Mutation in the Trapalpha/Ssr1 gene, encoding translocon-associated protein alpha, results in outflow tract morphogenetic defects.

Translocon-associated protein complex (TRAP) is thought to be required for efficient protein-specific translocation across the endoplasmic reticulum membrane. We created a mutation in the Trapalpha gene that leads to the synthesis of a truncated TRAPalpha protein fused to ShBle-beta-galactosidase. Analysis of Trapalpha cDNAs reveals that among three different messenger RNAs expressed in the mouse, one of them encodes a slightly larger protein that differs in its C-terminal end. This mRNA, specific for skeletal muscle and heart, is only expressed after birth. Homozygous Trapalpha mutant pups die at birth, likely as a result of severe cardiac defects. Indeed, the septation of the proximal part of the outflow tract is absent, resulting in a double-outlet right ventricle. Studies of protein secretion in transfected embryonic fibroblasts reveal that the TRAP complex does not function properly in homozygous mutant cells and confirm, in vivo, the involvement of TRAP in substrate-specific translocation. Our results provide the first in vivo demonstration that a member of the TRAP complex plays a crucial role in mammalian heart development and suggest that TRAPalpha could be involved in translocation of factors necessary for maturation of endocardial cushions.

63Cu-31P coupling constants and 63Cu quadrupole couplings from 31P CP/MAS spectra of copper (I)--phosphine complexes with aryldithiocarboxylates or benzoate.

Magic-angle spinning 31P NMR spectra of solid [CuS2C-Ph(PPh3)2] 1, [{CuS2C-pT}4(PPh3)2] 2, [{CuS2C-Ph}4(PPh3)2] 3. [CuS2C-Ph(dppm)]2 4 and [CuO2C-Ph(dppm)]2 5, (T = tolyl, dppm = bis(diphenylphosphino)methane) were obtained at 109.6 MH2. They consist of distorted quartets from non-equivalent phosphorus atoms and provide approximate values of the indirect spin-spin coupling constant J[63Cu,31P], that are indicative of the covalency of the dithiocarboxylate-copper bonding. The spacing distortions are related to a number of molecular and structural parameters and thereby allow an estimation of the copper quadrupole coupling constant e2qQ/h which, as expected, is smaller for tetra-coordinated (1, 2, 3 and 4) than for tri-coordinated (5) copper sites. The spectrum of 2 has been successfully simulated (including the isotope effects from the less abundant 65Cu isotope) using the full theory for calculation of the spin eigenfunctions of the quadrupolar nucleus.

Carcinoma ductal in situ de la mama: diagnóstico y alternativas terapéuticas / In situ ductal breast carcinoma: diagnosis and therapeutical alternatives

Se revisaron retrospectivamente las fichas clínicas de 51 casos de carcinoma ductal in situ (CDIS) de la mama. Los principales modos de detección del CDIS fueron un tumor palpable en 29 casos,secreción hemática por el pezón en 11 casos y una enfermedad de Paget en 4 casos. En 15 casos (29 por ciento) el diagnóstico se hizo exclusivamente por el hallazgo de microcalcificaciones mamográficas en pacientes asintomáticas. El tratamiento efectuado consistió en mastectomía parcial sola en 4 casos, mastectomía parcial con radioterapia en 29 y mastectomía total en 18 casos, con reconstrucción mamaria en 3. Se realizó disección linfática axilar en 20 pacientes, siendo en todas ellas negativa. Con una mediana de seguimiento de 39 meses, sólo una paciente ha presentado recidiva local (2 por ciento), siendo rescatada con una mastectomía. La sobrevida total es de un 100 por ciento. Se discute una revisión completa de la literatura y se presenta la clasificación pronóstica de Van Nuys para el CDIS. Se analizan las alternativas terapéuticas y se proponen pautas de tratamiento

Quimioterapia preoperatoria en cáncer de mama / Preoperatory chemotherapy in breast cancer

El uso de la quimioterapia preoperatoria (Qx preop) en cáncer de mama localmente avanzado ha disminuido la tasa de pacientes consideradas inoperables y las recidivas locaes, aumentando según algunos la sobrevida libre de enfermedad y la sobrevida total. El objetivo de este trabajo es medir la respuesta del tumos de mama primario a la Qx preop y evaluar la influencia de ésta en la elección del tipo de tratamiento quirúrgico. Entre mayo de 1990 y marzo de 1995, ingresaron al protocolo de Qx preop del IOCPC, 93 pacientes con diagnóstico de cáncer de mama localmente avanzado, siendo evaluables para este estudio 80 pacientes. La Qx preop consistió en 3 ciclos de drogas con los esquemas de (CMF) o (FEC/FAC). La respuesta fue evaluada en comité oncológico al finalizar el tercer ciclo, en que se decidió la secuencia a seguir con el tratamiento, ya sea primero radioterapia (RT) o cirugía dependiendo de la respuesta clínica. La Qx preop tuvo una respuesta clínica completa o parcial en un 39 por ciento de las pacientes, permitiendo realizar un tratamiento conservador en un 16 por ciento de ellas. Con la adición de RT preoperatoria es posible reducir significativamente el número de pacientes consideradas inoperables en el momento de la evaluación inicial

Mutagens produced by the pyrolysis of opium and its alkaloids as possible risk factors in cancer of the bladder and oesophagus.

Samples of opium pipe scrapings (opium dross, called sukhteh locally), but not of crude opium, collected in an area with a high incidence of oesophageal cancer in north-east Iran, were shown to contain pro-mutagens, producing mostly frameshift mutations in Salmonella typhimurium strains TA1538 and TA98 after metabolic activation. Pyrolysis of opium and of its major alkaloid, morphine, yielded smoke condensates with mutagenic activities 10 and 100 times higher, respectively, than that of the sukhteh samples tested. Heterocyclic aromatic hydrocarbons and primary aromatic amines present at different concentrations in these three pyrolysates are considered to be the major active principles. Opium addiction has been implicated as a risk factor in bladder cancer in humans and the ingestion of opium pyrolysates, in conjunction with dietary deficiencies, may be related to the high incidence of oesophageal cancer in north-east Iran, although causality has not been established.

Comparative mutagenicity of N-nitrosamines in a semi-solid and in a liquid incubation system in the presence of rat or human tissue fractions.

The rat liver microsome-mediated mutagenicities of a series of N-nitrosodialkylamines and heterocyclic N-nitrosamines were determined in a liquid incubation system using Salmonella typhimurium TA1530. The influence on mutation frequency of the concentration of co-factors for mixed-function oxidase and composition and molarity of the buffer was investigated, using N-nitrosomorpholine as substrate. The mutagenicity of the N-nitroso compounds in the liquid incubation system under optimal reaction conditions at equimolar concentration was compared quantitatively with that obtained in a soft-agar incorporation assay. N-Nitrosodi-n-pentylamine and N-nitrosodi-n-butylamine showed no enzyme-mediated mutagenicity in the liquid incubation system, and metabolically activated N-nitroso-dimethylamine and N-nitroso-diethylamine showed negligible mutagenic activity in the soft-agar assays. In contrast with these results with the N-nitrosodialkylamines, the mutagenic effects of heterocyclic N-nitrosamines were similar in the liquid incubation system and in soft-agar incorporation assays. The heterocyclic N-nitrosamines showed rat-liver microsome-mediated mutagenicity in the following descending order: N-nitrosomorpholine greater than N-nitrosopyrrolidine greater than N-nitrosopiperidine greater than N-nitroso-N'-methylpiperazine. Seven human liver specimens converted all heterocyclic N-nitrosamines into mutagens; this activity was similar to that of rat liver, except that for N-nitroso-N'-methylpiperazine, fractions from three human liver biopsies were three to 30 times more active than those from untreated rats. The specific reversion of S. typhimurium TA1530 to histidine prototrophy provides experimental evidence that all the N-nitrosamines studied were converted by liver microsomal enzymes into monofunctional alkylating agents.