[Requested comment: the viewpoint of a noncardiac surgeon].
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Attitude of Health Personnel↗
Biomedical subjects
L Chiche
Publications and source records attributed to L Chiche.
Solution structure of the squash trypsin inhibitor MCoTI-II. A new family for cyclic knottins.
The "knottin" fold is a stable cysteine-rich scaffold, in which one disulfide crosses the macrocycle made by two other disulfides and the connecting backbone segments. This scaffold is found in several protein families with no evolutionary relationships. In the past few years, several homologous peptides from the Rubiaceae and Violaceae families were shown to define a new structural family based on macrocyclic knottin fold. We recently isolated from Momordica cochinchinensis seeds the first known macrocyclic squash trypsin inhibitors. These compounds are the first members of a new family of cyclic knottins. In this paper, we present NMR structural studies of one of them, MCoTI-II, and of a beta-Asp rearranged form, MCoTI-IIb. Both compounds display similar and well-defined conformations. These cyclic squash inhibitors share a similar conformation with noncyclic squash inhibitors such as CPTI-II, and it is postulated that the main effect of the cyclization is a reduced sensitivity to exo-proteases. On the contrary, clear differences were detected with the three-dimensional structures of other known cyclic knottins, i.e., kalata B1 or circulin A. The two-disulfide cystine-stabilized beta-sheet motif [Heitz et al. (1999) Biochemistry 38, 10615-10625] is conserved in the two families, whereas in the C-to-N linker, one disulfide bridge and one loop are differently located. The molecular surface of MCoTI-II is almost entirely charged in contrast to circulin A that displays a well-marked amphiphilic character. These differences might explain why the isolated macrocyclic squash inhibitors from M. cochinchinensis display no significant antibacterial activity, whereas circulins and kalata B1 do.
Amino Acid Sequence↗
Aneurysms of the innominate artery: surgical treatment of 27 patients.
PURPOSE: Aneurysms of the innominate artery (AIA) are widely considered to be a rare entity. We describe our experience with AIAs in the last three decades. METHODS: From October 1973 to October 2000, we operated on 27 patients with an AIA. The underlying cause of aneurysm was Takayasu's disease in 7 patients, degenerative disease in 6 patients, syphilis in 5 patients, chronic dissection in 3 patients, trauma in 2 patients, infection in 2 patients, a postoperative complication in 1 patient, and Marfan syndrome in 1 patient. AIA was associated with an aortic aneurysm in 17 patients. Fourteen patients had no symptoms. The remaining patients had symptoms, with thromboembolic complications in 7 patients, pain without rupture in 3 patients, and a ruptured aneurysm in 3 patients. In two patients at high risk for surgery who had a small AIA with embolic complications, a cervical approach was used as a means of performing distal exclusion and crossover bypass. In the remaining 25 patients, a midline sternotomy was used. One patient with a ruptured AIA exsanguinated during sternotomy. Ten patients underwent a prosthetic replacement of the ascending aorta and/or aortic arch with a separate prosthetic branch to the innominate artery (IA). Thirteen patients underwent ascending aorta-to-IA prosthetic bypass in association with lateral suture (8 patients) or prosthetic patching (5 patients) of the aorta. One patient with an infected aneurysm was treated by means of resection of the aneurysm, proximal ligation of the IA, and transposition of the right into the left common carotid artery. Cardiopulmonary bypass with deep hypothermic circulatory arrest was used in 10 patients. RESULTS: Three perioperative deaths occurred (2 of 4 in association with emergency treatment and 1 of 23 with elective treatment). Respiratory complications requiring prolonged artificial ventilation developed in five patients. Two patients had transient worsening of preoperative neurologic deficits. Late results, with a mean follow-up of 85 months, were good. CONCLUSION: The etiology and presentation of AIAs are variable. Surgical management with current cardiovascular techniques achieves excellent results.
Adult↗
[Side-to-side porto caval anastomosis with stent].
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Dissection↗
[The precautionary principle: to be used with precaution].
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Humans↗
[Fortuitous discovery of gallbladder cancer].
The prognosis of gallbladder cancer is basically dependent on the histological stage at diagnosis. In practice, the discovery of a small cancer of the bladder, generally during cholecystectomy give the patient a better care for curative treatment. The advent of laparoscopy has increased the number of cholecstectomies and could increase the frequency of this situation but also raises the difficult problem of metastatic dissemination. In the literature the figures on parietal metastasis after laparoscopy have ranged from 125% to 19%. The median delay to diagnosis of recurrence is 6 months. The cause of this phenomenon (role of the pneumoperitoneum) remains poorly elucidated. Risk factors for the development of a metastasis on the trocar orifice are: rupture of the gallbladder perioperatively and extraction of the gallbladder without protection. It is important to keep in mind this exceptional but serious risk and apply rigorous operative technique. In case of suspected gallbladder we do not advocate laparoscopy. Surgery (hepatectomy, lymphodenectomy, possibly resection of the biliary tract) would be indicted for all stages except pTis and T1a, taking into consideration the localization of the tumor and the patient's general status. It is also classical to recommend resection of the trocar orifices after laparoscopic cholecystectomy. There is a dual challenge today for small-sized gallbladder cancer: improving treatment and avoiding poorer prognosis due to the specific problems raised by laparoscopy.
Gallbladder Neoplasms↗
Squash trypsin inhibitors from Momordica cochinchinensis exhibit an atypical macrocyclic structure.
Three trypsin inhibitors (TIs), from the seeds of the squash Momordica cochinchinensis (MCo), have been isolated and purified using gel filtration, ion exchange chromatography, and reverse-phase HPLC. Their sequences could be determined only after proteolytic cleavages. In the case of MCoTI-I and -II, it was shown that their polypeptide backbones are cyclic, a structure that has never been described in squash TIs. They contain 34 amino acid residues with 3 disulfide bridges and measured molecular masses of 3453.0 and 3480.7, respectively. They are the largest known macrocyclic peptides containing disulfide bridges. Their sequences show strong homology to other squash TIs, suggesting a similar three-dimensional structure and an analogous mechanism of action. A model of MCoTI-II was constructed by analogy to the crystal structure of the complex between bovine trypsin and CMTI-I, indicating that the linker connecting the two termini is flexible and does not impose significant geometrical constraints. This flexibility allows an Asp-Gly peptide bond rearrangement to occur in this region, giving rise to two isoforms of MCoTI-II. Although the importance of cyclization is not clear, it might confer increased stability and resistance to proteolysis. A minor species, MCoTI-III, was also characterized as containing 30 amino acid residues with a molecular mass of 3379.6. This component possesses a linear backbone with a blocked N-terminus. MCoTIs represent interesting candidates for drug design, either by changing their specificity of inhibition or by using their structure as natural scaffolds bearing new binding activities.
Amino Acid Sequence↗
[Penetrating atheromatous ulcers of the aorta].
UNLABELLED: THORACIC PAINFUL SYNDROME: Penetrating atherosclerotic aortic ulcers represent a condition in which an atherosclerotic plaque ulcerates and disrupts the internal elastic lamina, allowing intramural hematoma formation into the aortic media. Recently individualized as an entity from all vascular thoracic painful syndromes, they affect preponderantly the elderly patients with a medical hypertensive and atherosclerotic history and with multiple cardiovascular risk factors. The descending thoracic aorta is most frequently involved. IMAGING: Computed tomography scanning and magnetic resonance imaging tend to replace aortography in providing an accurate diagnosis of the ulceration and of its parietal extent. Moreover, they allow the discrimination with aortic dissection or with intramural hematoma without intimal rupture which outcome and treatment should differ. RISKS: In the absence of complication, progressive aneurysmal dilatation at the level of the ulcer is a rule. Pseudoaneurysms formation, embolization, and acute transmural aortic rupture can however occur and may justify, in selected cases, a preventive or curative surgical treatment. STENT-GRAFTING: Endovascular stent-grafting techniques may appear as a safe and effective less invasive choice in high-risk patients with suitable anatomical conditions.
Age Factors↗
Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature.
OBJECTIVE: Liver adenomatosis (LA) is a rare disease originally defined by Flejou et al in 1985 from a series of 13 cases. In 1998, 38 cases were available for analysis, including eight personal cases. The aim of this study was to review and reappraise the characteristics of this rare liver disease and to discuss diagnosis and therapeutic options. BACKGROUND: LA was defined as the presence of >10 adenomas in an otherwise normal parenchyma. Neither female predominance nor a relation with estrogen/progesterone intake has been noted. Natural progression is poorly known. METHODS: The clinical presentation, evolution, histologic characteristics, and therapeutic options and results were analyzed based on a personal series of eight new cases and an updated review of the literature. RESULTS: From a diagnostic standpoint, two forms of liver adenomatosis with different presentations and evolution can be defined: a massive form and a multifocal form. The role of estrogen and progesterone is reevaluated. The risks of hemorrhage and malignant transformation are of major concern. In the authors' series, liver transplantation was indicated in two young women with the massive, aggressive form, and good results were obtained. CONCLUSION: Liver adenomatosis is a rare disease, more common in women, where outcome and evolution vary and are exacerbated by estrogen intake. Most often, conservative surgery is indicated. Liver transplantation is indicated only in highly symptomatic and aggressive forms of the disease.
Adenoma, Liver Cell↗
[ [In Process Citation]
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Journal Article↗
[Renocutaneous fistula: report of a chronic inguinal fistula].
The authors report a new case of isolated spontaneous nephrocutaneous fistula revealed by a persisting draining sinus in the left groin. Their present causative factors are identified. The computed tomography and magnetic resonance imaging actually may resolve the diagnostic dilemma and are helpful in the surgical treatment.
Adult↗
[What's new in liver surgery in the year 2000?].
More than half a century ago, Ton That Tung, then Lortat-Jacob performed the first anatomic hepatectomies, marking the onset of the conquest of liver surgery. Shortly thereafter, a few pioneers took the leap, making the first attempts at total hepatectomy and liver transplantation. Within years, considerable progress was made in hepatobiliary surgery which rapidly became a full-fledged surgery specialty. Techniques were equally improved with new advances in imaging and technology. The last 15 years have been so rich at in the strict sense of the word, little is new in liver surgery in 2000. What has changed is the general perception that liver surgery is entering a new era in the third millennium: high-tech surgery, a surgery that is safe, self-confident, yet aggressive and ambitious, a surgery that is perfectly integrated into increasingly sophisticated and comprehensive therapeutic schemes.
Adult↗
Min-21 and min-23, the smallest peptides that fold like a cystine-stabilized beta-sheet motif: design, solution structure, and thermal stability.
Small disulfide-rich proteins provide examples of simple and stable scaffolds for design purposes. The cystine-stabilized beta-sheet (CSB) motif is one such elementary structural motif and is found in many protein families with no evolutionary relationships. In this paper, we present NMR structural studies and stability measurements of two short peptides of 21 and 23 residues that correspond to the isolated CSB motif taken from a 28-residue squash trypsin inhibitor. The two peptides contain two disulfide bridges instead of three for the parent protein, but were shown to fold in a native-like fashion, indicating that the CSB motif can be considered an autonomous folding unit. The 23-residue peptide was truncated at the N-terminus. It has a well-defined conformation close to that of the parent squash inhibitor, and although less stable than the native protein, it still exhibits a high T(m) of about 100 degrees C. We suggest that this peptide is a very good starting building block for engineering new bioactive molecules by grafting different active or recognition sites onto it. The 21-residue peptide was further shortened by removing two residues in the loop connecting the second and third cysteines. This peptide exhibited a less well-defined conformation and is less stable by about 1 kcal mol(-)(1), but it might be useful if a higher flexibility is desired. The lower stability of the 21-residue peptide is supposed to result from inadequate lengths of segments connecting the first three cysteines, thus providing new insights into the structural determinants of the CSB motif.
Amino Acid Sequence↗
In situ repair of a secondary aortoappendiceal fistula with a rifampin-bonded Dacron graft.
Secondary aortoenteric fistulas remain challenging diagnostic and therapeutic problems. Although the duodenum is most frequently involved, other intestinal segments are possible sites for fistulization. We report here a case of graft-appendiceal fistula revealed by recurrent gastrointestinal bleeding 11 years after abdominal aortic aneurysm replacement. The preoperative diagnosis was not achieved by endoscopy or imaging assessment. Despite recommended principles of total graft excision and extraanatomic bypass, appendectomy and in situ rifampin-bonded graft reconstruction were performed because of the advanced age and poor arterial runoff. The postoperative course was uneventful and the patient remains well 17 months after operation.
Aged↗
Refined solution structure and backbone dynamics of 15N-labeled C12A-p8MTCP1 studied by NMR relaxation.
MTCP1 (for Mature-T-Cell Proliferation) was the first gene unequivocally identified in the group of uncommon leukemias with a mature phenotype. The three-dimensional solution structure of the human p8MTCP1 protein encoded by the MTCP1 oncogene has been previously determined by homonuclear proton two-dimensional NMR methods at 600 MHz: it consists of an original scaffold comprising three alpha-helices, associated with a new cysteine motif. Two of the helices are covalently paired by two disulfide bridges, forming an alpha-hairpin which resembles an antiparallel coiled-coil. The third helix is orientated roughly parallel to the plane defined by the alpha-antiparallel motif and appears less well defined. In order to gain more insight into the details of this new scaffold, we uniformly labeled with nitrogen-15 a mutant of this protein (C12A-p8MTCP1) in which the unbound cysteine at position 12 has been replaced by an alanine residue, thus allowing reproducibly high yields of recombinant protein. The refined structure benefits from 211 additional NOEs, extracted from 15N-edited 3D experiments, and from a nearly complete set of phi angular restraints allowing the estimation of the helical content of the structured part of the protein. Moreover, measurements of 15N spin relaxation times and heteronuclear 15N¿1H¿NOEs provided additional insights into the dynamics of the protein backbone. The analysis of the linear correlation between J(0) and J(omega) was used to interpret relaxation parameters. It appears that the apparent relative disorder seen in helix III is not simply due to a lack of experimental constraints, but associated with substantial contributions of sub-nanosecond motions in this segment.
DNA-Binding Proteins↗
The chimeric peptide [Lys(-2)-Arg(-1)]-sarafotoxin-S6b, composed of the endothelin pro-sequence and sarafotoxin, retains the salt-bridge staple between Arg(-1) and Asp8 previously observed in [Lys(-2)-Arg(-1)]-endothelin. Implications of this salt-bridge in the contractile activity and the oxidative folding reaction.
The chimeric peptide [Lys(-2)-Arg(-1)]-sarafotoxin-S6b (KR-SRTb) designed from the Lys-2-Arg-1 dipeptide of the endothelin pro-sequence and the sarafotoxin-S6b sequence was synthesized. Its contractile activity was found to be decreased markedly when compared with that of the parent SRTb. In contrast, the extension by the Lys-Arg dipeptide was found to increase the formation of the native disulfide isomer (82/18 versus 96/4) when the reaction was carried out in the presence of redox reagents. The solution structure of KR-SRTb was determined by NMR as a function of pH. In the carboxylic acid state, the structure consists of the cystine-stabilized alpha-helical motif, with the alpha-helical part spanning residues 9-15, and of an unstructured C-terminal tail. In the carboxylate state, the structure is characterized by a salt-bridge between Arg(-1) and Asp8, which we identified previously in the [Lys(-2)-Arg(-1)]-endothelin-1 peptide (KR-ET-1). The fact that this salt-bridge is commonly observed in KR-SRTb and KR-ET-1, despite the 33% sequence difference between the corresponding parental peptides, highlights the remarkable adaptability of the Lys-Arg extension for the formation of a special salt-bridge. As a consequence, this salt-bridge, which does not depend on either the 4-7 sequence of the loop or the C-terminal sequence, appears to be particularly well suited to improve the stability of the cystine-stabilized alpha-helical motif. Therefore, because of its high yield in the native disulfide arrangement and its high permissiveness for sequence mutation in the 4-7 loop, such a stabilized cystine-stabilized alpha-helical motif could be a valuable scaffold for the presentation of a library of constrained short peptides.
Amino Acid Sequence↗
Direct selection of EGF mutants displayed on filamentous phage using cells overexpressing EGF receptor.
Understanding receptor-ligand interactions, and the signal transduction pathways they activate, is of great interest for the discovery of novel antagonists and agonists. In this report we describe a rapid and efficient procedure to evaluate the importance of several different epidermal growth factor (EGF) residues for the binding and activation of its receptor (EGFR). We constructed an EGF mutant library randomized at positions 13, 15 and 16 and expressed them on filamentous phages. Phage display is a powerful system, allowing rapid isolation of binding mutants. Since many of the most pharmacologically interesting receptors cannot be produced in a soluble form, we developed a technique to rapidly select receptor-binding molecules directly on cells. A luciferase assay, simple to perform, was then used to test their biological transduction activity and to rapidly detect mutants of interest. Analysis of the resulting sequences revealed that the wild-type amino acids at positions 13, 15 and 16 are optimized for binding and activity. EGF mutants with agonist properties were also isolated and tolerated substitutions were identified.
3T3 Cells↗
Formation of native disulfide bonds in endothelin-1. Structural evidence for the involvement of a highly specific salt bridge between the prosequence and the endothelin-1 sequence.
The [Lys-Arg]-endothelin-1 analogue (KR-ET-1) yields almost selectively the native disulfide pattern (96%), in contrast to endothelin-1 (ET-1) that gives at least 25% of the non-native disulfide pattern. We have previously shown that the carboxylate-state structure of KR-ET-1 is more constrained and stabilized by a salt bridge between Arg(-1) and the Asp8 or Glu10 side chain [Aumelas et al. (1995) Biochemistry 34, 4546-4561]. To identify this salt bridge and its potential involvement in the disulfide bond formation, [E10Q], [D18N], and [D8N] carboxamide analogues were studied, which led to the unambiguous identification of the Arg(-1)-Asp8 salt bridge. Furthermore, while [E10Q] and [D18N] analogues gave a high yield of the native isomer (>/=90%), the [D8N] analogue afforded a ratio of the two isomers close to that observed for ET-1 (68%) [Kubo et al. (1997) Lett. Pept. Sci. 4, 185-192]. Assuming that the formation of disulfide bonds occurs in a thermodynamically controlled step, we have hypothesized that the Arg(-1)-Asp8 salt bridge and concomitant interactions could be responsible for the increase in yield of the native isomer of KR-ET-1. In the present work, we describe the structural studies of the carboxamide analogues and of the minor non-native KR-ET-1 isomer. On the basis of 1H NMR and CD spectra as a function of pH, [E10Q] and [D18N] analogues display a conformational change similar to that of the parent peptide, whereas the structure of the [D8N] analogue is unchanged. For the non-native isomer, we measured a lower helical content than for the native isomer and observed a marked difference in the orientation of the KRCSC backbone. In addition, no salt bridge was experimentally observed. Altogether, these results allow us to hypothesize that the salt bridge between two highly conserved residues, one belonging to the prosequence [Arg(-1)] and the other to the mature sequence [Asp8], is involved in the formation of the native disulfide isomer of ET-1. The involvement of the prosequence in the formation of the native disulfide isomer strongly suggests that, in the maturation pathway of ET-1, cleavage of the Arg52-Cys53 amide bond occurs after native disulfide bond formation.
Amino Acid Sequence↗