Optimizing the timing of nephrology referral for patients with diabetic kidney disease

Diabetis mellitus; Malaltia renal diabètica; Atenció multidisciplinàriaDiabetes mellitus; Diabetic kidney disease; Multidisciplinary careDiabetes mellitus; Enfermedad renal diabética; Atención multidisciplinariaAge-standardized rates of diabetes mellitus (DM)-related complications, such as acute myocardial infarction, stroke or amputations, have decreased in recent years, but this was not associated with a clear reduction of the incidence of advanced chronic kidney disease (CKD) requiring renal replacement therapy. The early detection of diabetic kidney disease (DKD) is a key to reduce complications, morbidity and mortality. Consensus documents and clinical practice guidelines recommend referral of DM patients to nephrology when the estimated glomerular filtration rate falls below 30 mL/min/1.73 m2 or when albuminuria exceeds 300 mg/g urinary creatinine. Conceptually, it strikes as odd that patients with CKD are referred to the specialist caring for the prevention and treatment of CKD only when >70% of the functioning kidney mass has been lost. The increasing global health burden of CKD, driven in large part by DKD, the suboptimal impact of routine care on DKD outcomes as compared with other DM complications, the realization that successful therapy of CKD requires early diagnosis and intervention, the advances in earlier diagnosis of kidney injury and the recent availability of antidiabetic drugs with a renal mechanism of action and lack of hypoglycaemia risk, which additionally are cardio- and nephroprotective, all point towards a paradigm shift in the care for DM patients in which they should be referred earlier to nephrology as part of a coordinated and integrated care approach.Sources of support: FIS/Fondos FEDER PI18/01386, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM

Double stranded sperm DNA breaks, measured by comet assay, are associated with unexplained recurrent miscarriage in couples without a female factor

It is known that sperm samples from recurrent pregnancy loss (RPL) couples have an increase in their sperm DNA fragmentation (SDF), but no studies have been performed in order to identify differences between single stranded SDF (ssSDF) and double stranded SDF (dsSDF) in these patients. This could be relevant because the type of DNA damage could have different effects. Semen samples were classified attending their clinical status: 25 fertile donors and 20 RPL patients with at least two unexplained first trimester miscarriages. SDF was analysed using alkaline and neutral Comet assay, SCD test and pulsed-field gel electrophoresis (PFGE), and ROC analysis including data from 105 more infertile patients (n = 150) was performed to establish predictive threshold values. SDF for alkaline and neutral Comet, and the SCD test was analysed in these categories of individuals. Data revealed the presence of two subgroups within fertile donors. The values obtained were 21.10±9.13, 23.35±10.45 and 12.31±4.31, respectively, for fertile donors with low values for both ssSDF and dsSDF; 27.86±12.64, 80.69±12.67 and 12.43±5.22, for fertile donors with low ssSDF and high dsSDF; and 33.61±15.50, 84.64±11.28 and 19.28±6.05, for unexplained RPL patients, also showing a low ssSDF and high dsSDF profile. This latter profile was seen in 85% of unexplained RPL and 33% of fertile donors, suggesting that it may be associated to a male risk factor for undergoing RPL. ROC analysis regarding recurrent miscarriage set the cut-off value at 77.50% of dsDNA SDF. PFGE for low ssSDF and high dsSDF profile samples and positive controls treated with DNase, to induce dsDNA breaks, showed a more intense band of about 48 kb, which fits the toroid model of DNA compaction in sperm, pointing out that some nuclease activity may be affecting their sperm DNA in RPL patients. This work identifies a very specific SDF profile related to the paternal risk of having RPL

Prognostic factors of a lower CD4/CD8 ratio in long term viral suppression HIV infected children

CoRISpe (Cohorte Nacional de VIH pediátrica de la RED RIS).[Background] Combination antiretroviral therapy (cART) is associated with marked immune reconstitution. Although a long term viral suppression is achievable, not all children however, attain complete immunological recovery due to persistent immune activation. We use CD4/CD8 ratio like a marker of immune reconstitution.[Methods] Perinatal HIV-infected children who underwent a first-line cART, achieved viral suppression in the first year and maintained it for more than 5 years, with no viral rebound were included. Logistic models were applied to estimate the prognostic factors, clinical characteristics at cART start, of a lower CD4/CD8 ratio at the last visit.[Results] 146 HIV-infected children were included: 77% Caucasian, 45% male and 28% CDC C. Median age at cART initiation was 2.3 years (IQR: 0.5–6.2). 42 (30%) children received mono-dual therapy previously to cART. Time of undetectable viral load was 9.5 years (IQR: 7.8, 12.5). 33% of the children not achieved CD4/CD8 ratio >1. Univariate analysis showed an association between CD4/CD8 1 was not achieved in 33% of the children. Lower CD4 nadir and previous exposure to suboptimal therapy, before initiating cART, are factors showing independently association with a worse immune recovery (CD4/CD8 < 1).Peer reviewe

Predictive Value of Cardiac Magnetic Resonance Feature Tracking after Acute Myocardial Infarction: A Comparison with Dobutamine Stress Echocardiography

[EN] In acute ST-segment elevation myocardial infarction (STEMI) late gadolinium enhancement (LGE) may underestimate segmental functional recovery. We evaluated the predictive value of cardiac magnetic resonance (CMR) feature-tracking (FT) for functional recovery and whether it incremented the value of LGE compared to low-dose dobutamine stress echocardiography (LDDSE) and speckle-tracking echocardiography (STE). Eighty patients underwent LDDSE and CMR within 5-7 days after STEMI and segmental functional recovery was defined as improvement in wall-motion at 6-months CMR. Optimal conventional and FT parameters were analyzed and then also applied to an external validation cohort of 222 STEMI patients. Circumferential strain (CS) was the strongest CMR-FT predictor and addition to LGE increased the overall accuracy to 74% and was especially relevant in segments with 50-74% LGE (AUC 0.60 vs. 0.75, p = 0.001). LDDSE increased the overall accuracy to 71%, and in the 50-74% LGE subgroup improved the AUC from 0.60 to 0.69 (p = 0.039). LGE + CS showed similar value as LGE + LDDSE. In the validation cohort, CS was also the strongest CMR-FT predictor of recovery and addition of CS to LGE improved overall accuracy to 73% although this difference was not significant (AUC 0.69, p = 0.44). Conclusion: CS is the strongest CMR-FT predictor of segmental functional recovery after STEMI. Its incremental value to LGE is comparable to that of LDDSE whilst avoiding an inotropic stress agent. CS is especially relevant in segments with 50-74% LGE where accuracy is lower and further testing is frequently required to clarify the potential for recovery.This research was supported by the Instituto de Salud Carlos III and co-funded by Fondo Europeo de Desarrollo Regional (FEDER) (grant numbers PI17/01836 and CIBERCV16/11/00486). JG and DM acknowledge financial support from the "Agencia Valenciana de la Innovacion, Generalitat Valenciana" (grant) and from the "Conselleria d'Educacio, Investigacio, Cultura i Esport, Generalitat Valenciana" (grant number AEST/2019/037).Valente, FX.; Gavara-Doñate, J.; Gutiérrez, L.; Rios-Navarro, C.; Rello, P.; Maymi, M.; Fernandez-Galera, R.... (2021). Predictive Value of Cardiac Magnetic Resonance Feature Tracking after Acute Myocardial Infarction: A Comparison with Dobutamine Stress Echocardiography. Journal of Clinical Medicine. 10(22):1-12. https://doi.org/10.3390/jcm10225261S112102

Detection of novel fusion-transcripts by RNA-Seq in T-cell lymphoblastic lymphoma

Fusions transcripts have been proven to be strong drivers for neoplasia-associated mutations, although their incidence in T-cell lymphoblastic lymphoma needs to be determined yet. Using RNA-Seq we have selected 55 fusion transcripts identified by at least two of three detection methods in the same tumour. We confirmed the existence of 24 predicted novel fusions that had not been described in cancer or normal tissues yet, indicating the accuracy of the prediction. Of note, one of them involves the proto oncogene TAL1. Other confirmed fusions could explain the overexpression of driver genes such as COMMD3-BMI1, LMO1 or JAK3. Five fusions found exclusively in tumour samples could be considered pathogenic (NFYG-TAL1, RIC3-TCRBC2, SLC35A3-HIAT1, PICALM MLLT10 and MLLT10-PICALM). However, other fusions detected simultaneously in normal and tumour samples (JAK3-INSL3, KANSL1-ARL17A/B and TFG-ADGRG7) could be germ-line fusions genes involved in tumour-maintaining tasks. Notably, some fusions were confirmed in more tumour samples than predicted, indicating that the detection methods underestimated the real number of existing fusions. Our results highlight the potential of RNA-Seq to identify new cryptic fusions, which could be drivers or tumour-maintaining passenger genes. Such novel findings shed light on the searching for new T-LBL biomarkers in these haematological disorders.The authors would like to thank the Spanish Biobanks integrated in the Spanish Hospital Biobanks Network (RetBioH; www.redbiobancos.es) for providing us with the necessary T-LBL samples to elaborate this work. We thank all patients who were willing to donate their samples without their support the research work would not be possible. And to Isabel Sastre for her technical support. This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-70561-R; MINECO/FEDER, EU); the Autonomous Community of Madrid, Spain (B2017/BMD-3778; LINFOMAS-CM) and the Spanish Association Against Cancer (AECC, 2018; PROYE18054PIRI). Institutional grants from the Fundación Ramón Areces and Banco de Santander are also acknowledged.S

Anti-CXCR4 Antibody Combined With Activated and Expanded Natural Killer Cells for Sarcoma Immunotherapy

Sarcoma is one of the most severe forms of pediatric cancer and current therapies -chemotherapy and surgery- fail to eradicate the disease in half of patients. Preclinical studies combining new therapeutic approaches can be useful to design better therapies. On one hand, it is known that CXCR4 expression is implicated in rhabdomyosarcoma progression, so we analyzed relapses and chemotherapy-resistant rhabdomyosarcoma tumors from pediatric patients and found that they had particularly high levels of CXCR4 expression. Moreover, in assays in vitro, anti-CXCR4 blocking antibody (MDX1338) efficiently reduced migration and invasion of alveolar rhabdomyosarcoma RH30 cells. On the other hand, activated and expanded natural killer (NKAE) cell therapy showed high cytotoxicity against sarcoma cells in vitro and completely inhibited RH30 tumor implantation in vivo. Only the combination of MDX1338 and NKAE treatments completely suppressed metastasis in mice. In this study, we propose a novel therapeutic approach based on anti-CXCR4 blocking antibody in combination with NKAE cell therapy to prevent rhabdomyosarcoma tumor implantation and lung metastasis. These results provide the first evidence for the efficacy of this combined immunotherapy for preventing sarcoma disease dissemination.This work was supported in part by the National Health Service of Spain, Instituto de Salud Carlos III (ISCIII), FONDOS FEDER grant (FIS) PI15/00973; Asociacion Espanola Contra el Cancer to AP-M; CRIS Foundation to Beat Cancer grant to JV, LF, and AE; and Patients' Support Associations Fundacion Mari Paz Jimenez Casado and La Sonrisa de Alex to MV and the research project

Electrochemical immunosensing of Growth arrest‐specific 6 in human plasma and tumor cell secretomes

Growth arrest-specific 6 (GAS6) protein plays a key role in processes related toproliferation,inflammation,angiogenesis,andatheroscleroticplaqueformation.In addition, it has been reported that plasma levels of GAS6 are related to cancerprognosis and other relevant pathologies, such as heart failure or sepsis. Wereport here the first electrochemical immunoplatform for the determination ofGAS6, which has demonstrated to be competitive with other available method-ologies in terms of cost, simplicity, and decentralized application. The developedimmunoplatform involves a sandwich immunoassay using magnetic microparti-cles (MBs) and uses amperometric detection at disposable screen-printed carbonelectrodes (SPCEs). The MBs were modified with an antibody specific to GAS6for its selective capture, which is further recognized by a biotinylated secondaryantibody subsequently labeled with a streptavidin-horseradish peroxidase(Strep-HRP) conjugate. The electrochemical detection was carried out using thehydroquinone (HQ)/H2O2system. The developed bioplatform exhibits a greatselectivity and low limit of detection (27 pg/mL) that allowed the determinationof the GAS6 circulating level in plasma samples from patients suffering heartfailure (HF) and diagnosed with pancreatic ductal adenocarcinoma (PDAC),as well as the determination of the target protein in raw secretomes of humancolorectal cancer cell lines.This work is part of the POSITION-II project funded by the ECSEL Joint Undertaking under grant number Ecsel-783132-Position-II-2017-IA; www.position-2.eu, and PCI2018-093067 (Spanish Ministerio de Ciencia e Innovación) to M.P. The financial support of PID2019-103899RB-I00 (Spanish Ministerio de Ciencia e Innovación) Research Project to S.C., PI17CIII/00045 and PI20CIII/00019 grants from the AES-ISCIII program to R.B. and the TRANSNANOAVANSENS-CM Program from the Comunidad de Madrid (Grant S2018/NMT-4349) to S.C., RTI2018-095672-B-I00 (Spanish Ministerio de Ciencia e Innovación) to P.G.F.; Fundació la Marató de TV3 project 081010 to M.B.; research project PI20/00625, from the AES-ISCIII/FEDER program, to P.N, are gratefully acknowledged. A. Montero-Calle acknowledges the support of the FPU predoctoral contracts by the Spanish Ministerio de Educación, Cultura y Deporte. G.S-F. is recipient of a predoctoral contract (grant number 1193818N) supported by The Flanders Research Foundation (FWO). C. Muñoz-San Martín acknowledges a predoctoral contract from Complutense University of Madrid. R.M. Torrente-Rodríguez acknowledges a Talento-Contract from Comunidad de Madrid (2019-T2/IND-15965).S

The surveys: nexus between industry and academia

[EN] Analysis and improvement processes are key aspects in any quality management system and they have to be applied on the quality management systems that have all degrees currently taught at Spanish Universities. In this way, surveys can be an important tool. For this reason, the Faculty of Chemistry of the Universitat de Barcelona prepared a survey for chemical and pharmaceutical companies to identify the type of training that is required for students. The survey has questions related to the laboratory operations, chemical processes, calculation methods, management systems of quality, environment and safety, general management information, etc. The items are related to the formation given to the students in the Faculty. The scores obtained (minimum 1, maximum 4) are between 2 and 3 in all the items, both the required knowledge as to the skills demonstrated by students. This means a good agreement between the formation achieved by the students and the expectations of the industries. However, these results also show that the training ofstudents can still be improved.Fernandez, J.; Cruells, M.; Escaja, N.; Garrido, JA.; Giménez, J.; Llauradó, M.; Roca, A.... (2015). The surveys: nexus between industry and academia. En 1ST INTERNATIONAL CONFERENCE ON HIGHER EDUCATION ADVANCES (HEAD' 15). Editorial Universitat Politècnica de València. 662-667. https://doi.org/10.4995/HEAd15.2015.37066266

A correlative biomarker study and integrative prognostic model in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with enzalutamide

There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort. Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort. TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers

Ciencias de la Biología y Agronomía

Este volumen I contiene 17 capítulos arbitrados que se ocupan de estos asuntos en Tópicos Selectos de Ciencias de la Biología y Agronomía, elegidos de entre las contribuciones, reunimos algunos investigadores y estudiantes. Se presenta un Estudio Comparativo de los Recursos Hidrológico-Forestales de la Microcuenca de la Laguna de Epatlan, Pue. (1993 a 2014); la Situación Actual de la Mancha de Asfalto en Maíz (Zea mays L.) en los Municipios de Jiquipilas y Ocozocoautla, Chiapas, México; las poblaciones sobresalientes de maíz de la raza Zapalote Chico, en la Región Istmeña de Oaxaca; Se indica el índice de área foliar de cultivo de Chile Poblano mediante dos métodos en condiciones protegidas; Esquivel, Urzúa y Ramírez exploran el efecto de la biofertilización con Azospirillum en el crecimiento y producción de Jitomate; esbozan su artículo sobre la determinación del nivel de Heterosis en híbridos de Maíz para la Comarca Lagunera; una investigación sobre la estabilización de semilla de Solanum lycopersicum durante el almacenamiento y estimulación de la germinación; acotan sobre el CTAB como una nueva opción para la detección de Huanglongbing en cítricos, plantean su evaluación sobre el aluminio y cómo afecta la vida de florero de Heliconia psittacorum; indican sobre el impacto del H-564C, como un híbrido de maíz con alta calidad de proteina para el trópico húmedo de México; presetan su investigación sobre la producción de Piña Cayena Lisa y MD2 (Ananas comosus L.) en condiciones de Loma Bonita, en Oaxaca; acotan sobre el efecto de coberteras como control biológico por conservación contra áfidos en Nogal Pecanero; esbozan sobre la caracterización de cuatro genotipos de Frijol Negro en Martínez de la Torre, Veracruz, México; presentan una caracterización hidroecológica de la microcuenca de Arroyo Prieto, Yuriría, Gto., y alternativas para su restauración ambiental; presentan su investigación sobre el efecto del hongo Beauveria bassiana sobre solubilización de fosfatos y la disponibilidad de fósforo en el suelo; plantean su investigación sobre la Germinación y regeneración in vitro de Epidendrum falcatum LINDL; esbozan su artículo sobre genotipos de frijol negro y su tolerancia a sequía terminal en Veracruz, México