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Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load-were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.

Introduction: Coagulopathy associated with isolated traumatic brain injury (C-iTBI) is a frequent complication associated with poor outcomes, primarily due to its role in the development or progression of haemorrhagic brain lesions. The independent risk factors for its onset are age, severity of traumatic brain injury (TBI), volume of fluids administered during resuscitation, and pre-injury use of antithrombotic drugs. Although the pathophysiology of C-iTBI has not been fully elucidated, two distinct stages have been identified: an initial hypocoagulable phase that begins within the first 24 h, dominated by platelet dysfunction and hyperfibrinolysis, followed by a hypercoagulable state that generally starts 72 h after the trauma. The aim of this study was to design an acronym as a mnemonic device to provide clinicians with an auxiliary tool in the treatment of this complication., Methods: A narrative analysis was performed in which intensive care physicians were asked to list the key factors related to C-iTBI. The initial sample was comprised of 33 respondents. Respondents who were not physicians, not currently working in or with experience in coagulopathy were excluded. Interviews were conducted for a month until the sample was saturated. Each participant was asked a single question: Can you identify a factor associated with coagulopathy in patients with TBI? Factors identified by respondents were then submitted to a quality check based on published studies and proven evidence. Because all the factors identified had strong support in the literature, none was eliminated. An acronym was then developed to create the mnemonic device., Results and Conclusion: Eleven factors were identified: cerebral computed tomography, oral anticoagulant & antiplatelet use, arterial blood pressure (Hypotension), goal-directed haemostatic therapy, use fluids cautiously, low calcium levels, anaemia-transfusion, temperature, international normalised ratio (INR), oral antithrombotic reversal, normal acid-base status, forming the acronym "Coagulation." This acronym is a simple mnemonic device, easy to apply for anyone facing the challenge of treating patients of moderate or severe TBI on a daily basis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Quintana-Diaz, Anania, Juárez-Vela, Echaniz-Serrano, Tejada-Garrido, Sanchez-Conde, Nanwani-Nanwani, Serrano-Lázaro, Marcos-Neira, Gero-Escapa, García-Criado and Godoy.)

Background: The intensity of the thromboprophylaxis needed as a potential factor for preventing inpatient mortality due to coronavirus disease-19 (COVID-19) remains unclear., Objective: To explore the association between anticoagulation intensity and COVID-19 survival., Design and Setting: Retrospective observational study in a tertiary-level hospital in Spain., Methods: Low-molecular-weight heparin (LMWH) status was ascertained based on prescription at admission. To control for immortal time bias, anticoagulant use was analyzed as a time-dependent variable., Results: 690 patients were included (median age, 72 years). LMWH was administered to 615 patients, starting from hospital admission (89.1%). 410 (66.7%) received prophylactic-dose LMWH; 120 (19.5%), therapeutic-dose LMWH; and another 85 (13.8%) who presented respiratory failure, high D-dimer levels (> 3 mg/l) and non-worsening of inflammation markers received prophylaxis of intermediate-dose LMWH. The overall inpatient-mortality rate was 38.5%. The anticoagulant nonuser group presented higher mortality risk than each of the following groups: any LMWH users (HR 2.1; 95% CI: 1.40-3.15); the prophylactic-dose heparin group (HR 2.39; 95% CI, 1.57-3.64); and the users of heparin dose according to biomarkers (HR 6.52; 95% CI, 2.95-14.41). 3.4% of the patients experienced major hemorrhage. 2.8% of the patients developed an episode of thromboembolism., Conclusions: This observational study showed that LMWH administered at the time of admission was associated with lower mortality among unselected adult COVID-19 inpatients. The magnitude of the benefit may have been greatest for the intermediate-dose subgroup. Randomized controlled trials to assess the benefit of heparin within different therapeutic regimes for COVID-19 patients are required.

Aims: To determine the prognostic usefulness of the National Early Warning Score-2 (NEWS2) and quick Sepsis-related Organ Failure Assessment (qSOFA) scores, in isolation and combined with capillary lactate (CL), using the new NEWS2-L and qSOFA-L scores to predict the 30-day mortality risk., Methods: Prospective, multicentre and observational study in patients across four EDs. We collected sets of vital signs and CL and subsequently calculated NEWS2, qSOFA, NEWS2-L and qSOFA-L scores when patients arrived at the ED. The main outcome measure was all-cause mortality 30 days from the index event., Results: A total of 941 patients were included. Thirty-six patients (3.8%) died within 30 days of the index event. A high CL level has not been linked to a higher mortality. The NEWS2 presented AUROC of 0.72 (95% CI: 0.62-0.81), qSOFA of 0.66 (95% CI: 0.56-0.77) (P < .001 in both cases) and CL 0.55 (95% CI: 0.42-0.65; P = .229) to predict 30-day mortality. The addition of CL to the scores analysed does not improve the results of the scores used in isolation., Conclusion: NEWS2 and qSOFA scores are a very useful tool for assessing the status of patients who come to the ED in general for all types of patients in triage categories II and III and for detecting the 30-day mortality risk. CL determined systematically in the ED does not seem to provide information on the prognosis of the patients., (© 2020 John Wiley & Sons Ltd.)

Background: Crimean-Congo haemorrhagic fever (CCHF) is a widespread tick-borne viral disease caused by the Crimean-Congo haemorrhagic fever virus (CCHFV). CCHFV has been implicated in severe viral haemorrhagic fever outbreaks. During the summer of 2016, the first two cases with genotype III (Africa 3) were reported in Spain. The first objective of our study was to determine the presence of CCHFV among patients with febrile illness during the spring and summer periods in 2017 and 2018. Finally, we perform a phylogenetic analysis to determine the genotype of the virus., Methodology: We prospectively evaluated patients aged 18 years and older who came to the emergency department at the Salamanca's University Hospital (HUS) with fever. Specific IgM and IgG antibodies against CCHFV by ELISA and one immunofluorescence assay against two different proteins (nucleoprotein and glycoprotein C) was done. Moreover, molecular detection by Real Time PCR was performed in all collected samples. A phylogenetic analysis was carried out to genetically characterize CCHFV detected in this study., Principal Findings: A total of 133 patients were selected. The mean age was 67.63 years and 60.9% were male. One-third of the patients presented an acute undifferentiated febrile illness. Three patients had anti-CCHFV IgG antibodies, suggesting a previous infection. One patient had anti-CCHFV IgM antibodies and a confirmatory RT-PCR. Phylogenetic analysis indicated that the virus corresponds to the European genotype V. This patient came to the emergency department at HUS in August 2018 presenting an acute febrile syndrome with thrombopenia and liver impairment., Conclusions: We describe a new circulation of European genotype V CCHFV in Spain. Moreover, this study suggests that CCHFV is an identifiable cause of febrile illness of unknown origin in Spain. Thus, CCHF could be suspected in patients with fever, liver damage, and/or haemorrhagic disorders, particularly in people with risk activities who present in the spring or summer., Competing Interests: The authors have declared that no competing interests exist.

SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2 + /ERBB2 + breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2 + tumor behavior, Snai2 -deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2 + /ERBB2 + breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2 + /ERBB2 + tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2 + breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2 + /ERBB2 + breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis. SIGNIFICANCE: Stromal SNAI2 expression enhances the tumorigenicity of luminal B HER2 + breast cancers and can identify a subset of patients with poor prognosis, making SNAI2 a potential therapeutic target for this disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5216/F1.large.jpg., (©2020 American Association for Cancer Research.)

Background: An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels., Results: Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease., Conclusions: Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.

Background: Reactive oxygen species (ROS) have been shown to be involved in the reduction of glomerular filtration rate observed after gentamicin (Genta) treatment in vivo, a phenomenon directly related with mesangial cell (MC) contraction. Our previous study reported that Genta induces concentration-dependent MC contraction and proliferation in vitro., Methods: To study the possible mediation of ROS in the effect of Genta, ROS production was measured in primary cultures of rat MC stimulated with Genta (10-5 mol/L). In addition, the MC response to Genta in the presence of the ROS scavengers superoxide dismutase (SOD) and catalase (CAT) was studied. MC activation and O2- production were studied in the presence of an inhibitor of the NADP(H) oxidase, diphenylene iodinium (DPI), and in the presence of L-NAME, an inhibitor of nitric oxide synthases (NOS). Finally, the effects of Genta on SOD activity and mRNA expression were examined., Results: Genta (10-5 mol/L) induced an increase in O2- production and SOD activity that was neither accompanied by an elevation in cytosolic Cu/Zn-SOD mRNA expression nor by H2O2 accumulation. Genta induced MC contraction and proliferation that were inhibited by SOD plus CAT. Both the extracellular and intracellular ROS donor systems, xantine+xantine oxidase (X+XO) and dimethoxinaphtoquinone (DMNQ), respectively, also stimulated MC contraction and proliferation. Genta-induced MC activation and O2- production were inhibited by DPI. Genta-induced O2- production was inhibited by L-NAME. Furthermore, Genta did not induce detectable changes in membrane fluidity and lipid peroxidation., Conclusions: These results strongly suggest that an oxidative-mediated pathway exists in Genta-induced MC activation. A portion of the production of O2- may be due to NADP(H) oxidase and NOS activation. The amount of ROS produced, rather than having a toxic effect, might play a role as a mediator of Genta-induced MC activation

To assess the effect on tracheal graft preservation of perfusion of donor tissue with a Collins solution before extraction and immunosuppression of the recipient. An experimental study was performed in 36 albino rabbits with revascularized heterotopic cervical reconstruction of the trachea with omentum. The animals were distributed in four groups. Groups I (n = 9) and III (n = 9) were transplanted with non perfused donor tissue. Animals in groups II (n = 9) and IV (n = 9) received grafts perfused with Collins solution. Immunosuppression with steroids and cyclosporin was continued for 21 days in groups III and IV. In a mid portion of the trachea viewed under optical microscope, the degree of inflammation or circumferential necrosis was assessed on a scale of 0 to 9 by adding the scores for mucosa, submucosa and cartilage. The mean score for tracheal lesion was lower in group IV, with a likelihood of random difference of less than 5%. Perfusion of peritracheal tissues with Collins solution in the donor, in addition to immunosuppression decreases the extent of tissue damage in the tracheal graft.