Tumor xenograft modeling identifies an association between TCF4 loss and breast cancer chemoresistance

Understanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patientderived xenografts (PDXs), we show that adaptation to therapy is genetically complex and identify that loss of transcription factor 4 (TCF4; also known as ITF2) is associated with this process. A triple-negative BRCA1-mutaied PDX was used to study the genetics of chemoresistance. The PDX was treated in parallel with four chemotherapies for five iterative cycles. Exome sequencing identified few genes with de novo or enriched mutations in common among the different therapies, whereas many common depleted mutations/ genes were observed. Analysis of somatic mutations from The Cancer Genome Atlas (TCGA) supported the prognostic relevance of the identified genes. A mutation in TCF4 was found de novo in all treatments, and analysis of drug sensitivity profiles across cancer cell lines supported the link to chemoresistance. Loss of TCF4 conferred chemoresistance in breast cancer cell models, possibly by altering cell cycle regulation. Targeted sequencing in chemoresistant tumors identified an intronic variant of TCF4 that may represent an expression quantitative trait locus associated with relapse outcome in TCGA. Immunohistochemical studies suggest a common loss of nuclear TCF4 expression post-chemotherapy. Together, these results from tumor xenograft modeling depict a link between altered TCF4 expression and breast cancer chemoresistance

Famílies botàniques de plantes medicinals

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia, Assignatura: Botànica Farmacèutica, Curs: 2013-2014, Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són els recull de 175 treballs d’una família botànica d’interès medicinal realitzats de manera individual. Els treballs han estat realitzat per la totalitat dels estudiants dels grups M-2 i M-3 de l’assignatura Botànica Farmacèutica durant els mesos d’abril i maig del curs 2013-14. Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pel professor de l’assignatura i revisats i finalment co-avaluats entre els propis estudiants. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Caracterización de la osteocondrosis carpometacarpiana en el toro de lidia (Bos taurus) : Estudio de factores predisponentes

En esta tesis nos planteamos la caracterización de la osteocondrosis (OC) carpometacarpiana y el estudio de sus factores predisponentes en el toro de lidia. Para ello, se analizaron los miembros torácicos de 182 machos bovinos de raza de lidia, lidiados en plazas de toros, y 39 machos bovinos de aptitud cárnica. Se determinó el grado de OC y el de caída. Se realizó un estudio de la OC mediante radiografía, tomografía y artroscopia. Y se estudió la bioestática del miembro torácico. La prevalencia de la OC en el toro de lidia fue del 92,31% y en el bovino de aptitud cárnica del 97,4%. Las lesiones se localizaron de forma bilateral (93,41%) y simétrica (65,93%), con mayor incidencia en el miembro izquierdo, y siempre en el aspecto articular medial de los huesos metacarpiano III y IV, coincidiendo con la zona de mayor estrés biomecánico. Las lesiones se clasificaron en grado I (25,27%), grado II (32,9%) y grado III (34,07%). En el toro de lidia se presentó apoyo valgus en mayor o menor medida. El peso y el encaste fueron factores que influyeron en la aparición de OC. Por último, el grado de caída aumentó con el porcentaje de lesión de OC.In this thesis we consider the characterization of carpometacarpal osteochondrosis (OC) and the study of its predisposing factors in the fighting bull. To this end, the thoracic limbs of 182 fighting breed bovine males, fought in bullrings, and 39 beef cattle males were analyzed. The degree of OC and the degree of fall were determined. A study of the OC was carried out using radiography, tomography and arthroscopy. And the biostatics of the thoracic limb was studied. The prevalence of OC in fighting bulls was 92.31% and 97.4% in beef cattle. The lesions were located bilaterally (93.41%) and symmetrical (65.93%), with a higher incidence in the left limb, and always in the medial articular aspect of the III and IV metacarpal bones, coinciding with the area of increased biomechanical stress. The lesions were classified as grade I (25.27%), grade II (32.9%) and grade III (34.07%). In the fighting bull, valgus support was presented to a greater or lesser extent. Weight and lineage were factors that influenced the appearance of OC. Finally, the degree of fall increased with the percentage of OC injury

Primer caso de Thelaziosis ocular (Thelazia rhodesi) en toro de lidia en la Península Ibérica

Bovine thelaziosis is caused by Thelazia rhodesi, T. skrjabini and T. gulosa, although the most prevalent species in Europe is the first of them. Thelazia rhodesi is a nematode (order Spirurida, family Thelaziidae) para- sitizing the eye of cattle, buffalo, zebu, and bison and, less frequently, horses and small ruminants. It is located on the corneal surface, under the lids and nictitating membrane and in the conjunctival sac. Thelazia spp. has an indirect life cycle, acting diptera of the family Muscidae as intermediate hosts. This study presents a case of thelaziosis in a fighting bull (Bos taurus), dealt in the bullring of Murcia in September 2014, coming from a farmer located in the Southwest of the Iberian Peninsula. During the first and second veterinary examinations of the animal, abundant tearing was observed, but despite this, the animal reacted positively to visual stimuli made in the visual field of both eyes, jointly and independently. The fighting bull was considered useful during the mentioned veterinary examinations, although it presented constant epiphora. During the fight, no abnormality was observed in the behavior of the bull in relation to the sense of sight. The post mortem ocular inspection in the pit of the square revealed the presence of nematodes 8-20 mm length in both the conjunctival sac and the surface of the cornea, which were extracted using tweezers and preserved in 70% ethanol. The specimens were identified as T. rhodesi according to the morphometric criteria described by Gupta and Kalia (1978) and Naem (2007a, b). This is a nematode species with ocular tropism that can appear in the fighting bull, farms exploited in extensive regime in temperate or warm areas, whose environmental conditions will favor the proliferation of intermediate hosts and the development of parasitosis. Therefore, thelaziosis must be considered in the differential diagnosis of ocular pathologies of fighting bull whose signs include restlessness, decreased visual acuity, epiphora and pruritus in the periocular area. To the knowledge of the authors, no case of Thelazia rho- desi infection has been reported in fighting bull.La thelaziosis bovina está causada por Thelazia rhodesi, T. skrjabini y T. gulosa, aunque la especie más prevalente en Europa es la primera de ellas. Thelazia rhodesi es un nematodo (orden Spirurida, familia The- laziidae) que parasita el globo ocular del ganado vacuno, búfalos, cebúes, bisontes y, con menor frecuencia, caballos y pequeños rumiantes. Se localiza en la superficie corneal, sobre la membrana nictitante y en el saco conjuntival. Tiene un ciclo biológico indirecto, actuando como hospedadores intermediarios dípteros de la familia Muscidae. En este estudio se describe un caso de thelaziosis ocular en un toro de lidia (Bos taurus), muerto en la plaza de toros de Murcia en septiembre de 2014, procedente de una ganadería localizada en el su- roeste de la Península Ibérica. Durante el primer y segundo reconocimiento veterinario del animal en la plaza de toros, se observó la existencia de lagrimeo abundante, pero a pesar de ello el animal reaccionaba positivamente a estímulos visuales realizados en el campo visual de ambos ojos, conjunta e independientemente. A pesar del lagrimeo constante, el animal fue considerado apto para la lidia. Durante esta no se observó anormalidad alguna en el comportamiento del toro en relación con el sentido de la vista. La inspección ocular post mortem realizada en el desolladero de la plaza permitió detectar la presencia de nematodos de 8-20 mm de longitud tanto en el saco conjuntival como en la superficie de la córnea, que fueron extraídos con ayuda de pinzas y conservados en etanol al 70%. La identificación microscópica específica de los ejemplares encontrados se realizó en base a los criterios morfométricos descritos por Gupta y Kalia (1978) y Naem (2007a,b), siendo identificados como Thelazia rhodesi. Se trata de un nematodo con tropismo ocular que puede aparecer en el toro de lidia, gana- derías explotadas en régimen extensivo en zonas templadas o cálidas, cuyos condicionantes ambientales van a favorecer la proliferación de los hospedadores intermediarios y el desarrollo de la parasitosis. Por ello, la thelaziosis ha de considerarse en el diagnóstico diferencial de patologías oculares del toro de lidia cuyo cuadro sintomático incluya intranquilidad, agudeza visual disminuida, epífora y prurito en la zona periocular. En el conocimiento de los autores, esta es la primera vez que se publica un caso de parasitación por Thelazia rhodesi en el bovino de lidia

First case of ocular thelaziosis (Thelazía rhodesi) in fighting bull at the Iberian Peninsula

La thelaziosis bovina está causada por Thelazia rhodesi, T. skrjabini y T. gulosa, aunque la especie más prevalente en Europa es la primera de ellas. Thelazia rhodesi es un nematodo (orden Spirurida, familia The-laziidae) que parasita el globo ocular del ganado vacuno, búfalos, cebúes, bisontes y, con menor frecuencia, caballos y pequeños rumiantes. Se localiza en la superficie corneal, sobre la membrana nictitante y en el saco conjuntival. Tiene un ciclo biológico indirecto, actuando como hospedadores intermediarios dípteros de la familia Muscidae. En este estudio se describe un caso de thelaziosis ocular en un toro de lidia (Bos taurus), muerto en la plaza de toros de Murcia en septiembre de 2014, procedente de una ganadería localizada en el su-roeste de la Península Ibérica. Durante el primer y segundo reconocimiento veterinario del animal en la plaza de toros, se observó la existencia de lagrimeo abundante, pero a pesar de ello el animal reaccionaba positivamente a estímulos visuales realizados en el campo visual de ambos ojos, conjunta e independientemente. A pesar del lagrimeo constante, el animal fue considerado apto para la lidia. Durante esta no se observó anormalidad alguna en el comportamiento del toro en relación con el sentido de la vista. La inspección ocular post mortem realizada en el desolladero de la plaza permitió detectar la presencia de nematodos de 8-20 mm de longitud tanto en el saco conjuntival como en la superficie de la córnea, que fueron extraídos con ayuda de pinzas y conservados en etanol al 70%. La identificación microscópica específica de los ejemplares encontrados se realizó en base a los criterios morfométricos descritos por Gupta y Kalia (1978) y Naem (2007a,b), siendo identificados como Thelazia rhodesi. Se trata de un nematodo con tropismo ocular que puede aparecer en el toro de lidia, gana-derías explotadas en régimen extensivo en zonas templadas o cálidas, cuyos condicionantes ambientales van a favorecer la proliferación de los hospedadores intermediarios y el desarrollo de la parasitosis. Por ello, la thelaziosis ha de considerarse en el diagnóstico diferencial de patologías oculares del toro de lidia cuyo cuadro sintomático incluya intranquilidad, agudeza visual disminuida, epífora y prurito en la zona periocular. En el conocimiento de los autores, esta es la primera vez que se publica un caso de parasitación por Thelazia rhodesien el bovino de lidia.Bovine thelaziosis is caused by Thelazia rhodesi, T. skrjabini and T. gulosa, although the most prevalent species in Europe is the first of them. Thelazia rhodesi is a nematode (order Spirurida, family Thelaziidae) para-sitizing the eye of cattle, buffalo, zebu, and bison and, less frequently, horses and small ruminants. It is located on the corneal surface, under the lids and nictitating membrane and in the conjunctival sac. Thelazia spp. has an indirect life cycle, acting diptera of the family Muscidae as intermediate hosts. This study presents a case of thelaziosis in a fighting bull (Bos taurus), dealt in the bullring of Murcia in September 2014, coming from a farmer located in the Southwest of the Iberian Peninsula. During the first and second veterinary examinations of the animal, abundant tearing was observed, but despite this, the animal reacted positively to visual stimuli made in the visual field of both eyes, jointly and independently. The fighting bull was considered useful during the mentioned veterinary examinations, although it presented constant epiphora. During the fight, no abnormality was observed in the behavior of the bull in relation to the sense of sight. The post mortem ocular inspection in the pit of the square revealed the presence of nematodes 8-20 mm length in both the conjunctival sac and the surface of the cornea, which were extracted using tweezers and preserved in 70% ethanol. The specimens were identified as T. rhodesi according to the morphometric criteria described by Gupta and Kalia (1978) and Naem (2007a, b). This is a nematode species with ocular tropism that can appear in the fighting bull, farms exploited in extensive regime in temperate or warm areas, whose environmental conditions will favor the proliferation of intermediate hosts and the development of parasitosis. Therefore, thelaziosis must be considered in the differential diagnosis of ocular pathologies of fighting bull whose signs include restlessness, decreased visual acuity, epiphora and pruritus in the periocular area. To the knowledge of the authors, no case of Thelazia rho-desi infection has been reported in fighting bull

Tumor xenograft modeling identifies an association between TCF4 loss and breast cancer chemoresistance

Understanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patientderived xenografts (PDXs), we show that adaptation to therapy is genetically complex and identify that loss of transcription factor 4 (TCF4; also known as ITF2) is associated with this process. A triple-negative BRCA1-mutaied PDX was used to study the genetics of chemoresistance. The PDX was treated in parallel with four chemotherapies for five iterative cycles. Exome sequencing identified few genes with de novo or enriched mutations in common among the different therapies, whereas many common depleted mutations/ genes were observed. Analysis of somatic mutations from The Cancer Genome Atlas (TCGA) supported the prognostic relevance of the identified genes. A mutation in TCF4 was found de novo in all treatments, and analysis of drug sensitivity profiles across cancer cell lines supported the link to chemoresistance. Loss of TCF4 conferred chemoresistance in breast cancer cell models, possibly by altering cell cycle regulation. Targeted sequencing in chemoresistant tumors identified an intronic variant of TCF4 that may represent an expression quantitative trait locus associated with relapse outcome in TCGA. Immunohistochemical studies suggest a common loss of nuclear TCF4 expression post-chemotherapy. Together, these results from tumor xenograft modeling depict a link between altered TCF4 expression and breast cancer chemoresistance

Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure