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1.
J Plast Reconstr Aesthet Surg ; 74(9): 2042-2049, 2021 Sep.
Article in English | MEDLINE | ID: mdl-33455872

ABSTRACT

INTRODUCTION: The consequences on the cervicofacial venous circulation of major cervicofacial vein ligations are poorly known. We aimed to highlight by using Doppler Ultrasound flow differences in the cervicofacial venous network in the case of unilateral or bilateral ligation of main venous collector trunks (external jugular vein [EJV] and internal jugular vein [IJV]) METHODS: A Doppler ultrasound was performed on 10 healthy volunteers, 8 patients with previous bilateral ligation of the EJV, 8 with a unilateral ligation of the EJV, and 8 with a unilateral ligation of the EJV and IJV, after modified radical neck dissection. The diameter, the flow direction and the peak systolic velocity (PSV) of the superficial temporal vein, the facial vein (FV) and the IJV were measured. RESULTS: Healthy patients had a similar right and left PSV for all the veins studied, with always antegrade flows. Patients with previous ligations had some significant right/left differences and retrograde flows. CONCLUSION: A redistribution of venous blood flow on the contralateral side of the face and neck seems to take place in the case of unilateral ligation of the EJV and/or IJV. Retrograde flows are sometimes observed in the case of previous ligation of the EJV and/or IJV and might compromise the success of venous microanastomoses.


Subject(s)
Face/blood supply , Jugular Veins/physiology , Jugular Veins/surgery , Ligation , Microsurgery/methods , Neck/blood supply , Vascular Surgical Procedures/methods , Adult , Cerebral Veins/diagnostic imaging , Cerebral Veins/physiology , Face/surgery , Female , Head and Neck Neoplasms/surgery , Humans , Jugular Veins/diagnostic imaging , Male , Neck/surgery , Neck Dissection , Regional Blood Flow , Squamous Cell Carcinoma of Head and Neck/surgery , Ultrasonography, Doppler, Color , Veins/diagnostic imaging , Veins/physiology
2.
Eur Ann Otorhinolaryngol Head Neck Dis ; 135(2): 111-117, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29198646

ABSTRACT

OBJECTIVES: Salvage surgery is the gold-standard treatment for locoregional recurrence of laryngeal and hypopharyngeal cancer following radiation therapy. Imperfect oncologic and functional results, however, require patient selection. The main objective of the present study was to determine preoperative factors for survival. Secondary objectives were to study 5-year overall and disease-free survival, general and locoregional complications, and functional results in terms of feeding and tracheotomy closure. PATIENTS AND METHOD: A retrospective multicenter study included 52 patients treated by salvage surgery for recurrence of laryngeal or hypopharyngeal squamous cell carcinoma after radiation therapy between 2005 and 2013. RESULTS: Factors associated with improved 3-year overall survival on univariate analysis comprised laryngeal primary (P=0.001), laryngeal recurrence (P=0.026), rT1, rT2 or rT3 rather than rT4 tumor (P=0.007), previous chemotherapy (P=0.036), and neck dissection during salvage surgery (P=0.005), the last of these being confirmed on multivariate analysis. Five-year overall survival was 36.0% (range, 27.6-44.4%), for a median 23.04 months (95% CI, 19.44-26.64). Five-year disease-free survival was 23.5% (range, 16.0-31.0%), for a median 8.04 months (95% CI, 2.04-14.04). CONCLUSION: Salvage surgery for laryngeal or hypopharyngeal cancer is difficult, and survival is not good. Laryngeal primary and recurrence location, moderate tumor volume and extension (

Subject(s)
Carcinoma, Squamous Cell/surgery , Laryngeal Neoplasms/surgery , Laryngectomy , Neck Dissection , Neoplasm Recurrence, Local/surgery , Patient Selection , Salvage Therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/radiotherapy , Female , Humans , Hypopharyngeal Neoplasms/surgery , Laryngeal Neoplasms/mortality , Laryngeal Neoplasms/pathology , Laryngeal Neoplasms/radiotherapy , Laryngectomy/methods , Male , Middle Aged , Neck Dissection/methods , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/radiotherapy , Preoperative Care/methods , Prognosis , Radiotherapy, Adjuvant/methods , Retrospective Studies , Salvage Therapy/methods , Survival Analysis , Treatment Outcome
3.
Eur Ann Otorhinolaryngol Head Neck Dis ; 133(6): 387-391, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27502822

ABSTRACT

OBJECTIVES: Mucosal melanoma of the nasal cavity and paranasal sinuses is a rare and highly aggressive tumor. We report our experience over 20 years in management of this tumor. PATIENTS AND METHODS: A retrospective study included 14 patients with primary sinonasal mucosal melanoma. RESULTS: The series comprised 8 male and 6 female patients, with a median age at diagnosis of 67 years. Staging on the American Joint Committee on Cancer classification of sinus cancer was 14% T2, 22% T3, 75% T4a and 7% T4b. All patients underwent primary surgical treatment; 71% received adjuvant external radiotherapy. Median recurrence-free interval was 28.7 months. Two- and 5-year overall survival was 43% and 32%, respectively. Median follow-up was 43 months. CONCLUSIONS: Mucosal melanomas of the nasal cavity and paranasal sinuses are very specific entities. Limited pathophysiological knowledge still precludes effective medium- and long-term management. Future treatment will probably be based on global adjuvant or neoadjuvant-targeted chemotherapy.


Subject(s)
Melanoma/pathology , Nasal Cavity/pathology , Nasal Mucosa/pathology , Nose Neoplasms/pathology , Paranasal Sinus Neoplasms/pathology , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Melanoma/mortality , Melanoma/therapy , Middle Aged , Nasal Cavity/surgery , Nasal Mucosa/surgery , Neoplasm Recurrence, Local , Nose Neoplasms/mortality , Nose Neoplasms/therapy , Paranasal Sinus Neoplasms/mortality , Paranasal Sinus Neoplasms/therapy , Radiotherapy, Adjuvant , Retrospective Studies
4.
Cancer Radiother ; 18(7): 666-71, 2014 Nov.
Article in French | MEDLINE | ID: mdl-24981411

ABSTRACT

PURPOSE: To assess microscopic extensions of head and neck squamous cell carcinomas aiming at a proposal for target volumes of radiation therapy. MATERIALS AND METHODS: Surgical specimens were prospectively analysed macroscopically and microscopically. Tumour borders were identified per macroscopic visual examination and inked on stained slides. Then microscopic implants (perineural or lymphatic involvement, or in situ carcinomas) were looked for with an optic microscope in the macroscopic healthy tissue surrounding the tumour. The maximal length from tumour border was correlated with the maximal length of macroscopically healthy tissues assessable. RESULTS: Twenty-one specimens were analysed and 12 were locally advanced tumours. Mean and median maximal microscopic extensions were 2.9 and 1.0mm (0-15mm), respectively. The 90th and 95th percentiles were 5 and 11mm, respectively. The ratio between healthy tissue length and maximal microscopic tumour extension was 10%. No correlation was found with tumour grade or volume. CONCLUSION: The presence of microscopic tumour was unlikely after 5mm from macroscopic tumour (≤5% of patients in this series) but should be assessed along with other histoclinical factors and particularities of tumour behaviour by anatomic site. A rigorous terminology should authorize a relevant appreciation of local risk of recurrence, particularly in adjuvant setting or for clinical target volume definition. Larger and more homogenous confirmatory series are needed.


Subject(s)
Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/radiotherapy , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/radiotherapy , Radiotherapy Planning, Computer-Assisted/methods , Adult , Aged , Carcinoma, Squamous Cell/surgery , Female , Head and Neck Neoplasms/surgery , Humans , Male , Microscopy , Middle Aged , Neoplasm Invasiveness , Prospective Studies , Radiotherapy, Conformal , Staining and Labeling
5.
Eur Ann Otorhinolaryngol Head Neck Dis ; 129(6): 327-30, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22819223

ABSTRACT

OBJECTIVE: The present study describes the clinical, radiological and histological features of pharyngeal synovial sarcoma, on the basis of one clinical case, and discusses management. CASE STUDY: A male patient, aged 27 years, presented with synovial sarcoma of the lateral pharyngeal wall, revealed by pharyngeal discomfort and bloody sputum. CT and MRI showed a partially necrotic tumoral process centered on the upper half of the piriform sinus. Pathologic analysis found a malignant biphasic tumor, suggestive of synovial sarcoma. Partial pharyngolaryngectomy was performed on a lateral approach, with associated radiotherapy. DISCUSSION: Synovial sarcoma raises diagnostic and therapeutic issues. Prognostic factors are not clearly established. CONCLUSION: Pharyngeal synovial sarcoma is a rare tumor. Treatment is essentially surgical, requiring wide margins; radiotherapy is usually associated. The value of chemotherapy has yet to be assessed.


Subject(s)
Pharyngeal Neoplasms/diagnosis , Sarcoma, Synovial/diagnosis , Adult , Humans , Male
6.
Eur Ann Otorhinolaryngol Head Neck Dis ; 129(3): 160-2, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22475977

ABSTRACT

OBJECTIVES: To illustrate, via a case report, how a differential diagnosis of amyloidosis is to be suspected in case of a nasopharyngeal mass. CASE REPORT: A 59-year-old woman presented with bilateral nasal obstruction with associated episodic tubal dysfunction. Physical examination found a mass occupying the entire nasopharynx, initially suggestive of tumor. DISCUSSION: Amyloidosis was diagnosed on histopathologic study of the biopsy and surgical specimens. Exploration for systemic disease proved negative. The localized amyloidosis was managed conservatively. At 9 months' follow-up, there was no recurrence. CONCLUSION: Localized amyloidosis, however rare, should be considered as differential diagnosis in any case of nasal obstruction with tubal dysfunction, even if bilateral. ENT physicians need to recognize and understand this pathology for adapted diagnostic and treatment planning.


Subject(s)
Amyloidosis/diagnosis , Nasopharyngeal Diseases/diagnosis , Amyloidosis/pathology , Amyloidosis/surgery , Biopsy , Contrast Media/administration & dosage , Diagnosis, Differential , Female , Gadolinium , Humans , Magnetic Resonance Imaging , Middle Aged , Nasopharyngeal Diseases/pathology , Nasopharyngeal Diseases/surgery , Nasopharyngeal Neoplasms/diagnosis , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/surgery , Nasopharynx/pathology , Nasopharynx/surgery , Tomography, X-Ray Computed
7.
Ann Surg Oncol ; 19(7): 2311-9, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22402813

ABSTRACT

BACKGROUND: The management of the neck remains controversial in the definitive chemoradiation setting of advanced N2-3 head and neck squamous cell carcinoma. Most published data favor omission of neck dissection (ND) after complete response for N2-3 or selective ND for residual disease METHODS: We studied the patterns of care in the French-Belgian Groupe d'Etude des Tumeurs de la Tête Et du Cou (GETTEC) through a questionnaire-based survey. RESULTS: Eighteen percent of institutions never performed up-front ND, 20% rarely, 40% sometimes, 14% often, and 8% systematically. Induction chemotherapy was indicated in 30% of the cases, and most ND were performed either between induction and radiation or after chemoradiation for residual disease. Response to chemoradiation was assessed by computed tomographic scan and positron emission tomography in 72% of cases. Selective ND was more common than radical ND. CONCLUSIONS: Omission of ND based on computed tomographic scan and positron emission tomography-based complete response to chemoradiation is the most common strategy for advanced nodal disease among centers. However, neck management strategies vary among institutions, and some institutions continue advocating systematic ND before irradiation. The new treatment options and the changing epidemiology, namely docetaxel-based induction chemotherapy and human papilloma virus-related head and neck squamous cell carcinoma having better response profiles and prognosis, are adding to the nonconsensual approach. The best therapeutic index in terms of neck management remains to be defined in this evolving context.


Subject(s)
Carcinoma, Squamous Cell/therapy , Head and Neck Neoplasms/therapy , Induction Chemotherapy , Neck Dissection , Practice Patterns, Physicians'/standards , Carcinoma, Squamous Cell/pathology , Combined Modality Therapy , Consensus , Head and Neck Neoplasms/pathology , Humans , Positron-Emission Tomography , Prognosis , Radiotherapy Dosage , Tomography, X-Ray Computed
8.
Article in English | MEDLINE | ID: mdl-20822751

ABSTRACT

OBJECTIVE: To describe diagnostic and therapeutic management of a rare parotid lesion: sclerosing polycystic adenosis. PATIENT AND METHOD: We report a case of persistent right intraparotid tumefaction. RESULTS: A 68-year-old man was referred with a right parotid nodule of 2 years' evolution. Cytology diagnosed pleomorphic adenoma, verified on MRI. Conservative subtotal parotidectomy diagnosed sclerosing polycystic adenosis. Over 1 year's regular follow-up, there were no signs of local recurrence. CONCLUSION: Sclerosing polycystic adenosis of the parotid gland is a rare and recently described entity presenting several analogies to the much more frequent cystic mastitis. Although benign and well-delimited, it requires complete exeresis of the parotid, due to a non-negligible risk of recurrence.


Subject(s)
Adenoma, Pleomorphic/diagnosis , Parotid Neoplasms/diagnosis , Adenoma, Pleomorphic/pathology , Adenoma, Pleomorphic/surgery , Aged , Diagnosis, Differential , Humans , Magnetic Resonance Imaging , Male , Parotid Gland/pathology , Parotid Gland/surgery , Parotid Neoplasms/pathology , Parotid Neoplasms/surgery , Sclerosis
9.
Eur Ann Otorhinolaryngol Head Neck Dis ; 127(3): 117-9, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20822766

ABSTRACT

INTRODUCTION: Laryngeal paraganglioma is a rare, mainly supraglottic, tumor. CLINICAL CASE: A 67-year-old woman was operated on in June 2009 for supraglottic laryngeal paraganglioma, with simple postoperative course. DISCUSSION: Anatomopathologic features, malignant paraganglioma and the various possible treatments are presented and discussed. Surgical exeresis with an external approach should in our opinion remain the reference treatment, for optimal control of exeresis of this potentially hemorrhagic tumor with risk of recurrence in case of incomplete exeresis.


Subject(s)
Glottis , Laryngeal Neoplasms , Paraganglioma , Aged , Female , Humans , Laryngeal Neoplasms/diagnosis , Laryngeal Neoplasms/surgery , Paraganglioma/diagnosis , Paraganglioma/surgery
10.
Rev Laryngol Otol Rhinol (Bord) ; 131(4-5): 257-62, 2010.
Article in French | MEDLINE | ID: mdl-21866736

ABSTRACT

OBJECTIVES: The excellent effectiveness of both treatment modalities (radiotherapy, endoscopic laser surgery) for early glottic carcinoma (Tis, TlaN0) is similar (carcinologic, functional and QoL results). This is part of an evidence-based medicine policy, which is to choose the cheapest of various treatment modalities known as equally effective and equally morbid. Is analytical economic approach useful and efficient to guide decision making? The aim of this study is to perform a costminimization analysis using an objective clinical modeling. MATERIAL AND METHODS: For each modality, probabilities of various events were recorded from review of literature. Only local recurrences which constitute the major end-point affecting survival were considered. French national Health insurance's point of view (as the payer's point of view), with a 100% case-mix based payment system was used. Results of cost-minimization between laser endoscopic surgery and external radiation therapy are: Global Cost of laser endoscopic surgery is about 2613.01 euro. Without (90% of cases) and with recurrence it is about 1700.36 euro and 10826.87 euro respectively. Global Cost of external radiation therapy is about 4490.88 euro. Without (90% of cases) and with recurrence it is about 3578.23 euro and 12704.74 euro respectively. CONCLUSION: Cordectomy by CO2 laser seems to be an efficient cost-effective alternative to radiotherapy for early glottic carcinoma management from the French national Health insurance perspective.


Subject(s)
Laryngeal Neoplasms/therapy , Laser Therapy/economics , Radiotherapy/economics , Cost-Benefit Analysis , France , Glottis , Humans , Microsurgery/economics , National Health Programs
11.
Ann Otolaryngol Chir Cervicofac ; 126(4): 221-5, 2009 Sep.
Article in French | MEDLINE | ID: mdl-19560750

ABSTRACT

OBJECTIVE: To describe the diagnostic and therapeutic management of extrinsic tracheobronchial compression after thoracic aorta surgery. PATIENT AND METHODS: We report the case of a female patient with Marfan syndrome. RESULTS: A 27-year-old woman with Marfan syndrome presented respiratory distress after type III dissecting aneurysm of the descending aorta from extrinsic compression (hematoma) of the lower third of the trachea and the left bronchial stump. We placed a Y-stent (Y-Tracheobronxane, Novatech SA, France), thus restoring a satisfactory channel. A few days later, the patient developed right congestive heart failure from compression of the left pulmonary artery secondary to the progression of the hematoma. Medical treatment for this cardiological complication and the progressive resorption of the hematoma made it possible to remove the stent after 21 days with no dyspneic recurrence. CONCLUSION: Placing a Y-stent is possible and effective and has few iatrogenic consequences in cases of extrinsic tracheobronchial compression from a hematoma occurring during heavy thoracic vascular surgery. With surgical revision impossible given the risks, stent placement allows progressive resorption of the hematoma, thus ending the compression of the bronchial tree.


Subject(s)
Aortic Aneurysm, Thoracic/surgery , Aortic Dissection/surgery , Hematoma/surgery , Marfan Syndrome/surgery , Stents , Adult , Aortic Dissection/diagnosis , Aortic Dissection/etiology , Aorta, Thoracic/surgery , Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/etiology , Blood Vessel Prosthesis Implantation/adverse effects , Blood Vessel Prosthesis Implantation/methods , Female , Heart Failure/etiology , Hematoma/complications , Hematoma/etiology , Humans , Marfan Syndrome/complications , Marfan Syndrome/diagnosis , Respiratory Insufficiency/etiology , Treatment Outcome , Vascular Surgical Procedures
12.
Ann Otolaryngol Chir Cervicofac ; 126(1): 11-3, 2009 Mar.
Article in French | MEDLINE | ID: mdl-19232568

ABSTRACT

OBJECTIVE: Describe the management of bilateral hypopharyngocele in a trumpet player. MATERIAL AND METHOD: Case report of a professional trumpet player suffering from bilateral hypopharyngocele. RESULTS: A professional trumpet player was referred for an ORL consultation after he noticed that a bad sound was produced while he was playing associated with cervical pain. A CT scan demonstrated an asymmetric bilateral hypopharyngocele with no other abnormality. Because of the mild symptoms and the professional context, a successful conservative approach was used with antireflux medications. He was advised to seek professional instruction in order to improve his technique. On follow-up examination 6 months later, he had had no further problems since adopting the corrected techniques. CONCLUSION: Pharyngoceles are rare and easily misdiagnosed. Because of the mild symptoms and the professional context, a conservative medical approach should be proposed (antireflux medications) combined with specific orthophonic and physical therapy to modify breathing and trumpet playing techniques.


Subject(s)
Music , Occupations , Pharyngeal Diseases/diagnosis , Humans , Male , Middle Aged , Pharyngeal Diseases/therapy , Respiratory Therapy
14.
Ann Chir ; 129(9): 523-5, 2004 Nov.
Article in French | MEDLINE | ID: mdl-15556584

ABSTRACT

PURPOSE OF STUDY: To discuss the authors' experience with thyroglossal duct (TD) carcinoma and expose the interest of the thyroidectomy in the management of this entity. PATIENTS AND METHODS: A retrospective review of all patients with the diagnosis of TD operated on from 1985 to 2002 was performed. RESULTS: Four cases of papillary TD carcinoma were identified. Two patients were treated by a Sistrunk procedure associated with total thyroidectomy. One patient needed a thyroidectomy fifteen years after the initial management of the papillary thyroglossal duct carcinoma. The last patient had a medical treatment, with no evidence of complication after eleven years of follow up. CONCLUSION: A microscopic focus of papillary carcinoma, without cyst wall invasion, can be managed by a Sistrunk procedure, with the need for long-term follow up. Treatment of all other thyroglossal duct papillary carcinomas should include thyroidectomy followed by radioactive iodine treatment.


Subject(s)
Thyroglossal Cyst/surgery , Thyroidectomy , Adult , Female , Humans , Male , Middle Aged , Retrospective Studies
15.
J Antimicrob Chemother ; 54(3): 634-9, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15282240

ABSTRACT

OBJECTIVES: To evaluate the frequency and diversity of extended-spectrum beta-lactamases (ESBLs) produced by Enterobacteriaceae and Pseudomonas aeruginosa in one French region. METHODS: During 2001-2002, all the non-duplicate isolates of P. aeruginosa resistant to ceftazidime and of Enterobacteriaceae intermediate or resistant to ceftazidime and/or cefotaxime and/or aminoglycosides with an AAC(6') I phenotype were collected in nine hospitals of the area. ESBL isoelectric points were determined, bla genes were amplified and sequenced and epidemic isolates were genotyped with ERIC2-PCR. RESULTS: ESBLs were observed in 297 Enterobacteriaceae (0.8%). The most frequent were TEM-3 like (n=152; 51.2%) and TEM-24 (n=115; 38.7%). Four new enzymes were observed, TEM-112 (pI 5.4), TEM-113 (pI 6.3), TEM-114 (pI 5.9) and TEM-126 (pI 5.4). Other TEMs were TEM-8, TEM-12, TEM-16, TEM-19, TEM-20, TEM-21, TEM-29 and TEM-71. The other ESBLs were SHV-4, SHV-5 and SHV-12, CTX-M-1, CTX-M-3, CTX-M-14 and CTX-M-15. In 37 P. aeruginosa (0.7%) only one ESBL was observed, PER-1. Five epidemic strains were detected, Serratia marcescens TEM-3 and four observed in several hospitals, Enterobacter aerogenes TEM-24, Citrobacter koseri TEM-3, Proteus mirabilis TEM-3 and P. aeruginosa PER-1. CONCLUSION: ESBL frequency was lower than in 1998, and CTX-M-type frequency higher (2.1% of ESBLs in 2001, 4.9% in 2002). This long-term survey detected new sporadic enzymes (TEM-112, TEM-113, TEM-114 and TEM-126) and interhospital epidemic strains while avoiding any overestimation of ESBL frequency that may otherwise have occurred because of acute epidemics.


Subject(s)
Cross Infection/epidemiology , Cross Infection/microbiology , Enterobacteriaceae/drug effects , Enterobacteriaceae/genetics , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/genetics , beta-Lactamases/genetics , Amino Acid Substitution , Cloning, Molecular , DNA Primers , Enterobacteriaceae/enzymology , France/epidemiology , Gene Frequency , Humans , Isoelectric Focusing , Population Surveillance , Prospective Studies , Pseudomonas aeruginosa/enzymology , Reverse Transcriptase Polymerase Chain Reaction
16.
J Org Chem ; 66(14): 4743-51, 2001 Jul 13.
Article in English | MEDLINE | ID: mdl-11442398

ABSTRACT

The NS3 serine protease enzyme of the hepatitis C virus (HCV) is essential for viral replication. Short peptides mimicking the N-terminal substrate cleavage products of the NS3 protease are known to act as weak inhibitors of the enzyme and have been used as templates for the design of peptidomimetic inhibitors. Automated solid-phase synthesis of a small library of compounds based on such a peptidomimetic scaffold has led to the identification of potent and highly selective inhibitors of the NS3 protease enzyme.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Combinatorial Chemistry Techniques , Enzyme Inhibitors/pharmacology , Humans , Molecular Mimicry , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Peptide Library , Structure-Activity Relationship
17.
Cell ; 105(4): 459-72, 2001 May 18.
Article in English | MEDLINE | ID: mdl-11371343

ABSTRACT

At the onset of anaphase, a caspase-related protease (separase) destroys the link between sister chromatids by cleaving the cohesin subunit Scc1. During most of the cell cycle, separase is kept inactive by binding to an inhibitory protein called securin. Separase activation requires proteolysis of securin, which is mediated by an ubiquitin protein ligase called the anaphase-promoting complex. Cells regulate anaphase entry by delaying securin ubiquitination until all chromosomes have attached to the mitotic spindle. Though no longer regulated by this mitotic surveillance mechanism, sister separation remains tightly cell cycle regulated in yeast mutants lacking securin. We show here that the Polo/Cdc5 kinase phosphorylates serine residues adjacent to Scc1 cleavage sites and strongly enhances their cleavage. Phosphorylation of separase recognition sites may be highly conserved and regulates sister chromatid separation independently of securin.


Subject(s)
Cell Cycle Proteins/metabolism , Drosophila Proteins , Nuclear Proteins/metabolism , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Saccharomyces cerevisiae Proteins , Sister Chromatid Exchange/physiology , Ubiquitin-Protein Ligase Complexes , Amino Acid Sequence , Anaphase/physiology , Anaphase-Promoting Complex-Cyclosome , CDC2 Protein Kinase/metabolism , Cell Cycle Proteins/genetics , Centromere/genetics , Centromere/metabolism , Chromatin/genetics , Chromatin/metabolism , Chromosomal Proteins, Non-Histone , Conserved Sequence , Endopeptidases/genetics , Endopeptidases/metabolism , Fungal Proteins/genetics , Fungal Proteins/metabolism , Ligases/genetics , Ligases/metabolism , Metaphase/physiology , Molecular Sequence Data , Nuclear Proteins/genetics , Phosphoproteins , Phosphorylation , Securin , Serine , Telomere/genetics , Telomere/metabolism , Ubiquitin-Protein Ligases , Yeasts/enzymology , Yeasts/genetics , Cohesins
18.
Cell ; 103(3): 375-86, 2000 Oct 27.
Article in English | MEDLINE | ID: mdl-11081625

ABSTRACT

In eukaryotic cells, replicated DNA strands remain physically connected until their segregation to opposite poles of the cell during anaphase. This "sister chromatid cohesion" is essential for the alignment of chromosomes on the mitotic spindle during metaphase. Cohesion depends on the multisubunit cohesin complex, which possibly forms the physical bridges connecting sisters. Proteolytic cleavage of cohesin's Sccl subunit at the metaphase to anaphase transition is essential for sister chromatid separation and depends on a conserved protein called separin. We show here that separin is a cysteine protease related to caspases that alone can cleave Sccl in vitro. Cleavage of Sccl in metaphase arrested cells is sufficient to trigger the separation of sister chromatids and their segregation to opposite cell poles.


Subject(s)
Anaphase , Cell Cycle Proteins/metabolism , Protein Processing, Post-Translational , Yeasts/cytology , Yeasts/metabolism , Amino Acid Sequence , Amino Acid Substitution/genetics , Anaphase/drug effects , Animals , Binding Sites , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/chemistry , Cell Cycle Proteins/isolation & purification , Cell Line , Chromosomal Proteins, Non-Histone , Chromosome Segregation/drug effects , Chromosomes, Fungal/drug effects , Chromosomes, Fungal/metabolism , Conserved Sequence/genetics , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/classification , Cysteine Endopeptidases/isolation & purification , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Endopeptidases/metabolism , Fungal Proteins/antagonists & inhibitors , Fungal Proteins/chemistry , Fungal Proteins/isolation & purification , Fungal Proteins/metabolism , Mitosis/drug effects , Molecular Sequence Data , Nuclear Proteins , Phosphoproteins , Phosphorylation , Protein Binding , Protein Processing, Post-Translational/drug effects , Protein Structure, Tertiary , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Saccharomyces cerevisiae Proteins , Separase , Sequence Alignment , Spodoptera , Yeasts/drug effects , Yeasts/enzymology
19.
Bioorg Med Chem Lett ; 10(20): 2267-70, 2000 Oct 16.
Article in English | MEDLINE | ID: mdl-11055335

ABSTRACT

Structure-activity studies on a hexapeptide N-terminal cleavage product of a dodecamer substrate led to the identification of very potent and highly specific inhibitors of the HCV NS3 protease/NS4A cofactor peptide complex. The largest increase in potency was accomplished by the introduction of a (4R)-naphthalen-1-yl-4-methoxy substituent to the P2 proline. N-Terminal truncation resulted in tetrapeptides containing a C-terminal carboxylic acid, which exhibited low micromolar activity against the HCV serine protease.


Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Hepacivirus/enzymology , Oligopeptides/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cathepsin B/antagonists & inhibitors , Chymotrypsin/antagonists & inhibitors , Drug Design , Humans , Kinetics , Leukocyte Elastase/antagonists & inhibitors , Models, Molecular , Molecular Conformation , Oligopeptides/chemistry , Oligopeptides/pharmacology , Pancreatic Elastase/antagonists & inhibitors , Protein Conformation , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Swine
20.
Int J Radiat Oncol Biol Phys ; 48(2): 485-93, 2000 Sep 01.
Article in English | MEDLINE | ID: mdl-10974466

ABSTRACT

PURPOSE: To assess the possibility to deliver a high and homogeneous irradiation with respect to maximal tolerated dose to the visual pathways for paranasal sinus and nasal cavity tumors. METHODS AND MATERIALS: Forty patients with advanced stage malignant tumors were treated with postoperative (30) or primary (10 patients) conformal radiotherapy (CRT). Five patients were previously irradiated. Six to 15 individually shaped isocentric noncoplanar field arrangements, using a multileaf collimator were designed. Dose-volume histograms (DVH) for the planning target volumes (PTV) and the optic pathways were analyzed in 31 cases. RESULTS: Median and maximal delivered doses to the PTV were 60 (+/-3) and 66 (+/-4) Gy. Dose distributions for critical organs are detailed. Median follow-up was 19 months (3 to 48). Local, nodal, and metastatic recurrences occurred in 8, 2, and 7 cases, respectively. Major prognostic factor for local recurrences was central nervous system (CNS) involvement. One patient died of meningitis. Two patients developed cataract, and 1 patient ipsilateral blindness due to vascular glaucoma. CONCLUSION: CRT for locally advanced paranasal sinus and nasal cavity tumors enables the delivery of high homogeneous doses to the PTV with respect to critical organs, with a low toxicity and a high local control.


Subject(s)
Nose Neoplasms/radiotherapy , Radiotherapy Planning, Computer-Assisted/methods , Radiotherapy, Conformal/methods , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Nose Neoplasms/diagnostic imaging , Nose Neoplasms/pathology , Paranasal Sinus Neoplasms/diagnostic imaging , Paranasal Sinus Neoplasms/pathology , Paranasal Sinus Neoplasms/radiotherapy , Prognosis , Radiography , Radiotherapy Dosage , Survival Rate
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