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Purpose: Epidermal growth factor (EGF) might be a suitable immunotherapeutic target in nonŝ mall-cell lung cancer (NSCLC). Our approach consists of active immunotherapy with EGF. The aim of the study is to characterize the humoral response and its effects on signal transduction in relation with the clinical outcome. Experimental Design: Eighty NSCLC patients treated with first-line chemotherapy were randomized to receive the EGF vaccine or supportive care. EGF concentration in sera, anti-EGF antibodies and their capacity to inhibit the binding between EGF/EGF receptor (EGFR), and the EGFR phosphorylation were measured. Results: Seventy-three percent of vaccinated patients developed a good antibody response, whereas none of the controls did. In good antibody-responder patients, self EGF in sera was significantly reduced. In 58% of vaccinated patients, the post-immune sera inhibited EGF/EGFR binding; in the control group, no inhibition occurred. Post-immune sera inhibited the EGFR phosphorylation whereas sera from control patients did not have this capacity. Good antibodyresponder patients younger than 60 years had a significantly better survival. A high correlation between anti-EGF antibody titers, EGFR phosphorylation inhibition, and EGF/EGFR binding inhibition was found. There was a significantly better survival for vaccinated patients that showed the higher capacity to inhibit EGF/EGFR binding and for those who showed an immunodominance by the central region of EGF molecule. Conclusions: Immunization with the EGF vaccine induced neutralizing anti-EGF antibodies capable of inhibiting EGFR phosphorylation. There was a significant positive correlation between antibody titers, EGF/EGFR binding inhibition, immunodominance of anti-EGF antibodies, and survival in advanced NSCLC patients.

Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics.

What is known and Objective Controversy has arisen in the scientific community on whether the use of renin‐angiotensin system (RAS) inhibitors in the context of COVID‐19 would be beneficial or harmful. A meta‐analysis of eligible studies comparing the occurrence of severe and fatal COVID‐19 in infected hypertensive patients who were under treatment with angiotensin‐converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) vs no treatment or other antihypertensives was conducted. Methods PubMed, Google Scholar, the Cochrane Library, medRxiv and bioRxiv were searched for relevant studies. Fixed‐effects models or random‐effects models were used depending on the heterogeneity between estimates. Results and discussion A total of eighteen studies with 17 311 patients were included. The use of RAS inhibitors was associated with a significant 16% decreased risk of the composite outcome (death, admission to intensive care unit, mechanical ventilation requirement or progression to severe or critical pneumonia): RR: 0.84 (95% CI: 0.73‐0.95), P = .007, I2 = 65%. What is new and conclusion The results of this pooled analysis suggest that the use of ACEI/ARB does not worsen the prognosis of COVID‐19, and could even be protective in hypertensive subjects. Hypertensive patients should continue these drugs even if they become infected with SARS‐CoV‐2.

Dementia is a major health problem in developed countries with over 25 million people affected worldwide and probably over 75 million people at risk during the next 20 years. Alzheimer's disease (AD) is the most frequent cause of dementia (50-70%), followed by vascular dementia (30-40%), and mixed dementia (15-20%). AD pathogenesis is still to be elucidated but it is believed to be the complex interaction between genetic and environmental factors in later life. Three causative genes for familial AD have been identified: amyloid precursor protein, presenilin-1, and presenilin-2. There are 150 genes involved with increased neuronal vulnerability to premature death in the AD brain. Among these susceptibility genes, the apolipoprotein E (ApoE) gene is the most prevalent as a risk for AD pathogenic process in which complex interactions between genetic and environmental factors are involved, leading to a cascade of pathogenic events converging in final pathways to premature neuronal death. Some of these mechanisms are common to several neurodegenerative disorders that differ depending upon the genes affected and the involvement of environmental conditions.ApoE is a key lipoprotein in lipid and cholesterol metabolism and it is also the major risk gene for AD and many other central nervous system disorders. The pathogenic role of ApoE-4 is still to be clarified; however, diverse evidence suggests that ApoE may play pleiotropic functions in dementia and central nervous system disorders.

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Grounding refers to expressions that establish a connection between the ground and the content evoked by a nominal or finite clause. In this paper we report on two grammatical implementations of nominal grounding in Argentine Sign Language: pointing and placing. For pointing constructions, we also examine distal-proximal pointing and directive force. We introduce the concept of placing, in which a sign is produced at a specific meaningful location in space. Two types of placing are discussed: Placing-for-Creating, in which a new meaningful location is created, and Placing-by-Recruiting, which recruits an existing meaningful location. We suggest that our analysis of pointing and placing provides an account of nominal grounding unified by general cognitive principles as described within the theory of Cognitive Grammar. Pointing is known to occur in all signed languages studied to date. Although previously undocumented, we suggest that placing is also common to many, perhaps all, signed languages.

Objective: Resistant hypertension carries a poor prognosis and current guidelines recommend the exclusion of the white-coat phenomenon for proper diagnosis. However, guidelines do not focus on patients treated with at least three drugs whose blood pressure (BP) is controlled at the office but elevated out of it. We aimed at determining whether this masked uncontrolled apparent resistant hypertension (MUCRH) detected through home blood pressure monitoring (HBPM) has prognostic value for fatal and nonfatal events in these hypertensive patients. Methods: Hypertensive patients treated with at least three drugs who performed a baseline HBPM between 2008 and 2015 were followed to register the occurrence of total mortality, cardiovascular mortality, and fatal and nonfatal cardiac and cerebrovascular events. MUCRH was defined as office blood pressure less than 140/90 mmHg and home BP at least 135 and/or 85 mmHg. Multivariable Cox proportional hazard models were adjusted to determine the independent prognostic value of MUCRH for the events of interest. Results: We included 470 patients, 35.5% male, mean age 71.9 years, and treated with 3.3 antihypertensive drugs on average. Among study population, 15.5% had MUCRH (33.3% when considering only patients with adequate BP control at the office). Median follow-up was 6.7 years. In multivariable models, MUCRH was an independent predictor for cardiovascular mortality and cerebrovascular events: hazard ratio 4.9 (95% CI 1.2–19.9, P = 0.03) and 5.1 (95% CI 1.5–16.9, P = 0.01), respectively. Conclusion: MUCRH is not rare and is independently associated with cardiovascular morbidity and mortality. The systematic monitoring of intensively treated individuals through HBPM would be useful for the detection of patients at increased risk of events.