Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles.

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 (ß = 12.85; P < 0.001) that was independent of amyloid deposits (ß = 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 (ß = 3.64; P = 0.03) and argyrophilic grain disease (ß = -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.

Strategies for knowledge mobilization by advanced practice nurses in three hospitals in Spain: a qualitative study.

BACKGROUND: Evidence-based practice, in conjunction with optimum care quality, improves patients' clinical outcomes. However, its implementation in daily clinical practice continues to present difficulties. The aim of this study was to identify the strategies applied by Advanced Practice Nurses (APNs) to foster adherence to clinical practice guideline recommendations. METHODS: An exploratory qualitative study was conducted with six focus groups at three public hospitals belonging to the Balearic Islands Health Care Service (Spain). The study participants were 32 ward nurses and 5 advanced practice nurses working routinely with inpatients at these hospitals. The study was conducted from November 2020 to January 2021, using thematic analysis, based on the COREQ checklist. RESULTS: Four major themes related to the facilitation process were identified either by RNs and APNs: the context of the project, APN contribution to nursing team management, healthcare provision on the ward, and the acquisition and application of knowledge. CONCLUSIONS: The APNs adapted their actions to the characteristics and needs of the local context, employing strategies aimed at improving teamwork, healthcare, and knowledge management. Each of these contributions enhanced the sustainability of the changes made.

Hepatitis E Virus Seroprevalence is Associated with Neurodegenerative Disorders in Older People with Dementia: A Case-Control Study.

In this case-control study, we evaluated the association between serum antibodies against hepatitis E virus (HEV) and central nervous system (CNS) neurodegenerative disorders (NDs) in older people with dementia. The presence of anti-HEV antibodies was related to a higher adjusted odds ratio (aOR) of having CNS NDs by neuropathological diagnosis (aOR, 2.13; P = .007) and clinical/neuropathological diagnosis (1.84; P = .02). Besides, serum anti-HEV antibodies were directly related to neuropathological injury (higher vascular pathology [aOR, 1.97; P = .006]) and higher probability of Alzheimer-type pathology (1.84; P = .02). In conclusion, the presence of anti-HEV antibodies was related to higher odds of CNS NDs and neuropathological injury in older people.

Non-invasive biomarkers for mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease is the most common type of dementia in the elderly. It is a progressive degenerative disorder that may begin to develop up to 15 years before clinical symptoms appear. The identification of early biomarkers is crucial to enable a prompt diagnosis and to start effective interventions. In this work, we conducted a metabolomic study using proton Nuclear Magnetic Resonance (1H NMR) spectroscopy in serum samples from patients with neuropathologically confirmed Alzheimer's disease (AD, n = 51), mild cognitive impairment (MCI, n = 27), and cognitively healthy controls (HC, n = 50) to search for metabolites that could be used as biomarkers. Patients and controls underwent yearly clinical follow-ups for up to six years. MCI group included samples from three subgroups of subjects with different disease progression rates. The first subgroup included subjects that remained clinically stable at the MCI stage during the period of study (stable MCI, S-MCI, n = 9). The second subgroup accounted for subjects which were diagnosed with MCI at the moment of blood extraction, but progressed to clinical dementia in subsequent years (MCI-to-dementia, MCI-D, n = 14). The last subgroup was composed of subjects that had been diagnosed as dementia for the first time at the moment of sample collection (incipient dementia, Incp-D, n = 4). Partial Least Square Discriminant Analysis (PLS-DA) models were developed. Three models were obtained, one to discriminate between AD and HC samples with high sensitivity (93.75%) and specificity (94.75%), another model to discriminate between AD and MCI samples (100% sensitivity and 82.35% specificity), and a last model to discriminate HC and MCI with lower sensitivity and specificity (67% and 50%). Differences within the MCI group were further studied in an attempt to determine those MCI subjects that could develop AD-type dementia in the future. The relative concentration of metabolites, and metabolic pathways were studied. Alterations in the pathways of alanine, aspartate and glutamate metabolism, pantothenate and CoA biosynthesis, and beta-alanine metabolism, were found when HC and MCI- D patients were compared. In contrast, no pathway was found disturbed in the comparison of S-MCI with HC groups. These results highlight the potential of 1H NMR metabolomics to support the diagnosis of dementia in a less invasive way, and set a starting point for the study of potential biomarkers to identify MCI or HC subjects at risk of developing AD in the future.

Diagnostic accuracy of cerebrospinal fluid biomarkers in genetic prion diseases.

Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt-Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt-Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt-Jakob disease-E200K, Gerstmann-Sträussler-Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.

TNAP and P2X7R: New Plasma Biomarkers for Alzheimer's Disease.

Over the last few years, intense research efforts have been made to anticipate or improve the diagnosis of Alzheimer's disease by detecting blood biomarkers. However, the most promising blood biomarkers identified to date have some limitations, most of them related to the techniques required for their detection. Hence, new blood biomarkers should be identified to improve the diagnosis of AD, better discriminate between AD and mild cognitive impairment (MCI) and identify cognitively unimpaired (CU) older individuals at risk for progression to AD. Our previous studies demonstrated that both the purinergic receptor P2X7 and the tissue-nonspecific alkaline phosphatase ectoenzyme (TNAP) are upregulated in the brains of AD patients. Since both proteins are also present in plasma, we investigated whether plasma P2X7R and TNAP are altered in MCI and AD patients and, if so, their potential role as AD biomarkers. We found that AD but not MCI patients present increased plasma P2X7R levels. Nevertheless, TNAP plasma activity was increased in MCI patients and decreased in the AD group. ROC curve analysis indicated that measuring both parameters has a reasonable discriminating capability to diagnose MCI and AD conditions. In addition to confirming that individuals progressing to MCI have increased TNAP activity in plasma, longitudinal studies also revealed that CU individuals have lower plasma TNAP activity than stable controls. Thus, we propose that P2X7 and TNAP could serve as new plasma biomarkers for MCI and AD.

Linezolid induced thrombocytopenia in critically ill patients: Risk factors and development of a machine learning-based prediction model.

INTRODUCTION: Linezolid is an antimicrobial with broad activity against Gram-positive bacteria. Thrombocytopenia is one of its most common side effects often leading to severe complications. The aim of this study is to identify factors related with development of this condition in critically ill patients and to develop and evaluate a predictive machine learning-based model considering easy-to-obtain clinical variables. METHODS: Data was obtained from the Medical Information Mart for Intensive Care III. Patients who received linezolid for over three days were considered, excluding those under 18 years and/or lacking laboratory data. Thrombocytopenia was considered as a platelet decrease of at least 50% from baseline. RESULTS: Three hundred and twenty patients met inclusion criteria of which 63 developed thrombocytopenia and presented significant greater duration of treatment, aspartate-aminotransferase, bilirubin and international normalized ratio; and lower renal clearance and platelet count at baseline. Thrombocytopenia development was associated with a worse outcome (30 days mortality [OR: 2.77; CI95%: 1.87-5.89; P < .001], 60 days mortality [OR: 3.56; CI95%: 2.18-7.26; P < .001]). Thrombocytopenia was also correlated with higher length of hospital stays (35.56 [20.40-52.99] vs 22.69 [10.05-38.61]; P < .001). Median time until this anomaly was of 23 days (CI95%:19.0-NE). Two multivariate models were performed. Accuracy, sensitivity, specificity and AUROC obtained in the best of them were of 0.75, 0.78, 0.62 and 0.80, respectively. CONCLUSION: Linezolid associated thrombocytopenia entails greater mortality rates and hospital stays. Although the proposed predictive model has to be subsequently validated in a real clinical setting, its application could identify patients at risk and establish screening and surveillance strategies.

Impact of advanced practice nurses in hospital units on compliance with clinical practice guidelines: a quasi-experimental study.

BACKGROUND: Incorporating the best available evidence into clinical practice is a determining challenge for healthcare professionals and organisations. The role of advanced practice nurses is viewed as a facilitator to adapt guideline recommendations to suit specific contexts and to overcome barriers to implementation. In this study, we evaluate the impact of advanced practice nurses on clinical indicators of hospitalised patients and on adherence to recommendations derived from two clinical practice guidelines (pressure ulcer prevention and treatment and vascular access device management). METHODS: Quasi-experimental study in five intervention (IU) and five control (CU) hospital units at three hospitals in Spain (period 2018-19). Five advanced practice nurses were incorporated into IU, with the intention that would produce attitudinal changes and enhance the skills and knowledge of the nursing team regarding 18 clinical practice recommendations. In this study, 41 indicators were evaluated through direct observation of all patients admitted, at monthly intervals for 1 year. Outcomes were assessed by means of a descriptive, multi-line regression and association analysis. RESULTS: The study population was composed of 3742 inpatients admitted for pressure ulcer assessment and 2631 fitted with vascular access devices. By the end of the study period, all variables had improved in the IU, where average compliance with recommendations was statistically significantly higher (pressure ulcer guidance 7.9 ± 1.9 vs 6.0 ± 1.7. OR 1.86, 95% CI 1.67-2.05; vascular access devices guidance 5.4 ± 1.4 vs 4.4 ± 1,6. OR 1.06, 95% CI 0.95-1.17). The prevalence of pressure lesions and catheter-related adverse events decreased statistically significantly in the IU compared to the CU. The prevalence of pressure ulcers decreases (5.7% in IU vs 8.7% in CU p < 0.005) as well as the prevalence of adverse events related to the catheter (14% In IU vs 21.6% in CU p < 0.005). The unnecessary catheters decressed in IU 10.9% VS CU 15.8% (p < 0.005). CONCLUSIONS: The incorporation of an advanced practice nurse statistically significantly improves clinical indicators related to the prevention and treatment of pressure ulcers and to the management of vascular access devices. TRIAL REGISTRATION: ISRCTN18259923 retrospectively registered on 11/02/2022.

Association of clusterin with the BRI2-derived amyloid molecules ABri and ADan.

Familial British and Danish dementias (FBD and FDD) share striking neuropathological similarities with Alzheimer's disease (AD), including intraneuronal neurofibrillary tangles as well as parenchymal and vascular amyloid deposits. Multiple amyloid associated proteins with still controversial role in amyloidogenesis colocalize with the structurally different amyloid peptides ABri in FBD, ADan in FDD, and Aß in AD. Genetic variants and plasma levels of one of these associated proteins, clusterin, have been identified as risk factors for AD. Clusterin is known to bind soluble Aß in biological fluids, facilitate its brain clearance, and prevent its aggregation. The current work identifies clusterin as the major ABri- and ADan-binding protein and provides insight into the biochemical mechanisms leading to the association of clusterin with ABri and ADan deposits. Mirroring findings in AD, the studies corroborate clusterin co-localization with cerebral parenchymal and vascular amyloid deposits in both disorders. Ligand affinity chromatography with downstream Western blot and amino acid sequence analyses unequivocally identified clusterin as the major ABri- and ADan-binding plasma protein. ELISA highlighted a specific saturable binding of clusterin to ABri and ADan with low nanomolar Kd values within the same range as those previously demonstrated for the clusterin-Aß interaction. Consistent with its chaperone activity, thioflavin T binding assays clearly showed a modulatory effect of clusterin on ABri and ADan aggregation/fibrillization properties. Our findings, together with the known multifunctional activity of clusterin and its modulatory activity on the complex cellular pathways leading to oxidative stress, mitochondrial dysfunction, and the induction of cell death mechanisms - all known pathogenic features of these protein folding disorders - suggests the likelihood of a more complex role and a translational potential for the apolipoprotein in the amelioration/prevention of these pathogenic mechanisms.

TREM2 expression in the brain and biological fluids in prion diseases.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that regulates microglial function and is involved in the pathophysiology of several neurodegenerative diseases. Its soluble form (sTREM2) results from shedding of the TREM2 ectodomain. The role of TREM2 in prion diseases, a group of rapidly progressive dementias remains to be elucidated. In the present study, we analysed the expression of TREM2 and its main sheddase ADAM10 in the brain of sporadic Creutzfeldt-Jakob disease (sCJD) patients and evaluated the role of CSF and plasma sTREM2 as a potential diagnostic marker of prion disease. Our data indicate that, compared to controls, TREM2 is increased in sCJD patient brains at the mRNA and protein levels in a regional and subtype dependent fashion, and expressed in a subpopulation of microglia. In contrast, ADAM10 is increased at the protein, but not the mRNA level, with a restricted neuronal expression. Elevated CSF sTREM2 is found in sCJD, genetic CJD with mutations E200K and V210I in the prion protein gene (PRNP), and iatrogenic CJD, as compared to healthy controls (HC) (AUC = 0.78-0.90) and neurological controls (AUC = 0.73-0.85), while CSF sTREM2 is unchanged in fatal familial insomnia. sTREM2 in the CSF of cases with Alzheimer's disease, and multiple sclerosis was not significantly altered in our series. CSF sTREM2 concentrations in sCJD are PRNP codon 129 and subtype-related, correlate with CSF 14-3-3 positivity, total-tau and YKL-40, and increase with disease progression. In plasma, sTREM2 is increased in sCJD compared with HC (AUC = 0.80), displaying positive correlations with plasma total-tau, neurofilament light, and YKL-40. We conclude that comparative study of TREM2 in brain and biological fluids of prion diseases reveals TREM2 to be altered in human prion diseases with a potential value in target engagement, patient stratification, and disease monitoring.

Disposable immunoplatforms for the simultaneous determination of biomarkers for neurodegenerative disorders using poly(amidoamine) dendrimer/gold nanoparticle nanocomposite.

Early diagnosis in primary care settings can increase access to therapies and their efficiency as well as reduce health care costs. In this context, we report in this paper the development of a disposable immunoplatform for the rapid and simultaneous determination of two protein biomarkers recently reported to be involved in the pathological process of neurodegenerative disorders (NDD), tau protein (tau), and TAR DNA-binding protein 43 (TDP-43). The methodology involves implementation of a sandwich-type immunoassay on the surface of dual screen-printed carbon electrodes (dSPCEs) electrochemically grafted with p-aminobenzoic acid (p-ABA), which allows the covalent immobilization of a gold nanoparticle-poly(amidoamine) (PAMAM) dendrimer nanocomposite (3D-Au-PAMAM). This scaffold was employed for the immobilization of the capture antibodies (CAbs). Detector antibodies labeled with horseradish peroxidase (HRP) and amperometric detection at - 0.20 V (vs. Ag pseudo-reference electrode) using the H2O2/hydroquinone (HQ) system were used. The developed methodology exhibits high sensitivity and selectivity for determining the target proteins, with detection limits of 2.3 and 12.8 pg mL-1 for tau and TDP-43, respectively. The simultaneous determination of tau and TDP-43 was accomplished in raw plasma samples and brain tissue extracts from healthy individuals and NDD-diagnosed patients. The analysis can be performed in just 1 h using a simple one-step assay protocol and small sample amounts (5 µL plasma and 2.5 µg brain tissue extracts). Graphical abstract.

Residence, Clinical Features, and Genetic Risk Factors Associated with Symptoms of COVID-19 in a Cohort of Older People in Madrid.

BACKGROUND: The older population has been especially affected by the severe acute respiratory syndrome coronavirus 2 pandemic (COVID-19). OBJECTIVE: The aim of the study was to explore the incidence, severity, mortality rate, clinical features, and risk factors of symptoms of COVID-19 in home-dwelling older people, and its association with type of residence, cognitive deterioration, and neurodegenerative diseases. METHODS: Data about symptoms of COVID-19 were collected through a telephone survey in the cohort of 913 older volunteers of the Vallecas Project, aged 75-90 years, most of them (902) home-dwelling, in Madrid, Spain. The association of demographic and anthropometric measures, genetic polymorphisms, comorbidities, life habits, type of residence, and frailty surrogates were explored as potential risk factors for the incidence, severity, and mortality of COVID-19 in the older population. FINDINGS: Sixty-two cases reported symptoms compatible with COVID-19; 6 of them had died, 4 in their home and 2 in the nursing home. Moderate/severe cases were significantly older and more frequently males. The APOE ε4 allele was associated with the presence of symptoms of COVID-19. Higher systolic blood pressure, more intense smoking habit, more alcohol intake, lower consumption of coffee and tea, and cognitive impairment were associated with disease severity. CONCLUSIONS: The estimated incidence of symptomatic COVID-19 in this older cohort of Madrid was 6.8%, with an overall mortality rate of 0.7% (18.2% in those living in a nursing home) and a fatality rate of 9.9%. Our exploratory study indicates that life habits, other clinical conditions and, the ε4 variant of the APOE gene are associated with the presence and clinical severity of coronavirus infection.

Classification of Pressure Injury Stages and Skin Damage Photographs by RNs and Nursing Students in Spain: An Observational Comparison Study.

PURPOSE: The purpose of this study was to evaluate and classify pressure injuries (PIs) and other skin lesions according to the judgment of hospital-based RNs and nursing students who recently trained in wound care using photographs and comparing findings to those of wound care experts. DESIGN: Cross-sectional observational survey. SUBJECT AND SETTING: RNs working at Manacor Hospital, Mallorca, Spain, and third-year nursing students from the University of the Balearic Islands. Data were collected in June 2017. METHODS: The survey instrument was accompanied by a set of 24 photographs in 7 categories of skin lesions, such as PIs or moisture-associated skin damage, which the respondents were asked to classify. Descriptive analysis of the classifications was carried out, and levels of agreement using the chi-square test were compared with evaluations/classifications of a panel of experts. RESULTS: In total, 314 surveys (199 RNs and 115 students) were included in the analyses. Findings showed a wide variability among participants with levels of agreement, with expert opinion ranging from 91.4% to 15.61%. The levels of agreement were substantially lower for unstageable PIs (47.92%), those caused by moisture (53.50%), and mixed etiology (38.37%) than for stages 1-4 PIs. Of note, 62.12% of RNs had not received PI training or continuing education during the previous 2 years. This lack of education was statistically significantly associated with the accuracy of the classification made by the RNs for some of the photographs evaluated such as moisture-associated skin damage. CONCLUSIONS: We found discrepancies in the classification of PIs and other wounds/lesions among experts, RNs, and students. The regular provision of up-to-date information in training and continuing education programs is imperative to maintain nurses' abilities to identify and classify PIs and other skin-related damage.

Phase I Study of Veliparib on an Intermittent and Continuous Schedule in Combination with Carboplatin in Metastatic Breast Cancer: A Safety and [18F]-Fluorothymidine Positron Emission Tomography Biomarker Study.

BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA-mutated metastatic breast cancer. Furthermore, the BROCADE studies demonstrated benefit of adding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple-negative (TNBC) or hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA-repair pathway based on FA triple staining immunofluorescence assay. MATERIALS AND METHODS: Patients received escalating doses of veliparib on a 7-, 14-, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-3'-deoxythymidine (18 FLT) positron emission tomography (PET) imaging. RESULTS: Forty-four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1-36). Observed dose-limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n = 1), and G3 akathisia (n = 1). Common grade 3-4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression-free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1-21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUVmax ) of target lesions between baseline and early in cycle 1 based on 18 FLT-PET (day 7-21; ptrend = .006). CONCLUSION: The combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUVmax on 18 FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response. IMPLICATIONS FOR PRACTICE: The BROCADE studies suggest that breast cancer patients with BRCA mutation benefit from addition of veliparib to carboplatin plus paclitaxel. This study demonstrates that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging-based early response assessment, the authors demonstrate that decrease in [18]fluoro-3'-deoxythymidine positron emission tomography (FLT-PET) SUVmax during cycle 1 of therapy is associated with response. Collectively, this study established a safety profile of veliparib and carboplatin in advanced breast cancer while also providing additional data on the potential for FLT-PET imaging modality in monitoring therapy response.

The oncogenic potential of a mutant TP53 gene explored in two spontaneous lung cancer mice models.

BACKGROUND: Lung cancer is the number one cancer killer worldwide. A major drawback in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor protein p53 are among the most common alterations in human lung cancers. METHODS: Previously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H. RESULTS: We found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents. CONCLUSIONS: Oncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune checkpoint inhibitors or other therapeutic strategies in the treatment of lung cancer.

Type of TP53 mutation influences oncogenic potential and spectrum of associated K-ras mutations in lung-specific transgenic mice.

TP53 and K-ras mutations are two of the major genetic alterations in human nonsmall cell lung cancers. The association between these two genes during lung tumorigenesis is unknown. We evaluated the potential of two common Type I (273H, contact) and Type II (175H, conformational) TP53 mutations to induce lung tumors in transgenic mice, as well as K-ras status, and other driver mutations in these tumors. Among 516 (138 nontransgenic, 207 SPC-TP53-273H, 171 SPC-TP53-175H) mice analyzed, 91 tumors, all adenocarcinomas, were observed. Type II mutants developed tumors more frequently (as compared to nontransgenics, p = 0.0003; and Type I, p = 0.010), and had an earlier tumor onset compared to Type I (p = 0.012). K-ras mutations occurred in 21 of 50 (42%) of murine lung tumors sequenced. For both the nontransgenic and the SPC-TP53-273H transgenics, tumor K-ras codon 12-13 mutations occurred after 13 months with a peak incidence at 16-18 months. However, for the SPC-TP53-175H transgenics, K-ras codon 12-13 mutations were observed as early as 6 months, with a peak incidence between the ages of 10-12 months. Codons 12-13 transversion mutations were the predominant changes in the SPC-TP53-175H transgenics, whereas codon 61 transition mutations were more common in the SPC-TP53-273H transgenics. The observation of accelerated tumor onset, early appearance and high frequency of K-ras codon 12-13 mutations in the Type II TP53-175H mice suggests an enhanced oncogenic function of conformational TP53 mutations, and gains in early genetic instability for tumors containing these mutations compared to contact mutations.

Decreased generation of C-terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease.

Increasing evidence indicates that altered reelin signaling could contribute to synaptic dysfunction in Alzheimer's disease (AD). We found that reelin protein and mRNA levels were increased in the AD brain (particularly at advanced Braak stages in apolipoprotein E4 noncarriers), compared with that of control subjects. The ß-amyloid (Aß) protein impairs reelin activity and increases reelin expression through a mechanism that is not yet understood. To explore that mechanism, we examined the effect of Aß aa 1-42 (Aß42) on DNA methylation of the RELN promoter and the processing of reelin receptor apolipoprotein E receptor 2 (ApoER2) in differentiated SH-SY5Y cells because ApoER2 C-terminal fragments (CTFs), generated after reelin binding, regulate reelin expression. We found that Aß42 decreased nuclear levels of DNA-methyltransferase 1. However, RELN promoter methylation did not change in Aß42-treated cells or in AD brain extracts. Instead, the levels of ApoER2-CTF appeared significantly lower in Aß42-treated cells and in AD extracts from advanced Braak stages of apolipoprotein E4 noncarriers. Our data show that ApoER2-CTF levels are decreased, whereas reelin expression is increased in AD brain at advanced Braak stages and after Aß treatment, supporting the view that ApoER2-CTF exerts a modulatory role on reelin expression.-Mata-Balaguer, T., Cuchillo-Ibañez, I., Calero, M., Ferrer, I., Sáez-Valero, J. Decreased generation of C-terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease.

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.

INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.

EML4-ALK Rearrangement and Its Therapeutic Implications in Inflammatory Myofibroblastic Tumors.

With the advent of precision medicine, medical oncology is undergoing a transcendental change. These molecular studies have allowed us to learn about potential targeted therapies for patients with advanced cancers. Perhaps the best-known example of success in precision medicine is chronic myeloid leukemia and its response to tyrosine kinase inhibitors targeting the BCR-ABL kinase. Since that original discovery, the role of molecular therapeutics has expanded, and it now presents us with treatment options for common malignancies and rare atypical tumors. In this article, we present a case of a 61-year-old female with a recurrent pulmonary inflammatory myofibroblastic tumor. Subsequent molecular studies revealed an ALK rearrangement. The significance of this alteration in this tumor type and its therapeutic implications are discussed herein. KEY POINTS: This case exemplifies the heterogeneous behavior of inflammatory myofibroblastic tumors (IMTs) and the current role of targeted therapy in the therapeutic armamentarium of neoplastic processes.As evidenced by the different mutations found in IMTs, it is of great importance to perform next-generation sequencing in uncommon neoplasms.These studies can find different potential targets and therapeutic options for patients devoid of standard effective therapies.

Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

Background Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC.