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To better describe the genetic diversity of hantaviruses associated with human illness in South America, we screened blood samples from febrile patients in Chapare Province in central Bolivia during 2008-2009 for recent hantavirus infection. Hantavirus RNA was detected in 3 patients, including 1 who died. Partial RNA sequences of small and medium segments from the 3 patients were most closely related to Andes virus lineages but distinct (<90% nt identity) from reported strains. A survey for IgG against hantaviruses among residents of Chapare Province indicated that 12.2% of the population had past exposure to >1 hantaviruses; the highest prevalence was among agricultural workers. Because of the high level of human exposure to hantavirus strains and the severity of resulting disease, additional studies are warranted to determine the reservoirs, ecologic range, and public health effect of this novel strain of hantavirus. [ABSTRACT FROM AUTHOR]

Background: We evaluated associations between human immunodeficiency virus (HIV) infection, herpes simplex virus type 2 (HSV-2) infection, and syphilis among men who have sex with men (MSM) in Peru. Methods: A surveillance survey of 3280 MSM was conducted; sexual behavior was assessed with a structured computer-assisted self-interview, and serum antibody testing was performed for HIV, HSV-2, and Treponema pallidum. Results: HIV, HSV-2, and syphilis seroprevalences of 13.9%, 46.3%, and 13.4% were detected, respectively. HSV-2 seroprevalence was twice as high in HIV-infected subjects (80.5%) than it was in HIV-uninfected subjects (40.8%) (P < .01), and HSV-2 seropositivity (adjusted odds ratio [AOR], 5.66) was found to be strongly associated with HIV infection. In addition, homosexual self-definition (AOR, 3.12), exchange of sex for money (AOR, 1.61), unprotected sex (no condom) (AOR, 2.81), history of sex work (AOR, 1.89), oral receptive sex (AOR, 1.43), and cocaine use before/during sex (AOR, 2.53) within the preceding 6 months, as well as such sexually transmitted infections (STIs) and STI syndromes as proctitis (AOR, 2.80), genital ulcer disease (GUD) (AOR, 2.06), prior syphilis (AOR, 2.64), genital warts (AOR, 1.70), and self-reported STIs within the preceding 6 months (AOR, 1.61), were also found to be significant predictors of HIV infection. Conclusions: We found a strong association between HSV-2 seropositivity and HIV infection. Intervention measures against GUD due to HSV-2 infection and syphilis, such as routine testing, early detection, HSV-2 suppressive treatment, and condom distribution, need to be enhanced as part of STI prevention strategies at a national level to effectively reduce HIV infection among MSM in Peru. [ABSTRACT FROM AUTHOR]

After a human rabies outbreak in southeastern Peru, we collected bats to estimate the prevalence of rabies in various species. Among 165 bats from 6 genera and 10 species, 10.3% were antibody positive; antibody prevalence was similar in vampire and nonvampire bats. Thus, nonvampire bats may also be a source for human rabies in Peru. [ABSTRACT FROM AUTHOR]

The present study concerns the synthesis of zeolites from Neogene sedimentary and pyroclastic rocks exposed around the Sochagota Lake, Paipa (Boyacá). Two synthesis methods were used: conventional hydrothermal treatment and alkaline fusion followed by hydrothermal reaction. Both raw materials and synthesised zeolytic products were characterised by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). Several zeolytic phases were synthesised, including faujasite (FAU), phillipsite(PHI) and sodalite (SOD). The results showed that the alkaline fusion approach was more efficient regarding hydrothermal conversion of the raw materials than conventional hydrothermal treatment, taking into accountthat zeolytic products having a higher degree of crystallinity and few impurities were obtained in this way. This study was aimed at applying experimental mineralogy to a laboratory simulation of the geological conditions in which zeolites can occur as the basis for defining criteria for exploring natural zeolites in Colombia, with prospects for the profitable exploitation of these mineral resources in different parts of Colombia

Con ayuda de la teoría de los costos de transacción, este estudio evalúa la manera como los hospitales de tercer nivel de Bogotá seleccionan las formas de contratación con las empresas promotoras de salud. Para la prueba empírica se usan los aportes teóricos de Williamson. Las variables independientes se especifican mediante escalas Likert y las hipótesis se prueban con el método estocástico de análisis de aceptabilidad (SMAA) y el análisis discriminante múltiple (ADM). El resultado principal es que las empresas promotoras de salud y los hospitales de tercer nivel en Bogotá buscan reducir los costos de producción mientras que los costos de transacción no son relevantes en la decisión.

Entrevista a Guillermo Ulriksen Becker sobre el Plan Constructivo La Serena – Coquimbo, en 1952./ Interview with Gulliermo B. Ulriksen on the Development Plan of La Serena/Coquimbo (Chile), in 1952.

Cancer is the second leading cause of death worldwide. >90 % of cancer-related deaths are due to metastasis, a process that depends on the ability of cancer cells to leave the primary tumor, migrate, and colonize different tissues. Inositol 1,4,5-trisphosphate receptor (IP 3 R)-mediated Ca 2+ signaling plays an essential role in maintaining the homeostasis of cancer cells and the sustained proliferation. Desmethylxestospongin B (dmXeB) is a specific inhibitor of the IP 3 R that selectively arrests cell proliferation and promotes cancer cell death at high concentrations. However, whether migration, invasion and metastasis can be affected by this drug is unknown. Here, by using the highly metastatic triple negative breast cancer (TNBC) cell line MDA-MB-231, we demonstrate that a prolonged inhibition of IP 3 R-mediated Ca 2+ signals with dmXeB significantly reduces cell migration and invasion in vitro and metastasis in vivo. We found that this phenomenon was independent of the bioenergetic control of IP 3 R over the mitochondria and AMPK activation. Furthermore, employing a tandem LC3-GFP-mcherry assay, we found that prolonged inhibition of IP 3 R with dmXeB leads to diminished autophagic flux. This reduction can be attributed to impaired lysosomal acidification, as evidenced by assessments using DQ-BSA and pHrodo. Since cell migration requires appropriate assembly and disassembly of focal adhesions, along with the internalization and recycling of integrins via autophagy, we explored the dependency of integrin recycling from autophagosomes, finding that IP 3 R inhibition with dmXeB impaired the recycling of β1-integrins, which accumulated within autophagosomes. Our findings reveal an unexpected effect of IP 3 R inhibition with dmXeB in cancer cells that could represent a novel therapeutic strategy for the treatment of cancer metastasis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Armen Zakarian and J. Cesar Cardenas hold a patent on the synthesis of dmXeB., (Copyright © 2024. Published by Elsevier B.V.)

Tumor hypoxia has been associated with cancer progression, angiogenesis, and metastasis via modifications in the release and cargo composition of extracellular vesicles secreted by tumor cells. Indeed, hypoxic extracellular vesicles are known to trigger a variety of angiogenic responses via different mechanisms. We recently showed that hypoxia promotes endosomal signaling in tumor cells via HIF-1α-dependent induction of the guanine exchange factor ALS2, which activates Rab5, leading to downstream events involved in cell migration and invasion. Since Rab5-dependent signaling is required for endothelial cell migration and angiogenesis, we explored the possibility that hypoxia promotes the release of small extracellular vesicles containing ALS2, which in turn activate Rab5 in recipient endothelial cells leading to pro-angiogenic properties. In doing so, we found that hypoxia promoted ALS2 expression and incorporation as cargo within small extracellular vesicles, leading to subsequent transfer to recipient endothelial cells and promoting cell migration, tube formation, and downstream Rab5 activation. Consequently, ALS2-containing small extracellular vesicles increased early endosome size and number in recipient endothelial cells, which was followed by subsequent sequestration of components of the β-catenin destruction complex within endosomal compartments, leading to stabilization and nuclear localization of β-catenin. These events converged in the expression of β-catenin target genes involved in angiogenesis. Knockdown of ALS2 in donor tumor cells precluded its incorporation into small extracellular vesicles, preventing Rab5-downstream events and endothelial cell responses, which depended on Rab5 activity and guanine exchange factor activity of ALS2. These findings indicate that vesicular ALS2, secreted in hypoxia, promotes endothelial cell events leading to angiogenesis. Finally, these events might explain how tumor angiogenesis proceeds in hypoxic conditions., (© 2024 Federation of American Societies for Experimental Biology.)

Background: The Global Influenza Hospital Surveillance Network (GIHSN) has since 2012 provided patient-level data on severe influenza-like-illnesses from >100 participating clinical sites worldwide based on a core protocol and consistent case definitions., Methods: We used multivariable logistic regression to assess the risk of intensive care unit admission, mechanical ventilation, and in-hospital death among hospitalized patients with influenza and explored the role of patient-level covariates and country income level., Results: The data set included 73 121 patients hospitalized with respiratory illness in 22 countries, including 15 660 with laboratory-confirmed influenza. After adjusting for patient-level covariates we found a 7-fold increase in the risk of influenza-related intensive care unit admission in lower middle-income countries (LMICs), compared with high-income countries (P = .01). The risk of mechanical ventilation and in-hospital death also increased by 4-fold in LMICs, though these differences were not statistically significant. We also find that influenza mortality increased significantly with older age and number of comorbid conditions. Across all severity outcomes studied and after controlling for patient characteristics, infection with influenza A/H1N1pdm09 was more severe than with A/H3N2., Conclusions: Our study provides new information on influenza severity in underresourced populations, particularly those in LMICs., Competing Interests: Potential conflicts of interest . All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Nearly 90% of oral cancers are characterized as oral squamous cell carcinoma (OSCC), representing the sixth most common type of cancer. OSCC usually evolves from oral potentially malignant disorders that, in some cases, are histologically consistent with a oral dysplasia. The levels of 1α,25 dihydroxyvitamin D3 (1,25-(OH)2D3; calcitriol), the active form of vitamin D3, have been shown to be decreased in patients with oral dysplasia and OSCC. Moreover, treatment with 1,25-(OH)2D3 has been proven beneficial in OSCC by inhibiting the Wnt/β-catenin pathway, a signaling route that promotes cell migration, proliferation, and viability. However, whether this inhibition mechanism occurs in oral dysplasia is unknown. To approach this question, we used dysplastic oral keratinocyte cultures and oral explants (ex vivo model of oral dysplasia) treated with 1,25-(OH)2D3 for 48 h. Following treatment with 1,25-(OH)2D3, both in vitro and ex vivo models of oral dysplasia showed decreased levels of nuclear β-catenin by immunofluorescence (IF) and immunohistochemistry (IHC). Consistently, reduced protein and mRNA levels of the Wnt/β-catenin target gene survivin were observed after treatment with 1,25-(OH)2D3. Moreover, 1,25-(OH)2D3 promoted membranous localization of E-cadherin and nuclear localization of vitamin D receptor (VDR). Functionally, DOK cells treated with 1,25-(OH)2D3 displayed diminished cell migration and viability in vitro.

The author describes how she has earnestly struggled to find her fit in providing mental health services to Hispanic/Latino clients and the Latino communities that she belongs to. She wonders, if no one belongs, then who stands up for historically marginalized Latino communities? Personal and systemic biases and arbitrary criteria for being enough to serve Latino patients hurt providers and clients alike. Her work reminds her of the need to charge against stereotyping and racism to meet patients' needs regardless of skin color or linguistic abilities. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Purpose: Oral squamous cell carcinoma (OSCC) is commonly preceded by potentially malignant lesions, referred to as oral dysplasia. We recently reported that oral dysplasia is associated with aberrant activation of the Wnt/β-catenin pathway, due to overexpression of Wnt ligands in a Porcupine (PORCN)-dependent manner. Pharmacologic inhibition of PORCN precludes Wnt secretion and has been proposed as a potential therapeutic approach to treat established cancers. Nevertheless, there are no studies that explore the effects of PORCN inhibition at the different stages of oral carcinogenesis., Experimental Design: We performed a model of tobacco-induced oral cancer in vitro, where dysplastic oral keratinocytes (DOK) were transformed into oral carcinoma cells (DOK-TC), and assessed the effects of inhibiting PORCN with the C59 inhibitor. Similarly, an in vivo model of oral carcinogenesis and ex vivo samples derived from patients diagnosed with oral dysplasia and OSCC were treated with C59., Results: Both in vitro and ex vivo oral carcinogenesis approaches revealed decreased levels of nuclear β-catenin and Wnt3a, as observed by immunofluorescence and IHC analyses. Consistently, reduced protein and mRNA levels of survivin were observed after treatment with C59. Functionally, treatment with C59 in vitro resulted in diminished cell migration, viability, and invasion. Finally, by using an in vivo model of oral carcinogenesis, we found that treatment with C59 prevented the development of OSCC by reducing the size and number of oral tumor lesions., Conclusions: The inhibition of Wnt ligand secretion with C59 represents a feasible treatment to prevent the progression of early oral lesions toward OSCC., (©2023 American Association for Cancer Research.)

This paper analyses the prenatal representations on motherhood of 15 Spanish primiparous women who were in the dilemma of whether or not to continue with their pregnancies. Based on a qualitative methodological approach, semi-structured interviews were carried out which included in their design theoretical approaches of the so-called Maternal Constellation of Daniel Stern (1997). Through a content analysis of the interviews, an absence of mental representations of the baby in terms of both physical and characterological appearance was found in the sample, possibly due to the emotional impact generated by the news of the pregnancy. This absence of representations of the baby would reveal the importance of support and/or accompaniment by social and health care providers. It would also reveal the importance of the law in force maintaining the time for reflection, which, implemented with personalised, face-to-face and verbal counselling, would allow women who find themselves in this situation to choose freely, by providing them with all the information on alternatives for continuing their pregnancy with support and accompaniment.

The salivary peptide histatin-1 was recently described as a novel osteogenic factor that stimulates cell adhesion, migration, and differentiation in bone-lineage cells. Since these cell responses collectively contribute to bone regeneration, we hypothesized that histatin-1 harbors the capacity to enhance bone tissue repair at the preclinical level. By using a model of monocortical bone defect, we explored the effects of histatin-1 in tibial mineralization and organic matrix formation in vivo. To this end, different amounts of histatin-1 were embedded in one-mm 3 collagen sponges and then applied to tibial monocortical defects in C57bl/6 mice. After seven days, mice were euthanized, and samples were processed for subsequent analysis. Micro-computed tomography screening showed that histatin-1 increased intraosseous mineralization, and this phenomenon was accompanied by augmented collagen matrix deposition and closure of cortical defect edges, as determined by Hematoxylin-Eosin and Masson's Trichrome staining. Moreover, immunohistochemical analyses showed that histatin-1 increased the expression of the osteogenic marker alkaline phosphatase, which was accompanied by augmented blood vessel formation. Collectively, our findings show that histatin-1 itself promotes bone regeneration in an orthotopic model, proposing this molecule as a therapeutic candidate for use in bone regenerative medicine., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: Angiogenesis contributes to the development of apical periodontitis, periodontitis, and other oral pathologies; however, it remains unclear how this process is triggered. The aim was to evaluate whether lipopolysaccharide (LPS) from Porphyromonas endodontalis and Porphyromonas gingivalis induced angiogenesis-related effects in vitro via TLR2 and TLR4., Methodology: Porphyromonas endodontalis LPS (ATCC 35406 and clinical isolate) was purified with TRIzol, whereas P. gingivalis LPS was obtained commercially. The effects of the different LPS (24 h) in endothelial cell migration were analysed by Transwell assays, following quantification in an optical microscope (40×). The effects of LPS on FAK Y397 phosphorylation were assessed by Western blotting. Angiogenesis in vitro was determined in an endothelial tube formation assay (14 h) in Matrigel in the absence or presence of either LPS. IL-6 and VEGF-A levels were determined in cell supernatants, following 24 h treatment with LPS, and measured in multiplex bead immunoassay. The involvement of TLR2 and TLR4 was assessed with blocking antibodies. The statistical analysis was performed using STATA 12® (StataCorp LP)., Results: The results revealed that P. endodontalis LPS, but not P. gingivalis LPS, stimulated endothelial cell migration. Pre-treatment with anti-TLR2 and anti-TLR4 antibodies prevented P. endodontalis LPS-induced cell migration. P. endodontalis LPS promoted FAK phosphorylation on Y397, as observed by an increased p-FAK/FAK ratio. Both P. gingivalis and P. endodontalis LPS (ATCC 35406) induced endothelial tube formation in a TLR-2 and -4-dependent manner, as shown by using blocking antibodies, however, only TLR2 blocking decreased tube formation induced by P. endodontalis (clinical isolate). Moreover, all LPS induced IL-6 and VEGF-A synthesis in endothelial cells. TLR2 and TLR4 were required for IL-6 induction by P. endodontalis LPS (ATCC 35406), while only TLR4 was involved in IL-6 secretion by the other LPS. Finally, VEGF-A synthesis did not require TLR signalling., Conclusion: Porphyromonas endodontalis and P. gingivalis LPS induced angiogenesis via TLR2 and TLR4. Collectively, these data contribute to understanding the role of LPS from Porphyromonas spp. in angiogenesis and TLR involvement., (© 2023 British Endodontic Society. Published by John Wiley & Sons Ltd.)

The cytotoxic activity of combinations of masticadienonic (AMD) or 3αOH-hydroxy-masticadienonic (3αOH-AMD) acids with cisplatin (CDDP) was evaluated against PC3 prostate and HCT116 colon cancer cell lines. Combinations A (half the IC 50 value), B (IC 50 value), and C (twice the IC 50 value) were tested at a 1 : 1 ratio. All AMD plus CDDP combinations demonstrated increased cytotoxic effect, as determined by the sulforhodamine B test, in both cell types. The best combination was B, which showed 93 % and 91 % inhibition of the proliferation of PC3 and HCT116 cells, respectively. It also increased apoptosis in the PC3 cell lines, as evaluated by flow cytometry. However, in vivo tests showed no additional activity from the AMD plus CDDP combinations. These results showed that the increased cytotoxic activity of the combinations in vitro did not reflect in vivo tests. All combinations of 3αOH-AMD plus CDDP exerted antagonistic effects in both cell types., (© 2023 The Authors. Chemistry & Biodiversity published by Wiley-VHCA AG, Zurich, Switzerland.)

Objective: To promote equity for intersectionally disaster-vulnerable individuals and address three literature gaps: (1) incremental effects of collective and self-efficacy as preparedness predictors, (2) differentiation of fear and perceived severity of a disaster, and (3) clarification of the relationship between fear and preparedness., Methods: Due to infection risks associated with communal housing, early in the coronavirus disease (COVID-19) pandemic, many universities permitted students to remain in campus housing only if they were housing insecure, including many international students. We surveyed intersectionally-vulnerable students and their partners at a southeast US university, N = 54, who were international (77.8%), Asian (55.6%), and/or housing insecure at baseline (79.6%). In 14 waves from May-October 2020, we assessed pandemic preparedness/response behaviors (PPRBs) and potential PPRB predictors., Results: We examined within- and between-person effects of fear, perceived severity, collective efficacy, and self-efficacy on PPRBs. Within-person perceived severity and collective efficacy both significantly, positively predicted greater PPRBs. All effects of fear and self-efficacy were not significant., Conclusions: Perceived severity and confidence that one's actions positively impact one's community fluctuated throughout the pandemic and are linked to greater PPRB engagement. Public health messages and interventions to improve PPRB may benefit from emphasizing collective efficacy and accuracy over fear.

Background: The Global Influenza Hospital Surveillance Network (GIHSN) was established in 2012 to conduct coordinated worldwide influenza surveillance. In this study, we describe underlying comorbidities, symptoms, and outcomes in patients hospitalized with influenza., Methods: Between November 2018 and October 2019, GIHSN included 19 sites in 18 countries using a standardized surveillance protocol. Influenza infection was laboratory-confirmed with reverse-transcription polymerase chain reaction. A multivariate logistic regression model was utilized to analyze the extent to which various risk factors predict severe outcomes., Results: Of 16 022 enrolled patients, 21.9% had laboratory-confirmed influenza; 49.2% of influenza cases were A/H1N1pdm09. Fever and cough were the most common symptoms, although they decreased with age ( P < .001). Shortness of breath was uncommon among those <50 years but increased with age ( P < .001). Middle and older age and history of underlying diabetes or chronic obstructive pulmonary disease were associated with increased odds of death and intensive care unit (ICU) admission, and male sex and influenza vaccination were associated with lower odds. The ICU admissions and mortality occurred across the age spectrum., Conclusions: Both virus and host factors contributed to influenza burden. We identified age differences in comorbidities, presenting symptoms, and adverse clinical outcomes among those hospitalized with influenza and benefit from influenza vaccination in protecting against adverse clinical outcomes. The GIHSN provides an ongoing platform for global understanding of hospitalized influenza illness., Competing Interests: Potential conflicts of interest. MKA reports honoraria for advisory activities from Pfizer, Sanofi, and Seqirus and grant funding from Sanofi, GSK, Pfizer, Canadian Frailty Network, and Canadian Institutes of Health Research, unrelated to the current study. HP reports grant funding from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001. SSC works for Sanofi when not seconded to the Foundation for Influenza Epidemiology. GD reports research grant funding to his institution from Pfizer, Sanofi, and MSD and honoraria from Pfizer, MSD, Sanofi. MCN reports grants from the Bill & Melinda Gates Foundation, European & Developing Countries Clinical Trials Partnership, Pfizer, AstraZeneca, and Sanofi, and honoraria for advisory activities from Sanofi. JRO reports that his institution has received research grants from Pfizer and National Institutes of Health for vaccine research, and he has received honoraria for advisory activities from GSK, Moderna, Pfizer, and Seqirus, outside the submitted work. SM reports honoraria and consulting fees from Sanofi and GlaxoSmithKline. PV reports honoraria from Pfizer. JP and LS report grant funding from Sanofi Pasteur, unrelated to the current work. HIGG and SMR report conference attendance funding from Sanofi. SAM reports grant and clinical trials funding from GSK, Merck, Pfizer, and Sanofi and payments from GSK, Pfizer, Sanofi, and Merck outside the submitted work. Acd reports grant funding from the EU/EFPIA Innovative medicine Initiative 2 Joint Undertaking (DRIVE Grant Number 777363). TZ reports grants from Pfizer and MSD. BL serves as chair of the scientific committee of Immuniser Lyon and co-chair of the Global Influenza Initiative. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: International students face unique COVID-19-related stressors, such as financial aid loss, limited social support, and discrimination (e.g., verbal harassment, physical assault). Additionally, pandemic and chronic stress research is largely cross-sectional, and trajectories over time remain unclear for psychological and environmental factors predicting distress and peri-pandemic growth. Accordingly, the current study examined trajectories of psychological distress and growth, as well as weekly psychological and environmental predictors of psychological distress and growth, in international students during the early stages of the pandemic., Method: International students ( N = 42) at a U.S. university were surveyed weekly for 14 weeks., Results: Latent growth mixture modeling resulted in three trajectories over time of distress ( Minimal Impact, Emergent Resilience, and Increasing Distress ) and peri-pandemic growth ( Limited PrTG, Decreasing PrTG, and Increasing PrTG ). For multilevel models, within-person increases in meaning and self-efficacy as well as between-person changes in discrimination and emotional social support predicted distress. Within-person changes in meaning and self-efficacy and between-person changes in self-efficacy and discrimination predicted peri-pandemic growth., Conclusions: Despite the stressors they face, many international students demonstrated a trajectory of resilience. Positive coping factors and environmental factors predicted distress or peri-pandemic growth, which can inform interventions and studies examining trajectories of distress during prolonged adversity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

SALL2/Sall2 is a transcription factor associated with development, neuronal differentiation, and cancer. Interestingly, SALL2/Sall2 deficiency leads to failure of the optic fissure closure and neurite outgrowth, suggesting a positive role for SALL2/Sall2 in cell migration. However, in some cancer cells, SALL2 deficiency is associated with increased cell migration. To further investigate the role of Sall2 in the cell migration process, we used immortalized Sall2 knockout ( Sall2 -/- ) and Sall2 wild-type ( Sall2 +/+ ) mouse embryonic fibroblasts (iMEFs). Our results indicated that Sall2 positively regulates cell migration, promoting cell detachment and focal adhesions turnover. Sall2 deficiency decreased cell motility and altered focal adhesion dynamics. Accordingly, restoring Sall2 expression in the Sall2 -/- iMEFs by using a doxycycline-inducible Tet-On system recovered cell migratory capabilities and focal adhesion dynamics. In addition, Sall2 promoted the autophosphorylation of Focal Adhesion Kinase (FAK) at Y397 and increased integrin β1 mRNA and its protein expression at the cell surface. We demonstrated that SALL2 increases ITGB1 promoter activity and binds to conserved SALL2-binding sites at the proximal region of the ITGB1 promoter, validated by ChIP experiments. Furthermore, the overexpression of integrin β1 or its blockade generates a cell migration phenotype similar to that of Sall2 +/+ or Sall2 -/- cells, respectively. Altogether, our data showed that Sall2 promotes cell migration by modulating focal adhesion dynamics, and this phenotype is associated with SALL2/Sall2-transcriptional regulation of integrin β1 expression and FAK autophosphorylation. Since deregulation of cell migration promotes congenital abnormalities, tumor formation, and spread to other tissues, our findings suggest that the SALL2/Sall2-integrin β1 axis could be relevant for those processes., 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 © 2022 Riffo, Palma, Hepp, Benítez-Riquelme, Torres, Castro and Pincheira.)

Aging is a gradual and progressive deterioration of integrity across multiple organ systems that negatively affects gingival wound healing. The cellular responses associated with wound healing, such as collagen synthesis, cell migration, proliferation, and collagen contraction, have been shown to be lower in gingival fibroblasts (the most abundant cells from the connective gingival tissue) in aged donors than young donors. Cellular senescence is one of the hallmarks of aging, which is characterized by the acquisition of a senescence-associated secretory phenotype that is characterized by the release of pro-inflammatory cytokines, chemokines, growth factors, and proteases which have been implicated in the recruitment of immune cells such as neutrophils, T cells and monocytes. Moreover, during aging, macrophages show altered acquisition of functional phenotypes in response to the tissue microenvironment. Thus, inflammatory and resolution macrophage-mediated processes are impaired, impacting the progression of periodontal disease. Interestingly, salivary antimicrobial peptides, such as histatins, which are involved in various functions, such as antifungal, bactericidal, enamel-protecting, angiogenesis, and re-epithelization, have been shown to fluctuate with aging. Several studies have associated the presence of Porphyromonas gingivalis , a key pathogen related to periodontitis and apical periodontitis, with the progression of Alzheimer's disease, as well as gut, esophageal, and gastric cancers. Moreover, herpes simplex virus types 1 and 2 have been associated with the severity of periodontal disease, cardiovascular complications, and nervous system-related pathologies. This review encompasses the effects of aging on periodontal tissues, how P. gingivalis and HSV infections could favor periodontitis and their relationship with other pathologies., 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 © 2022 Villalobos, Garrido, Reyes, Fernández, Diaz, Torres, González and Cáceres.)

Quorum sensing (QS) and type III secretion systems (T3SSs) are among the most attractive anti-virulence targets for combating multidrug-resistant pathogenic bacteria. Some halogenated furanones reduce QS-associated virulence, but their role in T3SS inhibition remains unclear. This study aimed to assess the inhibition of these two systems on Pseudomonas aeruginosa virulence. The halogenated furanones ( Z )-4-bromo-5-(bromomethylene)-2(5 H ) (C-30) and 5-(dibromomethylene)-2(5 H ) (named hereafter GBr) were synthesized, and their ability to inhibit the secretion of type III exoenzymes and QS-controlled virulence factors was analyzed in P. aeruginosa PA14 and two clinical isolates. Furthermore, their ability to prevent bacterial establishment was determined in a murine cutaneous abscess model. The GBr furanone reduced pyocyanin production, biofilm formation, and swarming motility in the same manner or more effectively than C-30. Moreover, both furanones inhibited the secretion of ExoS, ExoT, or ExoU effectors in all tested strains. The administration of GBr (25 and 50 µM) to CD1 mice infected with the PA14 strain significantly decreased necrosis formation in the inoculation zone and the systemic spread of bacteria more efficiently than C-30 (50 µM). Molecular docking analysis suggested that the gem position of bromine in GBr increases its affinity for the active site of the QS LasR regulator. Overall, our findings showed that the GBr furanone displayed efficient multi-target properties that may favor the development of more effective anti-virulence therapies.

Histatin-1 is a salivary peptide with antimicrobial and wound healing promoting activities, which was previously shown to stimulate angiogenesis in vitro and in vivo via inducing endothelial cell migration. The mechanisms underlying the proangiogenic effects of Histatin-1 remain poorly understood and specifically, the endothelial receptor for this peptide, is unknown. Based on the similarities between Histatin-1-dependent responses and those induced by the prototypical angiogenic receptor, vascular endothelial growth factor receptor 2 (VEGFR2), we hypothesized that VEGFR2 is the Histatin-1 receptor in endothelial cells. First, we observed that VEGFR2 is necessary for Histatin-1-induced endothelial cell migration, as shown by both pharmacological inhibition studies and siRNA-mediated ablation of VEGFR2. Moreover, Histatin-1 co-immunoprecipitated and co-localized with VEGFR2, associating spatial proximity between these proteins with receptor activation. Indeed, pulldown assays with pure, tagged and non-tagged proteins showed that Histatin-1 and VEGFR2 directly interact in vitro. Optical tweezers experiments permitted estimating kinetic parameters and rupture forces, indicating that the Histatin-1-VEGFR2 interaction is transient, but specific and direct. Sequence alignment and molecular modeling identified residues Phe26, Tyr30 and Tyr34 within the C-terminal domain of Histatin-1 as relevant for VEGFR2 binding and activation. This was corroborated by mutation and molecular dynamics analyses, as well as in direct binding assays. Importantly, these residues were required for Histatin-1 to induce endothelial cell migration and angiogenesis in vitro. Taken together, our findings reveal that VEGFR2 is the endothelial cell receptor of Histatin-1 and provide insights to the mechanism by which this peptide promotes endothelial cell migration and angiogenesis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Antimicrobial resistance is one of the current public health challenges to be solved. The World Health Organization (WHO) has urgently called for the development of strategies to expand the increasingly limited antimicrobial arsenal. The development of anti-virulence therapies is a viable option to counteract bacterial infections with the possibility of reducing the generation of resistance. Here we report on the chemical structures of pyrrolidones DEXT 1-4 (previously identified as furan derivatives) and their anti-virulence activity on Pseudomonas aeruginosa strains. DEXT 1-4 were shown to inhibit biofilm formation, swarming motility, and secretion of ExoU and ExoT effector proteins. Also, the anti-pathogenic property of DEXT-3 alone or in combination with furanone C-30 (quorum sensing inhibitor) or MBX-1641 (type III secretion system inhibitor) was analyzed in a model of necrosis induced by P. aeruginosa PA14. All treatments reduced necrosis; however, only the combination of C-30 50 µM with DEXT-3 100 µM showed significant inhibition of bacterial growth in the inoculation area and systemic dispersion. In conclusion, pyrrolidones DEXT 1-4 are chemical structures capable of reducing the pathogenicity of P. aeruginosa and with the potential for the development of anti-virulence combination therapies.

Neuroblastoma is a highly metastatic tumor that emerges from neural crest cell progenitors. Focal Adhesion Kinase (FAK) is a regulator of cell migration that binds to the receptor Neogenin-1 and is upregulated in neuroblastoma. Here, we show that Netrin-1 ligand binding to Neogenin-1 leads to FAK autophosphorylation and integrin β1 activation in a FAK dependent manner, thus promoting neuroblastoma cell migration. Moreover, Neogenin-1, which was detected in all tumor stages and was required for neuroblastoma cell migration, was found in a complex with integrin β1, FAK, and Netrin-1. Importantly, Neogenin-1 promoted neuroblastoma metastases in an immunodeficient mouse model. Taken together, these data show that Neogenin-1 is a metastasis-promoting protein that associates with FAK, activates integrin β1 and promotes neuroblastoma cell migration.

Background: Socioeconomic status (SES) is a determinant of cognitive and academic functioning among healthy and ill children; however, few pediatric oncology studies examine SES and long-term cognitive functioning. The current study systematically investigated SES as a predictor of cognitive outcomes among children treated for localized brain tumors (BT) with photon radiation therapy (RT)., Methods: 248 children treated on a prospective, longitudinal, phase II trial of conformal RT (54-59.4 Gy) for ependymoma, low-grade glioma, or craniopharyngioma were monitored serially with cognitive assessments (intelligence quotient [IQ], reading, math, attention, adaptive function) for 10 years (2209 observations, median age at RT = 6.6 years, 48% male, 80% Caucasian). SES was derived from the Barratt Simplified Measure of Social Status, which incorporates parental occupation, education, and marital status., Results: Overall, SES scores fell in the low range (Barratt median = 37). At pre-RT baseline, linear mixed models revealed significant associations between SES and IQ, reading, math, attention, and adaptive function, with higher SES associated with better performance (P < .005). SES predicted change over time in IQ, reading, and math; higher SES was associated with less decline (P < .001). Accounting for sex and age at RT, SES remained predictive of IQ, reading, and math. Analysis of variance revealed a greater relative contribution of SES than sex or age at RT to reading and math., Conclusions: SES represents a novel predictor of cognitive performance before and after RT for pediatric BT. These findings have broad implications as high SES represents a protective factor. Developing interventions to mitigate the effects of low SES is warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca 2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca 2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2 D509V , a Ca 2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca 2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy. Abbreviations : ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A 1 ; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.

Aging is a gradual biological process characterized by a decrease in cellular and organism functions. Aging-related processes involve changes in the expression and activity of several proteins. Here, we identified the transmembrane protease serine 11a (TMPRSS11a) as a new age-specific protein that plays an important role in skin wound healing. TMPRSS11a levels increased with age in rodent and human skin and gingival samples. Strikingly, overexpression of TMPRSS11a decreased cell migration and spreading, and inducing cellular senescence. Mass spectrometry, bioinformatics, and functional analyses revealed that TMPRSS11a interacts with integrin β 1 through an RGD sequence contained within the C-terminal domain and that this motif was relevant for cell migration. Moreover, TMPRSS11a was associated with cellular senescence, as shown by overexpression and downregulation experiments. In agreement with tissue-specific expression of TMPRSS11a, shRNA-mediated downregulation of this protein improved wound healing in the skin, but not in the skeletal muscle of old mice, where TMPRSS11a is undetectable. Collectively, these findings indicate that TMPRSS11a is a tissue-specific factor relevant for wound healing, which becomes elevated with aging, promoting cellular senescence and inhibiting cell migration and skin repair., (© 2021 Federation of American Societies for Experimental Biology.)

Background: Head injuries are common injury in the fire service; however, very little data exist on the risks this may pose to the development of post-traumatic stress disorder (PTSD) and depression in this high-risk population., Aims: Our study aimed to compare levels of PTSD and depression symptoms in firefighters with a line-of-duty head injury, non-line-of-duty head injury and no head injury., Methods: In this cross-sectional study, we assessed current PTSD and depression symptoms as well as retrospective head injuries., Results: Seventy-six per cent of the total sample reported at least one head injury in their lifetime. Depression symptoms were significantly more severe among firefighters with a line-of-duty head injury compared to those with no head injury, but not compared to those who sustained a non-line-of-duty head injury. Depression symptoms did not differ between firefighters with a non-line-of-duty head injury and those with no head injury. PTSD symptoms were significantly more severe among firefighters with a line-of-duty head injury compared to both firefighters with no head injury and those with a non-line-of-duty head injury., Conclusions: We found that firefighters who reported at least one line-of-duty head injury had significantly higher levels of PTSD and depression symptoms than firefighters who reported no head injuries. Our findings also suggest head injuries sustained outside of fire service could have less of an impact on the firefighter's PTSD symptom severity than head injuries that occur as a direct result of their job., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Histatin-1 is a salivary antimicrobial peptide involved in the maintenance of enamel and oral mucosal homeostasis. Moreover, Histatin-1 has been shown to promote re-epithelialization in soft tissues, by stimulating cell adhesion and migration in oral and dermal keratinocytes, gingival and skin fibroblasts, endothelial cells and corneal epithelial cells. The broad-spectrum activity of Histatin-1 suggests that it behaves as a universal wound healing promoter, although this is far from being clear yet. Here, we report that Histatin-1 is a novel osteogenic factor that promotes bone cell adhesion, migration, and differentiation. Specifically, Histatin-1 promoted cell adhesion, spreading, and migration of SAOS-2 cells and MC3T3-E1 preosteoblasts in vitro, when placed on a fibronectin matrix. Besides, Histatin-1 induced the expression of osteogenic genes, including osteocalcin, osteopontin, and Runx2, and increased both activity and protein levels of alkaline phosphatase. Furthermore, Histatin-1 promoted mineralization in vitro, as it augmented the formation of calcium deposits in both SAOS-2 and MC3T3-E1 cells. Mechanistically, although Histatin-1 failed to activate ERK1/2, FAK, and Akt, which are signaling proteins associated with osteogenic differentiation or cell migration, it triggered nuclear relocalization of β-catenin. Strikingly, the effects of Histatin-1 were recapitulated in cells that are nonosteogenically committed, since it promoted surface adhesion, migration, and the acquisition of osteogenic markers in primary mesenchymal cells derived from the apical papilla and dental pulp. Collectively, these observations indicate that Histatin-1 is a novel osteogenic factor that promotes bone cell differentiation, surface adhesion and migration, as crucial events required for bone tissue regeneration., (© 2021 John Wiley & Sons Ltd.)

Tumor hypoxia and the hypoxia inducible factor-1, HIF-1, play critical roles in cancer progression and metastasis. We previously showed that hypoxia activates the endosomal GTPase Rab5, leading to tumor cell migration and invasion, and that these events do not involve changes in Rab protein expression, suggesting the participation of intermediate activators. Here, we identified ALS2, a guanine nucleotide exchange factor that is upregulated in cancer, as responsible for increased Rab5-GTP loading, cell migration and metastasis in hypoxia. Specifically, hypoxia augmented ALS2 mRNA and protein levels, and these events involved HIF-1α-dependent transcription, as shown by RNAi, pharmacological inhibition, chromatin immunoprecipitation and bioinformatics analyses, which identified a functional HIF-1α-binding site in the proximal promoter region of ALS2. Moreover, ALS2 and Rab5 activity were elevated both in a model of endogenous HIF-1α stabilization (renal cell carcinoma) and by following expression of stable non-hydroxylatable HIF-1α. Strikingly, ALS2 upregulation in hypoxia was required for Rab5 activation, tumor cell migration and invasion, as well as experimental metastasis in C57BL/6 mice. Finally, immunohistochemical analyses in patient biopsies with renal cell carcinoma showed that elevated HIF-1α correlates with increased ALS2 expression. Hence, this study identifies ALS2 as a novel hypoxia-inducible gene associated with tumor progression and metastasis.

Oral squamous cell carcinoma, the most common type of oral cancer, affects more than 275,000 people per year worldwide. Oral squamous cell carcinoma is very aggressive, as most patients die after 3 to 5 years post-diagnosis. The initiation and progression of oral squamous cell carcinoma are multifactorial: smoking, alcohol consumption, and human papilloma virus infection are among the causes that promote its development. Although oral squamous cell carcinoma involves abnormal growth and migration of oral epithelial cells, other cell types such as fibroblasts and immune cells form the carcinoma niche. An underlying inflammatory state within the oral tissue promotes differential stress-related responses that favor oral squamous cell carcinoma. Autophagy is an intracellular degradation process that allows cancer cells to survive under stress conditions. Autophagy degrades cellular components by sequestering them in vesicles called autophagosomes, which ultimately fuse with lysosomes. Although several autophagy markers have been associated with oral squamous cell carcinoma, it remains unclear whether up- or down-regulation of autophagy favors its progression. Autophagy levels during oral squamous cell carcinoma are both timing- and cell-specific. Here we discuss how autophagy is required to establish a new cellular microenvironment in oral squamous cell carcinoma and how autophagy drives the phenotypic change of oral squamous cell carcinoma cells by promoting crosstalk between carcinoma cells, fibroblasts, and immune cells., 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 © 2020 Peña-Oyarzún, Reyes, Hernández-Cáceres, Kretschmar, Morselli, Ramirez-Sarmiento, Lavandero, Torres and Criollo.)

Background: Mild traumatic brain injury (mTBI) is a nationwide problem; yet, no firefighter mTBI data are available. Methods: In this cross-sectional study, we assessed retrospective head injuries using WHO guidelines. We captured mTBI frequency and examined firefighters' symptoms (e.g., using Ohio State University Traumatic Brain Injury Identification method, Brief Traumatic Brain Injury Screen, Warrior Administered Retrospective Causality Assessment Tool). Findings: Of 1,112 firefighters contacted, 60 responses were included. Most participants were White (80%), male (90%), former athletes (75%). 62% met mTBI symptom criteria. 75% reported at least one lifetime head injury. Number of head injuries and depression symptoms were associated (r = .36, p < .05). Conclusion/application to practice: Overall, it appears most firefighters have sustained at least one lifetime mTBI. Those with multiple head injuries may be at increased risk of depression. Occupational health professionals should be aware of firefighters' mTBI risk. Further research is warranted given findings.

Aim: To determine the methylation pattern of TLR2 gene promoter and its association with the transcriptional regulation of periapical inflammatory and angiogenic responses in symptomatic and asymptomatic forms of apical periodontitis., Methodology: In this cross-sectional study, apical lesions were obtained from volunteers with asymptomatic apical periodontitis (AAP) (n = 17) and symptomatic apical periodontitis (SAP) (n = 17) scheduled for tooth extraction, and both total RNA and DNA were extracted. DNA was bisulfite-treated, a region of CpG island within the TLR2 gene was amplified by qPCR and the products were sequenced. Additionally, the mRNA expression of TLR2, TLR4, IL-6, IL-12, TNFalpha, IL-23, IL-10, TGFbeta, VEGFA and CDH5 was analysed by qPCR. The data were analysed with chi-square tests, Mann-Whitney or unpaired t-tests, and Spearman´s correlation; variable adjustments were performed using multiple linear regression (P < 0.05)., Results: TLR2 depicted a hypomethylated DNA profile at the CpG island in SAP when compared with AAP, along with upregulated expression of TLR2, with pro-inflammatory cytokines IL-6 and IL-23, and the angiogenesis marker CDH5 (P < 0.05). TLR2 methylation percentage negatively correlated with mRNA levels of IL-23 and CDH5 in apical periodontitis. Lower methylation frequencies of single CpG dinucleotides -8 and -10 localized in close proximity to nuclear factor κB (NFκB) binding within the TLR2 promoter were identified in SAP versus AAP (P < 0.05). Finally, unmethylated -10 and -8 single sites demonstrated up-regulation of IL-23, IL-10 and CDH5 transcripts compared to their methylated counterparts (P < 0.05)., Conclusions: TLR2 gene promoter hypomethylation was linked to transcriptional activity of pro-inflammatory cytokines and angiogenic markers in exacerbated periapical inflammation. Moreover, unmethylated single sites in close proximity to NFκB binding were involved in active transcription of IL-23, IL-10 and CDH5., (© 2020 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Oral carcinogenesis is a complex and multifactorial process that involves cumulative genetic and molecular alterations, leading to uncontrolled cell proliferation, impaired DNA repair and defective cell death. At the early stages, the onset of potentially malignant lesions in the oral mucosa, or oral dysplasia, is associated with higher rates of malignant progression towards carcinoma in situ and invasive carcinoma. Efforts have been made to get insights about signaling pathways that are deregulated in oral dysplasia, as these could be translated into novel markers and might represent promising therapeutic targets. In this context, recent evidence underscored the relevance of the Wnt/β-catenin signaling pathway in oral dysplasia, as this pathway is progressively "switched on" through the different grades of dysplasia (mild, moderate and severe dysplasia), with the consequent nuclear translocation of β-catenin and expression of target genes associated with the maintenance of representative traits of oral dysplasia, namely cell proliferation and viability. Intriguingly, recent studies provide an unanticipated connection between active β-catenin signaling and deregulated endosome trafficking in oral dysplasia, highlighting the relevance of endocytic components in oral carcinogenesis. This review summarizes evidence about the role of the Wnt/β-catenin signaling pathway and the underlying mechanisms that account for its aberrant activation in oral carcinogenesis., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript or in the decision to publish the results.

Caveolin-1 (CAV1) enhanced migration, invasion, and metastasis of cancer cells is inhibited by co-expression of the glycoprotein E-cadherin. Although the two proteins form a multiprotein complex that includes β-catenin, it remained unclear how this would contribute to blocking the metastasis promoting function of CAV1. Here, we characterized by mass spectrometry the protein composition of CAV1 immunoprecipitates from B16F10 murine melanoma cells expressing or not E-cadherin. The novel protein tyrosine phosphatase PTPN14 was identified by mass spectrometry analysis exclusively in co-immunoprecipitates of CAV1 with E-cadherin. Interestingly, PTPN14 is implicated in controlling metastasis, but only few known PTPN14 substrates exist. We corroborated by western blotting experiments that PTPN14 and CAV1 co-inmunoprecipitated in the presence of E-cadherin in B16F10 melanoma and other cancer cells. Moreover, the CAV1(Y14F) mutant protein was shown to co-immunoprecipitate with PTPN14 even in the absence of E-cadherin, and overexpression of PTPN14 reduced CAV1 phosphorylation on tyrosine-14, as well as suppressed CAV1-enhanced cell migration, invasion and Rac-1 activation in B16F10, metastatic colon [HT29(US)] and breast cancer (MDA-MB-231) cell lines. Finally, PTPN14 overexpression in B16F10 cells reduced the ability of CAV1 to induce metastasis in vivo. In summary, we identify here CAV1 as a novel substrate for PTPN14 and show that overexpression of this phosphatase suffices to reduce CAV1-induced metastasis.

Potentially malignant lesions, commonly referred to as dysplasia, are associated with malignant transformation by mechanisms that remain unclear. We recently reported that increased Wnt secretion promotes the nuclear accumulation of β-catenin and expression of target genes in oral dysplasia. However, the mechanisms accounting for nuclear re-localization of β-catenin in oral dysplasia remain unclear. In this study, we show that endosomal sequestration of the β-catenin destruction complex allows nuclear accumulation of β-catenin in oral dysplasia, and that these events depended on the endocytic protein Rab5. Tissue immunofluorescence analysis showed aberrant accumulation of enlarged early endosomes in oral dysplasia biopsies, when compared with healthy oral mucosa. These observations were confirmed in cell culture models, by comparing dysplastic oral keratinocytes (DOK) and non-dysplastic oral keratinocytes (OKF6). Intriguingly, DOK depicted higher levels of active Rab5, a critical regulator of early endosomes, when compared with OKF6. Increased Rab5 activity in DOK was necessary for nuclear localization of β-catenin and Tcf/Lef-dependent transcription, as shown by expression of dominant negative and constitutively active mutants of Rab5, along with immunofluorescence, subcellular fractionation, transcription, and protease protection assays. Mechanistically, elevated Rab5 activity in DOK accounted for endosomal sequestration of components of the destruction complex, including GSK3β, Axin, and adenomatous polyposis coli (APC), as observed in Rab5 dominant negative experiments. In agreement with these in vitro observations, tissue immunofluorescence analysis showed increased co-localization of GSK3β, APC, and Axin, with early endosome antigen 1- and Rab5-positive early endosomes in clinical samples of oral dysplasia. Collectively, these data indicate that increased Rab5 activity and endosomal sequestration of the β-catenin destruction complex leads to stabilization and nuclear accumulation of β-catenin in oral dysplasia., (© 2020 Federation of American Societies for Experimental Biology.)

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. It arises during development of the sympathetic nervous system. Netrin-4 (NTN4), a laminin-related protein, has been proposed as a key factor to target NB metastasis, although there is controversy about its function. Here, we show that NTN4 is broadly expressed in tumor, stroma and blood vessels of NB patient samples. Furthermore, NTN4 was shown to act as a cell adhesion molecule required for the migration induced by Neogenin-1 (NEO1) in SK-N-SH neuroblastoma cells. Therefore, we propose that NTN4, by forming a ternary complex with Laminin γ1 (LMγ1) and NEO1, acts as an essential extracellular matrix component, which induces the migration of SK-N-SH cells.

Hypoxia, a common condition of the tumor microenvironment, induces changes in the proteome of cancer cells, mainly via HIF-1, a transcription factor conformed by a constitutively expressed β-subunit and an oxygen-regulated α-subunit. In hypoxia, HIF-1α stabilizes, forms the heterodimeric complex with HIF-1β, and binds to Hypoxia Response Elements (HRE), activating gene expression to promote metabolic adaptation, cell invasion and metastasis. Furthermore, the focal adhesion kinase, FAK, is activated in hypoxia, promoting cell migration by mechanisms that remain unclear. In this context, integrins, which are glycoproteins required for cell migration, are possibly involved in hypoxia-induced FAK activation. Evidence suggests that cancer cells have an altered glycosylation metabolism, mostly by the expression of glycosyltransferases, however the relevance of glycosylation is poorly explored in the context of hypoxia. Here, we discuss the role of hypoxia in cancer, and its effects on protein glycosylation, with emphasis on integrins and cell migration.

Focal adhesion kinase (FAK) is a central regulator of integrin-dependent cell adhesion and migration and has recently been shown to co-localize with endosomal proteins. The early endocytic protein Rab5 controls integrin trafficking, focal adhesion disassembly, and cell migration and has been shown to be activated upon integrin engagement by mechanisms that remain unclear. Because FAK is a critical regulator of integrin-dependent signaling and Rab5 recapitulates FAK-mediated effects, we evaluated the possibility that FAK activates Rab5 and contributes to cell migration. Pulldown assays revealed that Rab5-GTP levels are decreased upon treatment with a pharmacological inhibitor of FAK, PF562,271, in resting A549 cells. These events were associated with decreased peripheral Rab5 puncta and a reduced number of early endosome antigen 1 (EEA1)-positive early endosomes. Accordingly, as indicated by FAK inhibition experiments and in FAK-null fibroblasts, adhesion-induced FAK activity increased Rab5-GTP levels. In fact, expression of WT FAK and FAK/Y180A/M183A (open conformation), but not FAK/Arg 454 (kinase-dead), augmented Rab5-GTP levels in FAK-null fibroblasts and A549 cells. Moreover, expression of a GDP-bound Rab5 mutant (Rab5/S34N) or shRNA-mediated knockdown of endogenous Rab5 prevented FAK-induced A549 cell migration, whereas expression of WT or GTP-bound Rab5 (Rab5/Q79L), but not Rab5/S34N, promoted cell migration in FAK-null fibroblasts. Mechanistically, FAK co-immunoprecipitated with the GTPase-activating protein p85α in a phosphorylation (Tyr 397 )-dependent manner, preventing Rab5-GTP loading, as shown by knockdown and transfection recovery experiments. Taken together, these results reveal that FAK activates Rab5, leading to cell migration., (© 2019 Arriagada et al.)

The Kingdom Plantae has provided several successful drugs for the treatment of different diseases, including cancer, and continues to be a source of new possible therapeutic molecules. For example, the annonaceous acetogenins (AAs) are secondary metabolites found in the Annonaceae family, which are plants employed in traditional medicine for the treatment of cancer and various other diseases. These polyketides are inhibitors of Complex I in the respiratory chain of tumor cells, a process that is closely related to tumor metabolism, cell death, apoptosis, and autophagy. The goal of this review is to update readers on the role of the AAs as antitumor agents using in vitro and in vivo studies to demonstrate their importance in the area of oncology drug discovery. For this purpose, we performed a literature search in the PubMed scientific database using a range of keywords, including acetogenins and cancer, acetogenins antitumor activity, acetogenins and cytotoxicity, and acetogenins mechanism of action, among others. As a result, we found that the AAs are cytotoxic compounds that can induce apoptosis, cell cycle arrest, and autophagy in vitro , in addition to exhibiting tumor growth inhibition in vivo . The functional group related to their antineoplastic activity is suggested to be the mono or bis tetrahydrofuran ring accompanied by two or more hydroxy groups. The versatility of the AA bioactivity therefore renders them potential therapeutic agents for cancer treatment. It is therefore apparent that nature is worth further examination to aid in the discovery of more effective, accurate, and less harmful therapies in the fight against cancer.

Objectives: To evaluate the localization of β-catenin in oral dysplastic cells, the expression of target genes upregulated in oral dysplasia, and the role of Wnt ligands in these events., Materials and Methods: Subcellular localization of total and non-phosphorylated (transcriptionally active) β-catenin was evaluated by immunofluorescence and biochemical fractionation in dysplastic oral keratinocytes (DOK), non-dysplastic oral keratinocytes (OKF6), oral squamous carcinoma cells (CAL27) and primary oral keratinocytes. Tcf/Lef-dependent transcription was measured by luciferase reporter assays. Expression of target genes, survivin and cyclin D1, was evaluated by RT-qPCR and Western blotting. Wnt secretion was inhibited with the inhibitor of porcupine, C59. Wnt3a and β-catenin were evaluated in biopsies by tissue immunofluorescence., Results: Immunofluorescence and fractionation experiments showed augmented nuclear β-catenin (total and transcriptionally active) in DOK, when compared with OKF6 and CAL27 cells. Intriguingly, conditioned medium from DOK promoted nuclear accumulation of β-catenin and Tcf/Lef-dependent transcription in OKF6 and primary oral keratinocytes, suggesting the participation of secreted factors. Treatment of DOK with C59 decreased Wnt3a secretion, nuclear β-catenin and the expression of survivin and cyclin D1 at both mRNA and protein levels. Accordingly, DOK secreted higher Wnt3a levels than OKF6, and inhibition of Wnt3a secretion prevented DOK-induced Tcf/Lef-dependent transcription in OKF6. These observations were confirmed in clinical samples, since tissue immunofluorescence analysis showed simultaneous expression of Wnt3a and nuclear β-catenin in oral dysplasia, but not in healthy mucosa biopsies., Conclusion: These data indicate that secretion of Wnt ligands is critical for β-catenin nuclear localization and expression of target genes in oral dysplasia., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Zoledronic acid, the most frequent agent associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ), has been reported as cytotoxic for bone and vascular cells. Hence, identification of novel approaches aiming to counteract its cytotoxic effects will be desirable to develop preventive therapies for BRONJ. The salivary peptide Histatin-1 was recently shown to promote oral wound healing, by acting in epithelial and endothelial cells; however, its effects on cells exposed to zoledronic acid have not been explored. This study aims to unveil the role of Histatin-1 in osteoblastic and vascular cell lineages challenged with zoledronic acid., Methods: The effects of zoledronic acid (1-100 µM), Histatin-1 (10 µM), or their combination was evaluated in cytotoxicity (Trypan Blue exclusion) and cell migration (Boyden Chamber) assays. Caspase-3 cleavage was evaluated by Western blot. The angiogenic capacity of endothelial cells was assessed in a tubule formation assay in vitro., Results: Zoledronic acid decreased cell viability and migration of osteosarcoma cells (SAOS-2) and preosteoblasts (MC3T3-E1), in a dose-response manner. Importantly, Histatin-1 restored both cell viability and migration in both cell lines upon challenge with zoledronic acid. These effects were recapitulated in endothelial cells (EA.hy926), as Histatin-1 counteracted cytotoxic and antimigratory effects of zoledronic acid, and restored the angiogenic capacity in vitro., Conclusion: We conclude that Histatin-1 counteracts the cytotoxic and antimigratory effects of zoledronic acid in osteoblast-like and endothelial cells. These observations highlight the potential use of Histatin-1, in the design of novel therapies aiming to prevent and treat BRONJ., (© 2019 American Academy of Periodontology.)

The importance of surveilling the circulation of the influenza virus and timely vaccination of different populations in Peru was analyzed in three sessions by a group of clinical experts from different specialties. The Peruvian national influenza surveillance system has many selected establishments that have become currently ineffective in terms of a timely report. Most of the samples come from Lima. The viral distribution is inadequately analyzed. The northern and jungle areas of the country have weather and season conditions different to those in Lima and on the southern highlands. This lack of coordination is accentuated by the opportunity of arrival of the influenza vaccine in the country. The Ministry of Health uses a trivalent vaccine but the possibility of a tetravalent vaccine with the two type-B lineages must be analyzed from a cost-benefit standpoint. The appropriateness of vaccinating two times a year, regionally, should be assessed.