Decolonizing approaches for transforming academic culture through authentic expression, community, and belonging.

The National Commission to Address Racism in Nursing (2022) cites structural and systemic racism in nursing education as significant factors contributing to retention disparities among minoritized students. Establishing a culture of belonging was outlined in the Commission's report as essential to addressing these disparities. At the University of California, Irvine, the Centering Youth & Families for Empowerment and Resilience (CYFER) Lab embraces belonging and collectivity as core principles. The CYFER Lab supports the well-being and professional development of minoritized and/or marginalized health sciences students through community-engaged research and self-care practices. Our commentary examines three core Lab practices-Buen Vivir, prioritizing well-being, and nonhierarchical structures-through the lens of decolonization, an approach we posit can enhance inclusivity and belonging in nursing education. The achievements and growth of our Lab members, along with our expanding body of community-based research, demonstrate that such practices provide an effective alternative model for success in research and education.

Interdisciplinary management of mpox-related local complications: report on a series of cases.

Monkeypox (mpox) is a viral zoonosis, and human-to-human transmission can result from close contact with the respiratory secretions and mucocutaneous lesions of an infected person. The prodromal phase is followed by an eruptive phase, with skin and/or mucosal lesions that progress through several stages at different sites. In this study, we describe the importance of interdisciplinary care management and follow-up of patients with complicated mpox. A cross-sectional study was conducted from May 2022 until August 2022 at a secondary hospital in Madrid (Spain). Out of 100 patients with mpox seen at this institution, we selected and analyzed 11 with local complications. All the patients were male at birth, and the mean age was 32 (30-42) years. The clinical manifestations included skin rash or mucosal lesions, fever, myalgia and lymphadenopathies. The most frequent local complications were pharyngitis associated with dysphagia, penile edema, infection of the mucocutaneous lesions, and ulceration of the genital lesions. A multidisciplinary team was created for the care of patients with complications secondary to mpox. The team comprised dermatologists and specialists in infectious diseases, preventive medicine, and emergency medicine. This approach improved the ability to diagnose and treat early with supportive, topical, and systemic treatment. In our center most of the cases were self-limiting, and none were life-threatening. An interdisciplinary response to a public health alert enhances the management of complex patients and should be implemented in successive outbreaks of mpox.

The importance of RHAMM in the normal brain and gliomas: physiological and pathological roles.

Although the literature about the functions of hyaluronan and the CD44 receptor in the brain and brain tumours is extensive, the role of the receptor for hyaluronan-mediated motility (RHAMM) in neural stem cells and gliomas remain poorly explored. RHAMM is considered a multifunctional receptor which performs various biological functions in several normal tissues and plays a significant role in cancer development and progression. RHAMM was first identified for its ability to bind to hyaluronate, the extracellular matrix component associated with cell motility control. Nevertheless, additional functions of this protein imply the interaction with different partners or cell structures to regulate other biological processes, such as mitotic-spindle assembly, gene expression regulation, cell-cycle control and proliferation. In this review, we summarise the role of RHAMM in normal brain development and the adult brain, focusing on the neural stem and progenitor cells, and discuss the current knowledge on RHAMM involvement in glioblastoma progression, the most aggressive glioma of the central nervous system. Understanding the implications of RHAMM in the brain could be useful to design new therapeutic approaches to improve the prognosis and quality of life of glioblastoma patients.

Senescence modulation as a key process in the dual role of hyaluronan in cancer: the deforestation allegory.

Cancer is one of the leading causes of death worldwide and has been associated with ageing. Although there are numerous reports that have demonstrated the dual role of hyaluronic acid and senescence induction in cancer prevention and promotion, both players have been linked to ageing in opposite ways. Hyaluronan is recognized for its antiaging role, whereas senescence is associated with ageing. In this review we address these dual roles, showing their interrelation, hypothesizing that the downregulation of senescence mediated by HA would be a key factor in the ambivalent effects described. Likewise, the deforestation allegory aims to explain, through the use of a metaphor, the contradictory yet valid results found in the literature. Considering this background, we propose new strategies for improving tumor therapy. Understanding the biology of these complex diseases and the temporal implication of the different players in dissimilar contexts could bring us closer to the therapeutic improvements needed in the field of oncology.

Antitumor effect of 4MU on glioblastoma cells is mediated by senescence induction and CD44, RHAMM and p-ERK modulation.

The extracellular matrix plays a key role in cancer progression. Hyaluronan, the main glycosaminoglycan of the extracellular matrix, has been related to several tumor processes. Hyaluronan acts through the interaction with cell membrane receptors as CD44 and RHAMM and triggers signaling pathways as MEK/ERK. 4-methylumbelliferone (4MU), a well-known hyaluronan synthesis inhibitor, is a promising alternative for cancer therapy. 4MU is a coumarin derivative without adverse effects that has been studied in several tumors. However, little is known about its use in glioblastoma (GBM), the most malignant primary brain tumor in adults. Glioblastoma is characterized by fast growth, migration and tissue invasiveness, and a poor median survival of the patients after treatment. Several reports linked glioblastoma progression with HA levels and even with CD44 and RHAMM expression, as well as MEK/ERK activation. Previously, we showed on a murine GBM cell line that HA enhances GBM migration, while 4MU markedly inhibits it. In this work we showed for the first time, that 4MU decreases cell migration and induces senescence in U251 and LN229 human GBM cell lines. Furthermore, we observed that HA promotes GBM cell migration on both cell lines and that such effects depend on CD44 and RHAMM, as well as MEK/ERK signaling pathway. Interestingly, we observed that the exogenous HA failed to counteract the effects of 4MU, indicating that 4MU effects are independent of HA synthesis inhibition. We found that 4MU decreases total CD44 and RHAMM membrane expression, which could explain the effect of 4MU on cell migration. Furthermore, we observed that 4MU increases the levels of RHAMM inside the cell while decreases the nucleus/cytoplasm relation of p-ERK, associated with 4MU effects on cell proliferation and senescence induction. Overall, 4MU should be considered as a promising therapeutic alternative to improve the outcome of patients with GBM.

4-Methylumbelliferone induces antitumor effects independently of hyaluronan synthesis inhibition in human acute leukemia cell lines.

AIMS: Despite continuous improvement in the treatment of acute leukemia, new therapies are still needed to overcome resistance and reduce adverse effects. The aim of this work was to study the tumor-suppressive effects of 4-methylumbelliferone (4MU) in human acute leukemia cell lines. In addition, we aimed to address the extent of these effects in relation to the inhibition of hyaluronic acid (HA) synthesis. MAIN METHODS: HA levels were measured by an ELISA-like assay. Human acute leukemia cell lines were treated with 4MU, HA or their combination. Cell proliferation was assessed by the [3H]-Tdr uptake assay, metabolic activity by the XTT assay and cell death was determined by DAPI, AO/EB and AnnexinV-PE/7-AAD staining. Senescence induction was evaluated by SA-ß-Gal and C12FDG staining. Total and surface RHAMM expression levels were assessed by flow cytometry and fluorescence microscopy. KEY FINDINGS: 4MU reduced metabolic activity and inhibited cell proliferation in all leukemia cells, and these effects were explained by the induction of senescence or cell death depending on the cell line evaluated. Exogenous HA failed to prevent most of the tumor-suppressive effects observed. Results from this work suggest that the tumor-suppressive effects exerted by 4MU would be explained by HA-synthesis-independent mechanisms. SIGNIFICANCE: These findings broaden the knowledge of 4MU as a potential treatment in acute leukemia. We report for the first time the existence of tumor-suppressive effects of 4MU on human acute leukemia cell lines that are independent of its role as HA-synthesis inhibitor.

The scrambled story between hyaluronan and glioblastoma.

Advances in cancer biology are revealing the importance of the cancer cell microenvironment on tumorigenesis and cancer progression. Hyaluronan (HA), the main glycosaminoglycan in the extracellular matrix, has been associated with the progression of glioblastoma (GBM), the most frequent and lethal primary tumor in the central nervous system, for several decades. However, the mechanisms by which HA impacts GBM properties and processes have been difficult to elucidate. In this review, we provide a comprehensive assessment of the current knowledge on HA's effects on GBM biology, introducing its primary receptors CD44 and RHAMM and the plethora of relevant downstream signaling pathways that can scramble efforts to directly link HA activity to biological outcomes. We consider the complexities of studying an extracellular polymer and the different strategies used to try to capture its function, including 2D and 3D in vitro studies, patient samples, and in vivo models. Given that HA affects not only migration and invasion, but also cell proliferation, adherence, and chemoresistance, we highlight the potential role of HA as a therapeutic target. Finally, we review the different existing approaches to diminish its protumor effects, such as the use of 4-methylumbelliferone, HA oligomers, and hyaluronidases and encourage further research along these lines in order to improve the survival and quality of life of GBM patients.

Apoptotic regulator BCL-2 blockade as a potential therapy in classical Hodgkin Lymphoma.

The challenge in classical Hodgkin Lymphoma (cHL) management is the 30-40% of refractory/relapsed cases. AIMS: The aim of this work was to determine whether NIK and BCL-2 could be useful as prognosis biomarkers in cHL. In addition, we evaluated BCL-2 as a directed-therapy in cHL cell lines using venetoclax. MAIN METHODS: We evaluated NIK and BCL-2 expression in 112 untreated cHL patients' lymph-node biopsies by immunohistochemistry. cHL cell lines were treated with venetoclax alone or combined with vincristine or doxorubicin. Cell viability, metabolic activity and cell death were analyzed by trypan-blue exclusion method, MTS assay and FDA/IP staining respectively. KEY FINDINGS: No correlation between NIK or BCL-2 expression and the majority of the clinical parameters was found. Patients with ≥60% BCL-2+ HRS-cells had a shorter disease-free survival (DFS) and overall survival (OS) (p = 0.002, p = 0.02 respectively). A decision tree analysis, in a 30 patients subgroup, showed that patients with <60% NIK+ HRS-cells but with ≥60% BCL-2+ HRS-cells had a worse outcome in terms of DFS and OS. These parameters performed better as prognosis indicators as compared to the diagnosis bone marrow status. Human cHL cell lines U-H01, KM-H2, L1236, SUPHD1, L540 showed sensitivity to venetoclax. The co-treatment effect of venetoclax and vincristine or doxorubicin on cell viability was diverse depending on the cell line evaluated. SIGNIFICANCE: BCL-2 should be considered as a prognosis biomarker as well as a potential new therapeutic target in cHL. We report for the first time the cytotoxic effect of venetoclax in human cHL cell lines.

Protein deficiency during Trichinella spiralis infection impairs lung immunity against newborn larvae.

The goal of this study was to analyse the effects of a protein-deficient (PD) diet on antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro against newborn larvae (NBL) of Trichinella spiralis in the lungs of infected rats. Two groups of weaning Wistar rats received a PD diet (6.5% casein) and other two received a control diet (C, 20% casein). After ten days, one group of each diet was infected (PDI and CI ) with muscle larvae. Lung tissue extracts (LTE) and lung cell suspension (LCS) were obtained. PDI had lower titres of anti-NBL antibodies in LTE than CI . In ADCC assays using control cells, NBL mortality percentage was lower with LTE from PDI than LTE from CI (P < .01). In assays using control cytotoxic sera, ADCC was exerted by LCS from CI at all days post-infection (p.i.), but only by LCS from 13 days p.i. from PDI . ADCC assays combining LTE and LCS from the same group showed a lower response for PDI than for CI (P < .0001). LCS from PDI contained lower numbers of neutrophils, eosinophils and FcεRI+ cells than CI . PD may diminish ADCC activity against T spiralis NBL in lungs through alterations in specific antibodies and effector cells.

4-Methylumbelliferone as a potent and selective antitumor drug on a glioblastoma model.

Glioblastoma (GBM), the most frequent primary tumor of the central nervous system, has a median survival of 14.6 months. 4-Methylumbelliferone (4MU) is a coumarin derivative widely used as a hyaluronan synthesis inhibitor with proven antitumor activity and without toxic effects reported. We aim to evaluate the antitumor effect of 4MU alone or combined with temozolomide (TMZ) on a GBM cell line, its absence of toxicity on brain cells and its selectivity for tumor cells. The antitumor effect of 4MU alone or combined with TMZ was evaluated on GL26 cells by assessing the metabolic activity through the XTT assay, cell proliferation by BrdU incorporation assay, migration by the wound healing assay, cell death by fluorescein diacetate/propidium iodide (FDA/PI) staining, apoptosis by membrane asymmetry and DNA fragmentation and metalloproteinase activity by zymography. The levels of hyaluronan and its capacity to counteract the effects of 4MU and the expression of RHAMM and CD44 were also determined. The toxicity and selectivity of 4MU were determined by XTT assay and PI staining on normal brain primary cell culture (NBPC-GFP) and GL26/NBPC-GFP cocultures. The GL26 cells expressed RHAMM but not CD44 while synthetized hyaluronan. 4MU decreased hyaluronan synthesis, diminished proliferation and induced apoptosis while reducing cell migration and the activity of metalloproteinases, which was restored by addition of hyaluronic acid. Furthermore, 4MU sensitized GL26 cells to the TMZ effect and showed selective toxicity on tumor cells without exhibiting neurotoxic effects. We demonstrated for the first time the cytotoxic effect of 4MU on GBM cells, highlighting its potential usefulness to improve GBM treatment.

Author Correction: Hyaluronan abrogates imatinib-induced senescence in chronic myeloid leukemia cell lines.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Hyaluronan abrogates imatinib-induced senescence in chronic myeloid leukemia cell lines.

Hyaluronan (HA) is the main glycosaminoglycan of the extracellular matrix. CD44 is the most important HA receptor, and both have been associated with poor prognosis in cancer. Chronic myeloid leukemia (CML) is characterized by the presence of a constitutively activated tyrosine kinase (Breakpoint Cluster Region - Abelson murine leukemia viral oncogene homolog1, BCR-ABL). It is mainly treated with BCR-ABL inhibitors, such as imatinib. However, the selection of resistant cells leads to treatment failure. The aim of this work was to determine the capacity of HA (high molecular weight) to counteract the effect of imatinib in human CML cell lines (K562 and Kv562). We demonstrated that imatinib decreased HA levels and the surface expression of CD44 in both cell lines. Furthermore, HA abrogated the anti-proliferative and pro-senescent effect of Imatinib without modifying the imatinib-induced apoptosis. Moreover, the inhibition of HA synthesis with 4-methylumbelliferone enhanced the anti-proliferative effect of imatinib. These results suggest that Imatinib-induced senescence would depend on the reduction in HA levels, describing, for the first time, the role of HA in the development of resistance to imatinib. These findings show that low levels of HA are crucial for an effective therapy with imatinib in CML.

Low molecular weight hyaluronan induces migration of human choriocarcinoma JEG-3 cells mediated by RHAMM as well as by PI3K and MAPK pathways.

Hyaluronan (HA) is the major glycosaminoglycan present in the extracellular matrix. It is produced by some tumours and promotes proliferation, differentiation and migration among others cellular processes. Gestational trophoblastic disease (GTD) is composed by non-tumour entities, such as hydatidiform mole (HM), which is the most common type of GTD and also malignant entities such as choriocarcinoma (CC) and placental site trophoblastic tumour (PSTT), being CC the most aggressive tumour. Although there is a growing understanding of GTD biology, the role of HA in the pathogenesis of this group of diseases remains largely unknown. The aim of this work was to study the role of HA in the pathogenesis of GTD by defining the expression pattern of HA and its receptors CD44 and RHAMM, as well as to determine if HA can modulate proliferation, differentiation and migration of CC cells. Receptors and signalling pathways involved were also analyzed. We demonstrated that HA and RHAMM are differently expressed among GTD entities and even among trophoblast subtypes. We also showed that HA is able to enhance the expression of extravillous trophoblast markers and also to induce migration of JEG-3 cells, the latter mediated by RHAMM as well as PI3K and MAPK pathways. These findings indicate a novel regulatory mechanism for CC cell biology and also contribute to the understanding of GTD pathophysiology.

4-methylumbelliferone and imatinib combination enhances senescence induction in chronic myeloid leukemia cell lines.

Chronic myeloid leukemia (CML) is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome which encodes a constitutively activated tyrosine kinase (BCR-ABL). The first line treatment for CML consists on BCR-ABL inhibitors such as Imatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Therefore, it is of great value to find molecules that enhance the anti-proliferative effect of first-line drugs. Hyaluronan is the main glycosaminglican of the extracellular matrix which is involved in tumor progression and multidrug resistance. We have previously demonstrated that the inhibition of hyaluronan synthesis by 4-methylumbelliferone (4MU) induces senescence and can revert Vincristine resistance in CML cell lines. However, the effect of 4MU on Imatinib therapy remains unknown. The aim of this work was to determine whether the combination of 4MU with Imatinib is able to modulate the proliferation as well as apoptosis and senescence induction in human CML cell lines. For this purpose the ATCC cell line K562, and its multidrug resistant derivate, Kv562 were used. Cells were exposed to 4MU, Imatinib or a combination of both. We demonstrated that 4MU and Imatinib co-treatment abrogated the proliferation of both cell lines. However, such co-treatment did not increase the levels of apoptosis when compared with the treatment with Imatinib alone. For both cell lines the mechanisms of tumor suppression involved was senescence, since the combination of 4MU and Imatinib arrested the cell cycle and increased senescence associated ß-galactosidase activity and senescence associated heterochromatin foci presence when compared to each drug alone. Moreover, 4MU, Imatinib and 4MU + Imatinib decreased pAkt/Akt ratio in both cell lines and reduced the pERK/ERK ratio only in K562 cells. These findings highlight the potential use of 4MU together with Imatinib for CML therapy.

Hyaluronan oligomers sensitize chronic myeloid leukemia cell lines to the effect of Imatinib.

Chronic myeloid leukemia is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome (Ph), generated by a reciprocal translocation occurring between chromosomes 9 and 22 [t(9;22)(q34;q11)]. As a consequence, a fusion gene (bcr-abl) encoding a constitutively active kinase is generated. The first-line treatment consists on BCR-ABL inhibitors such as Imatinib, Nilotinib and Dasatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Therefore, finding molecules that enhance the anti-proliferative effect of first-line drugs is of value. Hyaluronan oligomers (oHA) are known to be able to sensitize several tumor cells to chemotherapy. We have previously demonstrated that oHA can revert Vincristine resistance in mouse lymphoma and human leukemia cell lines. However, little is known about the role of oHA in hematological malignancies. The aim of this work was to determine whether oHA are able to modulate the anti-proliferative effect of Imatinib in chronic myeloid leukemia (CML) cell lines. The effect on apoptosis and senescence as well as the involvement of signaling pathways were also evaluated. For this purpose, the human CML cell lines K562 and Kv562 (resistant) were used. We demonstrated that oHA sensitized both cell lines to the anti-proliferative effect of Imatinib increasing apoptosis and senescence. Moreover, this effect would be accomplished through the down-regulation of the PI3K signaling pathway. These findings highlight the potential of oHA when used as a co-adjuvant therapy for chronic myeloid leukemia.

Safety characterization and antimicrobial properties of kefir-isolated Lactobacillus kefiri.

Lactobacilli are generally regarded as safe; however, certain strains have been associated with cases of infection. Our workgroup has already assessed many functional properties of Lactobacillus kefiri, but parameters regarding safety must be studied before calling them probiotics. In this work, safety aspects and antimicrobial activity of L. kefiri strains were studied. None of the L. kefiri strains tested caused α- or ß-hemolysis. All the strains were susceptible to tetracycline, clindamycin, streptomycin, ampicillin, erythromycin, kanamycin, and gentamicin; meanwhile, two strains were resistant to chloramphenicol. On the other hand, all L. kefiri strains were able to inhibit both Gram(+) and Gram(-) pathogens. Regarding the in vitro results, L. kefiri CIDCA 8348 was selected to perform in vivo studies. Mice treated daily with an oral dose of 10(8) CFU during 21 days showed no signs of pain, lethargy, dehydration, or diarrhea, and the histological studies were consistent with those findings. Moreover, no differences in proinflammatory cytokines secretion were observed between treated and control mice. No translocation of microorganisms to blood, spleen, or liver was observed. Regarding these findings, L. kefiri CIDCA 8348 is a microorganism isolated from a dairy product with a great potential as probiotic for human or animal use.