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Aims In cardiomyocytes, acute disturbances to intracellular pH (pHi) are promptly corrected by a system of finely tuned sarcolemmal acid–base transporters. However, these fluxes become thermodynamically re-balanced in acidic environments, which inadvertently causes their set-point pHi to fall outside the physiological range. It is unclear whether an adaptive mechanism exists to correct this thermodynamic challenge, and return pHi to normal. Methods and results Following left ventricle cryo-damage, a diffuse pattern of low extracellular pH (pHe) was detected by acid-sensing pHLIP. Despite this, pHi measured in the beating heart (13C NMR) was normal. Myocytes had adapted to their acidic environment by reducing Cl−/HCO3− exchange (CBE)-dependent acid-loading and increasing Na+/H+ exchange (NHE1)-dependent acid-extrusion, as measured by fluorescence (cSNARF1). The outcome of this adaptation on pHi is revealed as a cytoplasmic alkalinization when cells are superfused at physiological pHe. Conversely, mice given oral bicarbonate (to improve systemic buffering) had reduced myocardial NHE1 expression, consistent with a needs-dependent expression of pHi-regulatory transporters. The response to sustained acidity could be replicated in vitro using neonatal ventricular myocytes incubated at low pHe for 48 h. The adaptive increase in NHE1 and decrease in CBE activities was linked to Slc9a1 (NHE1) up-regulation and Slc4a2 (AE2) down-regulation. This response was triggered by intracellular H+ ions because it persisted in the absence of CO2/HCO3− and became ablated when acidic incubation media had lower chloride, a solution manoeuvre that reduces the extent of pHi-decrease. Pharmacological inhibition of FAK-family non-receptor kinases, previously characterized as pH-sensors, ablated this pHi autoregulation. In support of a pHi-sensing role, FAK protein Pyk2 (auto)phosphorylation was reduced within minutes of exposure to acidity, ahead of adaptive changes to pHi control. Conclusions Cardiomyocytes fine-tune the expression of pHi-regulators so that pHi is at least 7.0. This autoregulatory feedback mechanism defines physiological pHi and protects it during pHe vulnerabilities.

¿Quiénes cuidan a quienes nos cuidan? Es un interrogante que ha circulado en el espacio público estos últimos tiempos a raíz del impacto que tuvo la pandemia de COVID-19 a nivel global. Garantizar la salud y la asistencia alimentaria se tornó imprescindible. De este modo, el papel del personal sanitario resultó clave. Asimismo, la tarea de lxs referentes comunitarixs en los merenderos, comedores, puntos de acompañamiento y centros de cuidados para niñxs y adultxs mayores también fue una necesidad de primera instancia. El trabajo de lxs docentes, que en gran medida se desarrolló de manera virtual, también resultó de suma importancia para continuar garantizando el derecho a la educación luego del cierre de los establecimientos escolares.Las inquietudes planteadas nos llevan a interrogarnos sobre cómo los sindicatos encontraron resquicios o pliegues de actuación en defensa de lxs trabajadorxs de su sector a raíz de las consecuencias que generaron la pandemia y el ASPO en el ámbito del trabajo. Fil: Jacobo, Camila. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Centro de Investigaciones María Saleme Burnichón; Argentina Fil: Monterisi, Maria Celeste. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Centro de Investigaciones María Saleme Burnichón; Argentina Fil: Sapp, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Humanidades. Universidad Nacional de Córdoba. Instituto de Humanidades; Argentina

Purpose: To evaluate the clinical–pathological and prognostic significance of the circulating PD-L1 level in patients with surgically treated NSCLC, by combining data for PD-L1 expression with other immune-related markers and tumor metabolism. Methods: Overall, 40 patients with resected NSCLC (stage Ia–IIIa) who had preoperative blood storage and underwent staging PET/CT were enrolled for the study. In all cases, we determined plasma levels of PD-L1 (pg/ml), immune-reactive areas (IRA%) covered by CD3, CD68, CD20, CD8, PD-1, and PD-L1 in the tumor specimen, and metabolic parameters on PET, i.e., SUVmax, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Variables were statistically analyzed to establish their association with disease-free survival (DFS). Results: The circulating levels of PD-L1 in the bloodstream could be determined in 38/40 (95%) samples. The mean and median expression levels were 34.86pg/ml and 24.83pg/ml, respectively. We did not find any statistically significant correlation between circulating PD-L1 and tissue expression of PD-L1/PD-1. Some mild degree of positive correlation was determined between tissue PD-L1 and SUVmax (ρ = 0.390; p = 0.0148). Hierarchical clustering combining circulating, tissue, and metabolic parameters identified clusters with high metabolic tumor burden or high expression of plasma PD-L1 levels (Z score ≥ 2) as having a poor DFS (p = 0.033). The multivariate analysis detected stage and metabolism (i.e., SUVmax and SUVpeak) as independent prognostic factors for DFS. Conclusion: Plasma levels of PD-L1 are independent of the expression of PD-1/PD-L1 in NSCLC tumor tissue and, when combined with other clinical–pathological parameters, allow for the identification of clusters with different outcomes.

Supplemental Digital Content is available in the text., Background: Kinase oxidation is a critical signaling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, PKARIα (type-1 protein kinase A) can be reversibly oxidized, forming interprotein disulfide bonds in the holoenzyme complex. However, the effect of PKARIα disulfide formation on downstream signaling in the heart, particularly under states of oxidative stress such as ischemia and reperfusion (I/R), remains unexplored. Methods: Atrial tissue obtained from patients before and after cardiopulmonary bypass and reperfusion and left ventricular (LV) tissue from mice subjected to I/R or sham surgery were used to assess PKARIα disulfide formation by immunoblot. To determine the effect of disulfide formation on PKARIα catalytic activity and subcellular localization, live-cell fluorescence imaging and stimulated emission depletion super-resolution microscopy were performed in prkar1 knock-out mouse embryonic fibroblasts, neonatal myocytes, or adult LV myocytes isolated from “redox dead” (Cys17Ser) PKARIα knock-in mice and their wild-type littermates. Comparison of intracellular calcium dynamics between genotypes was assessed in fura2-loaded LV myocytes, whereas I/R-injury was assessed ex vivo. Results: In both humans and mice, myocardial PKARIα disulfide formation was found to be significantly increased (2-fold in humans, P=0.023; 2.4-fold in mice, P

Introduction: Kinase oxidation is a critical signaling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, the regulatory Iα subunit of Protein Kinase A (PKARIα) can be reversibly oxidised, forming interprotein disulfide bonds within the holoenzyme complex. However, the impact of disulfide formation on kinase function, and its influence on PKA signaling in the context of heart disease remains unknown. Methods & Results: Myocardial ischemia-reperfusion (I/R) was found to be a potent inducer of PKARIα disulfide formation in vivo , both in mice and in humans. Using imaging modalities with high spatial and temporal resolution, we found that this conformation did not increase intrinsic PKA catalytic activity, but rather facilitated enhanced AKAP-dependent compartmentation of PKARIα in the adult mouse left ventricular (LV) myocyte, with preferential localization to the lysosome under oxidized conditions (n=38-41 myocytes, N=3 animals, p Conclusions: Oxidised PKARIα acts as a potent inhibitor of intracellular calcium release in the heart through its redox-dependent interaction with the lysosome. In the setting of I/R, where PKA oxidation is induced, this regulatory mechanism is critical for protecting the heart from injury and offers a novel target for the design of cardioprotective therapeutics.

Circulating tumor cells (CTC) count and characterization have been associated with poor prognosis in recent studies. Our aim was to examine CTC count and its association with metabolic parameters and clinical outcomes in non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI). For this prospective study, data from 35 patients (23 males, 12 females) were collected and analyzed. All patients underwent an 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scan and CTC detection through Isolation by Size of Tumor/Trophoblastic Cells (ISET) from peripheral blood samples obtained at baseline and 8 weeks after ICI initiation. Association of CTC count with clinical and metabolic characteristics was studied. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan&ndash, Meier method and the log-rank test. Median follow-up was 13.2 months (range of 4.9&ndash, 21.6). CTC were identified in 16 out of 35 patients (45.7%) at baseline and 10 out of 24 patients at 8 weeks (41.7%). Mean CTC numbers before and after 8 weeks were 15 &plusmn, 28 and 11 &plusmn, 19, respectively. Prior to ICI, the mean CTC number was significantly higher in treatment-na&iuml, ve patients (34 &plusmn, 39 vs. 9 &plusmn, 21, p = 0.004). CTC count variation (&Delta, CTC) was significantly associated with tumor metabolic response set by European Organization for Research and Treatment of Cancer (EORTC) criteria (p = 0.033). At the first restaging, patients with a high tumor burden, that is, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), had a higher CTC count (p = 0.009). The combination of mean CTC and median MTV at 8 weeks was associated with PFS (p &lt, 0.001) and OS (p = 0.024). Multivariate analysis identified CTC count at 8 weeks as an independent predictor for PFS and OS, whereas &Delta, MTV and maximum standardized uptake value variation (&Delta, SUVmax) was predictive for PFS and OS, respectively. Our study confirmed that CTC number is modulated by previous treatments and correlates with metabolic response during ICI. Moreover, elevated CTC count, along with metabolic parameters, were found to be prognostic factors for PFS and OS.

Timely and accurate maps of land cover changes are crucial for understanding the evolution of Earth's features and, consequently, the relationships between individual and collective needs. Therefore, this information is extremely important to develop future planning strategies and tackle environmental issues. This paper aims to exploit the use of Google Earth Engine (GEE) platform to examine land cover changes over a period of about fiftheen years in the pilot site of Siponto, an historical municipality in Puglia, Southern Italy. Six atmospherically corrected Landsat data, two for each selected mission (5, 7 and 8), were collected: the former was acquired in fall and the latter in spring. Land cover information was automatically extracted from each image through the implementation of an innovative Landsat Images Classifications algorithm (LICA) based on spectral indices analysis. Six classes (water, built-up, mining areas, bare soil, dense and sparse vegetation) were detected from each image, with an average overall accuracy higher than 85%. Land cover changes were assessed comparing classification maps of the same season, showing bare soil areas as the most altered ones, having been converted into arable lands in consideration of the adavantageous geomorphological features of the investigated site. This is also confirmed by the historical events experienced by the area.

Land Use/Land Cover (LU/LC) data includes most of the information suitable for tackling many environmental issues. Remote sensing is largely recognized as the most significant method to extract them through the application of various techniques. They can be extracted through the application of many techniques. Among the several classification approaches, the index-based method has been recognized as the best one to gather LU/LC information from different images sources. The present work is intended to assess its performance exploiting the great potentialities of Google Earth Engine (GEE), a cloud-processing environment introduced by Google to storage and handle a large number of information. Twelve atmospherically corrected Landsat satellite images were collected on the experimental site of Siponto, in Southern Italy. Once the clouds masking procedure was completed, a large number of indices were implemented and compared in GEE platform to detect sparse and dense vegetation, water, bare soils and built-up areas. Among the tested algorithms, only NDBaI2, CVI, WI2015, SwiRed and STRed indices showed satisfying performance. Although NDBaI2 was able to extract all the main LU/LC categories with a high Overall Accuracy (OA) (82.59%), the other mentioned indices presented a higher accuracy than the first one but are able to identify just few classes. An interesting performance is shown by the STRed index since it has a very high OA and can extract mining areas, water and green zones. GEE appeared the best solution to manage the geospatial big data.

ResumenIntroducción: Streptococcus agalactiae (SGB) es un reconocido patógeno asociado a infecciones en recién nacidos y lactantes pequeños, en mujeres gestantes y en puérperas. En los últimos años se ha observado un incremento de infecciones por este agente en pacientes adultos no gestantes, siendo más frecuentes en mayores de 65 años y con alguna comorbilidad.Métodos: estudio retrospectivo y observacional de muestras de pacientes adultos no gestantes analizadas en el laboratorio de Bacteriología del Hospital Nacional de Clínicas de la ciudad de Córdoba, desde enero de 2008 a diciembre de 2017. Se analizó edad y sexo de los pacientes, comorbilidades y tipo de muestra.Resultados: El total de muestras positivas fue de 187, 91 (49%) correspondieron a mujeres y 96 (51%) a varones. La edad media fue de 67 años. De las muestras, orina fue la prevalente con 90 aislamientos (48.1%), seguidas de sangre con 39 (20.8%) y piel y partes blandas con 38 (20.3%). De los 187 adultos, 177 (95%) presentaron al menos una comorbilidad, siendo la más frecuente diabetes, seguida de neoplasias. Sólo 10 (5%) no presentaron comorbilidades.Conclusión: Los hallazgos en nuestro trabajo, como así también los publicados por diversos autores, ponen en evidencia la necesidad de considerar a Streptococcus agalactiae no sólo un patógeno de neonatos y embarazadas, sino también de pacientes adultos mayores y con diferentes comorbilidades, en especial aquellos que padecen DBT o neoplasias.Palabras claves: Streptococcus agalactiae; infecciones estreptocócicas; inmunosupresión; bacteriemia; comorbilidad

HOXB7 is a homeodomain (HOX) transcription factor involved in regional body patterning of invertebrates and vertebrates. We previously identified HOXB7 within a ten-gene prognostic signature for lung adenocarcinoma, where increased expression of HOXB7 was associated with poor prognosis. This raises the question of how HOXB7 overexpression can influence the metastatic behavior of lung adenocarcinoma. Here, we analyzed publicly available microarray and RNA-seq lung cancer expression datasets and found that HOXB7-overexpressing tumors are enriched in gene signatures characterizing adult and embryonic stem cells (SC), and induced pluripotent stem cells (iPSC). Experimentally, we found that HOXB7 upregulates several canonical SC/iPSC markers and sustains the expansion of a subpopulation of cells with SC characteristics, through modulation of LIN28B, an emerging cancer gene and pluripotency factor, which we discovered to be a direct target of HOXB7. We validated this new circuit by showing that HOXB7 enhances reprogramming to iPSC with comparable efficiency to LIN28B or its target c-MYC, which is a canonical reprogramming factor.

Mutations in the TREM2 gene confer risk for Alzheimer's disease and susceptibility for Parkinson's disease (PD). We evaluated the effect of TREM2 deletion in a 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)–induced PD mouse model, measuring neurodegeneration and microglia activation using a combined invivo imaging and postmortem molecular approach. In wild-type mice, MPTP administration induced a progressive decrease of [11C]FECIT uptake, culminating at day 7. Neuronal loss was accompanied by an increase of TREM2, IL-1β, and translocator protein (TSPO) transcript levels, [11C]PK11195 binding and GFAP staining (from day 2), and an early and transient increase of TNF-α, Galectin-3, and Iba-1 (from day 1). In TREM2 null (TREM2−/−) mice, MPTP similarly affected neuron viability and microglial cells, as shown by the lower level of Iba-1 staining in basal condition, and reduced increment of Iba-1, TNF-α, and IL-1β in response to MPTP. Likely to compensate for TREM2 absence, TREM2−/− mice showed an earlier increment of [11C]PK11195 binding and a significant increase of IL-4. Taken together, our data demonstrate a central role of TREM2 in the regulation of microglia response to acute neurotoxic insults and suggest a potential modulatory role of TSPO in response to immune system deficit.

Background Kinase oxidation is a critical signalling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, type-1 protein kinase A (PKARIα) can be reversibly oxidised, forming interprotein disulphide bonds within the holoenzyme complex. However, the effect of PKARIα oxidation on downstream signalling in the heart, particularly under states of oxidative stress, remains unexplored. Purpose To determine the direct functional consequences of PKARIα oxidation in the heart and investigate their impact on ischaemia/reperfusion (I/R) injury. Methods and results Experiments using the AKAR3ev FRET biosensor in murine left ventricular (LV) myocytes and Fluorescence Recovery After Photobleaching (FRAP) of GFP-tagged wild-type (WT) and mutant RIα proteins expressed in RIα-null fibroblasts showed that PKARIα oxidation does not increase the kinases' catalytic activity, but enhances its binding to A-kinase anchoring proteins (AKAP; n=30–39/N=3, p Displacement of PKARIα from lysosomes resulted in spontaneous sarcoplasmic reticulum calcium release and dramatic calcium oscillations in KI LV myocytes (panel B), which were preventable by ryanodine receptor blockade (1 mM tetracaine; n=14, p I/R (secondary to cardiopulmonary bypass) was found to induce PKARIα oxidation in the myocardium of patients undergoing cardiac surgery (panel C; n=18, p Conclusions Oxidised PKARIα acts as a potent inhibitor of intracellular calcium release in the heart through its redox-dependent interaction with the lysosome. In the setting of I/R, where PKARIα oxidation is induced, this regulatory mechanism is critical for protecting the heart from injury and offers a novel target for the design of cardioprotective therapeutics. Acknowledgement/Funding British Heart Foundation CH/12/3/29609, RG/16/12/32451; Garfield-Weston Foundation MPS/IVIMS-11/12-4032; Wellcome Trust Fellowship 0998981Z/12/Z

In the current paper, we aimed to investigate circulating tumor cells (CTCs) in non-small cell lung carcinoma (NSCLC) candidates to immunotherapy and correlate findings with clinical and metabolic parameters. Seventeen metastatic NSCLC patients (12 males, 5 females), were prospectively enrolled. All patients underwent (18)F-Fluorodeoxyglucose (FDG) PET/CT and CTCs detection before treatment. CTCs isolation by size was carried out with the ISET method. CTCs were characterized based on cytopathological features and were compared with smoking status, histological subtype, pre-immunotherapy treatment, PDL-1 expression, performance status, and semi-quantitative parameters on PET, including SUVmax, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG). We found CTCs in 10 out of 17 patients (59%). Mean number of CTCs was 3 (range 1-7). Only one cell with 3 malignant features was detected in the blood of a healthy control out of 7 (16%). A significantly lower number of CTCs was found in patients previously treated with chemotherapy (P=0.041). No correlation between CTCs and other clinical pathologic characteristics was observed. Patients with an extensive tumor burden, i.e. MTV and TLG, were associated with a higher number of CTCs (P=0.004 and P=0.028, respectively). Likewise, patients with a higher metabolism determined with SUVmean resulted having a higher CTCs count (P=0.048). The presence of CTCs was associated with tumor uptake and metabolic burden on PET/CT, while results were influenced by previous chemotherapy. Whether confirmed in larger series, the combination of the presence of CTCs and FDG PET metabolic parameters might improve prognostic stratification and allow more personalized treatment paradigm.

Aeromonas is a common cause of gastroenteritis but occasionally it can cause extraintestinal infections. The incidence of bacteremia by this genus is very low and in general the patients have associated base diseases.Retrospective analysis of episodes of bacteremia by Aeromonas spp. during a period of eight years in the National Hospital of Clinics of the city of Córdoba, emphasizing age, sex, associated comorbidities, clinical presentation, focus, origin of the infection, clinical evolution, species prevalence and antimicrobial sensitivity of the same .10 episodes of bacteremia were recorded by Aeromonas spp. 60% corresponded to women and 40% to men. The average age was 65 years. In seven patients the origin of the infection was community and in three nosocomial. 70% of the patients presented predisposing base pathologies. The focus of bacteremia was abdominal in two cases. A. hydrophila complex was responsible for 50% of the cases. 80% of bacteremia were monomicrobial. The isolates generally showed high percentages of sensitivity.Bacteremia occurred in elderly patients of both sexes, most of whom had associated comorbidities. The majority of the infections originated in the community. While bacteremia by Aeromonas spp. it is rare, the mortality found in our study was relatively high despite the high percentage of sensitivity to antimicrobials.Aeromonas es una causa habitual de gastroenteritis pero ocasionalmente puede producir infecciones extraintestinales. La incidencia de bacteriemia por este género es muy baja y en general los pacientes presentan enfermedades de base asociadas.Análisis retrospectivo de los episodios de bacteriemias por Aeromonas spp. durante un período de ocho años en el Hospital Nacional de Clínicas de la ciudad de Córdoba, haciendo hincapié en edad, sexo, comorbilidades asociadas, presentación clínica, foco, origen de la infección, evolución clínica, prevalencia de especies y sensibilidad antimicrobiana de las mismas.Se registraron 10 episodios de bacteriemias por Aeromonas spp. El 60% correspondieron a mujeres y el 40% a hombres. La edad promedio fue 65 años. En siete pacientes el origen de la infección fue comunitario y en tres nosocomial. El 70% de los pacientes presentaron patologías de base predisponentes. El foco de la bacteriemia fue abdominal en dos casos. A. complejo hydrophila fue responsable del 50% de los casos. El 80% de las bacteriemias fueron monomicrobianas. Los aislamientos generalmente presentaron altos porcentajes de sensibilidad.Las bacteriemias se presentaron en pacientes de ambos sexos, de edad avanzada, la mayoría de los cuales poseían comorbilidades asociadas. La mayoría de las infecciones tuvieron su origen en la comunidad. Si bien la bacteriemia por Aeromonas spp. es poco frecuente, la mortalidad encontrada en nuestro estudio fue relativamente elevada a pesar del alto porcentaje de sensibilidad a los antimicrobianos.

To produce physiological functions, many tissues require their cells to be connected by gap junctions. Such diffusive coupling is important in establishing a cytoplasmic syncytium through which cells can exchange signals, substrates and metabolites. Often the benefits of connectivity become apparent solely at the multicellular level, leading to the notion that cells work for a common good rather than exclusively in their self-interest. In some tumors, gap junctional connectivity between cancer cells is reduced or absent, but there are notable cases where it persists or re-emerges in late-stage disease. Diffusive coupling will blur certain phenotypic differences between cells, which may seem to go against the establishment of population heterogeneity, a central pillar of cancer that stems from genetic instability. Here, building on our previous measurements of gap junctional coupling between cancer cells, we use a computational model to simulate the role of connexin-assembled channels in exchanging lactate and bicarbonate ions down their diffusion gradients. Based on the results of these simulations, we propose that an overriding benefit of gap junctional connectivity may relate to lactate/bicarbonate exchange, which would support an elevated metabolic rate in hypoxic tumors. In this example of barter, hypoxic cancer cells provide normoxic neighbors with lactate for mitochondrial oxidation; in exchange, bicarbonate ions, which are more plentiful in normoxic cells, are supplied to hypoxic neighbors to neutralize the H+ ions co-produced glycolytically. Both cells benefit, and so does the tumor.

Purpose: The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab. Patients and Methods: Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics. Results: Nineteen patients were treated; 84% had grade 3/4 adverse events, and neither dose-limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n = 8) at week 4 (74.5%) and week 12 (75.5%) was significantly (P < 0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly (P < 0.05; Z score >2 or ←2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis (n = 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8+, PD-1+ T cells and in CD20+ B cells in posttreatment tumor cores. Conclusions: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.

Fluorine-18 labelled fluoroazomycinarabinoside (18F-FAZA) is a positron emission tomography (PET) biomarker for non-invasive identification of regional tumor hypoxia. Aim of the present Phase I study was to firstly evaluate in non-small cell lung cancer patients the human biodistribution and dosimetry of 18F-FAZA. Methods: Five patients awaiting surgical resection after histologically proven or radiologically suspected non-small cell lung cancer were prospectively enrolled for the study. The patients underwent a PET/computed tomography (CT) study after the injection of 371±32 MBq of 18F-FAZA. The acquisition protocol consisted of a 10-minutes dynamic imaging of the heart to calculate the activity in blood, followed by four whole body PET/CT scans, from the vertex to mid-thigh, at: 10, 60, 120 and 240-minutes post-injection. Urine samples were collected after each imaging session and at 360-minutes post-injection. Volumes of interest were drawn around visually identifiable sources organs to generate time-activity-curves (TACs). Residence time were determined from TACs and effective dose (ED) to individual organs and whole body were calculated using OLINDA/EXM 1.2 for standard male and female. Results: Blood clearance was characterized by a rapid distribution phase, followed by a first order elimination phase. The highest uptakes were found in muscle and liver with peaks of 42.7±5.3% and 5.5±0.6% of injected activity, respectively. The total urinary excretion was 15% of the injected activity. The critical organ was urinary bladder wall with the highest radiation-absorbed doses of 0.047±0.008 mGy/MBq and 0.067±0.007 mGy/MBq calculating on 2 and 4 hours voiding intervals. The ED for standard male and female was 0.013±0.004 mSv/MBq and 0.014±0.004 mSv/MBq depending on the voiding schedule. Conclusion: With respect to available literature, the biodistribution of 18F-FAZA appeared to be slightly different in humans than in mice, with a low clearance in humans. Therefore, estimated organ radiation doses from animal data could exhibit a moderate underestimation. Our data showed that dosimetry of 18F-FAZA, for an injection of 370 MBq of tracer, is safe for its clinical use and it is almost similar to other widely used PET ligands. In particular, the ED is not appreciably different from those obtained with other hypoxia tracers, such as 18F-fluoromisonidazole (18F-FMISO).

ResumenLa bacteriemia por Enterococcus adquirió un papel relevante en los últimos años, debido al incremento de casos intrahospitalarios. Nuestro objetivo fue describir los episodios ocurridos en pacientes adultos de nuestro hospital. Entre enero del 2000 y diciembre del 2013 se registraron 117 episodios. El 61% eran varones y el 39% mujeres. La edad promedio fue 68 años. El 91% presentaba condiciones predisponentes. El principal foco fue intraabdominal. Enterococcus faecalis fue responsable del 65% de los casos, Enterococcus faecium del 28% y otras especies del 7%. El 34% fueron bacteriemias polimicrobianas. Todas las cepas de E. faecalis fueron sensibles a ampicilina y vancomicina. El 88% de los aislamientos de E. faecium fue resistente a ampicilina y el 54% a vancomicina y teicoplanina. En nuestro hospital, el enterococo es el sexto patógeno causante de bacteriemia intrahospitalaria y predomina E. faecium resistente a ampicilina y vancomicina.AbstractEnterococcal bacteremia has acquired considerable importance in recent years, mainly due to an increased number of cases that occur during hospital admission. We describe the episodes of enterococcal bacteremia in adult patients recorded at our hospital. Between January 2000 and December 2013, 117 episodes were analyzed. Sixty one percent (61%) of the patients were male and 39% female. The mean age was 68. Predisposing factors were present in 91% of patients. The primary source of infection was intraabdominal. Enterococcus faecalis was responsible for 65% of the cases; E. faecium for 28%; and other species for 7%. Thirty four percent (34%) of cases were polymicrobial bacteremia. All E. faecalis isolates were susceptible to ampicillin and vancomycin. Eighty eight percent (88%) of E. faecium were resistant to ampicillin and 54% to vancomycin and teicoplanin. In our hospital, Enterococcus is the sixth pathogen causing nosocomial bacteremia, with high incidence of ampicillin and vancomycin-resistant E. faecium.

Streptococcus agalactiae (GBS) is a recognized pathogen associated with infections in newborns and small infants, pregnant women, and puerperal women. In recent years there has been an increase in infections by this agent in non-pregnant adult patients, being more frequent in people over 65 years of age and with some comorbidity.retrospective and observational study of samples from non-pregnant adult patients analyzed in the Bacteriology Laboratory of the Hospital Nacional de Clínicas of the city of Córdoba, from January 2008 to December 2017. Age and sex of the patients, comorbidities, and type of sample were analyzed shows.The total of positive samples was 187, 91 (49%) corresponded to women and 96 (51%) to men. The average age was 67 years. Of the samples, urine was the prevalent one with 90 isolates (48.1%), followed by blood with 39 (20.8%) and skin and soft tissues with 38 (20.3%). Of the 187 adults, 177 (95%) had at least one comorbidity, the most frequent being diabetes, followed by neoplasms. Only 10 (5%) did not present comorbidities.The findings in our work, as well as those published by various authors, show the need to consider Streptococcus agalactiae not only a pathogen of neonates and pregnant women, but also of elderly patients with different comorbidities, especially those who suffer from DBT or neoplasia.Streptococcus agalactiae (SGB) es un reconocido patógeno asociado a infecciones en recién nacidos y lactantes pequeños, en mujeres gestantes y en puérperas. En los últimos años se ha observado un incremento de infecciones por este agente en pacientes adultos no gestantes, siendo más frecuentes en mayores de 65 años y con alguna comorbilidad.estudio retrospectivo y observacional de muestras de pacientes adultos no gestantes analizadas en el laboratorio de Bacteriología del Hospital Nacional de Clínicas de la ciudad de Córdoba, desde enero de 2008 a diciembre de 2017. Se analizó edad y sexo de los pacientes, comorbilidades y tipo de muestra.El total de muestras positivas fue de 187, 91 (49%) correspondieron a mujeres y 96 (51%) a varones. La edad media fue de 67 años. De las muestras, orina fue la prevalente con 90 aislamientos (48.1%), seguidas de sangre con 39 (20.8%) y piel y partes blandas con 38 (20.3%). De los 187 adultos, 177 (95%) presentaron al menos una comorbilidad, siendo la más frecuente diabetes, seguida de neoplasias. Sólo 10 (5%) no presentaron comorbilidades.Los hallazgos en nuestro trabajo, como así también los publicados por diversos autores, ponen en evidencia la necesidad de considerar a Streptococcus agalactiae no sólo un patógeno de neonatos y embarazadas, sino también de pacientes adultos mayores y con diferentes comorbilidades, en especial aquellos que padecen DBT o neoplasias.Palabras claves: Streptococcus agalactiae; infecciones estreptocócicas; inmunosupresión; bacteriemia; comorbilidad.

Significance The selective phosphorylation of spatially distinct PKA targets is key for the pleiotropy of the cAMP cascade. This characteristic of the pathway is currently attributed to the ability of phosphodiesterases or adenylate cyclases to create subcellular sites (microdomains) where the concentration of cAMP is distinct from that of the surrounding areas. The role of phosphatases in this process has not been tested. Here we show that limited access of phosphatases to the PKA targets present at the outer mitochondrial membrane generates distinct microdomains of PKA phosphorylated proteins despite there being no differences in the local cAMP levels. These results describe an alternative mechanism capable of generating functional cAMP/PKA-dependent microdomains and may be extrapolated to the compartmentalization of other kinase-dependent events., Evidence supporting the heterogeneity in cAMP and PKA signaling is rapidly accumulating and has been largely attributed to the localization or activity of adenylate cyclases, phosphodiesterases, and A-kinase–anchoring proteins in different cellular subcompartments. However, little attention has been paid to the possibility that, despite homogeneous cAMP levels, a major heterogeneity in cAMP/PKA signaling could be generated by the spatial distribution of the final terminators of this cascade, i.e., the phosphatases. Using FRET-based sensors to monitor cAMP and PKA-dependent phosphorylation in the cytosol and outer mitochondrial membrane (OMM) of primary rat cardiomyocytes, we demonstrate that comparable cAMP increases in these two compartments evoke higher levels of PKA-dependent phosphorylation in the OMM. This difference is most evident for small, physiological increases of cAMP levels and with both OMM-located probes and endogenous OMM proteins. We demonstrate that this disparity depends on differences in the rates of phosphatase-dependent dephosphorylation of PKA targets in the two compartments. Furthermore, we show that the activity of soluble phosphatases attenuates PKA-driven activation of the cAMP response element-binding protein while concurrently enhancing PKA-dependent mitochondrial elongation. We conclude that phosphatases can sculpt functionally distinct cAMP/PKA domains even in the absence of gradients or microdomains of this messenger. We present a model that accounts for these unexpected results in which the degree of PKA-dependent phosphorylation is dictated by both the subcellular distribution of the phosphatases and the different accessibility of membrane-bound and soluble phosphorylated substrates to the cytosolic enzymes.

Estratto da: Archivio italiano per la storia della pieta, vol. VI, 1970