Hydrogels with stiffness-degradation spatial patterns control anisotropic 3D cell response.

In nature, tissues are patterned, but most biomaterials used in human applications are not. Patterned biomaterials offer the opportunity to mimic spatially segregating biophysical and biochemical properties found in nature. Engineering such properties allows to study cell-matrix interactions in anisotropic matrices in great detail. Here, we developed alginate-based hydrogels with patterns in stiffness and degradation, composed of distinct areas of soft non-degradable (Soft-NoDeg) and stiff degradable (Stiff-Deg) material properties. The hydrogels exhibit emerging patterns in stiffness and degradability over time, taking advantage of dual crosslinking: Diels-Alder covalent crosslinking (norbornene-tetrazine, non degradable) and UV-mediated peptide crosslinking (matrix metalloprotease sensitive peptide, enzymatically degradable). The materials were mechanically characterized using rheology for single-phase and surface micro-indentation for patterned materials. 3D encapsulated mouse embryonic fibroblasts (MEFs) allowed to characterize the anisotropic cell-matrix interaction in terms of cell morphology by employing a novel image-based quantification tool. Live/dead staining showed no differences in cell viability but distinct patterns in proliferation, with higher cell number in Stiff-Deg materials at day 14. Patterns of projected cell area became visible already at day 1, with larger values in Soft-NoDeg materials. This was inverted at day 14, when larger projected cell areas were identified in Stiff-Deg. This shift was accompanied by a significant decrease in cell circularity in Stiff-Deg. The control of anisotropic cell morphology by the material patterns was also confirmed by a significant increase in filopodia number and length in Stiff-Deg materials. The novel image-based quantification tool was useful to spatially visualize and quantify the anisotropic cell response in 3D hydrogels with stiffness-degradation spatial patterns. Our results show that patterning of stiffness and degradability allows to control cell anisotropic response in 3D and can be quantified by image-based strategies. This allows a deeper understanding of cell-matrix interactions in a multicomponent material.

Rhabdomyosarcoma in low- and middle-income countries: A report from the Asociacion de Hemato-oncología Pediatrica de Centro América (AHOPCA).

This report describes the results of an observational study dedicated to rhabdomyosarcoma developed by the Asociación de Hemato-oncología Pediatrica de Centro América (AHOPCA) between 2001 and 2018. Overall, 337 previously untreated patients < 18 years old were included in the analysis; 58% had unresected disease, and 19% were metastatic at diagnosis. With a median follow-up of 6.6 years, five-year event-free and overall survival rates were 30% and 33%, respectively. Local progression/relapse was the main cause of treatment failure.

Composición química y calidad proteica de fideos complementados con harina de Porphyra columbina / Chemical composition and protein quality of pasta complemented with Porphyra columbina

La harina de trigo es un alimento no balanceado, debido al bajo valor biológico de su proteína, originado por la deficiencia de lisina. Para mejorar las propiedades nutricionales de la pasta de trigo, se utilizan distintas fuentes con alto contenido y calidad de proteína. Las algas son un recurso abundante, económico y atractivo para utilizar como ingrediente en alimentos. Entre las macroalgas rojas comestibles, Porphyra columbina es una de las más importantes de la Patagonia Argentina. El objetivo de este trabajo fue comparar la composición química y la calidad proteica de fideos elaborados con harina de Triticum durum (FC) y fideos complementados al 30% en la fase sólida con harina de Porphyra columbina (F30). La composición centesimal se determinó por métodos oficiales de la AOAC. La determinación cuantitativa de aminoácidos se llevó a cabo mediante el método propuesto por Alaiz et al. (23). La separación de los aminoácidos se realizó mediante HPLC. Los resultados de composición química para FC y F30, expresados en g cada 100 g de pasta seca comestible, fueron respectivamente: humedad 7,9 ± 0,4 y 8,1 ± 0,2; cenizas 1,0 ± 0,1 y 1,7 ± 0,1; grasas 5,6 ± 0,2 y 4,7 ± 0,1; proteínas 15,8 ± 0,1 y 17,7 ± 0,1; fibra dietaria total 7,7 ± 0,3 y 19,8 ± 0,2 y carbohidratos 62,0 y 47,9. Los cálculos del puntaje químico, teniendo en cuenta las necesidades del preescolar, revelaron un valor de 55% y 94% para FC y F30, respectivamente. En FC la lisina se evidenció como el aminoácido limitante, mientras que en F30 el limitante fue el triptofano(AU).

The wheat pasta is an unbalanced food, due to the low biological value of its protein, caused by the deficiency of lysine. To improve the nutritional properties of wheat pasta, different sources with high protein content and quality are used. Seaweed is an abundant, economical and attractive resource to use as an ingredient in food. Among red edible macroalgae, Porphyra columbina is one of the most important ones in Argentine Patagonia. The objective of this work was to compare the chemical composition and protein quality of pasta made with Triticum durum flour (FC) and pasta supplemented at 30% in the solid phase with Porphyra columbina flour (F30). The centesimal composition was determined by AOAC official methods. The quantitative determination of amino acids was carried out by the method proposed by Alaiz, et al.(23). The separation of amino acids was carried out through HPLC. The chemical composition results for FC and F30, expressed in g per 100 g of edible dry pasta, were: water 7,9 ± 0,4 and 8,1 ± 0,2; ash 1,0 ± 0,1 and 1,7 ± 0,1; fat 5,6 ± 0,2 and 4,7 ± 0,1; protein 15,8 ± 0,1 and 17,7 ± 0,1; total dietary fiber 7,7 ± 0,3 and 19,8 ± 0,2 and carbohydrates 62,0 and 47,9, respectively. The chemical score, taking into account the needs of pre-schoolers, revealed a value of 55% and 94% for FC and F30, respectively. In FC, lysine was found to be the limiting amino acid, whereas in F30, the limiting factor was tryptophan(AU).

Outcome of pediatric non-Hodgkin lymphoma in Central America: A report of the Association of Pediatric Hematology Oncology of Central America (AHOPCA).

BACKGROUND: Treating B-non-Hodgkin lymphoma (B-NHL) in lower-income countries is challenging because of imprecise diagnosis, the increased risk of fatal toxicity associated with advanced disease at presentation, and limited supportive care. PROCEDURE: Central American patients with newly diagnosed stage I or II B-NHL received a modified Berlin-Frankfurt-Münster (BFM) regimen including a prephase (prednisone, cyclophosphamide) followed by A/B/A courses (A: cytarabine, dexamethasone, etoposide, ifosfamide, methotrexate, and intrathecal therapy; B: cyclophosphamide, dexamethasone, doxorubicin, methotrexate, and intrathecal therapy). Those with stage III or IV NHL received additional courses (B/A/B), intensified for stage IV disease by additional vincristine and methotrexate doses. Patients in poor condition received a second prephase treatment before their chemotherapy courses. RESULTS: Between March 2004 and June 2016, of 405 patients with B-NHL, 386 (109 females) were eligible for treatment. Immunohistochemistry was performed in 177 cases (47.4%) and characterized the disease as mature B-cell lymphoma. Stage distribution was as follows: I/II, 31 (8.1%); III, 252 (65.3%); IV, 93 (24.1%); 10 (2.6%) not available. The 3-year overall survival was 70% for the whole group (86% for stages I/II, 75% for stage III, 58% for stage IV). Events included death during induction (34 patients, 8.8%), relapse/progression (46, 11.9%), death in remission (9, 2.3%), second malignancy (1, 0.26%), and death of unknown cause (1, 0.26%). Twenty-three (6%) patients abandoned or refused therapy. CONCLUSIONS: Approximately 70% of children with B-NHL from Central America experienced long-term, disease-free survival with a modified BFM schedule. Toxic death and relapse/resistant disease were the main reasons for treatment failure.

Advancing Reliable Data for Cancer Control in the Central America Four Region.

The Central America Four (CA-4) region, comprising Guatemala, Honduras, El Salvador, and Nicaragua, is the largest low- and middle-income country region in the Western Hemisphere, with over 36 million inhabitants. The CA-4 nations share a common geography, history, language, and development indices, and unified with open borders in 2006. The growing CA-4 cancer burden among the noncommunicable diseases is expected to increase 73% by 2030, which argues for a regional approach to cancer control. This has driven efforts to establish population-based cancer registries as a central component of the cancer control plans. The involvement of international and academic partners in an array of initiatives to improve cancer information and control in the CA-4 has accelerated over the past several years. Existing data underscore that the infectious cancers (cervical, stomach, and liver) are a particular burden. All four countries have committed to establishing regional population-based cancer registries and have advanced significantly in pediatric cancer registration. The challenges common to each nation include the lack of national cancer control plans and departments, competing health priorities, lack of trained personnel, and sustainability strategies. General recommendations to address these challenges are outlined. The ongoing regional, international, and academic cooperation has proven helpful and is expected to continue to be a powerful instrument to contribute to the design and implementation of long-term national cancer control plans.

Visual outcome of penetrating keratoplasty, deep anterior lamellar keratoplasty and Descemet membrane endothelial keratoplasty.

PURPOSE: A single-center, cross-sectional study was designed to assess and compare objective and subjective quality of vision of patients intervened with penetrating keratoplasty (PK), deep anterior lamellar keratoplasty (DALK) and Descemet membrane endothelial keratoplasty (DMEK). METHODS: Forty-six patients previously intervened with PK (22 eyes), DALK (7 eyes) and DMEK (17 eyes) were recruited. Visual evaluation included spherical and cylindrical refraction, distance corrected visual acuity (DCVA), photopic contrast sensitivity (CS), optical quality, measured with the HD Analyzer (objective scattering index [OSI], MTF cut-off and Strehl ratio), and ocular and corneal aberrometry, measured with the KR-1W Wavefront Analyzer. RESULTS: Statistically significant between-group differences were found in age (p=0.006, DMEK patients were older) and time since surgery (p<0.001, longest time for PK patients). No statistically significant differences were found in DCVA between the techniques. Between-group differences were encountered in CS at 12 (p=0.007) and 18 (p<0.001) cycles per degree, with DMEK and DALK obtaining the best and worst outcomes, respectively. Differences in optical quality were found between the techniques (OSI, p=0.004; MTF cut-off, p=0.048; Strehl ratio p=0.022), with DMEK displaying the best outcomes. Highest and lowest values in ocular and corneal aberrations were for DALK and DMEK patients, respectively. Between-group differences were found in corneal astigmatism (p<0.001; -3.31±2.00 D in PK; -2.68±0.94 D in DALK; -1.09±0.62 D in DMEK). CONCLUSION: Overall, DMEK proved superior over PK and DALK in terms of quality of vision, with PK offering slightly better outcomes than DALK in most visual function parameters under evaluation.

Terapias para el tratamiento de la disartria en niños con parálisis cerebral: una revisión sistemática / Treatment of dysarthria in children with cerebrall palsy: a systematic review

Introduction: Dysarthria is a speech disorder most frequently associated with cerebral palsy (CP). The approach from the phono-audiology perspective is typically based on clinical observation criteria for assessment, diagnosis and intervention. Objective: Identify existing speech-language therapies for the treatment of dysarthria in children with cerebral palsy and assess their effectiveness according to the International Classification of Functioning, Disability and Health (ICF). Materials and Methods: Systematic review carried out according to Cochrane recommendations. Randomized and quasi-experimental clinical studies with children with CP and dysarthria were considered. The search was carried out through the on-line platforms CINAHL Plus, Central (Cochrane), Embase, SciELO and LILACS, Medline (Pub Med), Speech Bite and ScienceDirect. Identified studies were reviewed independently by two authors; disagreements were resolved by a third party. Risk of bias was assessed using Cochrane's risk of bias assessment tool. Results: 840 studies were identified in the on-line search. Only three studies met the inclusion criteria. These correspond to quasi-experimental studies and all three indicate that an intervention model focused on basic motor processes related to respiration, phonation, articulation, fluency and prosody, does improve voice and speech functions. Conclusions: There is no evidence to conclude that there is an effective treatment for dysarthria in children with CP.

Introducción: Uno de los trastornos del habla más frecuentemente asociado a la parálisis cerebral es la disartria. El abordaje fonoaudiológico suele basarse en criterios de observación clínica para la evaluación, diagnóstico e intervención. Objetivo: Identificar las terapias fonoaudiológicas existentes para el tratamiento de la disartria en niños con parálisis cerebral y evaluar la efectividad considerando el marco CIF. Materiales y Método: Revisión sistemática realizada de acuerdo a recomendaciones de la Colaboración Cochrane. Se incluyeron ensayos clínicos aleatorizados y cuasiexperimentales que tuvieran como población niños con parálisis cerebral y disartria. Se realizó la búsqueda a través de CINAHL Plus, Central (Cochrane), Embase, SciELO y LILACS, Medline (vía Pub Med), Speech Bite y ScienceDirect. Los estudios identificados fueron revisados en forma independiente por dos autores, los desacuerdos se resolvieron mediante un tercero. La evaluación del riesgo de sesgo se realizó con la herramienta de la Colaboración Cochrane. Resultados: Se identificaron 840 artículos en la búsqueda electrónica. Solo 3 artículos cumplieron los criterios de inclusión y corresponden a trabajos cuasiexperimentales. Coinciden en que el modelo de intervención enfocado en Procesos Motores Básicos (PMB), del habla respiración, fonación, articulación, resonancia y prosodia, como mejoran las funciones del habla y la voz. Conclusiones: No existe evidencia suficiente para declarar que existe una terapia efectiva para el manejo de los niños con disartria en parálisis cerebral.

The treatment of childhood acute lymphoblastic leukemia in Guatemala: Biologic features, treatment hurdles, and results.

BACKGROUND: The National Pediatric Oncology Unit (UNOP) is the only pediatric hemato-oncology center in Guatemala. METHODS: Patients ages 1 to 17 years with acute lymphoblastic leukemia (ALL) were treated according to modified ALL Intercontinental Berlin-Frankfurt-Münster (IC-BFM) 2002 protocol. Risk classification was based on age, white blood cell count, immunophenotype, genetics (when available), and early response to therapy. RESULTS: From July 2007 to June 2014, 787 patients were treated, including 160 who had standard-risk ALL, 450 who had intermediate-risk ALL, and 177 who had high-risk ALL. The induction death rate was 6.6%, and the remission rate was 92.9%. The rates of death and treatment abandonment during first complete remission were 4.8% and 2.5%, respectively. At a median observation time of 3.6 years, and with abandonment considered an event, the 5-year event-free survival and overall survival estimates ( ± standard error) were 56.2% ± 2.1% and 64.1% ± 2.1%, respectively, with a 5-year cumulative incidence of relapse of 28.9% ± 2.0%. Twenty-one of 281 patients (7.5%) investigated were positive for the ets variant 6/runt-related transcription factor 1 (ETV6/RUNX1) fusion. CONCLUSIONS: A well organized center in a low-middle-income country can overcome the disadvantages of malnutrition and reduce abandonment. Outcomes remain suboptimal because of late diagnosis, early death, and a high relapse rate, which may have a partly genetic basis. Earlier diagnosis, better management of complications, and better knowledge of ALL will improve outcomes. Cancer 2017;123:436-448. © 2016 American Cancer Society.

Socioeconomic status and global variations in the incidence of neuroblastoma: call for support of population-based cancer registries in low-middle-income countries.

Global variations in the incidence of pediatric cancers have been described; however, the causes of such differences are not known. We investigated the relationship between the incidence of embryonal tumors and human development index on a global scale. Increasing incidence of neuroblastoma correlates significantly with an increasing index of human development, with greater incidence among countries with high socioeconomic development, in apparent contrast to the incidence of retinoblastoma. While more data are needed to corroborate this observation, our findings suggest new avenues for etiological research and serve as a call for support of population-based cancer registries in low-middle-income countries.

Paediatric cancer stage in population-based cancer registries: the Toronto consensus principles and guidelines.

Population-based cancer registries generate estimates of incidence and survival that are essential for cancer surveillance, research, and control strategies. Although data on cancer stage allow meaningful assessments of changes in cancer incidence and outcomes, stage is not recorded by most population-based cancer registries. The main method of staging adult cancers is the TNM classification. The criteria for staging paediatric cancers, however, vary by diagnosis, have evolved over time, and sometimes vary by cooperative trial group. Consistency in the collection of staging data has therefore been challenging for population-based cancer registries. We assembled key experts and stakeholders (oncologists, cancer registrars, epidemiologists) and used a modified Delphi approach to establish principles for paediatric cancer stage collection. In this Review, we make recommendations on which staging systems should be adopted by population-based cancer registries for the major childhood cancers, including adaptations for low-income countries. Wide adoption of these guidelines in registries will ease international comparative incidence and outcome studies.

Contribución nutricional de minerales esenciales aportados por Mytilus edulis platensis (mejillones) del golfo San Jorge, Chubut / Nutritional contribution of essential minerals provided by Mytilus edulis platensis (mussels) from San Jorge gulf, Chubut

La recolección artesanal de moluscos bivalvos, actividad conocida como marisqueo, es una significativa fuente alimenticia y económica para grupos sociales de poblaciones costeras patagónicas. Además, se ha constituido como una importante alternativa de maricultura en la costa patagónica. El objetivo de este trabajo fue determinar las concentraciones de Ca, Mg, P, Cr, Cu, Fe, Mn, Mo, Se y Zn en Mytilus edulis platensis detres sitios de la costa del Golfo San Jorge, a fin de evaluar la variación geográfica y estacional de estos elementos y determinar su contribución nutricional. Los lugares de muestreo se centraron en dos sitios alejados de la actividad antrópica, Bahía Solano y Punta Maqueda, y un tercer sitio Playa Km 3, con actividad antropogénica. Las muestras fueron digeridas por vía húmeda con Bombas Parr. Los elementos fueron cuantificados mediante un espectrómetro de plasma inductivo (ICP-OES). Los resultados fueron expresados como porcentajes de cobertura considerando el promedio anual de cada elemento estudiado. En este sentido, según las Ingestas Dietéticas de Referencia, el consumo de 100 gramos de moluscos frescos cubrirían las necesidades para mujeres (M) y hombres (H) adultos en los siguientes porcentajes: Ca 26% (M y H), Mg 42% (M) y 35% (H), P 18% (M y H), Cr 176% (M) y 126% (H), Cu 11% (M y H), Fe 34% (M) y 70% (H),Mn 17% (M) y 13% (H), Mo 26% (M y H), Se 202% (M) y 155% (H)y Zn 30% (M) y 21% (H). Es posible concluir que 100 g de mejillones aportan elementos indispensables en niveles considerables, sujetos a variación temporal y geográfica, hecho que debería ser tenido en cuenta para ampliar y mejorar la información actualmente reflejada en tablas de composición de alimentos. Los resultados obtenidos proporcionan información de gran valor, dado que corresponden a un alimento originario de la costa Patagónica y consumido de forma habitual en nuestro país...

Anaplastic Large Cell Lymphoma in Central America: A Report From the Central American Association of Pediatric Hematology Oncology (AHOPCA).

BACKGROUND: Although anaplastic large cell lymphoma (ALCL) is curable in high-income countries (HIC), data from low- and middle-income countries (LMIC) are lacking. We therefore conducted a retrospective study of the Central American Association of Pediatric Hematology Oncology (AHOPCA) experience in treating ALCL. PROCEDURE: We included all patients age <18 years newly diagnosed with ALCL treated between 2000 and 2013 in seven AHOPCA institutions. Retrospective data were extracted from the Pediatric Oncology Network Database. RESULTS: Thirty-one patients met inclusion criteria. Twenty-five (81%) had advanced disease (stages III and IV), six (19%) were treated on the APO (doxorubicin, prednisone, vincristine) regimen, 15 (49%) on multi-agent chemotherapy designed for T-cell lineage malignancies (GuatALCL protocol), and 10 (32%) on BFM-based treatment regimens. Five-year overall event-free survival and overall survival were, respectively, 67.1 ± 8.6% and 66.7 ± 8.7%. All 10 events occurred in patients treated on BFM-based treatment regimens or the GuatALCL protocol, none on APO treatment: two patients experienced relapse, six treatment related mortality (TRM), and two abandonment. CONCLUSIONS: Treatment of ALCL in countries with limited resources is feasible with similar outcomes as in HIC, though the causes of treatment failure differ. Less intensive regimens may be preferable in order to decrease TRM and improve outcomes. Prospective clinical trials determining the ideal treatment for LMIC children with ALCL are necessary.

Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala.

Analysis of 327 consecutive cases at a pediatric referral hospital of Guatemala reveals that retinoblastoma accounts for 9.4% of all cancers and the estimated incidence is 7.0 cases/million children, higher than the United States or Europe. The number of familial cases is low, and there is a striking disparity in indigenous children due to late diagnosis, advanced disease, rapid progression and elevated mortality. Nine germline mutations in 18 patients were found; two known and five new mutations. Hypermethylation of RB1 was identified in 13% of the tumors. An early diagnosis program could identify cases at an earlier age and improve outcome of retinoblastoma in this diverse population.

Frequency of thiopurine S-methyltransferase mutant alleles in indigenous and admixed Guatemalan patients with acute lymphoblastic leukemia.

Thiopurine S-methyltransferase (TPMT) polymorphisms affect the enzyme's activity and are predictive for the efficacy and toxicity of thiopurine treatment of acute lymphoblastic leukemia (ALL), autoimmune diseases and organ transplants. Because inter-ethnic differences in the distribution of these polymorphisms have been documented, we sequenced the TMPT gene in 95 Guatemalans, yet identified no new alleles. We also determined the frequency of the TPMT 2, 3A, 3B and 3C alleles in 270 admixed and 177 indigenous pediatric patients with ALL and healthy subjects from Guatemala using TaqMan assays and DNA sequencing. Among the 447 subjects genotyped, 10.0 % of the ALL cases and 13.6 % of the healthy controls were heterozygous for one of the four TPMT variants screened. The genotype frequencies in ALL and control populations were 0.7 and 1.7 % for TPMT 1/ 2, 7.4 and 10 % for TPMT 1/3A, 0.3 and 0 % for TPMT 1/B, and 1.5 and 1.1 % for TPMT 1/C, respectively (p = 0.30). No statistically significant differences between admixed and indigenous ALL (p = 0.67) or controls (p = 0.41) groups were detected; however, 17 % of the admixed healthy group bore one TPMT mutant allele, and they have one of the highest reported frequencies of TPMT mutant allele carriers. Because of the clinical implications of these variants for therapeutic response, TPMT allele testing should be considered in all Guatemalan patients to reduce adverse side-effects from thiopurine drug treatments.

Treating Pediatric soft tissue sarcomas in a country with limited resources: the experience of the Unidad Nacional de Oncologia Pediatrica in Guatemala.

BACKGROUND: About 250-300 children with newly diagnosed cancer are treated each year at the Unidad Nacional de Oncologia Pediatrica in Guatemala City; less than 5% of them have soft tissue sarcomas (STS). The aim of the article was to evaluate whether the therapeutic standards achieved in STS in developed countries could be reproduced in a low-income country. PATIENTS AND METHODS: We reviewed the clinical data, treatment and outcome of 80 patients, 47 cases of rhabdomyosarcoma (RMS) and 33 of non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), treated between January 2000 and October 2007. RESULTS: Most of the RMS patients had advanced disease at diagnosis (87% groups III-IV). Their 3-year event-free survival rate (EFS) was 26.4% if abandoning the treatment was considered as an event, or 32.4% if it was censored (14 patients abandoned the treatment), and the 3-year overall survival rate (OS) was 43.5%. Local progression/relapse was the main cause of treatment failure. Among the patients with NRSTS, the EFS at 3 years was 36.4% (when abandoning the treatment was considered as an event) or 43.3% (when it was censored), and the OS was 44.2%. Outcome was satisfactory for synovial sarcoma patients, those with tumors < or =5 cm, and those with localized disease. CONCLUSIONS: Overall results were unsatisfactory compared to results reported from developed countries. Late diagnosis and the consequently high proportion of cases of advanced disease at diagnosis, the large number of patients failing to complete the treatment, and the poor quality of local control (in RMS) adversely influence outcome.