Cuando el carcinoma de tiroides no es indolente: carcinoma de alto grado derivado del epitelio folicular / When Thyroid Carcinoma is not Indolent: High-Grade Carcinoma Derived From The Follicular Epithelium

Los carcinomas de tiroides derivados de células foliculares de alto grado (HGFDTC) son tumores poco frecuentes con un pronóstico intermedio entre carcinomas tiroideos bien diferenciados y anaplásicos. La clasificación de la OMS más reciente identifica dos tipos distintos de HGFDTC: 1) carcinoma de tiroides mal diferenciado (arquitectura sólida, trabecular o insular, falta de características nucleares de núcleos nucleares papilares y contorneados, necrosis mitosis (≥3/2mm2), y 2 ) Diferenciar carcinoma de tiroides de alto grado (recuento mitótico alto (≥5/mm2) y/o necrosis). Estos tumores son frecuentemente refractarios de radioyodo, tienen una alta propensión a metástasis distantes y una mala supervivencia general a largo plazo. Desde un punto de vista molecular, HGFDTC comparten mutaciones del controlador es decir, BRAF) y, con menos frecuencia, las fusiones genéticas (es decir, NTRK, RET) con arcinomas de tiroides diferenciados. A medida que ocurre la desdiferenciación, se adquieren alteraciones secundarias (como el promotor TERT y TP53). En esta revisión, nuestro objetivo es describir las características clínicas, moleculares y patológicas de HGFDTC, así como su gestión e investigación futura

High-grade follicular cell derived thyroid carcinomas (HGFDTC) are infrequent tumors with a prognosis intermediate between well differentiated and anaplastic thyroid carcinomas. The most recent WHO classification identifies two distinct types of HGFDTC: 1) Poorly differentiated thyroid carcinoma (solid, trabecular or insular architecture, lack of nuclear features of papillary nuclear and either convoluted nuclei, necrosis or mitosis (≥3/2mm2), and 2) differentiated high-grade thyroid carcinoma (high mitotic count (≥5/mm2) and/or necrosis). These tumors are frequently radioiodine refractory, have a high propensity for distant metastases, and poor long term overall survival. From a molecular standpoint, HGFDTC share driver mutations (ie BRAF) and, less frequently, gene fusions (ie NTRK, RET) with differentiated thyroid carcinomas. As dedifferentiation occurs, secondary alterations (such as TERT promoter, and TP53) are acquired. In this review, we aim to describe the clinical, molecular and pathological characteristics of HGFDTC, as well as their management and future research

Biodistribution of progesterone in the eye after topical ocular administration via drops or inserts.

Progesterone (PG) has been shown to have a slowing effect on photoreceptor cell death in mouse models of retinitis pigmentosa when administered orally. The aim of this study was to investigate whether ophthalmically administered progesterone was able to reach neuroretina and thus, the distribution through ocular tissues of different PG formulations was studied. The effect of different initial PG concentration was also investigated. Different formulations with PG in their composition (drops, a corneal/scleral-insert and scleral-inserts) were prepared and assayed. Using whole porcine eyes, the different formulations were topically administered to the ocular surface. Frozen eyes were dissected, the PG in each tissue was extracted in acetonitrile and the amount of PG quantified by UHPLC-MS/MS. Our results show that after topical administration, PG diffuses from the ocular surface and distributes throughout all tissues of the eye. Lower levels of PG were found in sclera, choroid and neuroretina when PG was applied as drops compared to inserts. Our results also show that an increase in the initial PG concentrations applied, resulted in a statistically significant increase in the amounts of PG in aqueous humour, sclera, choroid and neuroretina.

Generation and Integrated Analysis of Advanced Patient-Derived Orthoxenograft Models (PDOX) for the Rational Assessment of Targeted Therapies in Endometrial Cancer.

Clinical management of endometrial cancer (EC) is handicapped by the limited availability of second line treatments and bona fide molecular biomarkers to predict recurrence. These limitations have hampered the treatment of these patients, whose survival rates have not improved over the last four decades. The advent of coordinated studies such as The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA_UCEC) has partially solved this issue, but the lack of proper experimental systems still represents a bottleneck that precludes translational studies from successful clinical testing in EC patients. Within this context, the first study reporting the generation of a collection of endometrioid-EC-patient-derived orthoxenograft (PDOX) mouse models is presented that is believed to overcome these experimental constraints and pave the way toward state-of-the-art precision medicine in EC. The collection of primary tumors and derived PDOXs is characterized through an integrative approach based on transcriptomics, mutational profiles, and morphological analysis; and it is demonstrated that EC tumors engrafted in the mouse uterus retain the main molecular and morphological features from analogous tumor donors. Finally, the molecular properties of these tumors are harnessed to assess the therapeutic potential of trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor with growing interest in EC, using patient-derived organotypic multicellular tumor spheroids and in vivo experiments.

Non-Invasive Iontophoretic Delivery of Cytochrome c to the Posterior Segment and Determination of Its Ocular Biodistribution.

The intact porcine eye globe model was used to demonstrate that transscleral iontophoresis could deliver a small protein, cytochrome c (Cyt c), to the posterior segment and to investigate post-iontophoretic biodistribution in the different ocular compartments. The effects of Cyt c concentration (1, 5, and 10 mg/mL), current density (3.5 and 5.5 mA/cm2), and duration of the current application (10 min and 1, 2, and 4 h) were evaluated. The data confirmed that transscleral iontophoresis enhanced the intraocular delivery of Cyt c under all conditions as compared to passive controls (same setup but without the current application). Increasing the Cyt c concentration resulted in a proportional enhancement in the Cyt c delivery. Increasing the current density from 3.5 to 5.5 mA/cm2 increased iontophoretic delivery at a Cyt c concentration of 10 mg/mL but did not appear to do so at 5 mg/mL; this was attributed in part to the effect of melanin binding. Short duration iontophoresis (10 min, 3.5 mA/cm2) of a 10 mg/mL Cyt c solution created a depot in the sclera. When this was followed by a 4 h incubation period, post-iontophoretic Cyt c diffusion from the sclera resulted in a different biodistribution, and Cyt c could be quantified in the posterior segment.

Renin-angiotensin system blockade on angiotensin-converting enzyme 2 and TMPRSS2 in human type II pneumocytes.

AIMS: Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. MAIN METHODS: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. KEY FINDINGS: We found that the ratio Ang-(1-7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. SIGNIFICANCE: ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies.

A microRNA Cluster Controls Fat Cell Differentiation and Adipose Tissue Expansion By Regulating SNCG.

The H19X-encoded miR-424(322)/503 cluster regulates multiple cellular functions. Here, it is reported for the first time that it is also a critical linchpin of fat mass expansion. Deletion of this miRNA cluster in mice results in obesity, while increasing the pool of early adipocyte progenitors and hypertrophied adipocytes. Complementary loss and gain of function experiments and RNA sequencing demonstrate that miR-424(322)/503 regulates a conserved genetic program involved in the differentiation and commitment of white adipocytes. Mechanistically, it is demonstrated that miR-424(322)/503 targets γ-Synuclein (SNCG), a factor that mediates this program rearrangement by controlling metabolic functions in fat cells, allowing adipocyte differentiation and adipose tissue enlargement. Accordingly, diminished miR-424(322) in mice and obese humans co-segregate with increased SNCG in fat and peripheral blood as mutually exclusive features of obesity, being normalized upon weight loss. The data unveil a previously unknown regulatory mechanism of fat mass expansion tightly controlled by the miR-424(322)/503 through SNCG.

El problema de la identificación en la conducción del análisis / The problem of identification in the conduct of the analysis

En "La dirección de la cura y los principios de su poder" Lacan cuestiona, dentro de lo que denomina "parcialidades" en el abordaje del problema de la transferencia (Apartado 3, parágrafo 2, p. 583), una tercera vía de abordaje del problema que postularía, como modo de resolución de la transferencia y culminación del análisis, una suerte de identificación del paciente con el analista ("introyección en Ferenczi, identificación con el superyó del analista en Strachey, trance narcisístico terminal en Balint", parágrafo 6, p. 587). Culmina y sintetiza de esta forma sus propios desarrollos sobre el tema llevados a cabo en los Seminarios 1 y 4. Sin embargo, y a nuestro entender, la problemática de la identificación y del objeto en la culminación del tratamiento analítico no queda resuelta, sino tan solo planteada. Serán necesarias nuevas reelaboraciones de la noción de "identificación" (Seminario 9) y de la de "objeto" (Seminario 10), para retomar esos desarrollos en un nuevo análisis del concepto de "transferencia" (Seminario 11), que busca delimitarlo en un esquema que propone una maniobra clínica para su resolución. El presente trabajo ofrece una síntesis del recorrido argumental de Lacan

In "The direction of cure" Lacan questions, within what he called "bias" in the approach to the problem of transfer (section 3, paragraph 2, p. 583), the problem of run, as a way of resolution of transfer and completion of the analysis, a third way of approach a sort of identification of the patient with the analyst ("introjection in Ferenczi, identification with the superego of the analyst in Strachey, trance terminal fusionary in Balint", paragraph 6, p. 587). It culminates and synthesized in this way their own development on the subject carried out in Seminars 1 and 4. However, and in our opinion, the problem identification and the object at the culmination of the analytic treatment is not resolved, but only raised. Necessary new reworkings of the notion of "identification" (Seminar 9) and the of "object" (Seminar 10), will be to return to these developments in a new analysis of the concept of "transfer..." which seeks to define it in a scheme that proposes a clinical move to its resolution. This paper provides a synthesis of the story journey of Lacan

Exercise Interventions for Improving Flexibility in People with Multiple Sclerosis: A Systematic Review and Meta-Analysis.

Background and objectives: People with multiple sclerosis (MS) often experience limitations in joint range of motion, which is linked to spasticity and continued inactivity. Low flexibility levels in this population have been linked to postural problems and muscular pain. Therefore, the purpose of this study was to conduct a systematic review and a meta-analysis aimed at identifying the characteristics and methodological quality of investigations studying the effects of exercise interventions on the flexibility levels of people with MS. Materials and Methods: Three electronic databases (MEDLINE/PubMed, SPORTDiscus and Scopus) were systematically searched up to May 2019 for intervention studies focused on the effects of exercise on the flexibility levels of people with MS. A meta-analysis, including randomized controlled trials (RCT), which reported information regarding the effects of exercise on flexibility, was also conducted. The methodological quality of included studies was assessed using the Physiotherapy Evidence Database, and the Quality Assessment Tool for Before-After Studies, with no control group. The quality of the information reported, regarding the programs conducted, was assessed by means of the Consensus on Exercise Reporting Template (CERT) scale. Results: Seven studies, four RCTs and three uncontrolled investigations were finally selected. The methodological quality of the RCTs was considered "poor" in one study, and "good" and "excellent" in two studies and one investigation, respectively. The three uncontrolled studies showed a methodological quality between "fair" and "poor". Following the CERT scale, four studies were graded as "high" and three as "low". Findings from the meta-analysis indicated no significant effects on hamstring flexibility, or the range of motion in the hips, knees or ankles. Conclusions: There is preliminary evidence from individual studies which indicates that people with MS can improve their lower limb flexibility following participation in physical exercise programs, but the meta-analysis did not confirm these findings.

Clinical-epidemiological study of Bordetella pertussis infection in the Gran Canaria island in the period, 2008-2016.

OBJECTIVE: Describe the epidemiological and clinical pattern of Bordetella pertussis infection (whooping cough) among hospitalised infants less than one year-old in a paediatric hospital in Gran Canaria. PATIENTS AND METHODS: A retrospective review of the patient hospital records was performed, and recording only those with a microbiological diagnosis of pertussis infection detected using polymerase chain reaction, from January 2008 to December 2016. RESULTS: A total of 110 patients were identified, of which 105 (95.4%) were less than 6 months old, and 59.1% were males. The annual incidence of hospital admissions was estimated between 13.7 and 425.0 cases per 100 000 infants <12 months old, with 2 peaks in 2011 and 2015. Household members were the main potential sources of infection. Main clinical features were pertussis cough associated with signs of catarrh, cyanosis, and lymphocytosis. Complications occurred in 15.4% of the patients (mainly pneumonia), but the outcome was favourable in all the cases. A lower age and non-vaccination were associated with an increased risk of developing complications (p < .05). Viral co-infection occurred in 31.6% of infants diagnosed with pertussis. CONCLUSIONS: The incidence of pertussis has increased in the last years in Gran Canaria, with a lower development of complications and mortality rates compared with the previous period. Lower age and non-vaccination status are considered risk factors for developing complications. Vaccination in pregnant women will probably lead to a decline in the incidence in the future, especially in infants younger than 6 months.

OBJETIVO: Describir el patrón epidemiológico y clínico de la infección por Bordetella pertussis (tosferina) en niños menores de un año hospitalizados en un hospital pediátrico de Gran Canaria. PACIENTES Y MÉTODOS: Se revisaron retrospectivamente las historias clínicas de los pacientes con diagnóstico microbiológico de infección por B. pertussis mediante reacción en cadena de la polimerasa, de enero de 2008 a diciembre de 2016. RESULTADOS: Se identificaron 110 pacientes, de los cuales 105 (95,4%) fueron menores de 6 meses y el 59,1% eran varones. La incidencia anual de hospitalización se estimó entre 13,7 y 425,0 casos por cada 100.000 lactantes menores de 12 meses, con 2 picos en 2011 y 2015. Los familiares cercanos fueron las principales fuentes de contagio potenciales. Las principales manifestaciones fueron la tos pertusoide asociada con signos catarrales, cianosis y linfocitosis. El 15,4% de los pacientes presentaron complicaciones (principalmente neumonía), pero la evolución fue favorable en todos los casos. La menor edad y la no vacunación se asociaron con un mayor riesgo de desarrollar complicaciones (p < 0,05). La coinfección viral ocurrió en el 31,6% de los pacientes diagnosticados de infección por B. pertussis. CONCLUSIONES: La incidencia de infección por B. pertussis ha aumentado en los últimos años en nuestra área, con un menor desarrollo de complicaciones y con tasas de mortalidad inferiores al período anterior. La menor edad y la no vacunación previa se consideran factores de riesgo para el desarrollo de complicaciones. La vacunación en mujeres embarazadas probablemente disminuirá la incidencia en el futuro, sobre todo en niños menores de 6 meses.

[Clinical-epidemiological study of Bordetella pertussis infection in the Gran Canaria island in the period, 2008-2016]. / Estudio clínico-epidemiológico de la infección por Bordetella pertussis en la isla de Gran Canaria en el período 2008-2016.

OBJECTIVE: Describe the epidemiological and clinical pattern of Bordetella pertussis infection (whooping cough) among hospitalised infants less than one year-old in a paediatric hospital in Gran Canaria. PATIENTS AND METHODS: A retrospective review of the patient hospital records was performed, and recording only those with a microbiological diagnosis of pertussis infection detected using polymerase chain reaction, from January 2008 to December 2016. RESULTS: A total of 110 patients were identified, of which 105 (95.4%) were less than 6 months-old, and 59.1% were males. The annual incidence of hospital admissions was estimated between 13.7 to 425.0 cases per 100,000 infants <12 months old, with 2peaks in 2011 and 2015. Household members were the main potential sources of infection. Main clinical features were pertussis cough associated with signs of catarrh, cyanosis, and lymphocytosis. Complications occurred in 15.4% of the patients (mainly pneumonia), but the outcome was favourable in all the cases. A lower age and non-vaccination were associated with an increased risk of developing complications (P<.05). Viral co-infection occurred in 31.6% of infants diagnosed with pertussis. CONCLUSIONS: The incidence of pertussis has increased in the last years in Gran Canaria, with a lower development of complications and mortality rates compared with the previous period. Lower age and non-vaccination status are considered risk factors for developing complications. Vaccination in pregnant women will probably lead to a decline in the incidence in the future, especially in infants younger than 6 months.

Radioactive iodine-refractory differentiated thyroid cancer: an uncommon but challenging situation.

Radioiodine (RAI)-refractory thyroid cancer is an uncommon entity, occurring with an estimated incidence of 4-5 cases/year/million people. RAI refractoriness is more frequent in older patients, in those with large metastases, in poorly differentiated thyroid cancer, and in those tumors with high 18-fluordeoxyglucose uptake on PET/CT. These patients have a 10-year survival rate of less than 10%. In recent years, new therapeutic agents with molecular targets have become available, with multikinase inhibitors (MKIs) being the most investigated drugs. Two of these compounds, sorafenib and lenvatinib, have shown significant objective response rates and have significantly improved the progression-free survival in the two largest published prospective trials on MKI use. However, no overall survival benefit has been achieved yet. This is probably related to the crossover that occurs in most patients who progress on placebo treatment to the open treatment of these studies. In consequence, the challenge is to correctly identify which patients will benefit from these treatments. It is also crucial to understand the appropriate timing to initiate MKI treatment and when to stop it. The purpose of this article is to define RAI refractoriness, to summarize which therapies are available for this condition, and to review how to select patients who are suitable for them.

Radioactive iodine-refractory differentiated thyroid cancer: an uncommon but challenging situation

ABSTRACT Radioiodine (RAI)-refractory thyroid cancer is an uncommon entity, occurring with an estimated incidence of 4-5 cases/year/million people. RAI refractoriness is more frequent in older patients, in those with large metastases, in poorly differentiated thyroid cancer, and in those tumors with high 18-fluordeoxyglucose uptake on PET/CT. These patients have a 10-year survival rate of less than 10%. In recent years, new therapeutic agents with molecular targets have become available, with multikinase inhibitors (MKIs) being the most investigated drugs. Two of these compounds, sorafenib and lenvatinib, have shown significant objective response rates and have significantly improved the progression-free survival in the two largest published prospective trials on MKI use. However, no overall survival benefit has been achieved yet. This is probably related to the crossover that occurs in most patients who progress on placebo treatment to the open treatment of these studies. In consequence, the challenge is to correctly identify which patients will benefit from these treatments. It is also crucial to understand the appropriate timing to initiate MKI treatment and when to stop it. The purpose of this article is to define RAI refractoriness, to summarize which therapies are available for this condition, and to review how to select patients who are suitable for them.

Modelos de dirección de la cura / Cure direction patterns

El presente texto es un resumen de los resultados obtenidos en nuestro proyecto de investigación 2008-9, en el que nos propusimos como objetivo general delimitar y formalizar modelos de dirección de la cura en la obra de Freud y Lacan.

The Fourth and Fifth Spectra of Vanadium (V iv and V v).

The V iv spectrum has been extended by using as light sources a condensed spark and a hollow cathode discharge. With the new data, the experimental interpretation of levels of the 3d 2, 3d 4d, 3d 5s, 3d 5p, 3d 4f, 3d 5d and 3d 6s configurations has been completed with the exception of three levels of the 3d 4f and 3d 5d configurations. Four levels of the 3d 5g electron configuration have also been found. These levels account for 340 of the 360 lines assigned to V iv in the region 675 Å-5940 Å. Three members of the 3d ns series give an ionization potential of 376730 ± 40 cm-1 = 46.70 volts. The 4d 2D term of V v has also been located in the course of this work. With the aid of the new observations between 675 Å and 2200 Å the value of some levels already known has been improved.

Interpretation of the Third Spectrum of Gold (Au iii).

A revision of the analysis of the Au iii spectrum is presented. Of 9 energy levels considered doubtful on the basis of a recent theoretical treatment, 6 are found to be real and 3 have been rejected as incorrect. Three new energy levels have also been found in agreement with theoretical predictions.