5-Arylisothiazol-3(2H)-one-1,(1)-(di)oxides: A new class of selective tumor-associated carbonic anhydrases (hCA IX and XII) inhibitors.

Sixteen 5-aryl-substituted isothiazol-3(2H)-one-1,(1)-(di)oxide analogs have been prepared from the corresponding 5-chloroisothiazol-3(2H)-one-1-oxide or -1,1-dioxide by a Suzuki-Miyaura cross-coupling reaction and screened for their inhibition potency against four human carbonic anhydrase isoenzymes: the transmembrane tumor-associated hCA IX and XII and the cytosolic off-target hCA I and II. Most of the synthesized derivatives inhibited hCA IX and XII isoforms in nanomolar range, whereas remained inactive or modestly active against both hCA I and II isoenzymes. In the N-tert-butylisothiazolone series, the 5-phenyl-substituted analog (1a) excelled in the inhibition of tumor-associated hCA IX and XII (Ki = 4.5 and Ki = 4.3 nM, respectively) with excellent selectivity against off target hCA I and II isoenzymes (S > 2222 and S > 2325, respectively). Since the highest inhibition activities were observed with N-tert-butyl derivatives, lacking a zinc-binding group, we suppose to have a new binding mode situated out of the active site. Additionally, three free-NH containing analogs (3a, 4a, 3i) have also been prepared in order to study the impact of free-NH containing N-acyl-sulfinamide- (-SO-NH-CO-) or N-acyl-sulfonamide-type (-SO2-NH-CO-) derivatives on the inhibitory potency and selectivity. Screening experiments evidenced 5-phenylisothiazol-3(2H)-one-1,1-dioxide (4a), the closest saccharin analog, to be the most active derivative with inhibition constants of Ki = 40.3 nM and Ki = 9.6 nM against hCA IX and hCA XII, respectively. The promising biological results support the high potential of 5-arylisothiazolinone-1,(1)-(di)oxides to be exploited for the design of potent and cancer-selective carbonic anhydrase inhibitors.

Conformation-dependent binding of a Tetrastatin peptide to αvß3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition.

Tetrastatin, a 230 amino acid sequence from collagen IV, was previously demonstrated to inhibit melanoma progression. In the present paper, we identified the minimal active sequence (QKISRCQVCVKYS: QS-13) that reproduced the anti-tumor effects of whole Tetrastatin in vivo and in vitro on melanoma cell proliferation, migration and invasion. We demonstrated that QS-13 binds to SK-MEL-28 melanoma cells through the αvß3 integrin using blocking antibody and ß3 integrin subunit siRNAs strategies. Relevant QS-13 conformations were extracted from molecular dynamics simulations and their interactions with αVß3 integrin were analyzed by docking experiments to determine the binding areas and the QS-13 amino acids crucial for the binding. The in silico results were confirmed by in vitro experiments. Indeed, QS-13 binding to SK-MEL-28 was dependent on the presence of a disulfide-bound as shown by mass spectroscopy and the binding site on αVß3 was located in close vicinity to the RGD binding site. QS-13 binding inhibits the FAK/PI3K/Akt pathway, a transduction pathway that is largely involved in tumor cell proliferation and migration. Taken together, our results demonstrate that the QS-13 peptide binds αvß3 integrin in a conformation-dependent manner and is a potent antitumor agent that could target cancer cells through αVß3.

Plasmin releases the anti-tumor peptide from the NC1 domain of collagen XIX.

During tumor invasion, tumor cells degrade the extracellular matrix. Basement membrane degradation is responsible for the production of peptides with anti-tumor properties. Type XIX collagen is associated with basement membranes in vascular, neuronal, mesenchymal and epithelial tissues. Previously, we demonstrated that the non-collagenous NC1, C-terminal, domain of collagen XIX [NC1(XIX)] inhibits the migration capacities of tumor cells and exerts a strong inhibition of tumor growth. Here, we demonstrate that plasmin, one of the most important enzyme involved in tumor invasion, was able to release a fragment of NC1(XIX), which retained the anti-tumor activity. Molecular modeling studies showed that NC1(XIX) and the anti-tumor fragment released by plasmin (F4) adopted locally the same type I ß-turn conformation. This suggests that the anti-tumor effect is conformation-dependent. This study demonstrates that collagen XIX is a novel proteolytic substrate for plasmin. Such release may constitute a defense of the organism against tumor invasion.

Lesiones endoperiodontales y mortalidad dentaria / Endoperiodontal lesions and dental mortality

Introducción: la caries dental afecta la integridad de los dientes, pudiendo provocar lesiones endodónticas irreversibles que le confieren un carácter incurable a los mismos. El periodonto está anatómicamente interrelacionado con la pulpa dental. Las lesiones resultantes de la interacción entre la enfermedad pulpar y periodontal son conocidas como lesiones endoperiodontales. Objetivo: evaluar el comportamiento de las lesiones endoperiodontales en el área de salud de la Facultad de Estomatología de enero de 1998 a diciembre de 2002. Material y Métodos: para ello se realizó un estudio descriptivo, retrospectivo y transversal con las historias clínicas de pacientes atendidos con este diagnóstico en la Facultad de Estomatología de La Habana, en el período comprendido entre enero de 1998 y diciembre del 2002. La muestra quedó constituida por 124 historias clínicas pertenecientes a pacientes con dientes afectados por estas lesiones.Resultados: el 15,6 por ciento de los pacientes presentaron lesión endoperiodontal, 60,5 por ciento tuvieron la causa endodóntica como origen de las lesiones. El 42 por ciento de los dientes afectados tuvo que ser extraído debido a causas periodontales. Conclusiones: dentro de las causas que favorecieron el origen del objeto de estudio, el endodóntico ocupó el lugar cimero. Las terapéuticas más realizadas fueron la endodóntica y combinadas ocupando el primero y segundo lugares respectivamente. El porcentaje de lesiones endoperiodontales fue bajo, aunque la mortalidad dentaria por este tipo de afecciones fue alta y estuvo fundamentalmente relacionada con la causa periodontal, y con el grupo de 35 a 59 años de edad(AU)

Introduction: dental caries affects the integrity of the teeth and can cause irreversible endodontic lesions that confer an incurable character to them. The periodontium is anatomically interconnected with the dental pulp. Injuries resulting from the interaction between the pulp and periodontal disease are known as Endoperiodontal injuries.Objective: to evaluate the behavior of Endoperiodontal injuries in the policlinic belongs to The Havana Dentistry Faculty from January 1998 to December 2002.Material and Methods: descriptive, retrospective and cross-sectional study was performed using the medical records of patients seen with this diagnosis in the Faculty of Dentistry of Havana, in the period between January 1998 and December 2002. The sample was composed of 124 medical records belonging to patients with teeth affected by these injuries. Results: 15.6 pr ciento of patients had Endoperiodontal injury, 60.5 por ciento of patients had the cause and origin of endodontic lesions. 42 por ciento of the affected teeth had to be extracted due to periodontal reasons. Conclusions: among the causes that favored the origin of the object of study, endodontic occupied the top place. Therapeutic most performed were combined endodontic and occupying the first and second place respectively. The percentage of endoperiodontales lesions was low, although the tooth mortality such conditions was high and was mainly related to periodontal cause, and the group of 35 to 59 years old(AU)

Protegendo a infância: análise da política de saúde da criança

Nos últimos anos ocorreram muitas modificações no âmbito da saúde da criança no Brasil, estimuladas pelas políticas públicas de saúde. Através de uma pesquisa qualitativa do tipo pós-estruturalista, buscou-se catalogar descritores que identificam a promoção dos princípios e diretrizes da PNAB referentes à saúde da criança. Avaliando os mesmos, constatou-se que cada um dos princípios e diretrizes é de suma importância a este cuidado, visto que cada um deles possui um importante impacto no desenvolvimento desta criança, sendo entendida esta como o sujeito de sua própria história. Por isto, a atenção à sua saúde deverá se organizar a partir de suas particularidades e subjetividades, incluindo a equipe de saúde, a família e a comunidade neste método de proteção.