BSA-capped gold nanoclusters as potential theragnostic for skin diseases: Photoactivation, skin penetration, in vitro, and in vivo toxicity

BSA-capped gold nanoclusters are promising theragnostic systems that can be excited to render both fluorescence emission and reactive oxygen species. Although their synthesis and photoluminescence properties are already well described, more accurate information about their use as photosensitizers is required in order to advance towards health applications. In this work, we have obtained BSA-capped gold nanoclusters and characterized their photophysics by different techniques. Singlet oxygen production was detected upon irradiation, which was enough to produce toxicity on two cell lines. Remarkably, an internal energy transfer, probably due to the presence of smaller nanoclusters and the contribution of oxidized residues of BSA in the system, caused fluorescence emission near 640 nm after excitation in the UV range. Additionally, the system was capable of penetrating human skin beyond the stratum corneum, which enhances the potential of these nanoclusters as bifunctional photodynamic therapy effectors and biomarkers with application in a diversity of skin diseases. In the absence of radiation, BSA-capped gold nanoclusters did not cause toxicity in vitro, while their toxic effect on an in vivo model as zebrafish was determined.Fil: Lillo, Rolando Cristian Rodrigo. Universidad Nacional de San Martin. Instituto de Nanosistemas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Calienni, Maria Natalia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB; ArgentinaFil: Rivas Aiello, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Prieto, Maria Jimena. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB; ArgentinaFil: Rodriguez, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Tuninetti, Jimena Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Toledo, Pamela Ludmila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB; ArgentinaFil: Alonso, Silvia del Valle. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB; ArgentinaFil: Moya, Sergio Enrique. Centro de Investigación Cooperativa en Biomateriales; España. Centro de Investigación Cooperativa en Biomateriales; EspañaFil: Gonzalez, Monica Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Martinetti Montanari, Jorge Anibal. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB; ArgentinaFil: Soler Illia, Galo Juan de Avila Arturo. Universidad Nacional de San Martin. Instituto de Nanosistemas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG- binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763

Evaluation of Adipose Tissue Zinc-Alpha 2-Glycoprotein Gene Expression and Its Relationship with Metabolic Status and Bariatric Surgery Outcomes in Patients with Class III Obesity

Zinc-α2 glycoprotein (ZAG) is an adipokine involved in adipocyte metabolism with potential implications in the pathogenesis of metabolic disorders. Our aim was to evaluate the relationship between visceral (VAT) and subcutaneous adipose tissue (SAT) ZAG expression and metabolic parameters in patients with class III obesity, along with the impact of basal ZAG expression on short- and medium-term outcomes related to bariatric surgery. 41 patients with class III obesity who underwent bariatric surgery were included in this study. ZAG gene expression was quantified in SAT and VAT. Patients were classified into two groups according to SAT and VAT ZAG percentile. Anthropometric and biochemical variables were obtained before and 15 days, 45 days, and 1 year after surgery. The lower basal SAT ZAG expression percentile was associated with higher weight and waist circumference, while the lower basal VAT ZAG expression percentile was associated with higher weight, waist circumference, insulin, insulin resistance, and the presence of metabolic syndrome. Basal SAT ZAG expression was inversely related to weight loss at 45 days after surgery, whereas no associations were found between basal VAT ZAG expression and weight loss after surgery. Additionally, a negative association was observed between basal SAT and VAT ZAG expression and the decrease of gamma-glutamyl transferase after bariatric surgery. Therefore, lower SAT and VAT ZAG expression levels were associated with an adverse metabolic profile. However, this fact did not seem to confer worse bariatric surgery-related outcomes. Further research is needed to assess the clinical significance of the role of ZAG expression levels in the dynamics of hepatic enzymes after bariatric surgeryThis study has been co-funded by FEDER funds (“A way to make Europe”). M.M. and L.G.S. are also supported by UMA18-FEDERJA-285 and UMA20-FEDERJA-144, co-funded by Malaga University, Junta de Andalucía and FEDER funds, CB06/03/0018, PI-0297-2018 and PI-0194-2017, co-funded by FEDER funds and Consejería de Salud y Familias, Junta de Andalucía, and CP17/00133, Instituto de Salud Carlos III (ISCIII), Ministry of Science, Innovation and Universities, Spain Partial funding for open access charge: Universidad de Málag

Duration and compliance with antidepressant treatment in immigrant and native-born populations in Spain: a four year follow-up descriptive study

<p>Abstract</p> <p>Background</p> <p>Non-compliance with antidepressant treatment continues to be a complex problem in mental health care. In immigrant populations non-compliance is one of several barriers to adequate management of mental illness; some data suggest greater difficulties in adhering to pharmacological treatment in these groups and an increased risk of therapeutic failure.</p> <p>The aim of this study is to assess differences in the duration and compliance with antidepressant treatment among immigrants and natives in a Spanish health region.</p> <p>Methods</p> <p>Population-based (n=206,603), retrospective cohort study including all subjects prescribed ADT between 2007 and 2009 and recorded in the national pharmacy claims database. Compliance was considered adequate when the duration was longer than 4months and when patients withdrew more than 80% of the packs required.</p> <p>Results</p> <p>5334 subjects (8.5% of them being immigrants) initiated ADT. Half of the immigrants abandoned treatment during the second month (median for natives=3months). Of the immigrants who continued, only 29.5% presented good compliance (compared with 38.8% in natives). The estimated risk of abandoning/ending treatment in the immigrant group compared with the native group, adjusted for age and sex, was 1.28 (95%CI 1.16-1.42).</p> <p>Conclusions</p> <p>In the region under study, immigrants of all origins present higher percentages of early discontinuation of ADT and lower median treatment durations than the native population. Although this is a complex, multifactor situation, the finding of differences between natives and immigrants in the same region suggests the need to investigate the causes in greater depth and to introduce new strategies and interventions in this population group.</p

Prognostic impact of bone marrow fibrosis in primary myelodysplastic syndromes

La mielofibrosis (MF) se observa en el 10-20% de los pacientes con síndrome mielodisplásico (SMD). Su presencia es reconocida como un hallazgo histológico adverso asociado a curso agresivo, fallo medular temprano, sobrevida acortada y evolución leucémica.El objetivo fue examinar la influencia de la MF (MF ≥1) en la sobrevida global (SG) y su asociacióncon variables clínicas e histopatológicas.Se identificaron 468 pacientes con SMD incluidos en el Registro Argentino de SMD de 2007 a 2017.La mediana de SG del subgrupo MF ≥1 fue de 20,1 meses (IC 95%: 10,1-30,0) versus 67,6 meses (IC95% 45,1-90,3) del subgrupo MF-0 (p2 (HR 2,07, 95% IC 1,44-2,96; p5% (HR 2,94,IC 95% 2,06-4,20; p3 (HR 2,17; IC 95%: 1,48-3,19;p1000 ug/L (OR 3,41; p= 0,006) y la localización eritroide atípica (OR 2,65; p=0,004) se asociaron significativamente con la presencia de MF ≥1.Los resultados destacan la presencia de MF ≥1 como un factor pronóstico adverso para la supervivencia en SMD, asociado con hiperferritinemia y alteración de la localización de la progenie eritroide en la MO.Myelofibrosis (MF) is observed in 10-20% of patients with myelodysplastic syndrome (MDS). The presence of MF has been recognized as an adverse histological finding associated with an aggressive course including early bone marrow (BM) failure, shortened survival and leukemic evolution. The aim of this study was to examine the influence of the myelofibrosis (MF ≥1) in the overall survival (OS) and its association with clinical and histopathologic variables. We identified 468 MDS patients who were included in the Argentinian Registry of MDS from 2007 to 2017. The median OS for the MF≥1 subgroup was 20.1 months (95% CI 10.1-30.0) versus 67.6 months (95% CI 45.1-90.3) for the MF-0 subgroup (p2 (HR 2.07, 95% CI 1.44-2.96; p5% (HR 2.94, 95% CI 2.06-4.20; p3 (HR 2.17, 95% CI 1.48- 3.19; p 1000 ug/L (OR 3.41; p=0.006) and the atypical erythroid localization (OR 2.65; p=0.004) were significantly associated with the presence of MF ≥1. Our results highlight the presence of any grade of myelofibrosis as an independent adverse prognostic factor for survival in MDS, associated with higher ferritin level and abnormal erythroid localization in the BM.Fil: Russo, Maria Florencia. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal General de Agudos Paroissien (higa Paroissien); ArgentinaFil: Belli, Carolina Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Enrico, Alicia. Hospital Italiano de La Plata; ArgentinaFil: Arbelbide, Jorge. Hospital Italiano; ArgentinaFil: Narbaitz, Marina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: de Dios Soler, Marcela. Hospital Municipal de Oncologia Maria Curie ; Gobierno de la Ciudad Autonoma de Buenos Aires;Fil: Garcia Rivello, Hernan Jorge. Hospital Italiano; ArgentinaFil: Martin, Carlos. Hospital Italiano de La Plata; ArgentinaFil: Iastrebner, Marcelo. Sanatorio Sagrado Corazón; ArgentinaFil: Gonzalez, Jacqueline. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Rosenhain, Mariana. Hospital General de Agudos Dr. Enrique Tornú; ArgentinaFil: Alfonso, Graciela. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Kornblihtt, Laura Inés. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Perusini, Agustina. Hospital Italiano; ArgentinaFil: Lazzarino, Carolina. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal General de Agudos Paroissien (higa Paroissien); Argentin

Reactivity of neonicotinoid insecticides with carbonate radicals

“NOTICE: this is the author’s version of a work that was accepted for publication in Water Research. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in WATER RESEARCH, [VOL46, ISSUE11, jul 2012] DOI10.1016/j.watres.2012.03.051¨ ©IWA Publishing 2012. The definitive peer-reviewed and edited version of this article is published in Water Research 46 11 3476-3489 2012 10.1016/j.watres.2012.03.051 and is available at www.iwapublishing.comThe reaction of three chloronicotinoid insecticides, namely Imidacloprid (IMD), Thiacloprid (THIA) and Acetamiprid (ACT), with carbonate radicals (CO3 center dot-) was investigated. The second order rate constants (4 +/- 1) x 10(6), (2.8 +/- 0.5) x 10(5), and (1.5 +/- 1) x 10(5) M-1 s(-1) were determined for IMD, THIA and ACT, respectively. The absorption spectra of the organic intermediates formed after CO3 center dot- is approximately equal to attack to IMD is in line with those reported for alpha-aminoalkyl radicals. A reaction mechanism involving an initial charge transfer from the amidine nitrogen of the insecticides to CO3 center dot- is proposed and further supported by the identified reaction products. The pyridine moiety of the insecticides remains unaffected until nicotinic acid is formed. CO3 center dot- radical reactivity towards IMD, ACT, and THIA is low compared to that of HO center dot radicals, excited triplet states, and O-1(2), and is therefore little effective in depleting neonicotinoid insecticides. (C) 2012 Elsevier Ltd. All rights reserved.This research was financially supported by Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Agencia Nacional de Promocion Cientifica y Tecnologica (Argentina, project PICT 2007 number 00308), and Agencia Espanola de Cooperacion Internacional (project A/8199/07). M.L.D. thanks CONICET for a graduate studentship. M.C.G. is a research member of CONICET. D.O.M. is a research member of Comision de Investigaciones Cientificas de la Provincia de Buenos Aires (CIC), Argentina. L.S.J. acknowledges Ministerio de Ciencia e Innovacion for his Juan de la Cierva scholarship.Dell'arciprete, ML.; Soler Escoda, JM.; Santos-Juanes Jordá, L.; Arques Sanz, A.; Martire, DO.; Furlong, JP.; González, MC. (2012). Reactivity of neonicotinoid insecticides with carbonate radicals. Water Research. 46(11):3476-3489. https://doi.org/10.1016/j.watres.2012.03.051S34763489461

RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer

Background: Around 15-20% of primary breast cancers are characterized by HER2 protein overexpression and/or HER2 gene amplification. Despite the successful development of anti-HER2 drugs, intrinsic and acquired resistance represents a major hurdle. This study was performed to analyze the RANK pathway contribution in HER2-positive breast cancer and anti-HER2 therapy resistance. Methods: RANK and RANKL protein expression was assessed in samples from HER2-positive breast cancer patients resistant to anti-HER2 therapy and treatment-naive patients. RANK and RANKL gene expression was analyzed in paired samples from patients treated with neoadjuvant dual HER2-blockade (lapatinib and trastuzumab) from the SOLTI-1114 PAMELA trial. Additionally, HER2-positive breast cancer cell lines were used to modulate RANK expression and analyze in vitro the contribution of RANK signaling to anti-HER2 resistance and downstream signaling. Results: RANK and RANKL proteins are more frequently detected in HER2-positive tumors that have acquired resistance to anti-HER2 therapies than in treatment-naive ones. RANK (but not RANKL) gene expression increased after dual anti-HER2 neoadjuvant therapy in the cohort from the SOLTI-1114 PAMELA trial. Results in HER2-positive breast cancer cell lines recapitulate the clinical observations, with increased RANK expression observed after short-term treatment with the HER2 inhibitor lapatinib or dual anti-HER2 therapy and in lapatinib-resistant cells. After RANKL stimulation, lapatinib-resistant cells show increased NF-κB activation compared to their sensitive counterparts, confirming the enhanced functionality of the RANK pathway in anti-HER2-resistant breast cancer. Overactivation of the RANK signaling pathway enhances ERK and NF-κB signaling and increases lapatinib resistance in different HER2-positive breast cancer cell lines, whereas RANK loss sensitizes lapatinib-resistant cells to the drug. Our results indicate that ErbB signaling is required for RANK/RANKL-driven activation of ERK in several HER2-positive cell lines. In contrast, lapatinib is not able to counteract the NF-κB activation elicited after RANKL treatment in RANK-overexpressing cells. Finally, we show that RANK binds to HER2 in breast cancer cells and that enhanced RANK pathway activation alters HER2 phosphorylation status. Conclusions: Our data support a physical and functional link between RANK and HER2 signaling in breast cancer and demonstrate that increased RANK signaling may contribute to the development of lapatinib resistance through NF-κB activation. Whether HER2-positive breast cancer patients with tumoral RANK expression might benefit from dual HER2 and RANK inhibition therapy remains to be elucidated

Differences in pharmaceutical consumption and expenses between immigrant and Spanish-born populations in Lleida, (Spain): A 6-months prospective observational study

<p>Abstract</p> <p>Background</p> <p>There are few studies comparing pharmaceutical costs and the use of medications between immigrants and the autochthonous population in Spain. The objective of this study is to evaluate whether there are differences in pharmaceutical consumption and expenses between immigrant and Spanish-born populations.</p> <p>Methods</p> <p>Prospective observational study in 1,630 immigrants and 4,154 Spanish-born individuals visited by fifteen primary care physicians at five public Primary Care Clinics (PCC) during 2005 in the city of Lleida, Catalonia (Spain). Data on pharmaceutical consumption and expenses was obtained from a comprehensive computerized data-collection system. Multinomial regression models were used to estimate relative risks and confidence intervals of pharmaceutical expenditure, adjusting for age and sex.</p> <p>Results</p> <p>The percentage of individuals that purchased medications during a six-month period was 53.7% in the immigrant group and 79.2% in the autochthonous group. Pharmaceutical expenses and consumption were lower in immigrants than in autochthonous patients in all age groups and both genders. The relative risks of being in the highest quartile of expenditure, for Spanish-born versus immigrants, were 6.9, 95% CI = (4.2, 11.5) in men and 5.3, 95% CI = (3.5, 8.0) in women, with the reference category being not having any pharmaceutical expenditure.</p> <p>Conclusion</p> <p>Pharmaceutical expenses are much lower for immigrants with respect to autochthonous patients, both in the percentage of prescriptions filled at pharmacies and the number of containers of medication obtained, as well as the prices of the medications used. Future studies should explore which factors explain the observed differences in pharmaceutical expenses and if these disparities produce health inequalities.</p

History Shaped the Geographic Distribution of Genomic Admixture on the Island of Puerto Rico

Contemporary genetic variation among Latin Americans human groups reflects population migrations shaped by complex historical, social and economic factors. Consequently, admixture patterns may vary by geographic regions ranging from countries to neighborhoods. We examined the geographic variation of admixture across the island of Puerto Rico and the degree to which it could be explained by historic and social events. We analyzed a census-based sample of 642 Puerto Rican individuals that were genotyped for 93 ancestry informative markers (AIMs) to estimate African, European and Native American ancestry. Socioeconomic status (SES) data and geographic location were obtained for each individual. There was significant geographic variation of ancestry across the island. In particular, African ancestry demonstrated a decreasing East to West gradient that was partially explained by historical factors linked to the colonial sugar plantation system. SES also demonstrated a parallel decreasing cline from East to West. However, at a local level, SES and African ancestry were negatively correlated. European ancestry was strongly negatively correlated with African ancestry and therefore showed patterns complementary to African ancestry. By contrast, Native American ancestry showed little variation across the island and across individuals and appears to have played little social role historically. The observed geographic distributions of SES and genetic variation relate to historical social events and mating patterns, and have substantial implications for the design of studies in the recently admixed Puerto Rican population. More generally, our results demonstrate the importance of incorporating social and geographic data with genetics when studying contemporary admixed populations

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.Peer reviewe