We report hereby an autopsy case of sporadic mixed phenotype CJD without hereditary burden and a long‐term clinical course. An 80‐year old man was diagnosed with mild cognitive impairment 27 months ...before death, caused by bronchopneumonia and severe respiratory impairment. During this time, the patient developed gradual mental deterioration, some sleeping problems and myoclonus. Other clinical manifestations were progressive gait problems, language deterioration, presence of primitive reflexes and irritability. In keeping with those symptoms, a rapidly evolving dementia was clinically suspected. Cerebrospinal fluid test for 14‐3‐3 protein was negative. However, an abnormal EEG and MRI at end‐stage of disease were finally consistent with CJD. Post‐mortem examination revealed a massive cortical neuronal loss with associated reactive astrocytosis, also evident in the white matter. Diffuse spongiform changes involving some basal ganglia, especially medial thalamus, some troncoencephalic nuclei, mainly inferior olivary nucleus and the molecular layer of the cerebellum were seen. Immunorreactive deposits for anti‐prion protein antibody were present at different areas of the CNS. Additionally, Lewy bodies were observed at the brainstem and amygdala. Furthermore, argirophilic grains together with oligodendroglial coiled bodies and pre‐tangle inclusions in the neurons from the limbic system containing hyperphosphorylated 4R tau were noted. To the best of our knowledge, this is the first case of CJD combined with Lewy body disease and argirophilic grain disease. Furthermore, we believe this case is an extremely rare combination of MM2‐cortical‐type and MM2‐thalamic‐type sporadic CJD (sCJD), which explains the broad spectrum of MM2‐type sCJD findings and symptoms. Moreover, histological features of possible Alzheimer's disease were also reported.
Research on m
6
A-associated SNPs (m
6
A-SNPs) has emerged recently due to their possible critical roles in many key biological processes. In this sense, several investigations have identified m
6
...A-SNPs in different diseases. In order to gain a more complete understanding of the role that m
6
A-SNPs can play in breast cancer, we performed an in silico analysis to identify the m
6
A-SNPs associated with breast cancer and to evaluate their possible effects. For this purpose, we downloaded SNPs related to breast cancer and a list of m
6
A-SNPs from public databases in order to identify which ones appear in both. Subsequently, we assessed the identified m
6
A-SNPs in silico by expression quantitative trait loci (eQTL) analysis and differential gene expression analysis. We genotyped the m
6
A-SNPs found in the in silico analysis in 35 patients with breast cancer, and we carried out a gene expression analysis experimentally on those that showed differences. Our results identified 981 m
6
A-SNPs related to breast cancer. Four m
6
A-SNPs showed an eQTL effect and only three were in genes that presented an altered gene expression. When the three m
6
A-SNPs were evaluated in the tissue sample of our breast cancer patients, only the m
6
A-SNP rs76563149 located in ZNF354A gene presented differences in allele frequencies and a low gene expression in breast cancer tissues, especially in luminal B HER2+ subtype. Future investigations of these m
6
A-SNPs should expand the study in different ethnic groups and increase the sample sizes to test their association with breast cancer and elucidate their molecular function.
Heparan sulfate proteoglycans (HSPGs) promote amyloid-β peptide and tau fibrillization in Alzheimer's disease (AD) and provide resistance against proteolytic breakdown. Heparanase (HPSE) is the only ...enzyme that cleaves heparan sulfate (HS). Heparanase 2 (HPSE2) lacks HS-degrading activity, although it is able to interact with HS with high affinity.
To analyze HPSE and HPSE2 expressions at different stages of AD.
RT-PCR was used to analyze transcription levels of both heparanases at different stages of AD, and immunohistochemistry was performed to localize each one in different parts of the brain.
Both proteins appeared overexpressed at different stages of AD. Immunohistochemistry indicated that the presence of the heparanases was related to AD pathology, with intracellular deposits found in degenerated neurons. At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well.
Given the involvement of HSPGs in AD pathology, there would seem to be a relationship between the regulation of heparanase expression, the features of the disease, and a possible therapeutic alternative.
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•Mutations in CD58 and TP53 seem the most promising predictors of poor outcome.•Combinations of alterations and other prognostic appears as a powerful strategy.•EZH2 inhibitors have ...been proposed as candidate drug against mutated EZH2 DLBCL.•Ibrutinib could be used for DLBCL with mutations in BCR signaling pathway.
Diffuse large B-cell lymphoma (DLBCL), the most common type of Non-Hodgkin lymphoma (NHL), is a highly heterogeneous and aggressive disease. Regardless of this heterogeneity, all patients receive the same first-line therapy, which fails in 30–40 % of patients, who are either refractory or relapse after remission. With the aim of stratifying patients to improve treatment outcome, different clinical and genetic biomarkers have been studied. The present systematic review aimed to identify somatic mutations that could serve as prognosis biomarkers or as therapeutic target mutations in DLBCL. Regarding their role as prognostic markers, mutations in CD58 and TP53 seem the most promising predictors of poor outcome although the combination of different alterations and other prognostic factors could be a more powerful strategy. On the other hand, different approaches regarding targeted therapy have been proposed. Therefore, mutational analysis could help guide treatment choice in DLBCL yet further studies and clinical trials are needed.
Vincristine is a component of acute lymphoblastic leukemia (ALL) treatment with the potential to induce peripheral neuropathy. Recently, the CEP72 rs924607 TT genotype was found to be associated with ...vincristine-induced toxicity during the continuation phase in pediatric ALL patients treated on the Total XIIIB and COG AALL0433 protocols at St Jude Children’s Research Hospital and Children’s Oncology Group. This finding could provide a base for safer dosing of vincristine. Nevertheless, there are variations in vincristine regimens among ALL treatment protocols and phases in different populations. Therefore, the aim of this study was to determine whether the CEP72 rs924607 TT genotype is a useful marker of vincristine neuropathy during induction therapy among Spanish children with B-ALL treated on the LAL-SHOP protocols. No association was found between neurotoxicity during the induction phase and the rs924607 TT genotype. This lack of association could be because of population differences and/or differences in neurotoxicity etiology between induction and continuation phases of treatment.
Research on m
A-associated SNPs (m
A-SNPs) has emerged recently due to their possible critical roles in many key biological processes. In this sense, several investigations have identified m
A-SNPs ...in different diseases. In order to gain a more complete understanding of the role that m
A-SNPs can play in breast cancer, we performed an
analysis to identify the m
A-SNPs associated with breast cancer and to evaluate their possible effects. For this purpose, we downloaded SNPs related to breast cancer and a list of m
A-SNPs from public databases in order to identify which ones appear in both. Subsequently, we assessed the identified m
A-SNPs
by expression quantitative trait loci (eQTL) analysis and differential gene expression analysis. We genotyped the m
A-SNPs found in the
analysis in 35 patients with breast cancer, and we carried out a gene expression analysis experimentally on those that showed differences. Our results identified 981 m
A-SNPs related to breast cancer. Four m
A-SNPs showed an eQTL effect and only three were in genes that presented an altered gene expression. When the three m
A-SNPs were evaluated in the tissue sample of our breast cancer patients, only the m
A-SNP rs76563149 located in
gene presented differences in allele frequencies and a low gene expression in breast cancer tissues, especially in luminal B HER2+ subtype. Future investigations of these m
A-SNPs should expand the study in different ethnic groups and increase the sample sizes to test their association with breast cancer and elucidate their molecular function.
Vincristine is an important component of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LAL/SHOP protocols often suffer from ...vincristine-related neurotoxicity in early phases of treatment. Recently, a genome-wide association study connected a SNP in CEP72, involved in vincristine pharmacodynamics, with neurotoxicity during later phases of therapy, which was not replicated during induction phase. These results, together with previous studies indicating that polymorphisms in pharmacokinetic genes are associated with drug toxicity, suggest that changes in the activity or levels of vincristine transporters or metabolizers could work as predictors of vincristine-related neurotoxicity in early phases of treatment in pediatric ALL.
We analyzed 150 SNPs in eight key genes involved in vincristine pharmacokinetics and in 13 miRNAs that regulate them. We studied their correlation with neurotoxicity during induction phase in 152 ALL patients treated with LAL/SHOP protocols.
The strongest associations with neurotoxicity were observed for two SNPs in ABCC2. The genotypes rs3740066 GG and rs12826 GG were associated with increased neurotoxicity.
Polymorphisms in ABCC2 could be novel markers for vincristine-related neurotoxicity in pediatric ALL in early phases.
To investigate the expression of major proteins related to primary neurodegenerative diseases and their prognostic significance in brains with Creutzfeldt-Jakob disease (CJD).
Thirty consecutive ...cases of confirmed CJD during the period 2010-2015 at Basque Brain bank were retrospectively reviewed. Moreover, major neurodegenerative-associated proteins (phosphorylated Tau, 4R tau, 3R tau, alpha-synuclein, TDP43, amyloid beta) were tested. Clinical data were reviewed. Cases were divided according to the presence or absence of copathology. Survival curves were also determined.
Copathology was significantly associated with survival in brains with CJD (4.2±1.2 vs 9.2±1.9; P=0.019) and in brains with MM1/MV1 CJD (2.1±1.0 vs 6.7±2.8; P=0.012). Besides, the presence of more than one major neurodegenerative-associated protein was significantly associated with survival (4.2±1.2 vs 10.7±2.6; P=0.017). Thus, univariate analyses further pointed out variables significantly associated with better survival: copathology in CJD (HR=0.430; P=0.033); more than one neurodegenerative-associated protein in CJD (HR=0.369; P=0.036) and copathology in MM1/MV1 CJD (HR=0.525; P=0.032).
The existence of copathology significantly prolongs survival in patients with rapidly progressive dementia due to CJD. The study of major neurodegenerative-associated proteins in brains with CJD could allow us to further understand the molecular mechanisms behind prion diseases.
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