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The increasing burden of cancer represents a substantial problem for Latin America and the Caribbean. Two Lancet Oncology Commissions in 2013 and 2015 highlighted potential interventions that could advance cancer care in the region by overcoming existing challenges. Areas requiring improvement included insufficient investment in cancer control, non-universal health coverage, fragmented health systems, inequitable concentration of cancer services, inadequate registries, delays in diagnosis or treatment initiation, and insufficient palliative services. Progress has been made in key areas but remains uneven across the region. An unforeseen challenge, the COVID-19 pandemic, strained all resources, and its negative effect on cancer control is expected to continue for years. In this Series paper, we summarise progress in several aspects of cancer control since 2015, and identify persistent barriers requiring commitment of additional resources to reduce the cancer burden in Latin America and the Caribbean.

BACKGROUND Late recurrences in postmenopausal women with hormone receptor-positive breast cancers remain an important challenge. Avoidance or delayed development of resistance represents the main objective in extended endocrine therapy (ET). In animal models, resistance was reversed with restoration of circulating estrogen levels during interruption of letrozole treatment. This phase III, randomized, open-label Study of Letrozole Extension (SOLE) studied the effect of extended intermittent letrozole treatment in comparison with continuous letrozole. In parallel, the SOLE estrogen substudy (SOLE-EST) analyzed the levels of estrogen during the interruption of treatment. PATIENTS AND METHODS SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012 and among them, 104 patients were enrolled in SOLE-EST. They must have undergone local treatment and have completed 4-6 years of adjuvant ET. Patients were randomized between continuous letrozole (2.5 mg/day orally for 5 years) and intermittent letrozole treatment (2.5 mg/day for 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during all of year 5). RESULTS Intention-to-treat population included 4851 women in SOLE (n��= 2425 in the intermittent and n��= 2426 in the continuous letrozole groups) and 103 women in SOLE-EST (n��= 78 in the intermittent and n��= 25 in the continuous letrozole groups). After a median follow-up of 84 months, 7-year disease-free survival (DFS) was 81.4% in the intermittent group and 81.5% in the continuous group (hazard ratio: 1.03, 95% confidence interval: 0.91-1.17). Reported adverse events were similar in both groups. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment. CONCLUSIONS Extended adjuvant ET by intermittent administration of letrozole did not improve DFS compared with continuous use, despite the recovery of circulating estrogen levels. The similar DFS coupled with previously reported quality-of-life advantages suggest intermittent extended treatment is a valid option for patients who require or prefer a treatment interruption.

We investigated the development of general teachers' and special education teachers' cooperation in teaching dyads in inclusive classes. At the beginning, the middle, and the end of the school year, 13 dyads reported on their cooperation behavior and 184 students rated their perception of these teaching dyads' cooperation. Multilevel analysis revealed no change in cooperation behavior for general and special education teachers. No reciprocal effects between the dyad members' cooperation behavior occurred. Students' perception of the dyadic cooperation decreased. The results indicate that the dyad members failed to harmonize as an effective teaching dyad.

In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women.We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing.Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [1%] vs seven [1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (1%) of 4851 patients died while on trial treatment (13 [1%] of 2417 patients in the intermittent letrozole group vs ten [1%] of 2411 in the continuous letrozole group).In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them.Novartis and the International Breast Cancer Study Group.

This study examined the effects of a syllable-based reading intervention for German second graders who demonstrated difficulties in the recognition of written words. The intervention focused on fostering word reading via syllable segmentation. The materials consisted of the 500 most frequent syllables typically read by 6- to 8-year-old children. The aims were to practice phonological recoding, consolidate orthographic representations of syllables, and routinize the access to these representations. Compared to children randomly assigned to a wait-list group, poor readers in the treatment condition showed significant improvements in standardized measures of phonological recoding, direct word recognition, and text-based reading comprehension after the 24-session intervention. Poor readers in the treatment condition also showed greater improvements in development of word recognition compared to children with efficient word recognition skills. The results provide evidence that a syllable-based reading intervention is a promising approach to increase struggling readers’ word recognition skills, which in turn will improve their reading comprehension.

Background: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence. Methods: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication. Results: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low. Conclusion: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs. Fil: Boekstegers, Felix. Ruprecht Karls Universitat Heidelberg; Alemania Fil: Marcelain, Katherine. Universidad de Chile; Chile Fil: Barahona Ponce, Carol. Ruprecht Karls Universitat Heidelberg; Alemania. Universidad de Chile; Chile Fil: Baez Benavides, Pablo F.. Universidad de Chile; Chile Fil: Müller, Bettina. Instituto Nacional del Cáncer, Chile; Chile Fil: de Toro, Gonzalo. Hospital Puerto Montt; Chile Fil: Retamales, Javier. Instituto Nacional del Cáncer, Chile; Chile Fil: Barajas, Olga. Hospital Clinico de la Universidad de Chile; Chile. Universidad de Chile; Chile Fil: Ahumada, Monica. Hospital Clínico de la Universidad de Chile; Chile. Universidad de Chile; Chile Fil: Morales, Erik. Regional Hospital; Chile Fil: Rojas, Armando. Universidad Catolica de Maule; Chile Fil: Sanhueza, Verónica. Hospital Padre Hurtado; Chile Fil: Loader, Denisse. Hospital Padre Hurtado; Chile Fil: Rivera, María Teresa. Hospital del Salvador; Chile Fil: Gutiérrez, Lorena. Hospital San Juan de Dios, Santiago de Chile; Chile Fil: Bernal, Giuliano. Universidad Católica del Norte; Chile Fil: Ortega, Alejandro. Hospital Regional, Arica; Chile Fil: Montalvo, Domingo. Hospital Regional de Arica Doctor Juan Noé Crevani; Chile Fil: Portiño, Sergio. Hospital Clinico de la Universidad de Chile; Chile Fil: Bertrán, Maria Enriqueta. Ministerio de Salud, Valdivia; Chile Fil: Gabler, Fernando. Universidad de Santiago de Chile. Hospital Clinico San Borja Arriaran; Chile Fil: Spencer, Loreto. Hospital Regional de Concepción - Dr. Guillermo Grant Benavente; Chile Fil: Olloquequi, Jordi. Universidad Autónoma de Chile; Chile Fil: González Silos, Rosa. Ruprecht Karls Universitat Heidelberg; Alemania Fil: Fischer, Christine. Ruprecht Karls Universitat Heidelberg; Alemania Fil: Scherer, Dominique. Ruprecht Karls Universitat Heidelberg; Alemania Fil: Jenab, Mazda. International Agency for Research on Cancer; Francia Fil: Aleksandrova, Krasimira. Universitat Potsdam; Alemania Fil: Katzke, Verena. German Cancer Research Center; Alemania Fil: Gonzalez-jose, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; Argentina Fil: Weiderpass, Elisabete. International Agency for Research on Cancer; Francia Fil: Moradi, Tahereh. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Fischer, Krista. University of Tartu; Estonia Fil: Bossers, Willem. Lifelines Cohort Study; Países Bajos Fil: Brenner, Hermann. German Cancer Research Center; Alemania Fil: Hveem, Kristian. Norges Teknisk naturvitenskapelige Universitet; Noruega Fil: Eklund, Niina. National Institute For Health And Welfare; Finlandia Fil: Völker, Uwe. Universitätsmedizin Greifswald; Alemania Fil: Waldenberger, Melanie. Helmholtz Center Munich German Research Center For Environmental Health; Alemania Fil: Fuentes Guajardo, Macarena. Universidad de Tarapaca.; Chile Fil: Bedoya, Gabriel. Universidad de Antioquia; Colombia Fil: Bortolini, Maria C.. Universidade Federal do Rio Grande do Sul; Brasil Fil: Canizales, Samuel. Universidad Nacional Autónoma de México; México Fil: Gallo, Carla. Universidad Peruana Cayetano Heredia; Perú Fil: Ruiz Linares, Andres. Fudan University; China Fil: Rothhammer, Francisco. Universidad de Tarapaca.; Chile Fil: Lorenzo Bermejo, Justo. Ruprecht Karls Universitat Heidelberg; Alemania

From a cognitive perspective, efficient word recognition processes are essential for the development of reading comprehension skills in primary school. In contrast, reading interventions are commonly evaluated for struggling readers as a group without assessing the influence of the students' word recognition efficiency. In this study, we followed an aptitude-treatment interaction approach to investigate the extent that the effectiveness of a reading strategy training for second graders with poor ( n = 119) and good reading comprehension ( n = 116) depends on the students' word reading skills. Compared with children randomly assigned to a control group, only poor readers with routinized word recognition benefited from the intervention, whereas the training was even harmful for poor readers with inefficient word recognition processes. Good comprehenders benefited from the training independently of their word reading efficiency. Hence, reading strategy interventions for poor readers should be implemented in consideration of the students' word recognition skills.

The extent of syntrophic acetate oxidation (SAO) and the levels of known SAO bacteria and acetate- and hydrogen-consuming methanogens were determined in sludge from 13 commercial biogas production plants. Results from these measurements were statistically related to the prevailing operating conditions, through partial least squares (PLS) analysis. This revealed that high abundance of microorganisms involved in SAO was positively correlated with relatively low abundance of aceticlastic methanogens and high concentrations of free ammonia (>160 mg/L) and volatile fatty acids (VFA). Temperature was identified as another influencing factor for the population structure of the syntrophic acetate oxidising bacteria (SAOB). Overall, there was a high abundance of SAOB in the different digesters despite differences in their operating parameters, indicating that SAOB are an enduring and important component of biogas-producing consortia.

One of the most consistent findings in postmortem studies of schizophrenia is increased GABAA receptor binding and reduced glutamic acid decarboxylase (GAD67) expression. Due to long-term antipsychotic treatment before death, these findings may reflect not only the consequences of schizophrenia but also medication effects. To differentiate between these options, we used an animal model and evaluated long-term effects of typical (haloperidol) and atypical (clozapine) antipsychotic drugs on the GABAergic system. A total of 33 adult male rats were treated in three cohorts over a period of 6 months. One cohort of 11 animals received clozapine (45 mg/kg/day), another one received haloperidol (1.5 mg/kg/day) and a third one received pH-adapted minimal concentrations of HCl in the drinking water. Receptor autoradiography of the GABAA receptor ([3H]-muscimol binding) and in situ hybridization in adjacent sections with 35S-labeled cRNA probes of the y-aminobutyric acid (GABA)-producing enzyme, GAD67, was performed. While haloperidol increased GABAA receptor binding in striatum and nucleus accumbens (NA), it suppressed GABAA receptor binding in temporal (TEMPC) and parietal (PARC) cortex. Clozapine induced GABAA receptor binding in infralimbic cortex (ILC) and similar like haloperidol in anterior cingulate cortex (ACC), two regions of the limbic cortex. In addition, either drug increased gene expression of GAD67. It is concluded that antipsychotic drugs differentially alter the GABAergic system, strongly suggesting that drug effects are partially responsible for the up-regulation of GABAA receptor binding in certain brain regions as observed in postmortem brains of schizophrenic patients. However, the reduced GAD67 expression seen in postmortem brains does not appear to reflect drug effects, since our animal model demonstrated increased gene expression.

The synapse-associated proteins SAP97 and SAP102 are mammalian proteins that are structurally related to the Drosophila tumor suppressor protein DlgA. Previous analyses revealed that DlgA is essential for the integrity of epithelia and neuromuscular synapses. Here we show that synaptic bouton structure is severely affected in mutant larvae carrying the dlg-1 XI-2 allele. We have tested SAP97 and SAP102 for functional homology to DlgA by heterologous expression in Drosophila . Both SAP97 and SAP102 can suppress tumor formation in dlg-1 mutant flies and mimic DlgA at larval neuromuscular junctions. Neuronal expression of SAP97 or SAP102 is required for morphological restoration of synaptic boutons, indicating that presynaptic DlgA function is essential for establishing structurally intact motor nerve terminals at larval neuromuscular junctions.

Synapse-associated proteins (SAPs) are constituents of the pre- and postsynaptic submembraneous cytomatrix. Here, we present SAP102, a novel 102 kDa SAP detected in dendritic shafts and spines of asymmetric type 1 synapses. SAP102 is enriched in preparations of synaptic junctions, where it biochemically behaves as a component of the cortical cytoskeleton. Antibodies directed against NMDA receptors coimmunoprecipitate SAP102 from rat brain synaptosomes. Recombinant proteins containing the carboxy-terminal tail of NMDA receptor subunit NR2B interact with SAP102 from rat brain homogenates. All three PDZ domains in SAP102 bind the cytoplasmic tail of NR2B in vitro. These data represent direct evidence that in vivo SAP102 is involved in linking NMDA receptors to the submembraneous cytomatrix associated with postsynaptic densities at excitatory synapses.

HuD belongs to a family of neurospecific RNA binding proteins found in man, frog and fly [49]. To investigate whether this protein is involved in regulation of neuronal differentiation of rodent cells in vivo and in vitro, the cDNA of the rat homolog gene (r-HuD) was cloned, its expression was studied in rat brain and in neurogenic cell lines, and the splicing of its RNA was analyzed. Coding sequences of HuD from man and rat were found to be 99.5 and 95% identical at protein and DNA level, respectively. In rat brain r-HuD transcripts 3.7 and 4.2 kb in length were detected by Northern blot analysis. RT-PCR and in situ hybridization revealed that rodent homologues of HuD transcripts are present in P19 mouse embryo carcinoma and in PC12 rat pheochromocytoma cell lines both able to differentiate into neurons. In contrast, r-HuD transcripts were not detectable in the rat glioma cell line C6. In P19 cells a strong induction of HuD mRNA was observed after triggering neuronal differentiation by retinoic acid, whereas in PC12 cells the mRNA was present before and after nerve growth factor (NGF) induced neuronal differentiation. In both neuronal cell lines and in brain of adult rat and mouse HuD mRNA is alternatively spliced in a region which encodes a proline rich linker domain between the second and third RNA recognition motif. This RNA processing event seems to be differently regulated in PC12 cells on the one hand, and in P19 cells and brain of rat and mouse on the other.

This paper empirically studies the impact of the adoption of open source software (OSS) on firms' labor productivity and innovative behavior. Using a representative sample of German firms, the results show that the adoption of OSS operating systems for servers and general OSS applications has no impact on firm level labor productivity, while the adoption of OSS operating systems for PCs impacts labor productivity negatively. This result points to the costs associated with the implementation of open source software. Moreover, the analysis shows that the adoption of OSS operating systems for PCs has a positive effect on the value of introduced process innovations, suggesting efficiency gains by adopting a tailored ICT infrastructure. These benefits might explain the positive correlation observed between OSS operating systems for servers and PCs, and firms' R&D intensities.

In this paper, I analyse how the survival of new firms is affected by the average ability level in the founding team, the team size, team members' homogeneity with respect to ability, and team members' heterogeneity with respect to education. As a theoretical basis, I apply the O-ring theory (Kremer (1993)). Using a rich employer-employee data set on the whole population of Danish firms founded in 1998, I find that the average ability level in a team and the team size have positive effects on firm survival. Having a team at all is the most crucial factor for the probability of survival of young firms. The degree of homogeneity with respect to ability and the degree of heterogeneity with respect to educations have no effect on the survival probability.

La structure de la phase stationnaire chirale est presentee. Elle est utilisee pour la separation des enantiomeres de differents acides amines