Implementing Standard Diagnosis and Treatment for Locally Advanced Breast Cancer Through Global Research in Latin America: Results From a Multicountry Pragmatic Trial.

PURPOSE: Breast cancer mortality rates in Latin America (LA) are higher than those in the United States, possibly because of advanced disease presentation, health care disparities, or unfavorable molecular subtypes. The Latin American Cancer Research Network was established to address these challenges and to promote collaborative clinical research. The Molecular Profiling of Breast Cancer Study (MPBCS) aimed to evaluate the clinical characteristics and treatment outcomes of LA participants with locally advanced breast cancer (LABC). PATIENTS AND METHODS: The MPBCS enrolled 1,449 participants from Argentina, Brazil, Chile, Mexico, and Uruguay. Through harmonized procedures and quality assurance measures, this study evaluated clinicopathologic characteristics, neoadjuvant chemotherapy response, and survival outcomes according to residual cancer burden (RCB) and the type of surgery. RESULTS: Overall, 711 and 480 participants in the primary surgery and neoadjuvant arms, respectively, completed the 5-year follow-up period. Overall survival was independently associated with RCB (worse survival for RCBIII-adjusted hazard ratio, 8.19, P < .001, and RCBII [adjusted hazard ratio, 3.69, P < .008] compared with RCB0 [pathologic complete response or pCR]) and type of surgery (worse survival in mastectomy than in breast-conserving surgery [BCS], adjusted hazard ratio, 2.97, P = .001). The hormone receptor-negative-human epidermal growth factor receptor 2-positive group had the highest proportion of pCR (48.9%). The analysis of the ASCO Quality Oncology Practice Initiative breast module revealed high compliance with pathologic standards but lower adherence to treatment administration standards. Notably, compliance with trastuzumab administration varied widely among countries (33.3%-88.7%). CONCLUSION: In LABC, we demonstrated the survival benefit of BCS and the prognostic effect of the response to available neoadjuvant treatments despite an important variability in access to key treatments. The MPBCS represents a significant step forward in understanding the real-world implementation of oncologic procedures in LA.

Psychological factors are associated with pain extent in patients with carpal tunnel syndrome.

INTRODUCTION: Widespread pain may be related to psychosocial aspects in several musculoskeletal conditions, but the literature on carpal tunnel syndrome (CTS) is scarce. OBJECTIVE: To determine the relationship between pain extent and psychological factors (catastrophizing, kinesiophobia, anxiety symptoms, and depression) in people with CTS. METHODS: A cross-sectional study was conducted. The independent variables were: pain intensity, disability (QuickDASH), duration of symptoms, anxiety and depressive symptoms, catastrophizing, and kinesiophobia. The main outcome was: pain extent (% of total area and categories "pain within the median nerve-innervated territory" versus "extra-median nerve pain"). Correlation analysis was performed using Spearman's correlation coefficient. A linear regression model and binary logistic regression (both with forward selection) were performed to determine the main predictors of pain extent. RESULTS: Forty-eight participants were included. A moderate positive correlation was found between catastrophizing (r = 0.455; p = 0.024) and disability (r = 0.448; p = 0.024) with total pain extent area. Regression models indicated that catastrophizing explained 22% of the variance in the pain extent (ß = 0.003; 95% CI: 0.002-0.005), while kinesiophobia was the variable that best explained the distribution of pain in the extra-median territory (R2 Nagelkerke = 0.182). Null or weak correlations were found for the rest of the associations. CONCLUSION: Catastrophizing and kinesiophobia were the main indicators of pain extent in people with CTS. Clinicians are advised to use specific questionnaires to check for the presence of catastrophizing or kinesiophobia in people with CTS and wider pain extension.

Assessing subjective cognitive decline in older adults attending primary health care centers: what question should be asked?

INTRODUCTION: Subjective Cognitive Decline (SCD) refers to a self-perceived experience of decreased cognitive function without objective signs of cognitive impairment in neuropsychological tests or daily living activities. Despite the abundance of instruments addressing SCD, there is no consensus on the methods to be used. Our study is founded on 11 questions selected due to their recurrence in most instruments. The objective was to determine which one of these questions could be used as a simple screening tool. METHODS: 189 participants aged 65 and over selected from Primary Care centers in Santiago de Chile responded to these 11 questions and were evaluated with the MiniMental State Examination (MMSE), the Free and Cued Selective Reminding Test (FCSRT), the Pfeffer functional scale, and the Geriatric Depression Scale (GDS). An Item ResponseTheory (IRT) method was performed to assess the contribution of each of the 11 questions to the SCD latent trait and its discrimination ability. RESULTS: Based on the results of the exploratory factor analysis showing very high/low saturation of several questions on the factors, and the high residual correlation between some questions, the IRT methods led to select one question ("Do you feel like your memory has become worse?") which revealed to be the most contributive and discriminant. Participants who answered yes had a higher GDS score. There was no association with MMSE, FCSRT, and Pfeffer scores. CONCLUSION: The question "Do you feel like your memory has become worse?" may be a good proxy of SCD and could be included in routine medical checkups.

A computational framework for testing hypotheses of the minimal mechanical requirements for cell aggregation using early annual killifish embryogenesis as a model.

Introduction: Deciphering the biological and physical requirements for the outset of multicellularity is limited to few experimental models. The early embryonic development of annual killifish represents an almost unique opportunity to investigate de novo cellular aggregation in a vertebrate model. As an adaptation to seasonal drought, annual killifish employs a unique developmental pattern in which embryogenesis occurs only after undifferentiated embryonic cells have completed epiboly and dispersed in low density on the egg surface. Therefore, the first stage of embryogenesis requires the congregation of embryonic cells at one pole of the egg to form a single aggregate that later gives rise to the embryo proper. This unique process presents an opportunity to dissect the self-organizing principles involved in early organization of embryonic stem cells. Indeed, the physical and biological processes required to form the aggregate of embryonic cells are currently unknown. Methods: Here, we developed an in silico, agent-based biophysical model that allows testing how cell-specific and environmental properties could determine the aggregation dynamics of early Killifish embryogenesis. In a forward engineering approach, we then proceeded to test two hypotheses for cell aggregation (cell-autonomous and a simple taxis model) as a proof of concept of modeling feasibility. In a first approach (cell autonomous system), we considered how intrinsic biophysical properties of the cells such as motility, polarity, density, and the interplay between cell adhesion and contact inhibition of locomotion drive cell aggregation into self-organized clusters. Second, we included guidance of cell migration through a simple taxis mechanism to resemble the activity of an organizing center found in several developmental models. Results: Our numerical simulations showed that random migration combined with low cell-cell adhesion is sufficient to maintain cells in dispersion and that aggregation can indeed arise spontaneously under a limited set of conditions, but, without environmental guidance, the dynamics and resulting structures do not recapitulate in vivo observations. Discussion: Thus, an environmental guidance cue seems to be required for correct execution of early aggregation in early killifish development. However, the nature of this cue (e.g., chemical or mechanical) can only be determined experimentally. Our model provides a predictive tool that could be used to better characterize the process and, importantly, to design informed experimental strategies.

The limitations and challenges in the assessment of executive dysfunction associated with real-world functioning: The opportunity of serious games.

Nowadays, there is a broad range of methods for detecting and evaluating executive dysfunction ranging from clinical interview to neuropsychological evaluation. Nevertheless, a critical issue of these assessments is the lack of correspondence of the neuropsychological test's results with real-world functioning. This paper proposes serious games as a new framework to improve the neuropsychological assessment of real-world functioning. We briefly discuss the contribution and limitations of current methods of evaluation of executive dysfunction (paper-and-pencil tests, naturalistic observation methods, and Information and Communications Technologies) to inform on daily life functioning. Then, we analyze what are the limitations of these methods to predict real-world performance: (1) A lack of appropriate instruments to investigate the complexity of real-world functioning, (2) the vast majority of neuropsychological tests assess well-structured tasks, and (3) measurement of behaviors are based on simplistic data collection and statistical analysis. This work shows how serious games offer an opportunity to develop more efficient tools to detect executive dysfunction in everyday life contexts. Serious games provide meaningful narrative stories and virtual or real environments that immerse the user in natural and social environments with social interactions. In those highly interactive game environments, the player needs to adapt his/her behavioral performance to novel and ill-structured tasks which are suited for collecting user interaction evidence. Serious games offer a novel opportunity to develop better tools to improve diagnosis of the executive dysfunction in everyday life contexts. However, more research is still needed to implement serious games in everyday clinical practice.

Palmitic acid control of ciliogenesis modulates insulin signaling in hypothalamic neurons through an autophagy-dependent mechanism.

Palmitic acid (PA) is significantly increased in the hypothalamus of mice, when fed chronically with a high-fat diet (HFD). PA impairs insulin signaling in hypothalamic neurons, by a mechanism dependent on autophagy, a process of lysosomal-mediated degradation of cytoplasmic material. In addition, previous work shows a crosstalk between autophagy and the primary cilium (hereafter cilium), an antenna-like structure on the cell surface that acts as a signaling platform for the cell. Ciliopathies, human diseases characterized by cilia dysfunction, manifest, type 2 diabetes, among other features, suggesting a role of the cilium in insulin signaling. Cilium depletion in hypothalamic pro-opiomelanocortin (POMC) neurons triggers obesity and insulin resistance in mice, the same phenotype as mice deficient in autophagy in POMC neurons. Here we investigated the effect of chronic consumption of HFD on cilia; and our results indicate that chronic feeding with HFD reduces the percentage of cilia in hypothalamic POMC neurons. This effect may be due to an increased amount of PA, as treatment with this saturated fatty acid in vitro reduces the percentage of ciliated cells and cilia length in hypothalamic neurons. Importantly, the same effect of cilia depletion was obtained following chemical and genetic inhibition of autophagy, indicating autophagy is required for ciliogenesis. We further demonstrate a role for the cilium in insulin sensitivity, as cilium loss in hypothalamic neuronal cells disrupts insulin signaling and insulin-dependent glucose uptake, an effect that correlates with the ciliary localization of the insulin receptor (IR). Consistently, increased percentage of ciliated hypothalamic neuronal cells promotes insulin signaling, even when cells are exposed to PA. Altogether, our results indicate that, in hypothalamic neurons, impairment of autophagy, either by PA exposure, chemical or genetic manipulation, cause cilia loss that impairs insulin sensitivity.

Automatic language analysis identifies and predicts schizophrenia in first-episode of psychosis.

Automated language analysis of speech has been shown to distinguish healthy control (HC) vs chronic schizophrenia (SZ) groups, yet the predictive power on first-episode psychosis patients (FEP) and the generalization to non-English speakers remain unclear. We performed a cross-sectional and longitudinal (18 months) automated language analysis in 133 Spanish-speaking subjects from three groups: healthy control or HC (n = 49), FEP (n = 40), and chronic SZ (n = 44). Interviews were manually transcribed, and the analysis included 30 language features (4 verbal fluency; 20 verbal productivity; 6 semantic coherence). Our cross-sectional analysis showed that using the top ten ranked and decorrelated language features, an automated HC vs SZ classification achieved 85.9% accuracy. In our longitudinal analysis, 28 FEP patients were diagnosed with SZ at the end of the study. Here, combining demographics, PANSS, and language information, the prediction accuracy reached 77.5% mainly driven by semantic coherence information. Overall, we showed that language features from Spanish-speaking clinical interviews can distinguish HC vs chronic SZ, and predict SZ diagnosis in FEP patients.

Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women.

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher's exact tests and the OS by Kaplan-Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (≥60 years) (1.84) compared with younger (≤40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.

The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients.

Purposes: Most molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches. Patients and Methods: We collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes. Results: PAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors. Conclusions: This is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America. Clinical Trial Registration: ClinicalTrials.gov (Identifier: NCT02326857).

Geometrical characterization of active contraction pulses in epithelial cells using the two-dimensional vertex model.

Several models have been proposed to describe the dynamics of epithelial tissues undergoing morphogenetic changes driven by apical constriction pulses, which differ in where the constriction is applied, either at the perimeter or in the medial regions. To help discriminate between these models, we analyse the impact of where constriction is applied on the final geometry of the active contracted cell, using the two-dimensional vertex model. We find that medial activity, characterized by a reduction in the reference area, generates anisotropic cell shapes, whereas isotropic cell shapes are produced when the reference perimeter is reduced. When plasticity is included, sufficiently slow processes of medial contractile activity, compared with the characteristic times of elasticity and plasticity, cells can achieve less elongated shapes. Similarly, for perimeter activity, the highest level of contraction is achieved. Finally, we apply the model to describe the apical contractile pulses observed within the epithelial enveloping cell layer during the pre-epiboly of the annual killifish Austrolebias nigripinnis. The analysis of the cell shape changes allowed a global fit of all parameters of the vertex model, with the pulses being quantitatively captured using perimeter activity and area plasticity.

The dendritic ERGIC: Microtubule and actin cytoskeletons participate in stop-and-go movement of mobile carriers between stable structures.

The endoplasmic reticulum (ER)-to-Golgi intermediate compartment (ERGIC) is a membranous organelle that mediates protein transport between the ER and the Golgi apparatus. In neurons, clusters of these vesiculotubular structures are situated throughout the cell in proximity to the ER, passing cargo to the cis-Golgi cisternae, located mainly in the perinuclear region. Although ERGIC markers have been identified in neurons, the distribution and dynamics of neuronal ERGIC structures have not been characterized yet. Here, we show that long-distance ERGIC transport occurs via an intermittent mechanism in dendrites, with mobile elements moving between stationary structures. Slow and fast live-cell imaging have captured stable ERGIC structures remaining in place over long periods of time, as well as mobile ERGIC structures advancing very short distances along dendrites. These short distances have been consistent with the lengths between the stationary ERGIC structures. Kymography revealed ERGIC elements that moved intermittently, emerging from and fusing with stationary ERGIC structures. Interestingly, this movement apparently depends not only on the integrity of the microtubule cytoskeleton, as previously reported, but on the actin cytoskeleton as well. Our results indicate that the dendritic ERGIC has a dual nature, with both stationary and mobile structures. The neural ERGIC network transports proteins via a stop-and-go movement in which both the microtubule and the actin cytoskeletons participate.

Adaptación de una metodología de especificaciones en la calificación y retroalimentación en la enseñanza de cursos de ciencias básicas en una carrera de la salud para mejorar los aprendizajes y la motivación / Adaptation of a specifications gradings and feedback methodology for basic sciences courses teaching in a health science career to improving learning and motivation

Introducción: la enseñanza de cursos de ciencias básicas en carreras de la salud es un desafío por no estar directa e inmediatamente rela-cionada con el ámbito profesional. Por otra parte, las condiciones de estrés que ha impuesto el trabajo a distancia requiere de metodologías motivantes, y, que a su vez permitan una evaluación significativa. Objetivos: reportar las adaptaciones metodológicas y los resultados de una adaptación local de la metodología de especificaciones de las calificaciones y retroalimentación del trabajo. Métodos: se aplica una metodología de formación basada en la retroalimentación en el curso de Física para estudiantes de Tecnología Médica (N=106) durante un semestre. Las calificaciones promedio de los estudiantes fueron comparadas con las obtenidas en años anteriores. Para evaluar el desempeño docente se realizaron 2 encuestas a los estudiantes. El cumplimiento de los logros de aprendizaje se midió mediante auto-evaluación (escala likert 1 a 5) al inicio y término de cada uno de los cuatro capítulos. Resultados: las reprobaciones y eliminaciones de estudiantes en el curso fueron menores a años anteriores, siendo las notas significativamente mayores subiendo desde 4,89 a 6,29 (escala de 1 a 7, p<0,001). Los estudiantes se mostraron en un 95% satisfechos con el desempeño docente y finalmente, la auto-evaluación de logros de aprendizaje mostró un aumento promedio de 1 punto. Conclusiones: la metodología de evaluación basada en especificaciones adaptada a dos entregas y con evaluaciones en una escala no-binaria mejoró el rendimiento, los logros de los aprendizajes esperados y la motivación de los estudiantes.

Background: Teaching basic science courses in health careers is a challenge because these courses are not directly linked to professional practice. On the other hand, the stressful conditions imposed by distance work require motivating methodologies and a meaningful evaluation. Objectives: To report the methodological adaptations and the results of a local adaptation of the specifications grading and feedback methodology. Methods: A training methodology based on feedback is applied in the Physics course for Medical Technology students (N = 106) during one semester. We compared the students' average grades to those obtained in previous years with the same topics. To evaluate the teaching performance, we conducted two student surveys. We measure compliance with learning achievements by self-assessment (Likert scale 1 to 5) at the beginning and end of each of the four chapters. Results: Failures and eliminations of students in the course were lower than previous years, with significantly higher grades from 4.89 to 6.29 (p <0.001). The students were 95% satisfied with the teaching performance, and finally, the self-evaluation of learning achievements showed an average increase of 1 point. Conclusion: The evaluation methodology based on specifications adapted to two deliveries and evaluations on a non-binary scale improved the performance, expected learning achievements, and students' motivation.

Qualitative ultrasonography scale of the intensity of local twitch response during dry needling and its association with modified joint range of motion: a cross-sectional study.

BACKGROUND: The relevance of local twitch response (LTR) during dry needling technique (DNT) is controversial, and it is questioned whether LTR is necessary for successful outcomes. Furthermore, because the LTR during the deep DNT may be evoked with different intensities, it is unknown whether the magnitude of LTR intensity is associated with optimal clinical results, especially concerning to the effects of joint maximal range of motion (ROM). This study aimed to (i) determine whether visual inspections can quantify the LTR intensity during the DNT through a qualitative ultrasonography scale of LTR intensity (US-LTR scale), and (ii) assess the differences of US-LTR scale associated with changes in the maximal joint ROM. METHODS: Using a cross-sectional design, seven asymptomatic individuals were treated with DNT in the latent myofascial trigger point in both medial gastrocnemius muscles. During DNT, three consecutive LTRs were collected. The US-LTR scale was used to classify the LTRs into strong, medium, and weak intensities. The categories of US-LTR were differentiated by the velocity of LTRs using the optical flow algorithm. ROM changes in ankle dorsiflexion and knee extension were assessed before and immediately after DNT. RESULTS: The US-LTR scale showed the third LTR was significantly smaller than the first one (p < 0.05). A significant difference in velocity was observed between US-LTR categories (p < 0.001). A significant difference in the ROM was observed between the strong and weak-medium intensity (p < 0.05). CONCLUSIONS: The present findings suggest that the LTR intensity can be assessed using a qualitative US-LTR scale, and the effects of DNT on joint maximal ROM is maximized with higher LTR intensity. This study reports a novel qualitative method for LTR analysis with potential applications in research and clinical settings. However, further research is needed to achieve a broader application.

RyR-mediated Ca2+ release elicited by neuronal activity induces nuclear Ca2+ signals, CREB phosphorylation, and Npas4/RyR2 expression.

The expression of several hippocampal genes implicated in learning and memory processes requires that Ca2+ signals generated in dendritic spines, dendrites, or the soma in response to neuronal stimulation reach the nucleus. The diffusion of Ca2+ in the cytoplasm is highly restricted, so neurons must use other mechanisms to propagate Ca2+ signals to the nucleus. Here, we present evidence showing that Ca2+ release mediated by the ryanodine receptor (RyR) channel type-2 isoform (RyR2) contributes to the generation of nuclear Ca2+ signals induced by gabazine (GBZ) addition, glutamate uncaging in the dendrites, or high-frequency field stimulation of primary hippocampal neurons. Additionally, GBZ treatment significantly increased cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation-a key event in synaptic plasticity and hippocampal memory-and enhanced the expression of Neuronal Per Arnt Sim domain protein 4 (Npas4) and RyR2, two central regulators of these processes. Suppression of RyR-mediated Ca2+ release with ryanodine significantly reduced the increase in CREB phosphorylation and the enhanced Npas4 and RyR2 expression induced by GBZ. We propose that RyR-mediated Ca2+ release induced by neuronal activity, through its contribution to the sequential generation of nuclear Ca2+ signals, CREB phosphorylation, Npas4, and RyR2 up-regulation, plays a central role in hippocampal synaptic plasticity and memory processes.

Perioperative chemotherapy in locally advanced gastric cancer in Chile: from evidence to daily practice.

Gastric cancer (GC) is a leading cause of cancer death in Chile. Although recommended in international guidelines since 2006, perioperative chemotherapy was not available to patients in the public health system in Chile until 2016. We conducted an observational study to assess the feasibility of this strategy in public hospitals in Chile (Observational Study of Perioperative Chemotherapy in Locally Advanced Gastric Cancer - PRECISO). Patients with locally advanced, operable GC were offered to receive preoperative chemotherapy with Epirubicin + Cisplatin + Capecitabine (ECX) for three cycles followed by curative surgery. Staging included abdominal CT scan and laparoscopy if peritoneal carcinomatosis was suspected. Postoperative ECX for three cycles was recommended. Between August 2010 and March 2013, 110 patients were screened and 61 enrolled. Median age was 62 years (23-76 years) and most patients had good performance status at baseline (Eastern Cooperative Oncology Group performance status score (ECOG) 0: 42, ECOG 1: 19). Tumour site was proximal in 32 (52%) and medial and distal in 29 (48%) patients. All but four patients (n = 57, 93%) completed three cycles of preoperative chemotherapy. Fifty-six patients were operated and 54 (89%) had a curative resection. Thirty-three patients (54%) had pT0-2, and 18 (30%) had pN0 tumours, with two patients achieving a complete response. As of 20 December 2020, 39 patients died, 32 due to GC, one within 30 days of surgery, two due to intestinal obstruction at 5 and 3 months after surgery and four due to other causes. Five-year survival rate was 38%. We conclude that perioperative chemotherapy is feasible in public hospitals in Chile and should be offered to patients with locally advanced GC.

Junctional ER Organization Affects Mechanotransduction at Cadherin-Mediated Adhesions.

Cadherin-mediated adhesions (also known as adherens junctions) are adhesive complexes that connect neighboring cells in a tissue. While the role of the actin cytoskeleton in withstanding tension at these sites of contact is well documented, little is known about the involvement of microtubules and the associated endoplasmic reticulum (ER) network in cadherin mechanotransduction. Therefore, we investigated how the organization of ER extensions in close proximity of cadherin-mediated adhesions can affect such complexes, and vice versa. Here, we show that the extension of the ER to cadherin-mediated adhesions is tension dependent and appears to be cadherin-type specific. Furthermore, the different structural organization of the ER/microtubule network seems to affect the localization of ER-bound PTP1B at cadherin-mediated adhesions. This phosphatase is involved in the modulation of vinculin, a molecular clutch which enables differential engagement of the cadherin-catenin layer with the actomyosin cytoskeleton in response to tension. This suggests a link between structural organization of the ER/microtubule network around cadherin-specific adhesions, to control the mechanotransduction of adherens junctions by modulation of vinculin conformational state.

Exergames and Telerehabilitation on Smartphones to Improve Balance in Stroke Patients.

Stroke is currently the world's second cause of disability. It can cause deficits such as postural control, and telerehabilitation could improve the therapeutic dose as well as functional results. The aim of this work is to determine the effectiveness and usability of a low-cost telerehabilitation system in patients with stroke. We developed a telerehabilitation system based on exergames on smartphones, inertial sensors, and a cloud database. We trained the balance of six participants (three men and three women) in early subacute stroke (seven weeks of progress). In addition to their conventional treatment, these participants trained for a total of nine sessions of 30 min per week, for four weeks. The telerehabilitation group was compared with a control group of four clinically similar participants (three men and one woman). Clinical and usability measurements were made before and after the training. The results show a significant improvement of 11.3 ± 3.5 points in the Berg Balance Scale, 8.3 ± 3.01 points in the Mini-BESTest, and 17.5 ± 9.87 points in the Barthel scale for the telerehabilitation group. However, only the improvements of Berg and Barthel scales were statistically higher for the telerehabilitation group compared to the control group. The proposed system achieved excellent usability on the System Usability Scale (87.5 ± 11.61). Our results demonstrate that a complementary low-cost telemedicine approach is feasible, and that it can significantly improve the balance of stroke patients; therefore, the proposed clinical strategy could potentially improve dosage and overall treatment effectiveness.

Aquatic community structure as sentinel of recent environmental changes unraveled from lake sedimentary records from the Atacama Desert, Chile.

The Atacama Desert (21-26°S) is currently one of the driest places on Earth and metal(loid)s are of special concern for this region, which hosts the largest-known porphyry copper deposits produced in Chile. Evidence of past environmental conditions is commonly preserved in natural archives, such as lacustrine sediments. Sediment records obtained from Inca Coya Lake (22°20'S-68°35'W, 2534 m.a.s.l.), a small lake located in the Atacama Desert, reflected the evolution of regional mining activity during the 20th century and sedimentation associated with decadal climate variability. We studied the aquatic community structure changes recorded in sediment records from Inca Coya Lake. By analysis of magnetic properties (susceptibility, hysteresis curves and Curie temperatures), grain size and geochemical composition of the sediments, we identified environmental periods and changes in the community of benthic and planktonic organisms (diatoms and diapausing egg bank). We identified three detrital episodes that we interpret as dry/wet phases during the last 90 years associated with the increase of flash flood events promoting hypoxia oscillations; anthropogenic (mining activity) signals were also identified. Invertebrate community structure (primary consumers) reflected the metal exposure, measured as changes in assemblage composition through species turnover. Diatom community composition was best associated with variables related to wetter/drier alternation and consequent changes in oxygen availability. Bioindicators analyzed (diatoms, diapausing egg bank and invertebrate community) demonstrated to be excellent indicators of the bioavailability of compounds in the aquatic ecosystem of Inca Coya Lake, allowing the environmental impact assessment of the water resources due to flash floods and mining activity in the driest desert of the world.

Chronic Fluoxetine Treatment Induces Maturation-Compatible Changes in the Dendritic Arbor and in Synaptic Responses in the Auditory Cortex.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) used to treat mood and anxiety disorders. Chronic treatment with this antidepressant drug is thought to favor functional recovery by promoting structural and molecular changes in several forebrain areas. At the synaptic level, chronic fluoxetine induces an increased size and density of dendritic spines and an increased ratio of GluN2A over GluN2B N-methyl-D-aspartate (NMDA) receptor subunits. The "maturation"-promoting molecular changes observed after chronic fluoxetine should also induce structural remodeling of the neuronal dendritic arbor and changes in the synaptic responses. We treated adult rats with fluoxetine (0.7 mg/kg i.p. for 28 days) and performed a morphometric analysis using Golgi stain in limbic and nonlimbic cortical areas. Then, we focused especially on the auditory cortex, where we evaluated the dendritic morphology of pyramidal neurons using a 3-dimensional reconstruction of neurons expressing mRFP after in utero electroporation. With both methodologies, a shortening and decreased complexity of the dendritic arbors was observed, which is compatible with an increased GluN2A over GluN2B ratio. Recordings of extracellular excitatory postsynaptic potentials in the auditory cortex revealed an increased synaptic response after fluoxetine and were consistent with an enrichment of GluN2A-containing NMDA receptors. Our results confirm that fluoxetine favors maturation and refinement of extensive cortical networks, including the auditory cortex. The fluoxetine-induced receptor switch may decrease GluN2B-dependent toxicity and thus could be applied in the future to treat neurodegenerative brain disorders characterized by glutamate toxicity and/or by an aberrant network connectivity.

Publisher Correction: Cdh2 coordinates Myosin-II dependent internalisation of the zebrafish neural plate.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.