Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal ...gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and occasionally extramedullary disease, is drastically affected by the tumor microenvironment (TME). Soluble factors and direct cell-cell interactions regulate MM plasma cell trafficking and homing to the BM niche. Mesenchymal stromal cells, osteoclasts, osteoblasts, myeloid and lymphoid cells present in the BM create a unique milieu that favors MM plasma cell immune evasion and promotes disease progression. Moreover, TME is implicated in malignant cell protection against anti-tumor therapy. This review describes the main cellular and non-cellular components located in the BM, which condition the immunosuppressive environment and lead the MM establishment and progression.
ICAP‐1 regulates β1‐integrin activation and cell adhesion. Here, we used ICAP‐1‐null mice to study ICAP‐1 potential involvement during immune cell development and function. Integrin α4β1‐dependent ...adhesion was comparable between ICAP‐1‐null and control thymocytes, but lack of ICAP‐1 caused a defective single‐positive (SP) CD8+ cell generation, thus, unveiling an ICAP‐1 involvement in SP thymocyte development. ICAP‐1 bears a nuclear localization signal and we found it displayed a strong nuclear distribution in thymocytes. Interestingly, there was a direct correlation between the lack of ICAP‐1 and reduced levels in SP CD8+ thymocytes of Runx3, a transcription factor required for CD8+ thymocyte generation. In the spleen, ICAP‐1 was found evenly distributed between cytoplasm and nuclear fractions, and ICAP‐1–/– spleen T and B cells displayed upregulation of α4β1‐mediated adhesion, indicating that ICAP‐1 negatively controls their attachment. Furthermore, CD3+‐ and CD19+‐selected spleen cells from ICAP‐1‐null mice showed reduced proliferation in response to T‐ and B‐cell stimuli, respectively. Finally, loss of ICAP‐1 caused a remarkable decrease in marginal zone B‐ cell frequencies and a moderate increase in follicular B cells. Together, these data unravel an ICAP‐1 involvement in the generation of SP CD8+ thymocytes and in the control of marginal zone B‐cell numbers.
Graphical : Lack of ICAP‐1 leads to impaired single‐positive CD8+ thymocyte development without affecting integrin α4β1‐dependent thymocyte adhesion. ICAP‐1 showed a strong nuclear distribution in thymocytes. ICAP‐1–/– spleen T and B cells displayed upregulation of α4β1‐mediated adhesion and reduced proliferation. Loss of ICAP‐1 led to decreased marginal zone B‐cell frequencies.
The α4β1 integrin regulates the trafficking of multiple myeloma (MM) cells and contributes to MM disease progression. MicroRNAs (miRNAs) can have both tumor suppressor and oncogenic roles and thus ...are key controllers of tumor evolution, and have been associated with different phases of MM pathogenesis. Using small RNAseq analysis, we show here that α4β1‐dependent MM cell adhesion regulates the expression of forty different miRNAs, therefore expanding our current view of the α4β1 involvement in MM cell biology. Specific upregulation of miR‐324‐5p and miR‐331‐3p in cells attached to α4β1 ligands was confirmed upon silencing the α4 integrin subunit, and their increased levels found to be dependent on Erk1/2‐ and PI3K‐Akt‐, but not Src‐dependent signaling. Enhanced miR‐324‐5p expression upon α4β1‐mediated MM cell adhesion aimed the hedgehog (Hh) component SMO, revealing that the miR‐324‐5p‐SMO module represents a α4β1‐regulated pathway that could control Hh‐dependent cellular responses in myeloma. Our results open new therapy research avenues around the α4β1 contribution to MM progression that deserve to be investigated.
Abbreviations ALT alanine aminotransferase ApoB apolipoprotein B AST aspartate aminotransferase FIB4 Fibrosis 4 score GGT gammaglutamyltransferase; glycated hemoglobin -HBa1C- HDLc high density ...lipoprotein cholesterol LDLc low density lipoprotein cholesterol Tc total cholesterol TG triglycerides VLDLc very low density lipoprotein cholesterol Dear Editor, In the present study, we have demonstrated that sofosbuvir (SOF) treatment improves systemic insulin resistance in hepatitis C virus (HCV)-patients, and, for the first time, revealed which molecular mechanisms are involved in SOF effects on the impaired insulin response induced by HCV in hepatocytes. ...we addressed that SOF-based treatments could effectively improve the insulin-resistant state of HCV-patients. SEE PDF On the other hand, HCV itself may also impair lipid metabolism since several studies have documented hypocholesterolemia and hypolipidemia, particularly lower levels of total cholesterol (Tc), low density lipoprotein cholesterol (LDLc) and apolipoprotein B (ApoB), the main protein constituent of LDLc and very low density lipoprotein cholesterol (VLDLc), in patients with chronic HCV infection.2 Although our study was not designed to clarify the effects of HCV on lipid profile, it has demonstrated that successful HCV clearance resulted in a rebound of circulating Tc, LDLc, and ApoB levels (P < .005) (Figure 1C and Figure S1B), according to observations in patients who achieved sustained virologic response with IFN-based or IFN-free DAA regimens.2,4 In order to explore the possible molecular mechanisms involved in SOF effects on the improvement of insulin resistance observed in patients, we performed an in vitro experimental model: HCV replicon-carrying cells treated with SOF for HCV clearance (Figure 2A and Figure S2) and further stimulated with different doses of insulin.
Nocturnal intermittent hypoxia (IH) featuring obstructive sleep apnea (OSA) dysregulates hepatic lipid metabolism and might contribute to the development of non-alcoholic fatty liver disease (NAFLD) ...observed in OSA patients. However, further research is required to better understanding the molecular mechanisms underlying IH-induced hepatic lipid accumulation. Therefore, the aim of the present study was to determine the effects of OSA on hepatic CD36 expression and the impact of IH by using a mouse model of OSA. Histological analysis, lipid content and CD36 expression were assessed in livers from subjects who underwent liver biopsy and polygraphic study during sleep, and in livers from mice submitted to chronic IH mimicking OSA. Among those who presented OSA features, NAFLD were significantly more frequent than in control subjects with normal respiratory function (77.8 vs. 36.4%, respectively), and showed more severe liver disease. Interestingly, CD36 expression was significantly overexpressed within the liver of OSA patients with respect to controls, and a significant positive correlation was observed between hepatic levels of CD36 and the values of two well-known respiratory parameters that characterized OSA: apnea/hypopnea index (AHI) and oxygen desaturation index (ODI). Moreover, hepatic lipid accumulation as well as induction of hepatic lipogenic genes, and CD36 mRNA and protein expression were significantly higher in livers from mice exposed to IH conditions for 8 weeks than in their corresponding littermates. This study provides novel evidence that IH featuring OSA could contribute to NAFLD setup partly by upregulating hepatic CD36 expression.
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The main objective of our study is to analyze the results in our hospital after launching a treatment protocol without antibiotic therapy for patients diagnosed with acute ...uncomplicated diverticulitis.
Our observational, prospective, single-center study was developed after launching a treatment protocol without antibiotic therapy for patients diagnosed with acute uncomplicated diverticulitis (AUD) in January 2021. The follow-up period was from January 1, 2021 to September 30, 2023. Variables evaluated by the study have included demographic and analytical variables, as well as those related to diagnosis and whether the patients needed to start antibiotic treatment, inpatient treatment, or surgical procedures.
In total, 199 patients were diagnosed with AUD, 75 of whom were treated without antibiotic therapy as outpatients. Seven of these patients needed to start antibiotic treatment because of adverse evolution; none of these patients required surgical procedures. The need for inpatient treatment, urgent care, or surgical procedures is similar to the group of patients treated with antibiotics.
The main risk factor of failure of outpatient treatment without antibiotic therapy identified by the study was the presence of bacteriuria at diagnosis.
Our results confirm previous reports, observing that treatment without antibiotic therapy in selected patients with AUD is safe.
El objetivo de nuestro estudio es analizar los resultados obtenidos en nuestro centro tras la puesta en marcha de un protocolo de tratamiento sin antibioterapia en pacientes diagnosticados de diverticulitis aguda no complicada.
Se trata de un estudio observacional prospectivo unicéntrico tras la implantación de un protocolo de tratamiento sin antibioterapia en pacientes con diverticulitis aguda no complicada (DANC) en enero de 2021. El periodo de seguimiento fue desde la implantación del protocolo el 1 de enero de 2021 hasta el 30 de septiembre de 2023. Se recogieron variables demográficas, analíticas y diagnósticas de los pacientes valorados, así como si precisaron el inicio de antibioterapia, ingreso o intervención quirúrgica.
199 pacientes fueron diagnosticados de DANC, de los cuales, 75 fueron tratados de forma ambulatoria sin antibioterapia. En 7 de los casos fue preciso iniciar el tratamiento antibiótico por evolución desfavorable, sin que en ninguno de los casos fuera necesario realizar una intervención quirúrgica o drenaje percutáneo urgente. Los resultados, en términos de necesidad de ingreso, reconsulta en urgencias o necesidad de intervención, fueron similares a aquéllos en el grupo de pacientes tratados con antibioterapia.
El principal factor de riesgo de fracaso del tratamiento sin antibioterapia identificado ha sido la presencia de bacteriuria al diagnóstico.
Nuestros resultados demuestran lo publicado hasta la fecha, que el tratamiento sin antibioterapia en pacientes muy seleccionados diagnosticados de DANC es seguro.
The present study consists of a descriptive and documentary review of the educational systems of 18 countries of the European Union. The main objective focuses on analysing and describing the policy ...of automatic promotion by making a comparison between European education systems in EU countries, focusing on learner progression and assessment. The data analysis process has been carried out using the MAXQDA 2022 qualitative analysis program, analyzing the information using a code system. The results show the most relevant information regarding progression and evaluation in Primary Education, serving as support for the educational community and contributing to academic knowledge through new approaches.
The expression of human erythropoietin in the mammary gland is an attractive approach to diminish its current production cost. Previous attempts to produce erythropoietin in the milk of transgenic ...animals resulted in very low expression levels and in a detrimental effect in the health of the founder animals. Here, we show that the direct transduction of the mouse mammary gland with an adenoviral vector carrying the cDNA of erythropoietin promotes its expression in milk at a level as high as 3.5 mg/ml. The recombinant erythropoietin derived from mouse milk showed a different migration and distribution after SDS-PAGE electrophoresis as well as a low in vivo hematopoietic activity. Enzymatic deglycosylation showed that these molecular weight disparities are in part due to differential glycosylation compared to with its counterpart produced in CHO and HC11 cell lines. The difference between in vivo and in vitro glycosylation of human erythropoietin expressed in adenovirally transduced mammary epithelial cells suggests that key enzymes in the glycosylation pathway may be insufficient during lactation. Thus, the direct transduction of the mammary epithelium seems to be a powerful tool to express toxic proteins in milk at levels high enough for their physical, chemical and biological characterization before undertaking the generation of a transgenic mammal.
Abstract
In 2020, the COVID-19 pandemic followed a two-wave pattern in most countries. Hospital admission for COVID-19 in one wave or another could have affected mortality, especially among the older ...persons. The objective of this study was to evaluate whether the admission of older patients during the different waves, before SARS-CoV-2 vaccination was available, was associated with a different mortality. We compared the mortality rates of patients hospitalized during 2020 before (first wave) and after (second wave) July 7, 2020, included in the SEMI-COVID-19 Registry, a large, multicenter, retrospective cohort of patients admitted to 126 Spanish hospitals for COVID-19. A multivariate logistic regression analysis was performed to control for changes in either the patient or disease profile. As of December 26, 2022, 22,494 patients had been included (17,784 from the first wave and 4710 from the second one). Overall mortality was 20.4% in the first wave and 17.2% in the second wave (risk difference (RD) − 3.2%; 95% confidence interval (95% CI) − 4.4 to − 2.0). Only patients aged 70 and older (10,973 patients: 8571 in the first wave and 2386 in the second wave) had a significant reduction in mortality (RD − 7.6%; 95% CI − 9.7 to − 5.5) (unadjusted relative risk reduction: 21.6%). After adjusting for age, comorbidities, variables related to the severity of the disease, and treatment received, admission during the second wave remained a protective factor. In Spain, patients aged 70 years and older admitted during the second wave of the COVID-19 pandemic had a significantly lower risk of mortality, except in severely dependent persons in need of corticosteroid treatment. This effect is independent of patient characteristics, disease severity, or treatment received. This suggests a protective effect of a better standard of care, greater clinical expertise, or a lesser degree of healthcare system overload.
To determine whether healthcare workers (HCW) hospitalized in Spain due to COVID-19 have a worse prognosis than non-healthcare workers (NHCW).
Observational cohort study based on the SEMI-COVID-19 ...Registry, a nationwide registry that collects sociodemographic, clinical, laboratory, and treatment data on patients hospitalised with COVID-19 in Spain. Patients aged 20-65 years were selected. A multivariate logistic regression model was performed to identify factors associated with mortality.
As of 22 May 2020, 4393 patients were included, of whom 419 (9.5%) were HCW. Median (interquartile range) age of HCW was 52 (15) years and 62.4% were women. Prevalence of comorbidities and severe radiological findings upon admission were less frequent in HCW. There were no difference in need of respiratory support and admission to intensive care unit, but occurrence of sepsis and in-hospital mortality was lower in HCW (1.7% vs. 3.9%; p = 0.024 and 0.7% vs. 4.8%; p<0.001 respectively). Age, male sex and comorbidity, were independently associated with higher in-hospital mortality and healthcare working with lower mortality (OR 0.211, 95%CI 0.067-0.667, p = 0.008). 30-days survival was higher in HCW (0.968 vs. 0.851 p<0.001).
Hospitalized COVID-19 HCW had fewer comorbidities and a better prognosis than NHCW. Our results suggest that professional exposure to COVID-19 in HCW does not carry more clinical severity nor mortality.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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