•Multiple sclerosis: the second cause of neurological disability in young adults.•Depression is present in up to 50% of people with multiple sclerosis.•Physical limitations and mood disorders ...influence perception on quality of life.•Quality of life in patients with multiple sclerosis must worries health personnel.
The aim of this work was to evaluate the quality of life of patients with multiple sclerosis and its association with depressive symptoms and physical health.
A total of 117 patients clinically diagnosed with Multiple Sclerosis (MS) were studied. The MSQOL-54 scale was applied. The depressive symptoms were assessed using the Beck Depression Inventory (BDI), while degree of physical disability was evaluated with the EDSS (Expanded Disability Status Scale). The results of these last two instruments were associated with MSQOL-54 to determine its influence on the perception of quality of life.
We evaluated 65 women (56%) and 52 men (44%), with a mean age of 35 years, a mean age of 27 years at the time of diagnosis, and a mean evolution of 8 years. 88% of the patients showed the relapsing-remitting subtype; 42% had paid employment; 29% of the studied patients required help to perform daily activities; 75% took disease-modifying medications. They obtained on average a score of 3.62 ± 2.30 on the EDSS and 11.5 ± 9.21 on the BDI. The general average in MSQOL-54 was 64.67 ± 17.52.
Quality of life, in patients with multiple sclerosis is an issue that worries health personnel, it is essential to implement strategies for reducing the impact of the disease on patients' lives, mainly through the application of programs aimed to decrees depression and improve social support.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Silicon blue-emitting nanoparticles (NPs) are promising effectors for photodynamic therapy and radiotherapy, because of their production of reactive oxygen species (ROS) upon irradiation.
...Amino-functionalized silicon NPs (NH
SiNP) were intrinsically nontoxic below 100 μg/ml in vitro (on two tumor cell lines) and in vivo (zebrafish larvae and embryos). NH
SiNP showed a moderate effect as a photosensitizer for photodynamic therapy and reduced ROS generation in radiotherapy, which could be indicative of a ROS scavenging effect. Encapsulation of NH
SiNP into ultradeformable liposomes improved their skin penetration after topical application, reaching the viable epidermis where neoplastic events occur.
Subsequent derivatizations after amino-functionalization and incorporation to nanodrug delivery systems could expand the spectrum of the biomedical application of these kind of silicon NPs.
•Treatment with NTZ is at risk of developing PML.•There is no correlation between anti-JC virus antibody index and JC virus DNA.•JC virus mutations in VP1 gene provide predictive information for PML ...development.•The identify the genotype of JC virus allows more efficient treatment and follow-up .
Patients with Multiple Sclerosis (MS) undergoing treatment with natalizumab (NTZ) are at risk of developing progressive multifocal leukoencephalopathy (PML) due to the reactivation of John Cunningham (JC) virus. A relevant characteristic among PML cases is the development of single nucleotide mutations in the VP1 gene of the causal JC virus. The identification of such mutations in timely manner can provide valuable information for MS management.
To identify mutations along the JC virus VP1 gene in MS patients undergoing treatment with NTZ, and correlate them with anti-JC virus antibody index.
Eighty-eight MS patients, one hundred twenty controls, and six patients with diagnosis of Human Immunodeficiency Virus (HIV) with and without secondary PML were included. JC virus was identified in peripheral blood mononuclear cells and cerebrospinal fluid by PCR. Amplification and sequencing of the entire length of the VP1 gene were performed in all positive clinical samples.
In MS cases no mutations were observed in the JC virus VP1 gene, but it was positive in HIV controls with PML. Interestingly, the JC virus VP1 gene sequence derived from the HIV patients exhibited a non-silent substitution in position 186 (G → C), leading to an amino acid change (Lys → Asp). We did not find correlation between anti-JC virus antibody index and DNA viral detection.
. The identification of single nucleotide mutants in the JC virus VP1 gene might be an early predictive marker to PML for efficient patient treatment and follow-up.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Multiple Sclerosis is the central nervous system's most common demyelinating disease.•Both, physical limitations and disorders that affect mood, can influence Multiple Sclerosis patients perceived ...discrimination against them.•Multiple Sclerosis Patients perceived discrimination is associated with depressive symptoms.•Perceived discrimination in patients with multiple sclerosis is an issue that worries health personnel.
Multiple Sclerosis is the central nervous system's most common demyelinating disease and the second leading cause of neurological disability in young adults. Its natural development involves physical and cognitive impairment. Patients commonly perceive discrimination against them, regardless of its occurrence, accepting it as an inherent part of the disease.
This study aimed to determine the association between perceived discrimination and the depressive symptoms and physical disability present in patients diagnosed with multiple sclerosis, treated at the Demyelinating Diseases Clinic of the National Institute of Neurology and Neurosurgery, Manuel Velasco Suárez.
A cross-sectional study was conducted in 98 patients diagnosed with multiple sclerosis. Demographic and clinical variables were obtained through clinical interviews. The severity of the disease was determined using the Extended Disability Status Scale (EDSS), depressive symptoms were assessed with the Beck Depression Inventory (BDI), and perceived discrimination was rated using the King Internalized Stigma Scale.
The studied sample's mean age was 36.3 years, schooling 13.6 years, symptoms onset was at 26.2 years (with a delay in diagnosis of 3.2 years), and a disease evolution of 10.9 years. 71.4% were single; 52% had an unpaid work activity and 57.1% were women.
The EDSS average was 3.5 points; 24.5% presented moderate to severe depressive symptoms and 53.1% referred perceived discrimination.
Perceived discrimination in patients with multiple sclerosis was associated with earlier disease onset, depressive symptoms, and the lack of caregivers. Medical care and life quality improvement for this vulnerable group require greater education regarding the disease and the establishment of patient support programs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Mortars, renders and plasters from an Iron Age site from the NW Iberian peninsula are studied.•Mineralogy, texture, and micromorphology confirmed the earthly nature of the samples.•A granitic ...saprolite rich in kaolin is the raw material used for the manufacture.•A rather poor kaolin enrichment of the raw material is confirmed.
Among many other issues, characterisation of construction techniques is very interesting for understanding protohistoric societies. In the case of Iron Age sites in the Iberian Peninsula, knowledge about materials and construction techniques is minimal. This work explores the challenges of the characterisation of earth mortars in Iron Age sites in the N.W. of the Iberian Peninsula, focusing the study on the archaeological site of Castro de Santa Trega (Galicia, Spain). Samples of mortars, renders and plasters were taken from walls, and mineral composition, texture and micromorphological features were obtained. The results, which are discussed taking into account the particular historiographic framework of this site, confirmed the absence of lime mortars and the widespread use of local raw materials for the production of complex construction materials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background:
The gene fusion between ETV6and RUNX1 generated by t(12;21)(p13; q22), is the most frequent chromosomal translocation in children with acute lymphoblastic leukemia (ALL). Patients ...carrying this translocation are associated with a good prognosis and excellent molecular response to treatment. However up to 20% of cases relapse. Furthermore, the response to the treatment of some relapse cases is associated by resistance to treatments such as glucocorticoids, and these patients must be treated with stem cell transplantation. Recent studies suggest that ETV6/RUNX1(E/R) plays a role in the initiation of leukemia and is also essential for disease progression and maintenance, through the deregulation different molecular pathways that contribute to leukemogenesis, such as the upregulation of PI3K/AKT/mTORpathway.
Aims:
To study the “in vitro” and “in vivo” effects of E/Rfusion gene abrogation by using CRISPR/Cas9, on the oncogenic potential of tumor cells (REH cell line).
Methods:
1)Based on CRISPR/Cas9 system, sgRNAs directed towards the fusion gene were designed to produce indels modifying the oncogene ORF and, therefore, the expression of the protein. Tumor cells (REH cell line expressingE/Rfusion gene) were electroporated (Amaxa nucleofector, Basilea, Switzerland) and sorting by flow cytometry.qPCR and Western Blot were used to checkE/R mRNA expression and downstream targets expression. 3) Cell viability was measured by MTT cell proliferation assays in E/RKO cells and E/Rpositive cells treated with copanlisib, a PI3K inhibitor, (10 nM) and prednisolone (250 μM). 4)In a xenograft model, E/Rpositive cells (right flank) and E/RKO cells (left flank) were subcutaneously injected in 16 NOD/SCID/IL2 receptor gamma chain null mice. Excised tumors were sampled just after sacrifice and stained with hematoxilin & eosin.
Results:
1)A total loss of E/R expression was observed in different E/R KO clones stablished by single cell, demonstrating an effective disruption of the oncogene in REH cells. Moreover, a decrease of downstream targets expression levels such us, phospho‐Akt (66%), BCL‐XL (48%) and BCL‐2 (52%) was observed. 2) Abrogation of E/R fusion gene showed a significantly decrease of oncogenic potential “in vivo”. Mice injected with E/RKO cells did not generated tumors or generated significantly smaller tumors than those generated by E/Rpositive cells. Furthermore, a higher rate of mitotic activity was observed in tumors from E/Rpositive cells (62 vs 20; p = 0.006). 3)Tumor cells showed a higher sensitivity to copanlisib and to combination of copanlisib and prednisolone “in vitro” after E/R depletion. Treatment with copanlisib raised to decrease the cell viability up to 35% in E/R KO cells vs. 55% in E/R positive cells (p < 0,05). In the same way, combination of copanlisib and prednisolone was more effective in E/R KO cells (26 % vs 34% of cell viability, p < 0.05).
Summary/Conclusion:
Avoiding the E/Rfusion gene expression reduces significantly the oncogenic potential of ALL cells (REH, E/Rpositive) both “in vivo” and “in vitro”. E/RKO cells also showed an increased sensitivity to copanlisib alone and in combination with prednisolone, suggesting E/Rexpression could be involved in the prednisolone resistance observed in some patients. These results showed that E/Rplays an important role in the maintenance of the leukemic phenotype. The fusion gene could therefore become a potential therapeutic target.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background:
Loss of the long arm of chromosome 11, del(11q), is one of the most common alterations in CLL. ATM gene is mutated in the remaining allele in one third of del(11q) CLL patients, resulting ...in a complete loss‐of‐function of ATM protein, which is related with poor clinical outcomes. Although targeted BCR inhibition has made a paradigm shift in CLL therapy, relapsed/refractory del(11q) CLLs still show inferior responses to ibrutinib and some patients have developed resistances to these inhibitors overtime. Therefore, novel therapeutic approaches need to be explored in this high‐risk subgroup of patients.
Aims:
To assess the antiproliferative effects of the combination of PARP inhibiton (olaparib) and BCR inhibition (ibrutinib) in CRISPR/Cas9‐engineeered del(11q)/ATM‐mutated CLL cell lines as well as in primary CLL cells with del(11q) in the presence of the stromal microenvironment.
Methods:
The CRISPR/Cas9 system was used to introduce del(11q) and ATM mutations (ATM
KO) into CLL cell lines (HG3, MEC1). In addition, 18 CLL primary cases (9 del(11q) and 9 non‐del(11q) patients) were used for ex vivo experiments. Primary CLL cells were stimulated to proliferate in a co‐culture with HS‐5 bone marrow stromal cells, CpG and IL‐2. Viability was assessed by CellTiter‐Glo luminescence assay at 5 days.
Results:
Olaparib treatment in monotherapy significantly inhibited proliferation of isogenic CRISPR/Cas9‐engineered HG3‐del(11q) ATM
KO and MEC1 ATM
KO cells, compared to HG3WT and MEC1WT cells, respectively (P = 0.006; P = 0.001). In addition, the combination olaparib+ibrutinib showed a synergistic effect in HG3‐del(11q) ATM
KO and MEC1 ATM
KO CLL cell lines (combination index = 0.7), by viability and annexin/PI studies. To test whether this combination was effective in primary del(11q) CLL cells ex vivo, 18 primary CLL cases were co‐cultured with HS‐5 BMSCs, CpG and IL‐2 to induce proliferation. Interestingly, dual PARP and BCR inhibition was more effective than ibrutinib monotherapy in both non‐del(11q) (P = 0.03) and del(11q) (P = 0.006) CLL samples. In addition, this combination significantly reduced the viability of proliferating CLL cells with ATM monoallelic (n = 6) and biallelic loss (n = 4), compared to ATM
WT CLL samples (n = 8) (P = 0.01, P = 0.001, respectively). To study the mechanisms leading to the drug synergy, we used a homologous recombination (HR) reporter assay showing that ibrutinib (1 uM) reduced the HR repair efficiency of HG3 cells (P = 0.001). Moreover, immunofluorescence and western blot experiments in HG3 and MEC1 cells revealed that ibrutinib impaired RAD51 foci formation in double strand breaks (P = 0.003; P = 0.018). RAD51 downregulation by ibrutinib was validated by qPCR in stimulated primary CLL samples, responders to ibrutinib monotherapy (P = 0.04). We further confirmed the off‐target effect of ibrutinib on HR repair by comet assays, since the addition of the alkylating agent bendamustine to ibrutinib or to olaparib+ibrutinib led to a synergistic increase of DNA damage accumulation (P < 0.001), and also a decrease of viability (P < 0.001). These effects were validated in stimulated primary CLLs, showing that the triple combination (bedamustine, olaparib and ibrutinib) was more effective than dual combinations, resulting in a decrease of viability (P < 0.01).
Summary/Conclusion:
Altogether, our results highlight that dual PARP and BCR inhibition is synergistic in del(11q) CLL cells, overcoming the induction of proliferation from the stromal microenvironment, providing a rationale for the use of this combination in del(11q) relapsed/refractory CLL patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
•This study deals with a biorefinery strategy for manufacturing “platform chemicals”.•Soluble hemicellulose derived saccharides are manufactured from Miscanthus by hydrothermal processing.•Furfural ...is obtained by hydrolysis-dehydration of hemicellulosic saccharides.•Hexoses are obtained by enzymatic processing of the solids previously subjected to autohydrolysis.•The suitability of glucose and fructose as substrates for HMF manufacture are also considered.
A biorefinery scheme was proposed for manufacturing platform chemicals (furfural, denoted F, and 5-hydroxymethylfurfural, denoted HMF) from Miscanthus polysaccharides (including hemicelluloses and cellulose). The feedstock was first subjected to hydrothermal processing, which caused an extensive hemicellulose solubilization, yielding solids enriched in cellulose and aqueous solutions rich in saccharides. The acidic processing of the aqueous solutions in the presence of methyl isobutyl ketone (MIBK), which acted as an extracting agent, led to the formation and the in situ separation of F from pentoses at high molar yields (up to 78%). Moreover, HMF and levulinic acid were obtained from the hexoses released from the feedstock.
The cellulose-enriched solids from hydrothermal processing were used as a substrate for HMF manufacture, employing a combination of enzymatic and chemical treatments. The enzymatic hydrolysis yielded glucose (in concentration up to 59 g /L), which was enzymatically isomerized into fructose in the presence of sodium tetraborate at yields up to 80%. Acidic treatments of the resulting reaction media at low temperature (134 °C) in the presence of H2SO4 enabled the formation of HMF at yields about 49%. Under the assayed conditions, glucose remained practically unaltered, facilitating its reutilization in the isomerization stage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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