolecular [2+2] Cycloaddition with Non-C2 Symmetric Digold Catalysts.

The enantioselective intermolecular gold(I)-catalyzed [2+2] cycloaddition of terminal alkynes and alkenes has been achieved using non-C2-chiral Josiphos digold(I) complexes as catalysts, by the formation of the monocationic complex. This new approach has been applied to the enantioselective total synthesis of rumphellaone A.

Gold(I) Carbenoids: On-Demand Access to Gold(I) Carbenes in Solution.

Chloromethylgold(I) complexes of phosphine, phosphite, and N-heterocyclic carbene ligands are easily synthesized by reaction of trimethylsilyldiazomethane with the corresponding gold chloride precursors. Activation of these gold(I) carbenoids with a variety of chloride scavengers promotes reactivity typical of metallocarbenes in solution, namely homocoupling to ethylene, olefin cyclopropanation, and Buchner ring expansion of benzene.

SARS-CoV-2 S Protein Reduces Cytoprotective Defenses and Promotes Human Endothelial Cell Senescence.

Premature vascular aging and endothelial cell senescence are major risk factors for cardiovascular diseases and atherothrombotic disturbances, which are main complications of both acute and long COVID-19. The S protein of SARS-CoV2, which acts as the receptor binding protein for the viral infection, is able to induce endothelial cells inflammation and it has been found as an isolated element in the circulation and in human tissues reservoirs months after infection. Here, we investigated whether the S protein is able to directly induce endothelial cell senescence and deciphered some of the mechanisms involved. In primary cultures of human umbilical vein endothelial cells (HUVEC), SARS-CoV-2 S protein enhanced in a concentration-dependent manner the cellular content of senescence and DNA damage response markers (senescence-associated-ß galactosidase, γH2AX), as well as growth-arrest effectors (p53, p21, p16). In parallel, the S protein reduced the availability of cytoprotective proteins, such as the anti-aging protein klotho, Nrf2 or heme oxygenase-1, and caused functional harm by impairing ex vivo endothelial-dependent vasorelaxation in murine microvessels. These effects were prevented by the pharmacological inhibition of the NLRP3 inflammasome with MCC950. Furthermore, the supplementation with either recombinant klotho or angiotensin-(1-7), equally protected against the pro-senescence, pro-inflammatory and pro-oxidant action of the S protein. Globally, this study proposes novel mechanisms of disease in the context of COVID-19 and its vascular sequelae and provides pharmacological clues in order to prevent such complications.

Reasons for choosing and completing nursing studies among incoming and outgoing students: A qualitative study.

BACKGROUND: The shortage of nurses is causing instability and crisis in health systems and will continue. The WHO reinforced the importance of recruiting and retaining new students. Authors of various studies recommend the need to identify and understand the reasons for pursuing a nursing degree. OBJECTIVES: To determine students' preference for nursing studies and to identify the reasons for choosing, continuing, and completing a bachelor's degree in nursing. DESIGN: Qualitative, descriptive study. PARTICIPANTS: 106 nursing students at the University of Huelva (Spain) participated during their first year (2017) and final year (2021) of the nursing degree. METHODS: This study was conducted with the same group of students in two phases. Data were collected in writing in a document with open-ended questions and no maximum wordcount. The responses were analysed using content analysis. RESULTS: A total of 76.4 % of participants stated that nursing had been their first choice. The main reasons for choosing a nursing degree were associated with fulfilment, and a desire to help others and interact with them. The reasons for completing their studies were primarily related to an interest in providing professional care, showing a deeper and more concrete knowledge of nursing care work. CONCLUSION: For most participants, nursing was their first choice due to a strong intrinsic motivation related to self-satisfaction in helping others. The reasons for completing this degree had extrinsic motivations linked to nursing activity in hospital. Areas such as management, teaching, or research were not interesting to our students. Knowing the causes of this lack of interest could help us attract them to these areas.

Barriers and Facilitators of Communication in the Medication Reconciliation Process during Hospital Discharge: Primary Healthcare Professionals' Perspectives.

The WHO established that medication errors are the most common and preventable errors and represent an expenditure of 42 billion U.S. dollars annually. The risk of medication errors increases in transitions between levels of care, mainly from hospital care to primary healthcare after hospital discharge. In this context, communication is a key element in the safety of the medication reconciliation process. The aim of this paper was to describe the barriers to, and facilitators of, effective communication during the medication reconciliation process at hospital discharge in people over 65 years of age, from the perspective of primary healthcare professionals. A qualitative descriptive study was designed, and in-depth interviews were conducted with 21 individuals, of whom 13 were nurses and 8 were physicians. This study was carried out with healthcare professionals belonging to primary healthcare centres in Huelva (Spain). Following content analysis of the discourses we identified 19 categories, grouped into three areas: interlevel communication, communication between primary healthcare professionals, and communication between healthcare professionals and patients/caregivers. The barriers found mainly relate to the adequacy and use of technological tools, time available, workload and the level of collaboration of patients/caregivers. Facilitating elements for communication in medication reconciliation included technologies, such as computerized medical history, protocolization of clinical sessions, the presence of case management nurse and interdisciplinary teamwork.

A Prospective Study of Longitudinal Risks of Cognitive Deficit for People Undergoing Glioblastoma Surgery Using a Tablet Computer Cognition Testing Battery: Towards Personalized Understanding of Risks to Cognitive Function.

Glioblastoma and the surgery to remove it pose high risks to the cognitive function of patients. Little reliable data exist about these risks, especially postoperatively before radiotherapy. We hypothesized that cognitive deficit risks detected before surgery will be exacerbated by surgery in patients with glioblastoma undergoing maximal treatment regimens. We used longitudinal electronic cognitive testing perioperatively to perform a prospective, longitudinal, observational study of 49 participants with glioblastoma undergoing surgery. Before surgery (A1), the participant risk of deficit in 5/6 cognitive domains was increased compared to normative data. Of these, the risks to Attention (OR = 31.19), Memory (OR = 97.38), and Perception (OR = 213.75) were markedly increased. These risks significantly increased in the early period after surgery (A2) when patients were discharged home or seen in the clinic to discuss histology results. For participants tested at 4-6 weeks after surgery (A3) before starting radiotherapy, there was evidence of risk reduction towards A1. The observed risks of cognitive deficit were independent of patient-specific, tumour-specific, and surgery-specific co-variates. These results reveal a timeframe of natural recovery in the first 4-6 weeks after surgery based on personalized deficit profiles for each participant. Future research in this period could investigate personalized rehabilitation tools to aid the recovery process found.

Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation.

PURPOSE: Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30%-50% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA. EXPERIMENTAL DESIGN: We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA_PDX). The CCA_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues. RESULTS: This collection of CCA_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD. CONCLUSIONS: Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.

Current Stereotypes Associated with Nursing and Nursing Professionals: An Integrative Review.

Nursing and nursing professionals are associated with social stereotypes, which may hinder the profession's development and future prospects as a scientific discipline. The aim of this study was to identify and describe the stereotypes associated with the nursing profession-students and professionals. Therefore, we carried out an integrative review. The search was conducted using PubMed, WOS, and CINAHL databases, and its search strategy was based on a combination of standardised keywords and natural vocabulary, with a temporal limit between 2016 and 2021. The data extraction and analysis was based on the conceptual framework developed by Whittemore and Knafl. Twenty-seven studies were included in the review, and their results were classified and coded. Two categories emerged, namely, stereotypes relating to the professionals' gender and stereotypes relating to the profession itself. We concluded that the nursing profession is viewed as female with low skills, social status, salary, academic level and entry requirements, and with little autonomy. Male nurses' professional competencies and masculinity are questioned, while the work carried out by female nurses is viewed as unprofessional. To reduce these stereotypes and bias we must present the nursing profession as a scientific discipline, developed by both men and women. Specific channels for this awareness-raising work include interventions from universities and the media, and participation in health policies.