Chemorefractory Gastric Cancer: The Evolving Terrain of Third-Line Therapy and Beyond

Gastric cancer; Molecular approach; Third line of treatmentCáncer gástrico; Enfoque molecular; Tercera línea de tratamientoCàncer gàstric; Enfocament molecular; Tercera línia de tractamentGastric and gastro-oesophageal junction cancer (GC) represent a global healthcare problem being the fifth most common tumour type and the fourth cause of cancer mortality. Extremely poor median survival of approximately 10 months is normally reported within advanced GC patients, mainly secondary to two factors, i.e., the fragility of these patients and the aggressiveness of this disease. In this context, the correct treatment of GC patients requires not only a multidisciplinary team with special attention to palliative and nutritional care but also a close follow-up with regular monitoring of disease symptoms and tumour evaluation. Sequential treatment lines with few toxic adverse events have emerged as the best therapeutic approach, and a third line of therapy could further improve survival and quality of life of GC patients. Chemotherapy, immunotherapy, and targeted agents -when indicated- constitute the treatment armamentarium of these patients. In this review, we discuss treatment options in the refractory setting as well as novel approaches to overcome the poor prognosis of GC

Topographical control of the source‐sink and wind stress‐driven planetary geostrophic circulation in a polar basin

The effects of topography on the barotropic circulation in a polar basin are examined analytically and numerically. New approximate linear analytical solutions are presented for steady‐state wind and boundary forced barotropic planetary geostrophic circulation in a circular polar basin with a step shelf. The solutions are obtained by retaining the full spherical geometry in the derivation of the forced potential vorticity equation; thereafter the colatitude is fixed in the coefficients of this governing equation. The accuracy of the analytical solutions is evaluated by comparing them with the equivalent numerical solutions obtained using the NEMO modeling system. Subsequently, the impact of a nonuniform width shelf on source‐sink‐driven circulation is investigated numerically. The equipartition of fluid entering the source strait into cyclonic and anticyclonic shelf currents, exiting the basin at the sink strait, in a basin with a uniform width shelf is shown to be modified when the shelf width varies. In general, the wider shelf supports a current with larger transport, irrespective of the azimuthal extent of the wider shelf. The study concludes with a numerical investigation of wind‐driven circulation in a basin with a step shelf, three straits, and a transpolar ridge, a prototype Arctic Ocean simulation. Topographic steering by the ridge supports a transpolar drift current, the magnitude of which depends on the ridge height. Without the ridge, the transpolar drift current is absent and the circulation is confined to gyres on the shelf and in the deep basin

Type-I InP/InGaAs DHBT modelling using ATLAS Numerical Simulator

Català: El present treball es desenvolupa entorn de la modelització d'un transistor bipolar de doble heterounió (DHBT). En concret, s'estudia un dispositiu Tipus-I basat en la utilització de materials semiconductors III-V com són el InP (fosfur d?indi) i InGaAs (aliatge ternari d'indi, gal-li i arseni). Per dur a terme totes les simulacions d'aquesta tesi, s'ha fet ús del simulador numèric ATLAS de la companyia SILVACO. Amb l'objectiu d'avaluar la bondat del model, es realitza una comparació amb valors experimentals i amb resultats de simulacions realitzades amb l'eina TCAD DESSIS de Synopsys del comportament en contínua del dispositiu. S'analitzen el models i paràmetres de transport i les propietats físiques del dispositiu estudiant i discutint els models disponibles a la literatura i la forma d'implementar-los al simulador. Finalment, es procedeix a analitzar el nivell d'influència de certs factors (paràmetres de transport com la movilitat de portadors o propietats físiques com per exemple el fenomen del band gap narrowing) sobre el comportament en contínua del dispositiu. Per últim, s'estudia l'impacte de l'escalat de diferents regions.Castellano: El presente trabajo se desarrolla en torno a la modelización de un transistor bipolar de doble heterounión (DHBT). En concreto, se estudia un dispositivo Tipo-I basado en la utilización de materiales semiconductores III-V como son el InP (fosfuro de indio) e InGaAs (aleación ternaria de indio, galio y arsenio). Para llevar a cabo todas las simulaciones de esta tesis, se ha hecho uso del simulador numérico ATLAS de la compañía SILVACO. Con el objetivo de evaluar la bondad del modelo, se realiza una comparación con valores experimentales y con resultados de simulaciones realizadas con la herramienta TCAD DESSIS de Synopsys del comportamiento en continua del dispositivo. Se analizan los modelos y parámetros de transporte y las propiedades físicas del dispositivo estudiando y discutiendo los modelos disponibles en la literatura y la forma de implementarlos en el simulador. Finalmente, se procede a analizar el nivel de influencia de ciertos factores (parámetros de transporte como la movilidad de portadores ó propiedades físicas como por ejemplo el fenómeno del band gap narrowing) sobre el comportamiento en continua del dispositivo. Por último se estudia el impacto del escalado de diferentes regiones del mismo.English: A double heterojunction bipolar transistor (DHBT) modeling has been developed in this work. In particular, a Type-I device is studied, which is based on the use of III-V semiconductor materials such as InP (indium phosphide) and InGaAs (ternary alloy of indium, gallium and arsenic). ATLAS numerical simulator from SILVACO company has been used to carry out all simulations in this thesis. In order to evaluate the model accuracy, a comparison is made with experimental data and simulation results from DESSIS TCAD tool from Synopsys. This exercise is focused on DC behavior of the device. Transport model and device physical propierties have been analyzed by means of studying and discussing the available models in the literature and its implementation in the simulator. Finally, relative impact of certain factors (transport parameters such as carrier mobility or physical properties as for instance band gap narrowing) has been analyzed over DC behavior of the device. To conclude, DHBT is vertically scaled with the purpose of studying the influence

Genome-Wide RNAi Screening Identifies Novel Pathways/Genes Involved in Oxidative Stress and Repurposable Drugs to Preserve Cystic Fibrosis Airway Epithelial Cell Integrity

Recurrent infection-inflammation cycles in cystic fibrosis (CF) patients generate a highly oxidative environment, leading to progressive destruction of the airway epithelia. The identification of novel modifier genes involved in oxidative stress susceptibility in the CF airways might contribute to devise new therapeutic approaches. We performed an unbiased genome-wide RNAi screen using a randomized siRNA library to identify oxidative stress modulators in CF airway epithelial cells. We monitored changes in cell viability after a lethal dose of hydrogen peroxide. Local similarity and protein-protein interaction network analyses uncovered siRNA target genes/pathways involved in oxidative stress. Further mining against public drug databases allowed identifying and validating commercially available drugs conferring oxidative stress resistance. Accordingly, a catalog of 167 siRNAs able to confer oxidative stress resistance in CF submucosal gland cells targeted 444 host genes and multiple circuitries involved in oxidative stress. The most significant processes were related to alternative splicing and cell communication, motility, and remodeling (impacting cilia structure/function, and cell guidance complexes). Other relevant pathways included DNA repair and PI3K/AKT/mTOR signaling. The mTOR inhibitor everolimus, the α1-adrenergic receptor antagonist doxazosin, and the Syk inhibitor fostamatinib significantly increased the viability of CF submucosal gland cells under strong oxidative stress pressure. Thus, novel therapeutic strategies to preserve airway cell integrity from the harsh oxidative milieu of CF airways could stem from a deep understanding of the complex consequences of oxidative stress at the molecular level, followed by a rational repurposing of existing "protective" drugs. This approach could also prove useful to other respiratory pathologies

Type-I InP/InGaAs DHBT modelling using ATLAS Numerical Simulator

Català: El present treball es desenvolupa entorn de la modelització d'un transistor bipolar de doble heterounió (DHBT). En concret, s'estudia un dispositiu Tipus-I basat en la utilització de materials semiconductors III-V com són el InP (fosfur d?indi) i InGaAs (aliatge ternari d'indi, gal-li i arseni). Per dur a terme totes les simulacions d'aquesta tesi, s'ha fet ús del simulador numèric ATLAS de la companyia SILVACO. Amb l'objectiu d'avaluar la bondat del model, es realitza una comparació amb valors experimentals i amb resultats de simulacions realitzades amb l'eina TCAD DESSIS de Synopsys del comportament en contínua del dispositiu. S'analitzen el models i paràmetres de transport i les propietats físiques del dispositiu estudiant i discutint els models disponibles a la literatura i la forma d'implementar-los al simulador. Finalment, es procedeix a analitzar el nivell d'influència de certs factors (paràmetres de transport com la movilitat de portadors o propietats físiques com per exemple el fenomen del band gap narrowing) sobre el comportament en contínua del dispositiu. Per últim, s'estudia l'impacte de l'escalat de diferents regions.Castellano: El presente trabajo se desarrolla en torno a la modelización de un transistor bipolar de doble heterounión (DHBT). En concreto, se estudia un dispositivo Tipo-I basado en la utilización de materiales semiconductores III-V como son el InP (fosfuro de indio) e InGaAs (aleación ternaria de indio, galio y arsenio). Para llevar a cabo todas las simulaciones de esta tesis, se ha hecho uso del simulador numérico ATLAS de la compañía SILVACO. Con el objetivo de evaluar la bondad del modelo, se realiza una comparación con valores experimentales y con resultados de simulaciones realizadas con la herramienta TCAD DESSIS de Synopsys del comportamiento en continua del dispositivo. Se analizan los modelos y parámetros de transporte y las propiedades físicas del dispositivo estudiando y discutiendo los modelos disponibles en la literatura y la forma de implementarlos en el simulador. Finalmente, se procede a analizar el nivel de influencia de ciertos factores (parámetros de transporte como la movilidad de portadores ó propiedades físicas como por ejemplo el fenómeno del band gap narrowing) sobre el comportamiento en continua del dispositivo. Por último se estudia el impacto del escalado de diferentes regiones del mismo.English: A double heterojunction bipolar transistor (DHBT) modeling has been developed in this work. In particular, a Type-I device is studied, which is based on the use of III-V semiconductor materials such as InP (indium phosphide) and InGaAs (ternary alloy of indium, gallium and arsenic). ATLAS numerical simulator from SILVACO company has been used to carry out all simulations in this thesis. In order to evaluate the model accuracy, a comparison is made with experimental data and simulation results from DESSIS TCAD tool from Synopsys. This exercise is focused on DC behavior of the device. Transport model and device physical propierties have been analyzed by means of studying and discussing the available models in the literature and its implementation in the simulator. Finally, relative impact of certain factors (transport parameters such as carrier mobility or physical properties as for instance band gap narrowing) has been analyzed over DC behavior of the device. To conclude, DHBT is vertically scaled with the purpose of studying the influence

Repopulation of decellularized retinas with hiPSC-derived retinal pigment epithelial and ocular progenitor cells shows cell engraftment, organization and differentiation

Decellularization; Ocular progenitors; RetinaDescelularización; Progenitores oculares; RetinaDescel·lularització; Progenitors oculars; RetinaThe retinal extracellular matrix (ECM) provides architectural support, adhesion and signal guidance that controls retinal development. Decellularization of the ECM affords great potential to tissue engineering; however, how structural retinal ECM affects in vitro development, differentiation and maturation of ocular cells remains to be elucidated. Here, mouse and porcine retinas were decellularized and the protein profile analyzed. Acellular retinal ECM (arECM) scaffolds were then repopulated with human iPSC-derived retinal pigment epithelial (RPE) cells or ocular progenitor cells (OPC) to assess their integration, proliferation and organization. 3837 and 2612 unique proteins were identified in mouse and porcine arECM, respectively, of which 93 and 116 proteins belong to the matrisome. GO analysis shows that matrisome-related proteins were associated with the extracellular region and cell junction and KEGG pathways related to signalling transduction, nervous and endocrine systems and cell junctions were enriched. Interestingly, mouse and porcine arECMs were successfully repopulated with both RPE and OPC, the latter exhibiting cell lineage-specific clusters. Retinal cells organized into different layers containing well-defined areas with pigmented cells, photoreceptors, Müller glia, astrocytes, and ganglion cells, whereas in other areas, conjunctival/limbal, corneal and lens cells re-arranged in cell-specific self-organized areas. In conclusion, our results demonstrated that decellularization of both mouse and porcine retinas retains common native ECM components that upon cell repopulation could guide similar ocular cell adhesion, migration and organization.This work was supported by La Marató de TV3 Foundation (484/C/2012); ERA-NET EuroNanoMed III-AC19/00080/ISCIII (CELLUX); Instituto de Salud Carlos III (CA18/00045 and PI18/00219); and the European Social Fund, the Ministerio de Ciencia, Innovación y Universidades, which is part of the Agencia Estatal de Investigación (PTA2018-016371-I). A.D. was supported by PT13/0001/0041 PRB2-ISCIII-SGEFI-FEDER-PE I+D+i 2013–2016 and ISCIII-FEDER RETICS (Oftared; RD16/0008). We thank the CERCA Programme/Generalitat de Catalunya for institutional support

Repopulation of decellularized retinas with hiPSC-derived retinal pigment epithelial and ocular progenitor cells shows cell engraftment, organization and differentiation

The retinal extracellular matrix (ECM) provides architectural support, adhesion and signal guidance that controls retinal development. Decellularization of the ECM affords great potential to tissue engineering; however, how structural retinal ECM affects in vitro development, differentiation and maturation of ocular cells remains to be elucidated. Here, mouse and porcine retinas were decellularized and the protein profile analyzed. Acellular retinal ECM (arECM) scaffolds were then repopulated with human iPSC-derived retinal pigment epithelial (RPE) cells or ocular progenitor cells (OPC) to assess their integration, proliferation and organization. 3837 and 2612 unique proteins were identified in mouse and porcine arECM, respectively, of which 93 and 116 proteins belong to the matrisome. GO analysis shows that matrisome-related proteins were associated with the extracellular region and cell junction and KEGG pathways related to signalling transduction, nervous and endocrine systems and cell junctions were enriched. Interestingly, mouse and porcine arECMs were successfully repopulated with both RPE and OPC, the latter exhibiting cell lineage-specific clusters. Retinal cells organized into different layers containing well-defined areas with pigmented cells, photoreceptors, Müller glia, astrocytes, and ganglion cells, whereas in other areas, conjunctival/limbal, corneal and lens cells re-arranged in cell-specific self-organized areas. In conclusion, our results demonstrated that decellularization of both mouse and porcine retinas retains common native ECM components that upon cell repopulation could guide similar ocular cell adhesion, migration and organization

The probiotic Shewanella putrefaciens PDP11 target virulence factors by modulating quorum sensing inhibition

Bacteria communicate with each other by producing signal molecules and regulating the production of virulence factors that have importance in pathogenicity. Quorum sensing (QS) is a bacterial communication mechanism based on the perception of population density and secretion of determining signal molecules called autoinducers (AI) such as the case of Acylhomoserine lactones (AHLs). AHLs-mediated QS processes seem to be common in the marine environment and among marine pathogenic bacteria, which pathogenesis could be mitigated by probiotics, among others. Probiotics are defined as live microbial cells that confer health benefits to the host and some of their mechanisms include the production of antagonistic compounds that are inhibitory toward pathogens. In this sense, Shewanella putrefaciens Pdp11, a strain described as a probiotic for use in aquaculture, has been analysed to mediate QS processes by quorum-quenching assays using synthetic AHLs. The enzymatic activity is estimated at around 80% and 30% for C8- and C10-HSL, respectively, while the rest of AHLs tested were not degraded by the Pdp11 strain. It would be an interesting feature of the probiotic Pdp11 strain since these AHLs are related to facilitating microbial adhesion by promoting biofilm formation among other virulence factors related to pathogens. On the other hand, a distinctive feature of AHL inactivated by lactonase is that it can be reactivated by acid treatment. In this way, little C8-AHL was recovered when it is extracted to pH2, which indicates the enzyme activity is not derived from the hydrolysis of the lactone ring derived from the action of lactonases, suggesting the enzyme activity in Pdp11 could be an AHL-acylase. The potential QQ activity of Pdp11 was unknown so, these preliminary studies led to a further as another promising probiotic QQ tool for aquaculture

Highlights from ASCO-GI 2021 from EORTC Gastrointestinal tract cancer group

Biliary tract cancer; Colorectal cancer; Drug developmentCáncer del tracto biliar; Cáncer colorrectal; Desarrollo de fármacosCàncer del tracte biliar; Càncer colorectal; Desenvolupament de fàrmacsLast year the field of immunotherapy was finally introduced to GI oncology, with several changes in clinical practice such as advanced hepatocellular carcinoma or metastatic colorectal MSI-H. At the virtual ASCO-GI symposium 2021, several large trial results have been reported, some leading to a change of practice. Furthermore, during ASCO-GI 2021, results from early phase trials have been presented, some with potential important implications for future treatments. We provide here an overview of these important results and their integration into routine clinical practice.Open Access funding provided by Université de Genève

ESMO Congress 2021: highlights from the EORTC gastrointestinal tract cancer group’s perspective

Neuroendocrine tumours; Pancreatic cancer; Stomach cancerTumores neuroendocrinos; Cáncer de páncreas; Cáncer de estómagoTumors neuroendocrins; Càncer de pàncrees; Càncer d'estómacThere has been no major change of practice in gastrointestinal oncology at the European Society for Medical Oncology (ESMO) symposium 2021, but confirmation that immunotherapy in combination with chemotherapy has become standard of care in several indications. The European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Track Cancer Group has selected important phase II and III trials presented during the symposium across all gastrointestinal cancers as well as early reports on new drugs or new combinations that may change practice in the future.This work was supported by a donation from the Swiss Cancer Research Foundation from Switzerland. MC was supported by a grant by EORTC Cancer Research Fund (ECRF) and the Gastrointestinal Tract Cancer Group