The Shoc2 protein has been implicated in the positive regulation of the Ras-ERK pathway by increasing the functional binding interaction between Ras and Raf, leading to increased ERK activity. Here ...we found that Shoc2 overexpression induced sustained ERK phosphorylation, notably in the case of EGF stimulation, and Shoc2 knockdown inhibited ERK activation. We demonstrate that ectopic overexpression of human Shoc2 in PC12 cells significantly promotes neurite extension in the presence of EGF, a stimulus that induces proliferation rather than differentiation in these cells. Finally, Shoc2 depletion reduces both NGF-induced neurite outgrowth and ERK activation in PC12 cells. Our data indicate that Shoc2 is essential to modulate the Ras-ERK signaling outcome in cell differentiation processes involved in neurite outgrowth.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between ...blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (β = 12.85; P < 0.001) that was independent of amyloid deposits (β = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (β = 3.64; P = 0.03) and argyrophilic grain disease (β = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological assessments are still scant, and further research is needed to replicate and validate these results in diverse populations.
Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data ...only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (
= 4.22 × 10
) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23,
= 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.
A total of 10-15% of human transmissible spongiform encephalopathies (TSEs) or prion diseases are characterised by disease-specific mutations in the prion protein gene (PRNP). We examined the ...phenotype, distribution, and frequency of genetic TSEs (gTSEs) in different countries/geographical regions. We collected standardised data on gTSEs between 1993 and 2002 in the framework of the EUROCJD collaborative surveillance project. Our results show that clinicopathological phenotypes include genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker disease (GSS). Genetic TSE patients with insert mutation in the PRNP represent a separate group. Point and insertional mutations in the PRNP gene varies significantly in frequency between countries. The commonest mutation is E200K. Absence of a positive family history is noted in a significant proportion of cases in all mutation types (12-88%). FFI and GSS patients develop disease earlier than gCJD. Base pair insertions associated with the Creutzfeldt-Jakob disease (CJD) phenotype, GSS, and FFI cases have a longer duration of illness compared to cases with point mutations and gCJD. Cerebrospinal fluid 14-3-3 immunoassay, EEG, and MRI brain scan are useful in the diagnosis of CJD with point mutations, but are less sensitive in the other forms. Given the low prevalence of family history, the term "gTSE" is preferable to "familial TSE". Application of genetic screening in clinical practice has the advantage of early diagnosis and may lead to the identification of a risk of a TSE.
Bronchioloalveolar carcinoma (BAC), a subtype of non-small cell lung cancer, is a difficult disease to treat with low response rates with cytotoxic chemotherapy. Bortezomib, a proteasome inhibitor, ...has demonstrated objective responses in patients with BAC in early-phase clinical trials. We conducted a phase II study of bortezomib in patients with advanced-stage BAC.
Patients with advanced BAC, adenocarcinoma with BAC features or BAC with adenocarcinoma features, and less than two prior regimens were eligible. Prior epidermal growth factor receptor (EGFR) inhibitor therapy was allowed. Bortezomib was administered intravenously at 1.6 mg/m2 on days 1 and 8 of every 21-day cycle until disease progression or unacceptable toxicity. The primary end point was response rate. The Simon two-stage design was used.
Forty-two patients were enrolled, and the study was halted early for slow accrual. Patient characteristics were female 55%, median age 68 years, and Eastern Cooperative Oncology Group performance status of 0 and 1 in 31 and 11 patients, respectively. Twenty-six (62%) patients had received prior therapy with an EGFR inhibitor. A median of four cycles of therapy were administered. Objective responses were noted in 5%, whereas 57% had disease stabilization. The median progression-free survival and overall survival were 5.5 and 13.6 months, respectively. Grade 3 diarrhea and fatigue were noted in three and five patients, respectively.
Bortezomib is tolerated well and is associated with modest anticancer activity in patients with advanced BAC, including patients who progressed on EGFR inhibitor therapy.
The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD). Multicenter (France, Germany, Japan, Spain) retrospective analyses of neuropathologically confirmed rpAD ...cases initially classified as prion disease due to their clinical phenotype were performed. Genetic properties, cerebrospinal fluid biomarkers, neuropathology, and clinical features were examined. Eighty-nine patients were included (median survival 10 months). APOE and PRNP codon 129 genotype distribution paralleled a healthy control group. APOE ε4 homozygosity was absent. Cerebrospinal fluid biomarkers were abnormal, but within a range as expected for classic AD, except for proteins 14-3-3, which were detectable in 42%. Thus, evidence of the existence of rpAD is accumulating. The APOE profile is intriguing, suggesting that this very rapid disease form might represent a distinct subtype of Alzheimer's disease.
Crimean–Congo haemorrhagic fever virus (CCHFV) is the causative agent of the severe tick‐borne, often fatal, zoonotic Crimean–Congo haemorrhagic fever (CCHF), which is widely distributed worldwide. ...The CCHFV transmission to humans occurs through tick bite, crushing of engorged ticks or contact with infected host blood. Previously, CCHFV genotype Africa III was reported in Spain. Given the emergence of CCHF and the role of ticks in pathogen maintenance and transmission, we investigated the presence and genotype identity of the virus in tick species parasitizing abundant wild host species in south‐western Spain. A total of 613 adult ticks were collected from hunter‐harvested wild ungulates in twenty locations throughout south‐western Spain. Ticks were identified, nucleic acids were extracted, RNA was analysed by a nested RT‐PCR targeting CCHFV S segment, and the amplicons were sequenced. According to the 212‐bp sequence amplified, the presence of CCHFV human genotype Europe V was detected in Hyalomma lusitanicum and Dermacentor marginatus ticks collected from red deer, fallow deer and Eurasian wild boar in different locations from south‐western Spain. Genotype Africa IV was also detected in a H. lusitanicum tick collected from a red deer. The detection of CCHFV in different tick species collected from various wild hosts and localities provided strong evidence of widespread CCHFV presence in the region, suggesting that the circulation of the virus in Spain requires more attention. Additionally, the identification of the CCHFV genotype Europe V in ticks suggested that its introduction in Spain was probably from Eastern Europe.
The sugarcane bagasse fly ash was used to evaluate its adsorption behavior for phenol removal from aqueous solution at three different temperatures. Adsorption tests were performed in batch reactors ...and also in fixed-bed columns. Pseudo-first order, pseudo-second order and intraparticle diffusion kinetic models were applied to describe adsorption kinetics in batch systems. The pseudo-second model fitted appropriately the obtained experimental data at the three different temperatures tested. Thomas, Yoon-Nelson, Adams-Bohart and Dose-Response mathematical models were tested for describing phenol adsorption in dynamic systems (fixed bed columns). Experimental data were well-fitted to the non-linear form of all these models with high regression coefficients.
Purpose
Metachronous peritoneal metastases (MPM) following a curative surgery procedure for pT4 colon cancer is a challenging condition. Current epidemiological studies on this topic are scarce.
...Methods
A retrospective multicentre trial was designed. All consecutive patients who underwent operations to treat pT4 cancers between 2015 and 2017 were reviewed. Demographic, clinical, operative, pathological and oncological follow-up variables were included. MPM were described as any oncological disease at the peritoneum, clearly different from a local recurrence. Univariate and multivariate Cox regression models were constructed. A risk stratification model was created on a cumulative factor basis. According to the calculated hazard ratio (HR), a scoring system was designed (HR < 3, 1 point; HR > 3, 2 points) and a scale from 0 to 6 was calculated for peritoneal disease-free rate (PDF-R). A risk stratification model was also created on the basis of these calculations.
Results
Fifty different hospitals were involved, which included a total of 1356 patients. Incidence of MPM was 13.6% at 50 months median follow-up. The strongest independent risk factors for MPM were positive pN stage HR 3.72 (95% CI 2.56–5.41;
p
< 0.01) for stage III disease, tumour perforation HR 1.91 (95% CI 1.26–2.87;
p
< 0.01), mucinous or signet ring cell histology HR 1.68 (95% CI 1.1–2.58;
p
= 0.02), poorly differentiated tumours HR 1.54 (95% CI 1.1–2.2;
p
= 0.02) and emergency surgery HR 1.42 (95% CI 1.01–2.01;
p
= 0.049). In the absence of additional risk factors, pT4 tumours showed 98% and 96% PDF-R in 1-year and 5-year periods based on Kaplan–Meier curves.
Conclusions
Cumulative MPM incidence was 13.6% at 5-year follow-up. The sole presence of a pT4 tumour resulted in high rates of PDF-R at 1-year and 5-year follow-up (98% and 96% respectively). Five additional risk factors different from pT4 status itself were identified as possible MPM indicators during follow-up.
PDF
