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Background: The global inequity in the distribution of COVID-19 vaccines underscores the urgent need for innovative and cost-effective vaccine technologies to address access disparities and implement local manufacturing capabilities. This is essential for achieving and sustaining widespread immunity, and for ensuring timely protection of vulnerable populations during future booster campaigns in lower- middle income countries (LMICs)., Methods: To address this need, we conducted a phase II clinical trial to evaluate the safety and immunogenicity of the locally manufactured AVX/COVID-12 "Patria" (AVX) vaccine as a booster dose. The vaccine was administered either intramuscularly (IM) or intranasally (IN) to participants who had previously completed a vaccination regimen for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using adenoviral vector, inactivated virus, or mRNA-based vaccines. Participants with initial anti-spike IgG titers below 1,200 U/mL were included, allowing us to observe the booster effect induced by vaccination., Results: Both IM and IN immunization with AVX were found to be safe and well-tolerated. The vaccine induced a significant (>2.5-fold) increase in neutralizing antibodies against the ancestral Wuhan strain and variants of concern (VOCs), including Alpha, Beta, Delta, and Omicron (BA.2 and BA.5). This immune response was further supported by increased cellular production of interferon-gamma (IFN-γ), demonstrating a robust and multifaceted immune reaction., Conclusions: The administration of AVX as a booster dose, whether through IM or IN routes, was safe and well-tolerated. The vaccine extended immune responses not only against the ancestral Wuhan-1 strain but also against various VOCs. Its ability to enhance preexisting immune responses suggests a potential contribution to expanding and sustaining herd immunity within the population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laboratorios Avimex S.A. de C.V. reports financial support was provided by Consejo Nacional de Humanidades, Ciencia y Tecnología. México. Bernardo Lozano-Dubernard reports financial support was provided by Laboratorios Avimex S.A. de C.V. P.P., F.K., and A.G.-S. has patent #62/994,252 pending to Mount Sinai. P.P., F.K., and A.G.-S. has patent #63/018,457 pending to Mount Sinai. P.P., F.K., and A.G.-S. has patent #63/020,503 pending to Mount Sinai. P.P., F.K., and A.G.-S. has patent #63/024,436 pending to Mount Sinai. P.P., F.K., and A.G.-S. has patent #63/251,020 pending to Mount Sinai. M.T., D.S.-M., C.L.-M., H.E.C.-C., F.C.-P., G.P.D.L., and B.L.-D. has patent #PCT/IB2022/058886. MX/a/2021/011439 pending to Avimex S.A. de C.V. The vaccine candidate administered in this study was developed by faculty members at the Icahn School of Medicine at Mount Sinai including P.P., F.K., and A.G.-S. Mount Sinai is seeking to commercialize this vaccine; therefore, the institution and its faculty inventors could benefit financially. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-849 CoV-2 serological assays (USA Provisional Application Numbers: 62/994,252, 63/018,457, 63/020,503, and 63/024,436) and NDV-based SARS-CoV-2 vaccines (USA Provisional Application Number: 63/251,020) which list F.K. as co-inventor. A.G.-S. and P.P. are co-inventors in the NDV-based SARS-CoV-2 vaccine patent application. Patent applications were submitted by the Icahn School of Medicine at Mount Sinai. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, CastleVax, to commercialize SARS-CoV-2 vaccines. F.K., P.P., and A.G.-S. serve on the scientific advisory board of CastleVax and are listed as co-founders of the company. F.K. has consulted for Merck, Seqirus, Curevac, and Pfizer, and is currently consulting for Gritstone, Third Rock Ventures, GSK, and Avimex. The F.K. laboratory has been collaborating with Pfizer on animal models of SARS-CoV-2. C.L.-M. has consulted for AstraZeneca. The A.G.-S. laboratory has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories, and Merck. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus, Pfizer, and Prosetta. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and AstraZeneca. PP has a consulting agreement with Avimex. Members of Avimex developed the live vaccine used in this study. Avimex filed patent applications with Mount Sinai and CONAHCYT. M.T., D.S.-M., C.L.-M., H.E.C.-C., F.C.-P., G.P.D.L., and B.L.-D. are named as inventors on at least one of those patent applications. The clinical study was entirely performed in Mexico, and Mount Sinai had no role in it. The rest of the participants are employees of their corresponding institutions and declare no competing interests. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cervical cancer is among the most frequently occurring neoplasms worldwide, and it particularly affects individuals in developing countries. Factors such as the low quality of screening tests, the high incidence of locally advanced cancer stages and the intrinsic resistance of certain tumors are the main causes of failure in the treatment of this neoplasm. Due to advances in the understanding of carcinogenic mechanisms and bioengineering research, advanced biological nanomaterials have been manufactured. The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including IGF receptor 1. These receptors are activated by binding to their respective growth factor ligands, IGF-1 and IGF-2, and insulin, and play an important role in the development, maintenance, progression, survival and treatment resistance of cervical cancer. In the present review, the role of the IGF system in cervical cancer and three nanotechnological applications that use elements of this system are described, namely Trap decoys, magnetic iron oxide nanoparticles and protein nanotubes. Their use in the treatment of resistant cervical cancer tumors is also discussed., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Morales-Rodríguez et al.)

Background: SARS-CoV-2, the etiological agent causing COVID-19, has infected more than 27 million people with over 894000 deaths worldwide since its emergence in December 2019. Factors for severe diseases, such as diabetes, hypertension, and obesity have been identified however, the precise pathogenesis is poorly understood. To understand its pathophysiology and to develop effective therapeutic strategies, it is essential to define the prevailing immune cellular subsets., Methods: We performed whole circulating immune cells scRNAseq from five critically ill COVID-19 patients, trajectory and gene ontology analysis., Results: Immature myeloid populations, such as promyelocytes-myelocytes, metamyelocytes, band neutrophils, monocytoid precursors, and activated monocytes predominated. The trajectory with pseudotime analysis supported the finding of immature cell states. While the gene ontology showed myeloid cell activation in immune response, DNA and RNA processing, defense response to the virus, and response to type 1 interferon. Lymphoid lineage was scarce. Expression of genes such as C/EBPβ, IRF1and FOSL2 potentially suggests the induction of trained immunity., Conclusions: Our results uncover transcriptomic profiles related to immature myeloid lineages and suggest the potential induction of trained immunity., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

Cannabidiol (CBD) has been used to treat a variety of cancers and inflammatory conditions with controversial results. In previous work, we have shown that breast cancer MCF-7 cells, selected by their response to inflammatory IL-1β cytokine, acquire a malignant phenotype (6D cells) through an epithelial-mesenchymal transition (EMT). We evaluated CBD as a potential inhibitor of this transition and inducer of reversion to a non-invasive phenotype. It decreased 6D cell viability, downregulating expression of receptor CB1. The CBD blocked migration and progression of the IL-1β-induced signaling pathway IL-1β/IL-1RI/β-catenin, the driver of EMT. Cannabidiol reestablished the epithelial organization lost by dispersion of the cells and re-localized E-cadherin and β-catenin at the adherens junctions. It also prevented β-catenin nuclear translocation and decreased over-expression of genes for ∆Np63α, BIRC3, and ID1 proteins, induced by IL-1β for acquisition of malignant features. Cannabidiol inhibited the protein kinase B (AKT) activation, a crucial effector in the IL-1β/IL-1RI/β-catenin pathway, indicating that at this point there is crosstalk between IL-1β and CBD signaling which results in phenotype reversion. Our 6D cell system allowed step-by-step analysis of the phenotype transition and better understanding of mechanisms by which CBD blocks and reverts the effects of inflammatory IL-1β in the EMT.

The mechanisms behind the induction of malignancy and chemoresistance in breast cancer cells are still not completely understood. Inflammation is associated with the induction of malignancy in different types of cancer and is highlighted as an important factor for chemoresistance. In previous work, we demonstrated that the inflammatory cytokine interleukin 1β (IL-1β)-induced upregulation of genes was associated with chemoresistance in breast cancer cells. Here, we evaluated the participation and the expression profile of TP63 in the induction of resistance to cisplatin. By loss-of-function assays, we identified that IL-1β particularly upregulates the expression of the tumor protein 63 (TP63) isoform ΔNP63α, through the activation of the IL-1β/IL-1RI/β-catenin signaling pathway. Upregulation of ΔNP63α leads to an increase in the expression of the cell survival factors epidermal growth factor receptor (EGFR) and phosphatase 1D (Wip1), and a decrease in the DNA damage sensor, ataxia-telangiectasia mutated (ATM). The participation of these processes in the increase of resistance to cisplatin was confirmed by silencing TP63 expression or by inhibition of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) activity in the IL-1β/IL-1RI/β-catenin signaling pathway. These data reinforced the importance of an inflammatory environment in the induction of drug resistance in cancer cells and uncovered a molecular mechanism where the IL-1β signaling pathway potentiates the acquisition of cisplatin resistance in breast cancer cells.

Cervical cancer (CC) is one of the most common cancers diagnosed in women worldwide, and it is estimated that ~500,000 new patients are diagnosed with cervical cancer annually and that ~270,000 deaths occur each year. Patients with cervical cancer are treated with different radiotherapy schedules, either alone or with adjuvant chemotherapy. Unfortunately, nearly 50% of all patients with cervical cancer do not respond to standard treatment due to tumor radioresistance. In this scenario, several microRNAs (miRNAs) have been associated with the acquisition of the radioresistance phenotype. The aim of the present study was to evaluate the possible role of miR‑125a in the acquisition of radioresistance in cervical cancer. The expression of miR‑125a was assessed by means of RT‑qPCR in 30 cervical cancer samples from patients receiving standard treatment and 3 induced radioresistant cervical cancer cell lines. In addition, we employed miR‑125a mimics and inhibitors to evaluate its function in the induction of radioresistance. We showed that miR‑125a was downregulated in patients with cervical cancer who did not respond to standard treatment. Concordantly, radioresistant SiHa, CaSki and HeLa cell lines had low levels of miR‑125a with respect to the sensitive cell lines. Finally, we demonstrated that overexpression of miR‑125a sensitized cervical cancer cells to radiation therapy through the downregulation of CDKN1A. Our data corroborate previously published studies in which it was demonstrated that miRNAs could play a role in the regulation of the process of radioresistance. Additionally, we showed that overexpression of miR‑125a could be used as a radioresistance biomarker in patients with cervical cancer.

Dim light exposure of the mother during pregnancy has been proposed as one of the environmental factors that affect the fetal brain development in schizophrenia. Melatonin circulating levels are regulated by the environmental light/dark cycle. This hormone stimulates neuronal differentiation in the adult brain. However, little is known about its role in the fetal human brain development. Olfactory neuronal precursors (ONPs) are useful for studying the physiopathology of neuropsychiatric diseases because they mimic all the stages of neurodevelopment in culture. Here, we first characterized whether melatonin stimulates neuronal differentiation in cloned ONPs obtained from a healthy control subject (HCS). Then, melatonin effects were evaluated in primary cultures of ONPs derived from a patient diagnosed with schizophrenia (SZ) and an age- and gender-matched HCS. Axonal formation was evidenced morphologically by tau immunostaining and by GSK3β phosphorylated state. Potassium-evoked secretion was assessed as a functional feature of differentiated neurons. As well, we report the expression of MT1/2 receptors in human ONPs for the first time. Melatonin stimulated axonal formation and ramification in cloned ONPs through a receptor-mediated mechanism and enhanced the amount and velocity of axonal and somatic secretion. SZ ONPs displayed reduced axogenesis associated with lower levels of pGSK3β and less expression of melatonergic receptors regarding the HCS ONPs. Melatonin counteracted this reduction in SZ cells. Altogether, our results show that melatonin signaling is crucial for functional differentiation of human ONPs, strongly suggesting that a deficit of this indoleamine may lead to an impaired neurodevelopment which has been associated with the etiology of schizophrenia., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cervical cancer is one of the leading causes of death in women worldwide, which mainly affects developing countries. The patients who suffer a recurrence and/or progression disease have a higher risk of developing distal metastases. Proteases comprising the degradome given its ability to promote cell growth, migration, and invasion of tissues play an important role during tumor development and progression. In this study, we used high-density microarrays and quantitative reverse transcriptase polymerase chain reaction to evaluate the degradome profile and their inhibitors in 112 samples of patients diagnosed with locally advanced cervical cancer. Clinical follow-up was done during a period of 3 years. Using a correlation analysis between the response to treatment and the development of metastasis, we established a molecular signature comprising eight degradome-related genes (FAM111B, FAM111A, CFB, PSMB8, PSMB9, CASP7, PRSS16, and CD74) with the ability to discriminate patients at risk of distal metastases. In conclusion, present results show that molecular signature obtained from degradome genes can predict the possibility of metastasis in patients with locally advanced cervical cancer.

Background: Interleukin 1 beta (IL-1beta) and other inflammatory cytokines are reported to induce phenotypic changes in epithelial breast cancer tumor cells related to increased invasiveness. Mechanisms involved in the process are not well understood., Methods: The noninvasive breast cancer epithelial cell line MCF-7 was used to investigate the IL-1beta-induced phenotype. Live cells expressing EGFP-actin were monitored for cell morphology changes and actin cytoskeleton dynamics by time-lapse video microscopy in the presence of IL-1beta and specific inhibitors of actin signaling pathways. Chemotaxis, invasion of Matrigel, MMP activity and expression of S100A4 in cells treated with IL-1beta were assessed by migration assays, zymograms and immunoblots., Results: Exposure to IL-1beta specifically induced a change in MCF-7 cells from a typical epithelial morphology into elongated cells, showing numerous dynamic actin-rich lamellae and peripheral ruffles characteristic of fibroblasts. These cells could scatter from compact cell colonies and respond to chemoattractants such as the homing-associated chemokine CXCL-12. Pharmacological blockage of actin signaling pathways and negative mutants of RhoGTPases revealed that actin reorganization and enhanced motility are regulated via PI3K/Rac 1 activation. IL-1beta-stimulated cells expressed the metastasis promoter S100A4, increased secretion of active MMP-9 and MMP-2 and invasion of extracellular matrix proteins., Conclusions: IL-1beta induces a PI3K/Rac 1-regulated reorganization of the actin cytoskeleton of MCF-7 cells that is required for cell scattering, elongation and migration. The enhanced motility is accompanied by expression of protein markers correlated with invasive behavior., (Copyright 2010 IMSS. Published by Elsevier Inc. All rights reserved.)

Infection with dengue virus type-2 (DENV-2) begins with virus adherence to cell surface receptors. In endothelial cells (HMEC-1), a cell model for DENV-2 infection, alpha 5 beta 3 integrin has been identified as a putative receptor for the virus. Previous work had suggested that the actin cytoskeleton of HMEC-1 cells plays an important role in virus entry and infection. In the present work, fixed and living HMEC-1 cells expressing enhanced green fluorescent protein-actin were monitored for actin reorganization after virus inoculation, utilizing fluorescence and time lapse microscopy. Cell infection and production of infective viruses were quantified using an anti-E protein antibody and by measuring the p.f.u. ml(-1). Specific drugs that antagonize actin organization and regulate actin-signalling pathways were tested in viral adhesion and infection assays, as were the expression of dominant-negative Rac1 and Cdc42 proteins. Disorganization of actin precluded infection, while microtubule depolymerization had no effect. Activation of Rac1 and Cdc42 signalling, which occurs upon virus binding, induced reorganization of actin to form filopodia in the cellular periphery. Formation of filopodia was a requirement for virus entry and further cell infection. Expression of the dominant-negative proteins Rac1 and Cdc42 confirmed the role of these GTPases in the actin reorganization that is required to form filopodia. In addition, inhibition of the ATPase activity of myosin II greatly decreased infection, suggesting its participation in filopodial stability. We show here, for the first time, that internalization of DENV-2 into endothelial cells requires viral induction of dynamic filopodia regulated by Rac1 and Cdc42 cross-talk and myosin II motor activities.

Interaction of Entamoeba histolytica trophozoites with target cells and substrates activates signaling pathways in the parasite. Phosphorylation cascades triggered by phospho-inositide and adenyl-cyclase-dependent pathways modulate reorganization of the actin cytoskeleton to form structures that facilitate adhesion. In contrast, little is known about participation of Rho proteins and Rho signaling in actin rearrangements. We report here the in vivo expression of at least one Rho protein in trophozoites, whose activation induced actin reorganization and actin-myosin interaction. Antibodies to EhRhoA1 recombinant protein mainly localized Rho in the cytosol of nonactivated amoebae, but it was translocated to vesicular membranes and to some extent to the plasma membrane after treatment with lysophosphatidic acid (LPA), a specific agonist of Rho activation. Activated Rho was identified in LPA-treated trophozoites. LPA induced striking polymerization of actin into distinct dynamic structures. Disorganization of these structures by inhibition of Rho effector, Rho-kinase (ROCK), and by ML-7, an inhibitor of myosin light chain kinase dependent phosphorylation of myosin light chain, suggested that the actin structures also contained myosin. LPA stimulated concanavalin-A-mediated formation of caps, chemotaxis, invasion of extracellular matrix substrates, and erythrophagocytosis, but not binding to fibronectin. ROCK inhibition impaired LPA-stimulated functions and to some extent adhesion to fibronectin. Similar results were obtained with ML-7. These data suggest the presence and operation of Rho-signaling pathways in E. histolytica, that together with other, already described, signaling routes modulate actomyosin-dependent motile processes, particularly stimulated during invasive behavior., (Copyright (c) 2006 Wiley-Liss, Inc.)