Bowel symptoms associated with coronavirus disease 19 in hospitalized patients with moderate to severe illness

Bowel symptoms, such as diarrhea, have higher prevalence during coronavirus disease 2019 (COVID-19). The correlation between the severity of these symptoms and their prognosis has not been defined yet. Furthermore, higher prevalence of gastrointestinal symptoms after recovery from COVID-19 has been reported. This study aimed to analyze the correlation of potential factors with the severity of diarrhea during COVID-19 and to assess the progression of post-COVID-19 bowel symptoms. This prospective longitudinal cohort included 109 patients with moderate to severe COVID-19 symptoms who were hospitalized from May to July 2021. Patients were interviewed to assess the presence and intensity of bowel symptoms during COVID-19 and 3–6 months after hospital discharge using the Gastrointestinal Symptom Rating Scale questionnaire. Demographic and clinical data were obtained and their correlations with the intensity of bowel symptoms were examined. The presence of severe diarrhea was correlated with the need for ventilatory support and the use of anticoagulants but not with the use of antibiotics. In addition, bowel symptoms, such as loose stools and incomplete evacuation but not diarrhea, constipation, or abdominal pain, persisted for at least 3–6 months after hospital discharge. These results suggest that the severity of diarrhea during COVID-19 may be associated with worsening of the disease and that only loose stools and incomplete evacuation are present after COVID-19. The chronicity of these bowel symptoms should be evaluated to improve the treatment of patients with COVID-19

Assay strategies for the discovery and validation of therapeutics targeting <i>Brugia pahangi</i> Hsp90

The chemotherapy of lymphatic filariasis relies upon drugs such as diethylcarbamazine and ivermectin that largely target the microfilarial stages of the parasite, necessitating continued treatment over the long reproductive life span of the adult worm. The identification of compounds that target adult worms has been a long-term goal of WHO. Here we describe a fluorescence polarization assay for the identification of compounds that target Hsp90 in adult filarial worms. The assay was originally developed to identify inhibitors of Hsp90 in tumor cells, and relies upon the ability of small molecules to inhibit the binding of fluorescently labelled geldanamycin to Hsp90. We demonstrate that the assay works well with soluble extracts of Brugia, while extracts of the free-living nematode C. elegans fail to bind the probe, in agreement with data from other experiments. The assay was validated using known inhibitors of Hsp90 that compete with geldanamycin for binding to Hsp90, including members of the synthetic purine-scaffold series of compounds. The efficacy of some of these compounds against adult worms was confirmed in vitro. Moreover, the assay is sufficiently sensitive to differentiate between binding of purine-scaffold compounds to human and Brugia Hsp90. The assay is suitable for high-throughput screening and provides the first example of a format with the potential to identify novel inhibitors of Hsp90 in filarial worms and in other parasitic species where Hsp90 may be a target

Dependent seniors garment design

This paper is part of a PhD research in Textile Engineering at University of Minho and aims to establish an ergonomic pattern design methodology to be used in the construction of garments for elderly women, aged 65 and over, dependent of care. The research was developed with a close contact with four institutions involved in supporting this aged population, located in the cities of Guimaraes (Portugal) and Teresina (Brazil). These clothes should be adequate to their anthropometrics and their special needs, in accordance with important functional factors for the dependency of their caregiver, such as: care for the caregiver and comfort for the user. Questions regarding the functional properties of the materials, the pattern design process, trimmings and the assembling process of the garments are specially considered in the desired comfort levels, in order to provide an adequate handling by facilitating the dressing and undressing tasks, but also to assure the user the needed comfort in all its variables.This work is supported by FEDER funds through the Competitive Factors Operational Program (COMPETE) POCI-01-0145-FEDER-007136 and by national funds through Portuguese Foundation for Science and Technology (FCT), under the project UID/CTM/000264 financed by Science Without Borders/CAPEs.info:eu-repo/semantics/publishedVersio

The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1

<p>Abstract</p> <p>Background</p> <p>Heat shock protein 90 (HSP90) inhibitors have emerged as a promising class of anti-cancer drugs in both solid and hematologic malignancies. The HSP90 family includes the cytosolic HSP90 (HSP90AA1), the ER paralogue gp96 (HSP90B1) and the mitochondrial member TRAP1 (HSP90L). We evaluated the <it>in vitro </it>anti-tumor activity and mechanism of action of PU-H71, a novel purine scaffold HSP90 inhibitor in human multiple myeloma cell lines.</p> <p>Methods</p> <p>Multiple human myeloma cell lines including cells that are resistant to corticosteroids and bortezimab were treated with PU-H71, followed by analysis of cell viability, cell cycle progression and apoptosis, by flow cytometry and caspase 3 immunoblot. Induction of unfolded protein response was studied by XBP-1 s immunoblot. The role of gp96 was further assessed by small hairpin RNA knockdown of gp96 before treatment with PU-H71.</p> <p>Results</p> <p>PU-H71 has potent <it>in vitro </it>anti-myeloma activity in both drug-sensitive and drug-resistant cell lines. PU-H71 activates the unfolded protein response and induces caspase-dependent apoptosis. The stable gp96 knockdown human myeloma cell line was found to be more resistant to PU-H71 and other HSP90 inhibitors including 17-AAG and 17-DMAG, even though these cells are more sensitive to conventional anti-myeloma drugs.</p> <p>Conclusion</p> <p>We conclude that PU-H71 is a promising drug for the treatment of myeloma. Our finding further suggests that PU-H71 and the geldanamycin analogues work in part by inhibiting the endoplasmic reticulum gp96 along with the cytosolic HSP90.</p

Experiences of women who faced a pregnancy between 35 and 45 years of age / Experiencias de mulheres ao vivenciarem uma gravidez entre 35 e 45 anos de idade

Objetivo: identificar a experiência de mulheres ao vivenciarem uma gravidez tardia. Método: estudo descritivo, quantitativo, desenvolvido no município de Ouro Velho-PB, com mulheres na faixa etária entre 35 a 45 anos de idade. A amostra gerou em torno de 19 mulheres que engravidaram nesta faixa etária, cadastradas na Unidade Básica de Saúde da Família do município. Resultados: observou-se que a maioria estava entre 35 a 40 anos (58%), casadas, pardas e ensino superior, entretanto, a gravidez tardia possibilitou significados na vida destas mulheres, permeadas de sentimentos de satisfação pessoal, familiar, possibilitando maior segurança na relação com o companheiro, família e bebê. Conclusão: identificou-se complicações como hipertensão, prematuridade, aborto e pós-datismo, que influenciaram no tipo da via de parto, sendo a cesariana a de maior evidência. O preparo psicológico para a maternidade nessa faixa etária é acompanhado de sentimentos de desejo, alegria, ansiedade e medo do desconhecido.

Hsp90 inhibition differentially destabilises MAP kinase and TGF-beta signalling components in cancer cells revealed by kinase-targeted chemoproteomics

<p>Abstract</p> <p>Background</p> <p>The heat shock protein 90 (Hsp90) is required for the stability of many signalling kinases. As a target for cancer therapy it allows the simultaneous inhibition of several signalling pathways. However, its inhibition in healthy cells could also lead to severe side effects. This is the first comprehensive analysis of the response to Hsp90 inhibition at the kinome level.</p> <p>Methods</p> <p>We quantitatively profiled the effects of Hsp90 inhibition by geldanamycin on the kinome of one primary (Hs68) and three tumour cell lines (SW480, U2OS, A549) by affinity proteomics based on immobilized broad spectrum kinase inhibitors ("kinobeads"). To identify affected pathways we used the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway classification. We combined Hsp90 and proteasome inhibition to identify Hsp90 substrates in Hs68 and SW480 cells. The mutational status of kinases from the used cell lines was determined using next-generation sequencing. A mutation of Hsp90 candidate client RIPK2 was mapped onto its structure.</p> <p>Results</p> <p>We measured relative abundances of > 140 protein kinases from the four cell lines in response to geldanamycin treatment and identified many new potential Hsp90 substrates. These kinases represent diverse families and cellular functions, with a strong representation of pathways involved in tumour progression like the BMP, MAPK and TGF-beta signalling cascades. Co-treatment with the proteasome inhibitor MG132 enabled us to classify 64 kinases as true Hsp90 clients. Finally, mutations in 7 kinases correlate with an altered response to Hsp90 inhibition. Structural modelling of the candidate client RIPK2 suggests an impact of the mutation on a proposed Hsp90 binding domain.</p> <p>Conclusions</p> <p>We propose a high confidence list of Hsp90 kinase clients, which provides new opportunities for targeted and combinatorial cancer treatment and diagnostic applications.</p

Lysophosphatidic Acid Induces MDA-MB-231 Breast Cancer Cells Migration through Activation of PI3K/PAK1/ERK Signaling

Enhanced motility of cancer cells is a critical step in promoting tumor metastasis. Lysophosphatidic acid (LPA), representing the major mitogenic activity in serum, stimulates migration in various types of cancer cells. However, the underlying signaling mechanisms for LPA-induced motility of cancer cells remain to be elucidated.In this study, we found that LPA dose-dependently stimulated migration of MDA-MB-231 breast cancer cells, with 10 µM being the most effective. LPA also increased ERK activity and the MEK inhibitor U0126 could block LPA-induced ERK activity and cell migration. In addition, LPA induced PAK1 activation while ERK activation and cell migration were inhibited by ectopic expression of an inactive mutant form of PAK1 in MDA-MB-231 cells. Furthermore, LPA increased PI3K activity, and the PI3K inhibitor LY294002 inhibited both LPA-induced PAK1/ERK activation and cell migration. Moreover, in the breast cancer cell, LPA treatment resulted in remarkable production of reactive oxygen species (ROS), while LPA-induced ROS generation, PI3K/PAK1/ERK activation and cell migration could be inhibited by N-acetyl-L-Cysteine, a scavenger of ROS.Taken together, this study identifies a PI3K/PAK1/ERK signaling pathway for LPA-stimulated breast cancer cell migration. These data also suggest that ROS generation plays an essential role in the activation of LPA-stimulated PI3K/PAK1/ERK signaling and breast cancer cell migration. These findings may provide a basis for designing future therapeutic strategy for blocking breast cancer metastasis