Cyclic ruthenium-peptide conjugates as integrin-targeting phototherapeutic prodrugs for the treatment of brain tumors

To investigate the potential of tumor-targeting photoactivated chemotherapy, a chiral ruthenium-based anticancer warhead, Λ/Δ-[Ru(Ph2phen)2(OH2)2]2+, was conjugated to the RGD-containing Ac-MRGDH-NH2 peptide by direct coordination of the M and H residues to the metal. This design afforded two diastereoisomers of a cyclic metallopeptide, Λ-[1]Cl2 and Δ-[1]Cl2. In the dark, the ruthenium-chelating peptide had a triple action. First, it prevented other biomolecules from coordinating with the metal center. Second, its hydrophilicity made [1]Cl2 amphiphilic so that it self-assembled in culture medium into nanoparticles. Third, it acted as a tumor-targeting motif by strongly binding to the integrin (Kd = 0.061 μM for the binding of Λ-[1]Cl2 to αIIbβ3), which resulted in the receptor-mediated uptake of the conjugate in vitro. Phototoxicity studies in two-dimensional (2D) monolayers of A549, U87MG, and PC-3 human cancer cell lines and U87MG three-dimensional (3D) tumor spheroids showed that the two isomers of [1]Cl2 were strongly phototoxic, with photoindexes up to 17. Mechanistic studies indicated that such phototoxicity was due to a combination of photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) effects, resulting from both reactive oxygen species generation and peptide photosubstitution. Finally, in vivo studies in a subcutaneous U87MG glioblastoma mice model showed that [1]Cl2 efficiently accumulated in the tumor 12 h after injection, where green light irradiation generated a stronger tumoricidal effect than a nontargeted analogue ruthenium complex [2]Cl2. Considering the absence of systemic toxicity for the treated mice, these results demonstrate the high potential of light-sensitive integrin-targeted ruthenium-based anticancer compounds for the treatment of brain cancer in vivo.Metals in Catalysis, Biomimetics & Inorganic MaterialsAnimal science

The genomic basis of the plant island syndrome in Darwin’s giant daisies

The repeated, rapid and often pronounced patterns of evolutionary divergence observed in insular plants, or the ‘plant island syndrome’, include changes in leaf phenotypes, growth, as well as the acquisition of a perennial lifestyle. Here, we sequence and describe the genome of the critically endangered, Galápagos-endemic species Scalesia atractyloides Arnot., obtaining a chromosome-resolved, 3.2-Gbp assembly containing 43,093 candidate gene models. Using a combination of fossil transposable elements, k-mer spectra analyses and orthologue assignment, we identify the two ancestral genomes, and date their divergence and the polyploidization event, concluding that the ancestor of all extant Scalesia species was an allotetraploid. There are a comparable number of genes and transposable elements across the two subgenomes, and while their synteny has been mostly conserved, we find multiple inversions that may have facilitated adaptation. We identify clear signatures of selection across genes associated with vascular development, growth, adaptation to salinity and flowering time, thus finding compelling evidence for a genomic basis of the island syndrome in one of Darwin’s giant daisies

Cichlid biogeography: comment and review

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72313/1/j.1467-2979.2004.00148.x.pd

Consenso mexicano sobre dolor torácico no cardiaco

Introducción: Dolor torácico no cardíaco (DTNC) se define como un síndrome clínico caracte-rizado por dolor retroesternal semejante a la angina de pecho, pero de origen no cardiaco ygenerado por enfermedades esofágicas, osteomusculares, pulmonares o psiquiátricas.Objetivo: Presentar una revisión consensuada basada en evidencias sobre definición, epidemio-logía, fisiopatología, diagnóstico y opciones terapéuticas para pacientes con DTNC.Métodos: Tres coordinadores generales realizaron una revisión bibliográfica de todas las publi-caciones en inglés y espa˜nol sobre el tema y elaboraron 38 enunciados iniciales divididosen tres categorías principales: 1) definiciones, epidemiología y fisiopatología; 2) diagnóstico,y 3) tratamiento. Los enunciados fueron votados (3 rondas) utilizando el sistema Delphi, y losque alcanzaron un acuerdo > 75% fueron considerados y calificados de acuerdo con el sistemaGRADE. Resultados y conclusiones: El consenso final incluyó 29 enunciados Todo paciente que debutacon dolor torácico debe ser inicialmente evaluado por un cardiólogo. La causa más común deDTNC es la enfermedad por reflujo gastroesofágico (ERGE). Como abordaje inicial, si no existensíntomas de alarma, se puede dar una prueba terapéutica con inhibidor de bomba de pro-tones (IBP) por 2-4 semanas. Si hay disfagia o síntomas de alarma, se recomienda hacer unaendoscopia. La manometría de alta resolución es el mejor método para descartar trastornosmotores espásticos y acalasia. La pHmetría ayuda a demostrar exposición esofágica anormal alácido. El tratamiento debe ser dirigido al mecanismo fisiopatológico, y puede incluir IBP, neu-romoduladores y/o relajantes de músculo liso, intervención psicológica y/o terapia cognitiva,y ocasionalmente cirugía o terapia endoscópica. ABSTRACT Introduction: Non-cardiac chest pain is defined as a clinical syndrome characterized by retros-ternal pain similar to that of angina pectoris, but of non-cardiac origin and produced byesophageal, musculoskeletal, pulmonary, or psychiatric diseases.Aim: To present a consensus review based on evidence regarding the definition, epidemiology,pathophysiology, and diagnosis of non-cardiac chest pain, as well as the therapeutic options forthose patients. Methods: Three general coordinators carried out a literature review of all articles published inEnglish and Spanish on the theme and formulated 38 initial statements, dividing them into 3 maincategories: (i) definitions, epidemiology, and pathophysiology; (ii) diagnosis, and (iii) treatment.The statements underwent 3 rounds of voting, utilizing the Delphi system. The final statementswere those that reached > 75% agreement, and they were rated utilizing the GRADE system.Results and conclusions: The final consensus included 29 statements. All patients presentingwith chest pain should initially be evaluated by a cardiologist. The most common cause ofnon-cardiac chest pain is gastroesophageal reflux disease. If there are no alarm symptoms, the initial approach should be a therapeutic trial with a proton pump inhibitor for 2-4 weeks. Ifdysphagia or alarm symptoms are present, endoscopy is recommended. High-resolution mano-metry is the best method for ruling out spastic motor disorders and achalasia and pH monitoringaids in demonstrating abnormal esophageal acid exposure. Treatment should be directed at thepathophysiologic mechanism. It can include proton pump inhibitors, neuromodulators and/orsmooth muscle relaxants, psychologic intervention and/or cognitive therapy, and occasionallysurgery or endoscopic therapy

The Mexican consensus on non-cardiac chest pain

Introduction: Non-cardiac chest pain is defined as a clinical syndrome characterized by ret-rosternal pain similar to that of angina pectoris, but of non-cardiac origin and produced byesophageal, musculoskeletal, pulmonary, or psychiatric diseases. Aim: To present a consensus review based on evidence regarding the definition, epidemiology,pathophysiology, and diagnosis of non-cardiac chest pain, as well as the therapeutic options forthose patients. Methods Three general coordinators carried out a literature review of all articles published inEnglish and Spanish on the theme and formulated 38 initial statements, dividing them into 3 maincategories: 1) definitions, epidemiology, and pathophysiology, 2) diagnosis, and 3) treatment.The statements underwent 3 rounds of voting, utilizing the Delphi system. The final statementswere those that reached > 75% agreement, and they were rated utilizing the GRADE system. Results and conclusions The final consensus included 29 statements. All patients presentingwith chest pain should initially be evaluated by a cardiologist. The most common cause of non-cardiac chest pain is gastroesophageal reflux disease. If there are no alarm symptoms, the initialapproach should be a therapeutic trial with a proton pump inhibitor for 2-4 weeks. If dysphagiaor alarm symptoms are present, endoscopy is recommended. High-resolution manometry isthe best method for ruling out spastic motor disorders and achalasia and pH monitoring aidsin demonstrating abnormal esophageal acid exposure. Treatment should be directed at thepathophysiologic mechanism. It can include proton pump inhibitors, neuromodulators and/orsmooth muscle relaxants, psychologic intervention and/or cognitive therapy, and occasionallysurgery or endoscopic therapy