Symptom-related screening programme for early detection of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: the SYSPPE study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is the most severe long-term complication of acute pulmonary embolism (PE). We aimed to evaluate the impact of a symptom screening programme to detect CTEPH in PE survivors. METHODS: This was a multicentre cohort study of patients diagnosed with acute symptomatic PE between January 2017 and December 2018 in 16 centres in Spain. Patients were contacted by phone 2 years after the index PE diagnosis. Those with dyspnoea corresponding to a New York Heart Association (NYHA)/WHO scale≥II, visited the outpatient clinic for echocardiography and further diagnostic tests including right heart catheterisation (RHC). The primary outcome was the new diagnosis of CTEPH confirmed by RHC. RESULTS: Out of 1077 patients with acute PE, 646 were included in the symptom screening. At 2 years, 21.8% (n=141) reported dyspnoea NYHA/WHO scale≥II. Before symptom screening protocol, five patients were diagnosed with CTEPH following routine care. In patients with NYHA/WHO scale≥II, after symptom screening protocol, the echocardiographic probability of pulmonary hypertension (PH) was low, intermediate and high in 76.6% (n=95), 21.8% (n=27) and 1.6% (n=2), respectively. After performing additional diagnostic test in the latter 2 groups, 12 additional CTEPH cases were confirmed. CONCLUSIONS: The implementation of this simple strategy based on symptom evaluation by phone diagnosed more than doubled the number of CTEPH cases. Dedicated follow-up algorithms for PE survivors help diagnosing CTEPH earlier. TRIAL REGISTRATION NUMBER: NCT03953560.

Diagnostic pathways of Chagas disease in Spain: a qualitative study.

BACKGROUND: Due to the mobility of the population in recent years and the spread of Chagas disease (CD) to non-endemic regions, early diagnosis and treatment of CD has become increasingly relevant in non-endemic countries. In order for screening to be effective, health system accessibility must be taken into consideration. This study uses Tanahashi's Health Service Coverage model to gain a deeper understanding of the main diagnostic pathways for Chagas disease in a non-endemic country and the barriers and bottlenecks present in each pathway. METHODS: This study used a qualitative design with a phenomenological approach. Twenty-one interviews, two focus group sessions, and two triangular group sessions were conducted between 2015 and 2018 with 37 Bolivian men and women diagnosed with CD in Madrid, Spain. A topic guide was designed to ensure that the interviewers obtained the data concerning knowledge of CD (transmission, symptoms, and treatment), attitudes towards CD, and health behaviour (practices in relation to CD). All interviews, focus groups and triangular groups were recorded and transcribed. A thematic, inductive analysis based on Grounded Theory was performed by two researchers. RESULTS: Three main pathways to CD diagnosis were identified: 1) pregnancy or blood/organ donation, with no bottlenecks in effective coverage; 2) an individual actively seeking CD testing, with bottlenecks relating to administrative, physical, and time-related accessibility, and effectiveness based on the healthcare professional's knowledge of CD; 3) an individual not actively seeking CD testing, who expresses psychological discomfort or embarrassment about visiting a physician, with a low perception of risk, afraid of stigma, and testing positive, and with little confidence in physicians' knowledge of CD. CONCLUSIONS: Existing bottlenecks in the three main diagnostic pathways for CD are less prevalent during pregnancy and blood donation, but are more prevalent in individuals who do not voluntarily seek serological testing for CD. Future screening protocols will need to take these bottlenecks into consideration to achieve effective coverage.

Low-molecular-weight heparin beyond 12 months in patients with cancer-associated thrombosis.

BACKGROUND: Clinical guidelines indicate that in patients with cancer-associated thrombosis (CAT), anticoagulant treatment should be continued beyond 6 months as long as the cancer is active. We aimed to analyse the safety of low-molecular-weight heparin (LMWH) beyond 12 months in patients with CAT. METHODS: We performed a post hoc analysis of consecutive CAT patients from October 2008 to December 2019. The primary outcome was the rate of clinically relevant bleeding (CRB), and we compared two periods (1-12 vs. 12-24 months). Hazard ratio (HR), competing risk analysis and sensitivity analyses were performed. RESULTS: Of the 588 patients included, 30.1% (n = 177) received LMWH beyond 12 months. The rate of CRB in the first 12 months compared to the 12-24 month period was 3.2 per 100 patients/month (95% CI 2.5-4.1) vs. 0.9 per 100 patients/month (95% CI 0.4-1.5), (P < 0.0001). The competing risk analysis of CRB comparing both periods showed a lower sub-distribution hazard ratio (SHR) during the period 12-24 months (SHR: 0.5, 95% CI: 0.3-0.8, P < 0.001). CONCLUSION: In patients with cancer-associated thrombosis under anticoagulant treatment with LMWH, the rate of clinically relevant bleeding and major bleeding were lower beyond 12 months.

Cytotoxicity, cellular uptake and apoptotic responses in human coronary artery endothelial cells exposed to ultrasmall superparamagnetic iron oxide nanoparticles.

Ultrasmall superparamagnetic iron oxide nanoparticles (USPION) possess reactive surfaces, are metabolized and exhibit unique magnetic properties. These properties are desirable for designing novel theranostic biomedical products; however, toxicity mechanisms of USPION are not completely elucidated. The goal of this study was to investigate cell interactions (uptake and cytotoxicity) of USPION using human coronary artery endothelial cells as a vascular cell model. Polyvinylpirrolidone-coated USPION were characterized: average diameter 17 nm (transmission electron microscopy [TEM]), average hydrodynamic diameter 44 nm (dynamic light scattering) and zeta potential -38.75 mV. Cells were exposed to 0 (control), 25, 50, 100 or 200 µg/mL USPION. Concentration- and time-dependent cytotoxicity were observed after 3-6 hours through 24 hours of exposure using Alamar Blue and Real-Time Cell Electronic Sensing assays. Cell uptake was evaluated by imaging using live-dead confocal microscopy, actin and nuclear fluorescent staining, and TEM. Phase-contrast, confocal microscopy, and TEM imaging showed significant USPION internalization as early as 3 hours after exposure to 25 µg/mL. TEM imaging demonstrated particle internalization in secondary lysosomes with perinuclear localization. Three orthogonal assays were conducted to assess apoptosis. TUNEL staining demonstrated a marked increase in fragmented DNA, a response pathognomonic of apoptosis, after a 4-hour exposure. Cells subjected to agarose gel electrophoresis exhibited degraded DNA 3 hours after exposure. Caspase-3/7 activity increased after a 3-hour exposure. USPION uptake resulted in cytotoxicity involving apoptosis and these results contribute to further mechanistic understanding of the USPION toxicity in vitro in cardiovascular endothelial cells.

Evaluation of microvascular changes in the perifoveal vascular network using optical coherence tomography angiography (OCTA) in type I diabetes mellitus: a large scale prospective trial.

BACKGROUND: Diabetic retinopathy (DR) is the leading cause of blindness in type 1 Diabetes Mellitus (DM) patients, as a consequence of impaired blood flow in the retina. Optical coherence tomography angiography (OCTA) is a newly developed, non-invasive, retinal imaging technique that permits adequate delineation of the perifoveal vascular network. It allows the detection of paramacular areas of capillary non perfusion and/or enlargement of the foveal avascular zone (FAZ), representing an excellent tool for assessment of DR. The relationship of these microvascular changes with systemic factors such as metabolic control or duration of the disease still needs to be elucidated. METHODS: Prospective, consecutive, large-scale OCTA study. A complete ocular examination including a comprehensive series of OCTA images of different scan sizes captured with 2 OCT devices (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA, USA, and Triton Deep Range Imaging OCT, Topcon Corp, Topcon, Japan) will be obtained as part of the yearly routine follow up visits in type 1 DM patients seen in the Diabetes Unit of the Endocrinology department which give written informed consent to participate in the project. The aim of this study is to investigate the relationship between OCTA-derived parameters and systemic factors, as metabolic control (Hb1Ac, lipid profile, cholesterol, etc), and other relevant clinical factors as demographics or duration of the disease. DISCUSSION: This study is directed to investigate the relationship between the status of the perifoveal vascular network and systemic markers of the disease, and in particular to study whether these changes reflect those occurring elsewhere in the body affected by diabetic microvascular disease, as the kidneys or the brain. If these relationships were demonstrated, early detection of these microvascular changes by OCTA could lead to modifications in the pharmacological management of type 1 diabetic patients, as a way to reduce the risk of future complications in both the eye and other organs. TRIAL REGISTRATION: ClinicalTrials.gov, trial number NCT03422965.

Instability severity index score values below 7 do not predict recurrence after arthroscopic Bankart repair.

PURPOSE: To evaluate the efficacy of the Instability Severity Index Score (ISIS) in predicting an increased recurrence risk after an arthroscopic Bankart repair. METHODS: Retrospective review of a cohort of patients operated in three different centres. The inclusion criteria (recurrent anterior instability [dislocation or subluxation] with or without hyperlaxity, arthroscopic Bankart repair) and the exclusion criteria (concomitant rotator cuff lesion, acute first-time dislocation, surgery after a previous anterior stabilization, surgery for an unstable shoulder without true dislocation or subluxation; multidirectional instability) were those used in the study that defined the ISIS score. The medical records and a telephone interview were used to identify the six variables that define the ISIS and identify recurrences. RESULTS: One hundred and sixty-three shoulders met the inclusion and exclusion criteria. Of these, 140 subjects (22 females/118 males; mean age 35.5 ± 7.9) with 142 (89.0%) shoulders were available for follow-up after 5.3 (1.1) (range 3.1-7.4) years. There were 20 recurrences (14.1%). The mean (SD) preoperative ISIS was 1.8 (1.6) in the patients without recurrence and 1.8 (1.9) in the patients with recurrence (n.s.). In the 117 subjects with ISIS between 0 and 3 the recurrence rate was 12.8%; in the 25 with ISIS 4 to 6 the rate was 20% (n.s.). CONCLUSION: For subjects with anterior shoulder instability in which an arthroscopic Bankart repair is being considered, the use of the ISIS, when the values obtained are ≤ 6 was not useful to predict an increased recurrence risk in the midterm in this retrospectively evaluated case series. The efficacy of the ISIS score in defining a group of subjects with a preoperative increased risk of recurrence after an arthroscopic Bankart instability repair is limited in lower risk populations (with ISIS scores ≤ 6). LEVEL OF EVIDENCE: Retrospective case series, Level IV.

D-dimer and high-sensitivity C-reactive protein levels to predict venous thromboembolism recurrence after discontinuation of anticoagulation for cancer-associated thrombosis.

BACKGROUND: Optimal duration of anticoagulation for cancer-associated thrombosis (CAT) remains unclear. This study assessed D-dimer (DD) and high-sensitivity C-reactive protein (hs-CRP) levels after the withdrawal of anticoagulation treatment to predict the risk of venous thromboembolism (VTE) recurrence among patients with CAT. METHODS: Prospective, multicentre study to evaluate CAT with ≥3 months of anticoagulation that was subsequently discontinued. Blood samples were taken when patients stopped the anticoagulation and 21 days later to determine the DD and hs-CRP levels. All patients were followed up for 6 months to detect VTE recurrence. RESULTS: Between 2013 and 2015, 325 patients were evaluated and 114 patients were ultimately enrolled in the study. The mean age was 62 ± 14 years and nearly 40% had metastasis. Ten patients developed VTE recurrence within 6 months (8.8%, 95% confidence interval [CI]: 4.3-15.5%). The DD and hs-CRP levels after 21 days were associated with VTE recurrence. The subdistribution hazard ratios were 9.82 for hs-CRP (95% CI: 19-52) and 5.81 for DD (95% CI: 1.1-31.7). CONCLUSIONS: This study identified that hs-CRP and DD were potential biomarkers of VTE recurrence after discontinuation of anticoagulation in CAT. A risk-adapted strategy could identify low-risk patients who may benefit from discontinuation of anticoagulation.

The active microbial diversity drives ecosystem multifunctionality and is physiologically related to carbon availability in Mediterranean semi-arid soils.

Biogeochemical processes and ecosystemic functions are mostly driven by soil microbial communities. However, most methods focus on evaluating the total microbial community and fail to discriminate its active fraction which is linked to soil functionality. Precisely, the activity of the microbial community is strongly limited by the availability of organic carbon (C) in soils under arid and semi-arid climate. Here, we provide a complementary genomic and metaproteomic approach to investigate the relationships between the diversity of the total community, the active diversity and ecosystem functionality across a dissolved organic carbon (DOC) gradient in southeast Spain. DOC correlated with the ecosystem multifunctionality index composed by soil respiration, enzyme activities (urease, alkaline phosphatase and ß-glucosidase) and microbial biomass (phospholipid fatty acids, PLFA). This study highlights that the active diversity (determined by metaprotoemics) but not the diversity of the whole microbial community (evaluated by amplicon gene sequencing) is related to the availability of organic C and it is also connected to the ecosystem multifunctionality index. We reveal that DOC shapes the activities of bacterial and fungal populations in Mediterranean semi-arid soils and determines the compartmentalization of functional niches. For instance, Rhizobales thrived at high-DOC sites probably fuelled by metabolism of one-C compounds. Moreover, the analysis of proteins involved in the transport and metabolism of carbohydrates revealed that Ascomycota and Basidiomycota occupied different nutritional niches. The functional mechanisms for niche specialization were not constant across the DOC gradient.

The cohesin subunit RAD21L functions in meiotic synapsis and exhibits sexual dimorphism in fertility.

The cohesin complex is a ring-shaped proteinaceous structure that entraps the two sister chromatids after replication until the onset of anaphase when the ring is opened by proteolytic cleavage of its α-kleisin subunit (RAD21 at mitosis and REC8 at meiosis) by separase. RAD21L is a recently identified α-kleisin that is present from fish to mammals and biochemically interacts with the cohesin subunits SMC1, SMC3 and STAG3. RAD21L localizes along the axial elements of the synaptonemal complex of mouse meiocytes. However, its existence as a bona fide cohesin and its functional role awaits in vivo validation. Here, we show that male mice lacking RAD21L are defective in full synapsis of homologous chromosomes at meiotic prophase I, which provokes an arrest at zygotene and leads to total azoospermia and consequently infertility. In contrast, RAD21L-deficient females are fertile but develop an age-dependent sterility. Thus, our results provide in vivo evidence that RAD21L is essential for male fertility and in females for the maintenance of fertility during natural aging.

Nanoparticle stability in biologically relevant media: influence of polymer architecture.

We have contrasted the behavior of nanoparticles formed by the self-assembly of polymers based on poly(ethylene glycol) (PEG) and poly(D,L-lactide), with linear, linear-dendritic and bottle-brush architectures in biologically relevant media. Polymer PEG content ranged between 14% and 46% w/w, and self-assembly was triggered by a rapid and large change in solvent quality inside a four-stream vortex mixer. We examined nanoparticle interaction with human serum albumin (HSA), and solute release in the presence of fetal bovine serum. Dynamic light scattering data showed that PEG surface brushes of all nanoparticles provided effective steric stabilization, thus limiting their interaction with human serum albumin. Calorimetric experiments revealed that nanoparticle-HSA interaction was relatively weak and enthalpically driven, whereas dynamic light scattering results of incubated nanoparticles showed the absence of larger aggregates for most of the polymers examined. Solute core partitioning was examined by the loss of Forster resonance energy transfer (FRET) from a core-loaded donor-acceptor pair. The rate and magnitude of FRET efficiency loss was strongly dependent on the polymer architecture, and was found to be lowest for the bottle-brush, attributed to its covalent nature. Collectively, these findings are expected to impact the molecular design of increasingly stable polymeric carriers for drug delivery applications.

Secretory meningioma with KLF4 K409Q mutation in collision with glioma.

AIMS: The simultaneous occurrence of two primary intracranial tumors is a rare event, especially if unrelated to radiotherapy or genetic disorders. We present two patients, both with two primary intracranial tumors simultaneously present at adjacent sites, in order to explore a possible mechanism of synchronous tumor formation. METHODS: We performed a molecular analysis of the K409Q mutation of the KLF4 gene, in addition to conventional immunohistochemistry. RESULTS: Preoperative gadolinium-enhanced magnetic resonance imaging revealed a necrotic mass with an irregular ring-like enhancement adjacent to a frontal meningioma in patient 1, and an infiltrative non-enhancing glial tumor with no evidence of another tumor in patient 2. Postoperative histological examination revealed the presence of two distinct tumors in both cases: secretory meningioma and glioblastoma in patient 1 and secretory meningioma and anaplastic astrocytoma in patient 2. Secretory meningiomas both showed the KLF4 K409Q mutation, while none of the glial tumors had it. CONCLUSIONS: To our knowledge, these are the first two cases reported of the simultaneous occurrence of secretory meningiomas with mutation of KLF4 in collision with a glioblastoma and an anaplastic astrocytoma, respectively. These collision tumors presumably have different molecular origins.

Response of soil microbial activity and biodiversity in soils polluted with different concentrations of cypermethrin insecticide.

We performed a laboratory study into the effect of cypermethrin insecticide applied to different concentrations on biological properties in two soils [Typic Xerofluvent (soil A) and Xerollic Calciorthid (soil B)]. Two kg of each soil were polluted with cypermethrin at a rate of 60, 300, 600, and 1,200 g ha(-1) (C1, C2, C3, and C4 treatments). A nonpolluted soil was used as a control (C0 treatment). For all treatments and each experimental soil, soil dehydrogenase, urease, ß-glucosidase, phosphatase, and arylsulphatase activities and soil microbial community were analysed by phospholipid fatty acids, which were measured at six incubation times (3, 7, 15, 30, 60, and 90 days). The behavior of the enzymatic activities and microbial population were dependent on the dose of insecticide applied to the soil. Compared with the C0 treatment, in soil A, the maximum inhibition of the enzymatic activities was at 15, 30, 45, and 90 days for the C1, C2, C3, and C4 treatments, respectively. However, in soil B, the maximum inhibition occurred at 7, 15, 30, and 45 days for the C1, C2, C3, and C4 treatments, respectively. These results suggest that the cypermethrin insecticide caused a negative effect on soil enzymatic activities and microbial diversity. This negative impact was greater when a greater dose of insecticide was used; this impact was also greater in soil with lower organic matter content. For both soils, and from these respective days onward, the enzymatic activities and microbial populations progressively increased by the end of the experimental period. This is possibly due to the fact that the insecticide or its breakdown products and killed microbial cells, subsequently killed by the insecticide, are being used as a source of energy or as a carbon source for the surviving microorganisms for cell proliferation.

Effect of soaking and fermentation on content of phenolic compounds of soybean (Glycine max cv. Merit) and mung beans (Vigna radiata [L] Wilczek).

Mung beans (Vigna radiata [L] Wilczek) purchased from a Spanish company as "green soybeans", showed a different phenolic composition than yellow soybeans (Glycine max cv. Merit). Isoflavones were predominant in yellow soybeans, whereas they were completely absent in the green seeds on which flavanones were predominant. In order to enhance their health benefits, both types of bean were subjected to technological processes, such as soaking and fermentation. Soaking increased malonyl glucoside isoflavone extraction in yellow beans and produced an increase in apigenin derivatives in the green beans. Lactobacillus plantarum CECT 748 T fermentation produced an increase in the bioactivity of both beans since a conversion of glycosylated isoflavones into bioactive aglycones and an increase of the bioactive vitexin was observed in yellow and green beans, respectively. In spite of potential consumer confusion, since soybean and "green soybean" are different legumes, the health benefits of both beans were enhanced by lactic fermentation.

Factors associated with the utilization of primary care emergency centers in a Spanish region with high population dispersion: a mixed-methods study.

BACKGROUND: Adequate access to primary care emergency centers is particularly important in rural areas isolated from urban centers. However, variability in utilization of emergency services located in primary care centers among inhabitants of nearby geographical areas is understudied. The objectives of this study are twofold: 1) to analyze the association between the availability of municipal emergency care centers and utilization of primary care emergency centers (PCEC), in a Spanish region with high population dispersion; and 2) to determine healthcare providers' perceptions regarding PCEC utilization. METHODS: A mixed-methods study was conducted. Quantitative phase: multilevel logistic regression modeling using merged data from the 2003 Regional Health Survey of Castile and Leon and the 2001 census data (Spain). Qualitative phase:14 in-depth- interviews of rural-based PCEC providers. RESULTS: Having PCEC as the only emergency center in the municipality was directly associated with its utilization (p < 0.001). Healthcare providers perceived that distance to hospital increased PCEC utilization, and distance to PCEC decrease its use. PCEC users were considered to be predominantly workers and students with scheduling conflicts with rural primary care opening hours. CONCLUSIONS: The location of emergency care centers is associated with PCEC utilization. Increasing access to primary care by extending hours may be an important step toward optimal PCEC utilization. Further research would determine whether lower PCEC use by certain groups is associated with disparities in access to care.

Clinically relevant bleeding according to location of metastases in cancer-associated thrombosis.

BACKGROUND: Patients with cancer-associated thrombosis (CAT) face a heightened risk of clinically relevant bleeding (CRB). However, the relationship between these risks and the location of metastasis remains unclear. METHODS: A single-center, non-interventional study of consecutive patients was conducted between 2007 and 2022, involving patients with CAT (n = 1,277). Our primary objectives were: 1) To estimate the rate of CRB based on metastasis location. 2) To assess the long-term risk of CRB. RESULTS: Over a median follow-up of 14.2 months, 144 CRB were observed. The most frequent cancers were colon (19.2 %), lung (16.1 %), and breast (12.4 %). Fifty-two per-cent had metastases. Compared to patients without metastases, metastasis locations associated with CRB were lung metastases (rate 10.0 per 100 patients/year; 95 % confidence interval [CI] 6.6 to 14.6; risk ratio [RR]: 2; 95 % CI: 1.3-3.1), liver metastases (rate 10.1 per 100 patients/year; 95 % CI 6.5-14.9; RR: 2.0; 95 % CI: 1.3-3.2) and adenopathy metastases (rate 11.9 per 100 patients/year; 95 % CI 6.8-19.3; RR: 2.4; 95 % CI: 1.4-4.1). Multivariate analysis of variables associated to CRB at long term follow-up included ECOG > 1 (HR 3.0, 95 % CI 1.7-5.3), bladder cancer (HR 2.5, 95 % CI 1.3-4.8), prostate cancer (HR 2.2, 95 % CI 1.1-4.8) and lung metastases (HR 2.1, 95 % CI 1.3-3.6). CONCLUSIONS: The bleeding rate seem differ depending on the location of metastasis. Additionally, lung metastasis was found to be associated with a long-term risk of CRB. These findings may justify the use of low dose of anticoagulation, although clinical trials need to demonstrate the efficacy and safety of this strategy.

Occult cancer in patients with unprovoked venous thromboembolism: A nested case-control study.

OBJECTIVES: Detecting occult cancer in patients with unprovoked venous thromboembolism (VTE) remains a significant challenge. Our objective was to investigate the potential predictive role of coagulation-related biomarkers in the diagnosis of occult malignancies. METHODS: We conducted a nested case-control study with a 1-year prospective cohort of 214 patients with unprovoked VTE, with a focus on identifying occult cancer. At the time of VTE diagnosis, we measured various biomarkers, including soluble P-selectin (sP-selectin), dimerized plasmin fragment D (D-dimer), platelets, leukocytes, hemoglobin, total extracellular vesicles (EVs), EVs expressing tissue factor on their surface (TF+EVs), and EVs expressing P-selectin on their surface (Psel+EVs) in all participants. RESULTS: We observed statistically significant increased levels of sP-selectin (P = .015) in patients with occult cancer. Despite an increase in Psel+EVs, TF+EVs, D-dimer, and platelets within this group, however, no significant differences were found. When sP-selectin exceeded 62 ng/mL and D-dimer surpassed 10,000 µg/L, the diagnosis of occult cancer demonstrated a specificity of up to 91% (95% CI, 79.9%-96.7%). CONCLUSIONS: The combination of sP-selectin and D-dimer can be a valuable biomarker in detecting occult cancer in patients with unprovoked VTE. Further research is necessary to ascertain whether easily measurable biomarkers such as sP-selectin and D-dimer can effectively distinguish between patients who have VTE with and without hidden malignancies.

Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin.

Testicular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulated following cisplatin exposure, even in the absence of p53, in NTERA2 cisplatin-sensitive cells but not in 1411HP-resistant cells. Blockade of Noxa reduced the apoptotic response of embryonal carcinoma (EC) NTERA2 cells to cisplatin. A detailed analysis of the Noxa promoter revealed that p73 and Sp1-like factors, Sp1 and KLF6, played key roles in the transcriptional control of this gene. Overexpression of TAp73 induced Noxa whereas the dominant negative isoform ΔNp73, reduced the levels of Noxa after cisplatin exposure in NTERA2 and 2102EP. Interestingly, down-regulation of Sp1 increased Noxa expression in response to cisplatin. However, blockade of KLF6 decreased cisplatin-induced up-regulation of Noxa in EC cell lines. In addition, tissue microarray analyses of TGCTs revealed that expression of Noxa correlates with good clinical prognosis in patients with embryonal carcinoma. Thus, our data show the transcriptional network that regulates Noxa in EC cells, which is key for their apoptotic response to cisplatin-based chemotherapy, and propose Noxa as a predictive factor of therapeutic response.

Influence of the activity of Allobophora molleri in microbial activity and metal availability of arsenic-polluted soils.

We investigate the use of Allolobophora molleri as a biomarker of arsenic (As)-polluted soils and study the influence of A. molleri on the metabolic activity and microbial biodiversity of soil polluted with As. Because there are no experimental data available regarding the effect of the pollutant rate of As on A. molleri, we determined the LC50 that was 143.5 mg As kg(-1). Sodium arsenite was added at two rates, equivalent to 143.5 and 71.8 mg As kg(-1) soil, to a soil that was then maintained with and without worms for 120 days. In addition, a nonpolluted soil without and with earthworms was used as the control. The As concentration in the soil was measured after 7 and 120 and the worm weight and As concentration after 120 days of exposure. Soil enzymatic activities and the structure of the soil microbial community, by analysis of phospholipid fatty acids, were determined. At the end of the experiment, the highest earthworm As contents were found in soils polluted with the highest rate of As. Earthworm weights significantly decreased in soil polluted with 143.5 or 71.8 mg As kg(-1), by 49.9 and 29.8% of initial weight, because the worm consumption rate decreased. These results suggest that A. molleri can be used as a good biomarker of the As toxicity. The As available fraction decreased in polluted soil with worms because the metal was accumulated in worm tissues. However, this assimilation was lower than other worms such as L. rubbellus or L. terrestris. Soil enzymatic activities were decreased in As-polluted soils but were increased significantly by the presence of earthworms. The earthworms modified the soil microbial diversity. In this respect, A. molleri significantly increased (p < 0.05) the bacterial and fungal populations. Soil As pollution decreased microbial biodiversity but to a lesser extent in the presence of A. molleri.

Do the emotions of tourist agents contribute to improving the sustainable planning of a territory?

The sustainability of a territory is achieved through orderly, balanced and harmonious planning over time. Sustainable tourism planning must incorporate the emotions of interest groups. Based on a scale of negative and positive emotions that has already been validated, a participatory study of a qualitative nature has been developed with 118 hotel managers from the region of Extremadura, in the south-west of Spain. In addition, another quantitative research study has been carried out, using a longitudinal exploratory model analyzed in three phases throughout the years 2021 and 2022, using the SEM-PLS methodology. The objective is to detect if the II Tourism Plan (2021-2023) can influence the willingness of hotel managers to participate, and if this participation generates emotions that enrich the planning process of the tourist authorities. The results highlight the importance of completing decision making (cognitive part) with the measurement of emotions (sensitive part) of private agents to involve them in the planning process.