Evaluation of PLA-Based Composite Films Filled with Cu2(OH)3NO3 Nanoparticles as an Active Material for the Food Industry: Biocidal Properties and Environmental Sustainability.

The globalization of markets has diversified the food supply, but it has also made the distribution chain more difficult, increasing the risk of microbial contamination. One strategy to obtain safer food and extend its shelf life is to develop active packaging with antimicrobial properties that prevent the growth of pathogenic microorganisms or spoilage in food products. In this context, and in line with the growing social awareness about the environmental impact generated by plastic waste, this work evaluated the effectiveness of polylactic acid (PLA) films loaded with different concentrations of copper (II) hydroxynitrate nanoparticles (CuHS) against the microbiota of fresh foods (chicken, fish and cheese). The results showed that the developed films containing 1, 3 and 5% w/w of CuHS in the polymeric matrix caused a decrease in the microbial abundance equal to or higher than 3 logarithmic units in all foods tested. Moreover, the mechanical and thermal properties of the formulated composites showed that the added CuHS concentrations did not substantially modify these properties compared to the PLA films. Taking into account the results obtained for antimicrobial activity, Cu (II) migration levels and the cytotoxicity of the films formulated, the PLA composite loaded with 1% CuHS (w/w) was the most suitable for its potential use as food packaging material. In addition, the biodegradation of this composite film was studied under conditions simulating intensive aerobic composting, demonstrating that almost 100% disintegration after 14 days of testing was achieved. Therefore, the innovative PLA-based films developed represent a promising strategy for the fabrication of packaging and active surfaces to increase food shelf life while maintaining food safety. Moreover, their biodegradable character will contribute to efficient waste management, turning plastic residues into a valuable resource.

Induction of Extracellular Hydroxyl Radicals Production in the White-Rot Fungus Pleurotus eryngii for Dyes Degradation: An Advanced Bio-oxidation Process.

Among pollution remediation technologies, advanced oxidation processes (AOPs) are genuinely efficient since they are based on the production of strong, non-selective oxidants, mainly hydroxyl radicals (·OH), by a set of physicochemical methods. The biological counterparts of AOPs, which may be referred to as advanced bio-oxidation processes (ABOPs), have begun to be investigated since the mechanisms of induction of ·OH production in fungi are known. To contribute to the development of ABOPs, advanced oxidation of a wide number of dyes by the white-rot fungus Pleurotus eryngii, via a quinone redox cycling (QRC) process based on Fenton's reagent formation, has been described for the first time. The fungus was incubated with 2,6-dimethoxy-1,4-benzoquinone (DBQ) and Fe3+-oxalate, with and without Mn2+, leading to different ·OH production rates, around twice higher with Mn2+. Thanks to this process, the degradative capacity of the fungus increased, not only oxidising dyes it was not otherwise able to, but also increasing the decolorization rate of 20 dyes by more than 7 times in Mn2+ incubations. In terms of process efficacy, it is noteworthy that with Mn2+ the degradation of the dyes reached values of 90-100% in 2-4 h, which are like those described in some AOPs based on the Fenton reaction.

Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient-derived orthotopic xenografts, cell lines and tumor entities.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heterogeneity could be partly responsible for the observed disparity in treatment response due to the inherent diversity of the preclinical models used. For several years, our group has been generating a large patient-derived orthotopic xenograft (PDOX) MPNST platform for identifying new precision medicine treatments. Herein, we describe the expansion of this platform using six primary tumors clinically diagnosed as MPNSTs, from which we obtained six additional PDOX mouse models and three cell lines, thus generating three pairs of in vitro-in vivo models. We extensively characterized these tumors and derived preclinical models, including genomic, epigenomic, and histological analyses. Tumors were reclassified after these analyses: three remained as MPNSTs (two being classic MPNSTs), one was a melanoma, another was a neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasm, and, finally, the last was an unclassifiable tumor bearing neurofibromin-2 (NF2) inactivation, a neuroblastoma RAS viral oncogene homolog (NRAS) oncogenic mutation, and a SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (SMARCA4) heterozygous truncated variant. New cell lines and PDOXs faithfully recapitulated histology, marker expression, and genomic characteristics of the primary tumors. The diversity in tumor identity and their specific associated genomic alterations impacted treatment responses obtained when we used the new cell lines for testing compounds against known altered pathways in MPNSTs. In summary, we present here an extension of our MPNST precision medicine platform, with new PDOXs and cell lines, including tumor entities confounded as MPNSTs in a real clinical scenario. This platform may constitute a useful tool for obtaining correct preclinical information to guide MPNST clinical trials.

Effect of Concomitant Use of Proton Pump Inhibitors on Immunotherapy Clinical Response in Advanced Cancer Patients: Real-Life Setting.

The alteration of the gut microbiota mediated by proton pump inhibitor (PPI) drugs could be involved in the clinical response associated with immunotherapy [immunocheckpoint inhibitors (ICIs)] in cancer patients. Due to the current controversy in the scientific evidence, it has been proposed to evaluate the correlation between the concomitant use of PPIs and the effectiveness of immunotherapy in a real clinical practice setting. Single-center retrospective cohort study that included patients treated with anti-PD-1 or anti-CTLA4, including nivolumab, pembrolizumab, atezolizumab, or the combination ipilimumab-nivolumab in metastatic neoplastic disease. The clinical effectiveness of ICI, measured in progression-free survival (PFS) and overall survival (OS), was compared between the PPI-use versus PPI-no-use group. PPI-use group was associated with lower PFS [hazard ratio (HR):1.89 (1.38-2.59), P<0.001] and OS [HR: 2.02 (1.45-2.82), P<0.001] versus PPI-no-use group. However, this difference was not observed for pembrolizumab PFS [HR: 1.38 (0.93-2.39), P=0.160] and OS [HR: 1.41 (0.81-2.44), P=0.187]. The study showed significantly lower PFS and OS in the chronic PPI-use group (P<0.001), recent PPI-use group (P<0.001) and concomitant PPI-use group (P=0.001, 0.007) versus PPI-no-use group. However, late PPI use >30 days after the onset of ICI has no significant effect on the efficacy of treatment [HR: 0.92 (0.49-1.70), P=0.791; HR: 1.10 (0.59-2.05), P=0.756]. The concomitant use of PPIs in immunotherapy is associated with worse clinical outcomes compared with the group without PPI use. In addition, the study shows how the late use of PPIs does not have a significant effect on clinical benefit.

Endoglin, a Novel Biomarker and Therapeutical Target to Prevent Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGFß coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. EXPERIMENTAL DESIGN: ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis, were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. RESULTS: ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma-circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis. CONCLUSIONS: Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.

Approach to anaerobic bio-degradation of natural and synthetic fabrics: Physico-chemical study of the alteration processes.

In this paper, the mesophilic Biochemical Methane Potential of several fabrics was assessed at different Total Solid concentrations (1-4%TS). Physico-chemical techniques were applied to explore the arising structural changes on fibers during the anaerobic digestion process. Additionally, the modified Gompertz model was used to assess and compare the AD performance of the fabrics. In cellulose-based fibers the production of biogas was enhanced thanks to the easy solubilization of acetate, which is generated upon partial breakage of cellulose bonds. The crystallinity of vegetal fibers decreased significantly from day 19. The highest methane yields were attained for silk and wool fabrics at the lowest TS concentrations. Conformational changes in fibroin and keratin were detected. The highest degrees of degradation were observed in solid samples with lower solid concentrations. Accordingly, the maximum methane yields were reported in the reactors operating with lower TS.

Capability of Copper Hydroxy Nitrate (Cu2(OH)3NO3) as an Additive to Develop Antibacterial Polymer Contact Surfaces: Potential for Food Packaging Applications.

The globalization of the market, as well as the increasing world population, which require a higher demand for food products, pose a great challenge to ensure food safety and prevent food loss and waste. In this sense, active materials with antibacterial properties are an important alternative in the prolongation of shelf life and ensuring food safety. In this work, the ability of copper(II) hydroxy nitrate (CuHS) to obtain antibacterial films based on low density polyethylene (LDPE) and polylactic acid (PLA), was evaluated. The thermal properties of the composites, evaluated using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), showed that the concentrations of added CuHS do not particularly change these characteristics with respect to the neat polymer matrix films. The mechanical properties, determined using dynamic mechanical analysis (DMTA), indicate a small increase in the brittleness of the material in PLA-based composites. The antibacterial properties against Listeria monocytogenes and Salmonella enterica were evaluated using a surface contact test, and a bacterial reduction of at least 8 to 9 logarithmic units for the composites with 0.3% CuHS, both in LDPE and PLA and against both bacteria, were achieved. The reusability of the composite films after their first use demonstrated a higher stability against Listeria monocytogenes. The migration and cytotoxicity of the composites loaded with 0.3% CuHS was evaluated, demonstrating the safety of these materials, which reinforces their potential use in food packaging applications.

Generation of human iPSC-derived neurofibromaspheres for in vitro and in vivo uses.

Neurofibromas are benign peripheral nervous system tumors associated with neurofibromatosis type 1, which originate from NF1(-/-) Schwann cell precursors. We describe a protocol to generate neurofibromaspheres by differentiating NF1(-/-) Schwann cells from induced pluripotent stem cells and combining them with neurofibroma primary fibroblasts. We also describe the development of neurofibroma-like tumors when neurofibromaspheres are engrafted in the sciatic nerve of nude mice. This model constitutes a versatile platform for drug screening and the study of neurofibroma biology. For complete details on the use and execution of this protocol, please refer to Mazuelas et al. (2022).1.

Promoting the Circular Economy on an Island: Anaerobic Co-Digestion of Local Organic Substrates as a Possible Renewable Energy Source.

The local waste co-digestion is an interesting option to tackle in reduced and isolated areas like the islands. The islands have limited territory and scarce fuel production. Moreover, organic waste can create serious environmental problems in soil, water and air. Anaerobic co-digestion (AcoD) is a technology fulfilling the concept of waste-to-energy (WtE) based on local resources. The valorisation of organic waste through AcoD on an island would prevent environmental impacts, while being a source of renewable energy. In this study, cow manure (outdoor and indoor), pig slurry, bird manure, kitchen waste, sewage sludge and oily lacteous waste produced on Island Terceira (Portugal) were tested in mesophilic -35 °C- Biochemical Methane Potential (BMP) co-digestion assays. The goals were to analyse the recalcitrant and high potential produced waste and to estimate the energetic supply source on the island. The cow manure and pig slurry were used as inocula and specific methanogenic activities (SMAs) were carried out. The results showed that both substrates have a significant methanogenic activity-SMA 0.11 g-COD/(g-VSS.d) and 0.085 g-COD/(g-VSS.d), respectively. All the studied combinations were feasible in AcoD, showing TS removals in the range of 19-37%; COD removals in the range 67-78% and specific methane yields from 0.14 to 0.22 L/gCOD removed, but some differences were found. The modified Gompertz model fitted the AcoD assays (R2 0.982-0.998). The maximum biogas production rate, Rmax. was highest in the AcoD of Cow+Pig+Oily and in the Cow+Pig+Sludge with 0.017 and 0.014 L/g-VSadded.day, respectively, and the lowest in Cow+Pig+Bird with 0.010 L/g-VSadded. In our AcoD studies, the bird manure limited the performance of the process, since it was recalcitrant to anaerobic degradation. On the other hand, the oily lacteous waste showed a great potential in the anaerobic digestion. The estimated biogas production, from the best-studied condition, could cover the 11.4% of the energy supply of the inhabitants. These preliminary results would prevent the environmental impact of organic waste on the island and promote the use of local waste in a circular economy scenario.

Efficacy and safety of Obex® in overweight and obese subjects: a randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Obex® may be helpful in reducing body weight and fat. The current study was carried out to evaluate the efficacy and safety of Obex® in the treatment of overweight and obese subjects. METHODS: A double-blind, randomised, controlled phase III clinical trial was conducted involving 160 overweight and obese subjects (BMI ≥ 25.0 and < 40 kg/m2) aged 20 to 60 years, who received Obex® (n = 80) and placebo (n = 80) plus non-pharmacological treatment (physical activity and nutritional counseling). One sachet of Obex® or placebo were administered before the two main meals each day for 6 months. In addition to anthropometric measurements and blood pressure, fasting plasma and 2 h glucose levels during the oral glucose tolerance test, lipid profile, insulin, liver enzymes, creatinine, and uric acid (UA) were determined, insulin resistance (HOMA-IR) beta-cell function (HOMA-ß) were assessed and insulin sensitivity (IS) was calculated with three indirect indexes. RESULTS: After 3 months of Obex®, 48.3% of the participants (28/58) achieved complete success in reducing both weight and waist circumference by greater than or equal to 5% from baseline, as opposed to 26.0% (13/50) of individuals receiving placebo (p = 0.022). Compared to baseline, at 6 months no differences were found between the groups concerning anthropometric and biochemical measurements, except for high-density lipoprotein cholesterol (HDL-c) levels, which were higher in subjects receiving Obex® compared to those receiving placebo (p = 0.030). After 6 months of treatment, both groups showed reduced cholesterol and triglyceride levels (p < 0.012) compared to baseline value. However, only those intake Obex® showed reduced insulin concentrations and HOMA-IR, improved IS (p < 0.05), and decreased creatinine and UA levels (p < 0.005). CONCLUSIONS: The consumption of Obex® together with lifestyle changes increased HDL-c, contributed to a rapid reduction of weight and waist circumference, as well as improved insulin homeostasis, which did not occur in the placebo group, and appears to be safe as an adjunct at conventional obesity treatment. TRIAL REGISTRATION: Clinical trial protocol was registered in the Cuban public registry of clinical trials under code RPCEC00000267 on 17/04/2018 and also registered in the international registry of clinical trials, ClinicalTrials.gov, under code: NCT03541005 on 30/05/2018.

Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis.

Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas of the peripheral nervous system that develop either sporadically or in the context of neurofibromatosis type 1 (NF1). MPNST diagnosis can be challenging and treatment outcomes are poor. We present here a resource consisting of the genomic characterization of 9 widely used human MPNST cell lines for their use in translational research. NF1-related cell lines recapitulated primary MPNST copy number profiles, exhibited NF1, CDKN2A, and SUZ12/EED tumor suppressor gene (TSG) inactivation, and presented no gain-of-function mutations. In contrast, sporadic cell lines collectively displayed different TSG inactivation patterns and presented kinase-activating mutations, fusion genes, altered mutational frequencies and COSMIC signatures, and different methylome-based classifications. Cell lines re-classified as melanomas and other sarcomas exhibited a different drug-treatment response. Deep genomic analysis, methylome-based classification, and cell-identity marker expression, challenged the identity of common MPNST cell lines, opening an opportunity to revise MPNST differential diagnosis.

Post-transplant diabetes mellitus and renal cell cancer after renal transplantation.

BACKGROUND: Diabetes is a risk factor for cancer in the general population. However, few data are available on the association between post-transplant diabetes mellitus (PTDM) and cancer after transplantation. METHODS: We analyzed this issue in a Spanish cohort of patients without diabetes before transplantation. PTDM was diagnosed with consensus criteria at 12 months after transplantation and 12 months before the diagnosis of cancer. The association between PTDM and cancer (overall and specific types) was evaluated with regression analysis. RESULTS: During a follow-up of 12 years (interquartile range 8-14), 85 cases of 603 developed cancer (829/100 000/year) and 164 (27%) PTDM. The most frequent cancers were renal cell cancer (RCC) n = 15, 146/cases/100 000/year), lung (n = 12, 117/cases/100 000/year), colon (n = 9, 88/cases/100 000/year) and prostate (n = 9, 88/cases/100 000/year). In logistic regression, PTDM was not associated with cancer. Eight of the 164 patients with PTDM (4.9%) vs 7 of the 439 without PTDM developed RCC (1.6%) (P = .027). In multivariate analysis, PTDM was independently associated with RCC [odds ratio (OR) 2.92, confidence interval (CI) 1.03-8.27], adjusting for smoking (OR 4.020, 95% CI 1.34-12.02) and other covariates. PTDM was not associated with other types of cancer. CONCLUSIONS: Patients with PTDM must be considered a population at risk for RCC and accordingly, the subject of active surveillance.

Biological Solubilisation of Leather Industry Waste in Anaerobic Conditions: Effect of Chromium (III) Presence, Pre-Treatments and Temperature Strategies.

Collagen-based polymers and their blends have attracted considerable interest for new materials development due to their unique combination of biocompatibility, physical and mechanical properties and durability. Leather, a modified natural biopolymer made from animal rawhide and the first synthetic collagen-based polymer known since the dawn of civilization, combines all these features. Rawhide is transformed into leather by tanning, a process in which the collagen is cross-linked with different agents to make it stronger and more durable and to prevent its decay. Research on the development of environmentally friendly procedures and sustainable materials with higher efficiency and lower costs is a rapidly growing field, and leather industry is not an exemption. Chrome-tanned and vegetable-tanned (chromium-free) shavings from the leather industry present a high content of organic matter, yet they are considered recalcitrant waste to be degraded by microbiological processes like anaerobic digestion (AD), a solid technology to treat organic waste in a circular economy framework. In this technology however, the solubilisation of organic solid substrates is a significant challenge to improving the efficiency of the process. In this context, we have investigated the process of microbial decomposition of leather wastes from the tannery industry to search for the conditions that produce optimal solubilisation of organic matter. Chrome-tanned and chromium-free leather shavings were pre-treated and anaerobically digested under different temperature ranges (thermophilic-55 °C-, intermediate-42 °C- and mesophilic-35 °C) to evaluate the effect on the solubilisation of the organic matter of the wastes. The results showed that the presence of chromium significantly inhibited the solubilization (up to 60%) in the mesophilic and intermediate ranges; this is the fastest and most efficient solubilization reached under thermophilic conditions using the chromium-free leather shaving as substrates. The most suitable temperature for the solubilization was the thermophilic regime (55 °C) for both chromium-free and chrome-tanned shavings. No significant differences were observed in the thermophilic anaerobic digestion of chromium-free shavings when a pre-treatment was applied, since the solubilisation was already high without pre-treatment. However, the pre-treatments significantly improved the solubilisation in the mesophilic and intermediate configurations; the former pre-treatment was better suited in terms of performance and cost-effectiveness compared to the thermophilic range. Thus, the solubilisation of chromium-free tannery solid wastes can be significantly improved by applying appropriate pre-treatments at lower temperature ranges; this is of utter importance when optimizing anaerobic processes of recalcitrant organic wastes, with the added benefit of substantial energy savings in the scaling up of the process in an optimised circular economy scenario.

Antibacterial Capability of MXene (Ti3C2Tx) to Produce PLA Active Contact Surfaces for Food Packaging Applications.

The globalization of the market and the increase of the global population that requires a higher demand of food products superimposes a big challenge to ensure food safety. In this sense, a common strategy to extend the shelf life and save life of food products is by avoiding bacterial contamination. For this, the development of antibacterial contact surfaces is an urgent need to fulfil the above-mentioned strategy. In this work, the role of MXene (Ti3C2Tx) in providing antibacterial contact surfaces was studied through the creation of composite films from polylactic acid (PLA), as the chosen polymeric matrix. The developed PLA/MXene films maintained the thermal and mechanical properties of PLA and also presented the attractive antibacterial properties of MXene. The composites' behaviour against two representative foodborne bacteria was studied: Listeria mono-cytogenes and Salmonella enterica (representing Gram-positive and Gram-negative bacteria, respectively). The composites prevented bacterial growth, and in the case of Listeria only 0.5 wt.% of MXene was necessary to reach 99.9999% bactericidal activity (six log reductions), while against Salmonella, 5 wt.% was necessary to achieve 99.999% bactericidal activity (five log reductions). Cy-totoxicity tests with fHDF/TER166 cell line showed that none of the obtained materials were cytotoxic. These results make MXene particles promising candidates for their use as additives into a polymeric matrix, useful to fabricate antibacterial contact surfaces that could prove useful for the food packaging industry.

Vancomycin versus daptomycin for the treatment of confirmed gram-positive catheter-related bloodstream infections in oncology patients.

OBJECTIVE: To analyse the effectiveness and safety of daptomycin versus vancomycin on the management catheter-related bloodstream  nfections in oncology patients. METHOD: A retrospective study was carried out including all patients admitted  at the Medical Oncology Unit between 2010 and 2018 with positive blood  cultures confirmed catheter-related bloodstream infections due to gram- positive microorganism, who were treated with either vancomycin or  daptomycin. The primary end point was all cause 30-days mortality, 30-days  hospital readmission and length of hospital stay (length of hospital stay). Results: A total of 70 patients with catheter-related bloodstream infections were included in the present study: vancomycin was administered to  61.4% (n = 43) and daptomycin to 38.6% (n = 27) of  patients. 78.5% (n = 55) of isolated bacteria showed a vancomycin minimum  inhibitory concentration ≤ 1 µg/ml. No differences were observed  between the two groups of patients regarding the 30-day mortality rate rate  (32.6% [n = 14] versus 29.6% [n = 8]; p = 0.797), the 30-day re-admission rate (30.2% [n = 13] versus 29.6% [n = 8]; p = 0.957) or the length of  hospital stay (18.9 versus 16.5 days; p = 0.562). Nephrotoxicity rate was  equivalent in both groups: a 7% (n = 3) of vancomycin goup versus a 7.4% (n  = 2) of daptomycin group (p = 0.946). CONCLUSIONS: Our results show that both antibiotics are equivalent in their  safety and effectiveness. Therefore, vancomycin should continue being the  treatment of chose for gram-positive catheter-related bloodstream infections,  in particular at hospital centres with a low prevalence of strains that show  diminished susceptibility to vancomycin.

OBJETIVO: Analizar la eficacia y seguridad de la daptomicina frente a la  vancomicina en el tratamiento de las infecciones del torrente sanguíneo asociadas a catéter vascular en pacientes oncológicos.Método: Se realizó un estudio retrospectivo que incluyó a los pacientes ingresados en la Unidad de Oncología-Médica entre 2010-2018 con infección del torrente sanguíneo asociada a catéter vascular causada por  grampositivos, y que fueron tratados con vancomicina o daptomicina. Como  objetivos principales se determinaron la tasa de mortalidad por todas las  causas a los 30 días, el reingreso hospitalario a los 30 días y la duración de la  estancia hospitalaria. RESULTADOS: El estudio incluyó 70 pacientes con infecciones del torrente sanguíneo asociadas a catéter vascular: el 61,4% (n = 43) recibió  vancomicina y el 38,6% (n = 27) daptomicina. El 78,5% (n = 55) de las  bacterias aisladas presentaron una concentración mínima inhibitoria de  vancomicina ≤ 1 µg/ml. No se observaron diferencias entre ambos grupos de  pacientes en cuanto a la tasa de mortalidad a 30 días (32,6% [n = 14]  frente al 29,6% [n = 8]; p = 0,797), la tasa de reingreso a 30 días (30,2% [n  = 13] frente al 29,6% [n = 8]; p = 0,957) o la duración de la hospitalización (18,9 frente a 16,5 días; p = 0,562). La tasa de nefrotoxicidad fue equivalente  en ambos grupos: 7% (n = 3) para vancomicina frente al 7,4% (n = 2) para  daptomicina (p = 0,946). CONCLUSIONES: Nuestros resultados muestran que ambos antibióticos son equivalentes en su seguridad y eficacia. Por ello, vancomicina debería seguir siendo el tratamiento de elección para la infección del torrente sanguíneo asociada a catéter vascular, especialmente en centros con  una baja prevalencia de cepas con una susceptibilidad disminuida a  ancomicina.

[Gastric metastases with a choriocarcinoma component from a postpuberal teratoma with mature histology]. / Metástasis gástricas con componente de coriocarcinoma de un teratoma testicular pospuberal con histología madura.

Germ cell tumors are the most frequent neoplasia in young males. The aims of this study is to describe a case in which a postpuberal teratoma suffers a transformation to choriocarcinoma and metastasize to stomach. We have made a systematic review in PubMed and consensus documents to study this mismatch between the tumour, metastasis and the exception of gastric metastatic affectation. We describe three options to explain this discordance: a mixed germ cells tumour, a burned out tumour or a germ cells tumour derived from a malignant germ cell tumour precursor or different clonal strains. After made a thorough investigation we conclude that the most truly option is the last one as we extensive explain below. Once the gastric metastatic lesions are extremely rare and reach to <5%, but there are not conclusive assessments.

Retinopatía diabética y diabetes mellitus pregestacional: una mirada integral desde la oftalmología / Diabetic Retinopathy and Pregestational Diabetes Mellitus: a Comprehensive View from Ophthalmology

El incremento de la prevalencia de diabetes mellitus a nivel global en los últimos años la convierte en un desafío para los sistemas de salud. La retinopatía diabética como una de sus complicaciones crónicas más frecuentes se convierte en una de las principales causas de ceguera prevenible en el mundo, convirtiéndose el embarazo en un factor de riesgo importante para el desarrollo de esta enfermedad. El embarazo en mujeres con diagnóstico previo de diabetes mellitus, puede favorecer la aparición y la progresión de la retinopatía diabética. En esta etapa, las alteraciones metabólicas descritas de la diabetes mellitus se unen a las propias del embarazo con lo que el cuadro clínico se refuerza y acentúa, de hecho, se considera el mayor factor de riesgo y se asocia con un incremento en su prevalencia y gravedad. La presencia de retinopatía diabética no es una contraindicación para el embarazo, pero su diagnóstico y tratamiento precoz para prevenir la pérdida de visión, es esencial para preservar la calidad de vida de las gestantes previa y posterior al parto. La aparición y progresión de la retinopatía diabética en mujeres con diabetes mellitus pregestacional, se puede prevenir o reducir con una adecuada atención preconcepcional, un riguroso seguimiento clínico durante el embarazo y un temprano tratamiento, contribuyendo así a evitar la pérdida visual por esta causa(AU)

The increase in the prevalence of diabetes mellitus globally in recent years makes it a challenge for health systems. Diabetic retinopathy as one of its most frequent chronic complications has become one of the main causes of preventable blindness in the world, and pregnancy has become an important risk factor for the development of this disease. Pregnancy in women previously diagnosed with diabetes mellitus may favor the onset and progression of diabetic retinopathy. At this stage, the metabolic alterations described for diabetes mellitus are added to those of pregnancy itself, so that the clinical picture is reinforced and accentuated, in fact, it is considered the greatest risk factor and is associated with an increase in its prevalence and severity. The presence of diabetic retinopathy is not a contraindication for pregnancy, but its early diagnosis and treatment to prevent vision loss is essential to preserve the quality of life of pregnant women before and after delivery. The onset and progression of diabetic retinopathy in women with pregestational diabetes mellitus can be prevented or reduced with adequate preconception care, rigorous clinical follow-up during pregnancy and early treatment, thus helping to prevent visual loss due to this cause(AU)

A High-Throughput Screening Platform Identifies Novel Combination Treatments for Malignant Peripheral Nerve Sheath Tumors.

Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that are the leading cause of mortality in patients with Neurofibromatosis type 1 (NF1). Single chemotherapeutic agents have shown response rates ranging from 18% to 44% in clinical trials, so there is still a high medical need to identify chemotherapeutic combination treatments that improve clinical prognosis and outcome. We screened a collection of compounds from the NCATS Mechanism Interrogation PlatE (MIPE) library in three MPNST cell lines, using cell viability and apoptosis assays. We then tested whether compounds that were active as single agents were synergistic when screened as pairwise combinations. Synergistic combinations in vitro were further evaluated in patient-derived orthotopic xenograft/orthoxenograft (PDOX) athymic models engrafted with primary MPNST matching with their paired primary-derived cell line where synergism was observed. The high-throughput screening identified 21 synergistic combinations, from which four exhibited potent synergies in a broad panel of MPNST cell lines. One of the combinations, MK-1775 with Doxorubicin, significantly reduced tumor growth in a sporadic PDOX model (MPNST-SP-01; sevenfold) and in an NF1-PDOX model (MPNST-NF1-09; fourfold) and presented greater effects in TP53 mutated MPNST cell lines. The other three combinations, all involving Panobinostat (combined with NVP-BGT226, Torin 2, or Carfilzomib), did not reduce the tumor volume in vivo at noncytotoxic doses. Our results support the utility of our screening platform of in vitro and in vivo models to explore new therapeutic approaches for MPNSTs and identified that combination MK-1775 with Doxorubicin could be a good pharmacologic option for the treatment of these tumors.

Vancomicina frente a daptomicina como tratamiento de las bacteriemias asociadas a catéter y causadas por grampositivos en el paciente oncológico / Vancomycin versus daptomycin for the treatment of confirmed gram-positive catheter-related bloodstream infections in oncology patients

Objetivo: Analizar la eficacia y seguridad de la daptomicina frente ala vancomicina en el tratamiento de las infecciones del torrente sanguíneoasociadas a catéter vascular en pacientes oncológicos.Método: Se realizó un estudio retrospectivo que incluyó a los pacientesingresados en la Unidad de Oncología-Médica entre 2010-2018 coninfección del torrente sanguíneo asociada a catéter vascular causadapor grampositivos, y que fueron tratados con vancomicina o daptomicina.Como objetivos principales se determinaron la tasa de mortalidad portodas las causas a los 30 días, el reingreso hospitalario a los 30 días yla duración de la estancia hospitalaria.Resultados: El estudio incluyó 70 pacientes con infecciones del torrentesanguíneo asociadas a catéter vascular: el 61,4% (n = 43) recibió vancomicinay el 38,6% (n = 27) daptomicina. El 78,5% (n = 55) de las bacteriasaisladas presentaron una concentración mínima inhibitoria de vancomicina≤ 1 μg/ml. No se observaron diferencias entre ambos grupos depacientes en cuanto a la tasa de mortalidad a 30 días (32,6% [n = 14] frente al 29,6% [n = 8]; p = 0,797), la tasa de reingreso a 30 días (30,2%[n = 13] frente al 29,6% [n = 8]; p = 0,957) o la duración de la hospitalización(18,9 frente a 16,5 días; p = 0,562). La tasa de nefrotoxicidadfue equivalente en ambos grupos: 7% (n = 3) para vancomicina frente al7,4% (n = 2) para daptomicina (p = 0,946).Conclusiones: Nuestros resultados muestran que ambos antibióticos sonequivalentes en su seguridad y eficacia. Por ello, vancomicina deberíaseguir siendo el tratamiento de elección para la infección del torrentesanguíneo asociada a catéter vascular, especialmente en centros con unabaja prevalencia de cepas con una susceptibilidad disminuida a vancomicina.

Objective: To analyse the effectiveness and safety of daptomycin versusvancomycin on the management catheter-related bloodstream infectionsin oncology patients.Method: A retrospective study was carried out including all patientsadmitted at the Medical Oncology Unit between 2010 and 2018 withpositive blood cultures confirmed catheter-related bloodstream infectionsdue to gram-positive microorganism, who were treated with either vancomycinor daptomycin. The primary end point was all cause 30-daysmortality, 30-days hospital readmission and length of hospital stay (lengthof hospital stay).Results: A total of 70 patients with catheter-related bloodstream infectionswere included in the present study: vancomycin was administeredto 61.4% (n = 43) and daptomycin to 38.6% (n = 27) of patients.78.5% (n = 55) of isolated bacteria showed a vancomycin minimuminhibitory concentration ≤ 1 μg/ml. No differences were observed betweenthe two groups of patients regarding the 30-day mortality rate rate (32.6% [n = 14] versus 29.6% [n = 8]; p = 0.797), the 30-day re-admissionrate (30.2% [n = 13] versus 29.6% [n = 8]; p = 0.957) or the lengthof hospital stay (18.9 versus 16.5 days; p = 0.562). Nephrotoxicity ratewas equivalent in both groups: a 7% (n = 3) of vancomycin goup versus a7.4% (n = 2) of daptomycin group (p = 0.946).Conclusions: Our results show that both antibiotics are equivalent intheir safety and effectiveness. Therefore, vancomycin should continuebeing the treatment of chose for gram-positive catheter-related bloodstreaminfections, in particular at hospital centres with a low prevalence ofstrains that show diminished susceptibility to vancomycin.

Modeling iPSC-derived human neurofibroma-like tumors in mice uncovers the heterogeneity of Schwann cells within plexiform neurofibromas.

Plexiform neurofibromas (pNFs) are developmental tumors that appear in neurofibromatosis type 1 individuals, constituting a major source of morbidity and potentially transforming into a highly metastatic sarcoma (MPNST). pNFs arise after NF1 inactivation in a cell of the neural crest (NC)-Schwann cell (SC) lineage. Here, we develop an iPSC-based NC-SC in vitro differentiation system and construct a lineage expression roadmap for the analysis of different 2D and 3D NF models. The best model consists of generating heterotypic spheroids (neurofibromaspheres) composed of iPSC-derived differentiating NF1(-/-) SCs and NF1(+/-) pNF-derived fibroblasts (Fbs). Neurofibromaspheres form by maintaining highly proliferative NF1(-/-) cells committed to the NC-SC axis due to SC-SC and SC-Fb interactions, resulting in SC linage cells at different maturation points. Upon engraftment on the mouse sciatic nerve, neurofibromaspheres consistently generate human NF-like tumors. Analysis of expression roadmap genes in human pNF single-cell RNA-seq data uncovers the presence of SC subpopulations at distinct differentiation states.