Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.

BACKGROUND: Vaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors. PATIENTS AND METHODS: Eleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression. RESULTS: We observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8+ T cells and elevation of expression of multiple immune response genes. Borderline or undetectable p53-specific T cell responses in 7/11 patients were related to no immediate clinical benefit. The first study patient had a grade 5 fatal myocarditis. After the study was amended for enhanced cardiac monitoring, no additional cardiac toxicities were noted. CONCLUSION: We have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.

Impedance spectroscopy for monosaccharides detection using responsive hydrogel modified paper-based electrodes.

Herein we present a novel sensor for the detection of monosaccharides (e.g. glucose, fructose) in solution, using electrical impedance spectroscopy. The sensor is based on carbon interdigitated electrodes, printed on paper using screen printing. The surface of the electrodes was modified with a thin layer of hydrogel containing acrylamide copolymerised with 20 mol% 3-(Acrylamido)phenylboronic acid (PBA). It was observed that the hydrogel layers containing 20 mol% PBA swell considerably in the presence of glucose and fructose. This in turn changes the measured impedance across the electrodes, making it a suitable sensor for the quantitative detection of saccharides. We investigated the impedance and capacitance variations with different concentrations of glucose and fructose (0-5 mM) in aqueous phosphate buffer solutions. Variations in impedance were attributed to changes in the dielectric properties of the hydrogel under an applied electric field, due to swelling of the hydrogel layer induced by uptake and binding of sugar molecules to the boronate species within the gel. Impedance measurements at 1 kHz demonstrated that hydrogel swelling leads to an increased mobility of ions within the swollen hydrogel layer. The impedance decreased with increasing sugar concentration and the relative capacitance curves are markedly different for fructose and glucose, as the hydrogel exhibits greater swelling in the presence of fructose than glucose over the same concentration range. As the proposed sensor was shown to be suitable for the detection of glucose at concentration levels found in human sweat, future work will focus on the incorporation of these modified paper-based electrodes into wearable skin patches for non-invasive sugar monitoring in sweat.

Chronic inflammation is associated with overweight in Colombian school children.

BACKGROUND AND AIMS: To examine the cross-sectional associations of inflammatory markers in plasma including C-reactive protein (CRP) and ferritin, and white blood cell (WBC) count, with overweight, skinfold sum (subscapular + triceps), and skinfold ratio (subscapular/triceps) among children from Bogotá, Colombia. METHODS AND RESULTS: The sample (n = 2614) represented low- and middle-income children, aged 5-12 years, from Bogotá. We assessed their anthropometry, sociodemographic characteristics, and circulating inflammatory markers. We defined overweight, including obesity, according to the International Obesity Task Force BMI criteria. After adjustment for potential confounders, children in the fourth quartile of the CRP distribution had a 37% higher prevalence of overweight compared to those in the first quartile (P for trend = 0.03); and children in the fourth quartile of ferritin had a 67% greater prevalence of overweight compared to children in the first quartile (P for trend <0.001). Children in the highest 3 quartiles of the WBC distribution had a 35% higher prevalence of overweight than those in the first quartile (P = 0.03). Ferritin was significantly and positively associated with skinfold sum (P for trend < 0.001), while WBC was significantly and positively associated with skinfold ratio (P for trend < 0.001). There was a significant interaction between CRP and ferritin; children in the highest quartiles of CRP and ferritin had twice the prevalence of overweight compared to those below the highest quartiles (P = 0.001). CONCLUSION: Biomarkers of chronic inflammation are positively associated with child overweight. WBC is positively related to skinfold ratio, a proxy for truncal adiposity.

Nodular Leydig cell hyperplasia in a boy with familial male-limited precocious puberty.

In boys with familial male-limited precocious puberty, an activating mutation of the luteinizing hormone receptor causes Leydig cell hyperplasia, resulting in excess testosterone production. There are no reports of Leydig cell masses in boys with familial male-limited precocious puberty. We describe a 10-year-old boy with familial male-limited precocious puberty who developed Leydig cell nodules.

ATLS-based videotape trauma resuscitation review: education and outcome.

Trauma resuscitations (TRs) can be improved with ongoing videotape review. Unrecognized errors, delays, and system problems can be identified and corrected. Previous studies have demonstrated the importance of a short TR on survival and that videotape education can shorten TR time. Trauma resuscitation efficiency depends on details of TR including timing, organization, and appropriateness of care. Videotape education review monitors TR detail and improves TR efficiency by eliminating wasted time and treatment errors. Eight hundred eighty-three patients were evaluated. Group I included a control group prior to the incorporation of an ATLS based videotape review process. Group II included patients who were resuscitated after the educational review process was established. Subgroups based on ISS, direct OR transfer, DPL, and CT scan were also compared. Time and outcome were compared. Videotape educational review based on ATLS guidelines has improved TR efficiency. The benefits of ongoing videotape review include more efficient time utilization, correction of conceptual and technical errors, elimination of "wasted time," and improved survival.

Adrenalectomy reduces the threshold for hippocampal primed burst potentiation in the anesthetized rat.

Previously we demonstrated that the threshold for inducing hippocampal long-term potentiation (LTP) was reduced when the pattern of electrical stimulation mimicked physiological activity. This form of LTP, termed primed burst (PB) potentiation, is blocked by stress. In the present study, we tested the possibility that adrenal hormones contribute to the stress-related inhibition of PB potentiation. Our primary finding is that the amount of stimulation current necessary to induce PB potentiation was lower in adrenalectomized rats than in controls. This finding indicates that adrenal hormones exert an inhibitory influence on the induction of physiological plasticity in the hippocampus.