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1.
Curr Oncol ; 26(1): 37-42, 2019 02.
Article in English | MEDLINE | ID: mdl-30853796

ABSTRACT

For more than a decade, there has been no improvement in outcomes for patients with unresectable locally advanced (la) non-small-cell lung cancer (nsclc). The standard treatment in that setting is definitive concurrent chemotherapy and radiation (ccrt). Although the intent of treatment is curative, most patients rapidly progress, and their prognosis is poor, with a 5-year overall survival (os) rate in the 15%-25% range. Those patients therefore represent a critical unmet need, warranting expedited approval of, and access to, new treatments that can improve outcomes. The pacific trial, which evaluated durvalumab consolidation therapy after ccrt in unresectable la nsclc, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (pfs) and a significant improvement in os. Durvalumab thus fills a critical unmet need in the setting of unresectable la nsclc and provides a new option for patients treated with curative intent. Here, we review the treatment of unresectable la nsclc, with a focus on the effect of the clinical data for durvalumab.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Non-Small-Cell Lung/therapy , Chemoradiotherapy , Lung Neoplasms/therapy , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Lung Neoplasms/pathology , Neoplasm Staging
2.
Curr Oncol ; 24(2): 103-110, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28490924

ABSTRACT

BACKGROUND: Although molecular testing has become standard in managing advanced nonsquamous non-small-cell lung cancer (nsclc), most patients undergo minimally invasive procedures, and the diagnostic tumour specimens available for testing are usually limited. A knowledge translation initiative to educate diagnostic specialists about sampling techniques and laboratory processes was undertaken to improve the uptake and application of molecular testing in advanced lung cancer. METHODS: A multidisciplinary panel of physician experts including pathologists, respirologists, interventional thoracic radiologists, thoracic surgeons, medical oncologists, and radiation oncologists developed a specialty-specific education program, adapting international clinical guidelines to the local Ontario context. Expert recommendations from the program are reported here. RESULTS: Panel experts agreed that specialists procuring samples for lung cancer diagnosis should choose biopsy techniques that maximize tumour cellularity, and that conservation strategies to maximize tissue for molecular testing should be used in tissue processing. The timeliness of molecular reporting can be improved by pathologist-initiated reflex testing upon confirmation of nonsquamous nsclc and by prompt transportation of specimens to designated molecular diagnostic centres. To coordinate timely molecular testing and optimal treatment, collaboration and communication between all clinicians involved in diagnosing patients with advanced lung cancer are mandatory. CONCLUSIONS: Knowledge transfer to diagnostic lung cancer specialists could potentially improve molecular testing and treatment for advanced lung cancer patients.

3.
Curr Oncol ; 23(4): e362-8, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27536185

ABSTRACT

PURPOSE: In the present study, we determined the association of pretreatment circulating neutrophils, monocytes, and lymphocytes with clinical outcomes after lung stereotactic body radiotherapy (sbrt). METHODS: All patients with primary lung cancer and with a complete blood count within 3 months of lung sbrt from 2005 to 2012 were included. Overall survival (os) was calculated using the Kaplan-Meier method. Factors associated with os were investigated using univariable and multivariable Cox proportional hazards regression. Fine-Gray competing risk regression was performed to test the association of the neutrophil:lymphocyte (nlr) and monocyte:lymphocyte (mlr) ratios with two types of failure: disease-related failure and death, and death unrelated to disease. RESULTS: Of the 299 sbrt patients identified, 122 were eligible for analysis. The median and range of the nlr and mlr were 3.0 (0.3-22.0) and 0.4 (0.1-1.9) respectively. On multivariable analysis, sex (p = 0.02), T stage (p = 0.04), and nlr (p < 0.01) were associated with os. On multivariable analysis, T stage (p < 0.01) and mlr (p < 0.01) were associated with disease-related failure; mlr (p = 0.03), nlr (p < 0.01), and sbrt dose of 48 Gy in 4 fractions (p = 0.03) and 54 Gy or 60 Gy in 3 fractions (p = 0.02) were associated with disease-unrelated death. Median survival was 4.3 years in the nlr≤3 group (95% confidence interval: 3.5 to not reached) and 2.5 years in the nlr>3 group (95% confidence interval: 1.7 to 4.8; p < 0.01). CONCLUSIONS: In lung sbrt patients, nlr and mlr are independently associated with os and disease-unrelated death. If validated, nlr and mlr could help to identify patients who would benefit most from sbrt.

4.
Curr Oncol ; 21(2): e340-4, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24764717

ABSTRACT

Hepatocellular carcinoma (hcc) is a leading cause of cancer mortality, and its incidence is increasing in developed countries. Risk factors include cirrhosis from viral hepatitis or alcohol abuse. Metabolic syndrome is a newly recognized, but important, risk factor that is likely contributing to the increased incidence of hcc. Surgery is the therapy of choice for hcc, but local therapies are often contraindicated, usually because of advanced disease or comorbid conditions such as cardiac disease (which is associated with metabolic syndrome). Current radiation therapy techniques such as stereotactic body radiotherapy allow for treatment plans that highly conform to the target and provide excellent sparing of normal structures. Radiation therapy is emerging as a viable option in patients not eligible for surgery or other locoregional therapies. Here, we report a case of a large hcc presenting in a patient with metabolic syndrome without significant alcohol history or biochemical liver dysfunction. The patient was not a candidate for locoregional therapies because of cardiac and renal comorbidities typical of patients experiencing the long-term sequelae of metabolic syndrome. Treatment using an arc-based volumetric-modulated arc therapy technique allowed for the highest dose of radiation to be delivered to the tumour while the peripheral radiation dose was minimized. A complete local response was confirmed by computed tomography imaging 21 months after treatment completion.

5.
Clin Oncol (R Coll Radiol) ; 26(4): 203-9, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24462333

ABSTRACT

AIMS: To determine the efficacy of induction gemcitabine followed by biweekly gemcitabine concurrent with radiotherapy for locally advanced pancreatic cancer. MATERIALS AND METHODS: Between March 2001 and August 2009, 90 patients with unresectable (78) or resected (12) pancreatic cancer were treated with a standard treatment policy of induction gemcitabine (seven doses of weekly gemcitabine at 1000 mg/m(2)) followed by concurrent radiotherapy (52.5 Gy) and biweekly gemcitabine (40 mg/m(2)). RESULTS: After induction gemcitabine, 17.8% of patients did not proceed to chemoradiotherapy, due to either disease progression, performance status deterioration or gemcitabine toxicity. Of the patients who received chemoradiotherapy, 68.9% completed the course of 52.5 Gy, whereas 79.7% received more than 45 Gy. Chemoradiotherapy was stopped early due to treatment toxicity in 22.9% of patients. On intention to treat analysis, the median overall survival was 12.7 months in the locally advanced group and 18.2 months in the resected group. On multivariate analysis for the unresectable patients, a larger gross tumour volume was a significant poor prognostic factor for overall survival and local progression-free survival. CONCLUSION: This large series confirms, in a standard practice setting, similar efficacy and tolerability of treatment as previously reported in our phase I-II study. The benefit to patients with a gross tumour volume >48 cm(3) may be limited.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Deoxycytidine/analogs & derivatives , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Radiation-Sensitizing Agents/administration & dosage , Adult , Aged , Aged, 80 and over , Chemoradiotherapy , Deoxycytidine/administration & dosage , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Induction Chemotherapy , Male , Middle Aged , Retrospective Studies , Survival Analysis , Gemcitabine , Pancreatic Neoplasms
6.
Curr Oncol ; 19(4): e264-9, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22876155

ABSTRACT

PURPOSE: Outcomes after treatment with accelerated hypofractionated radiotherapy in stage i medically inoperable non-small-cell lung cancer (nsclc) patients were determined. METHODS: Our single-institution retrospective review looked at medically inoperable patients with T1-2N0M0 nsclc treated with accelerated hypofractionated curative-intent radiotherapy between 1999 and 2009. Patients were staged mainly by computed tomography imaging of chest and abdomen, bone scan, and computed tomography/magnetic resonance imaging of brain. Positron-emission tomography (pet) staging was performed in 6 patients. Medical charts were reviewed to determine demographics, radiotherapy details, sites of failure, toxicity (as defined by the Common Terminology Criteria for Adverse Events, version 3.0) and vital status. The cumulative incidence of local and distant failure was calculated. Overall (os) and cause-specific (css) survival were estimated by the Kaplan-Meier method. RESULT: In the 60 patients treated during the study period, the dose regimens were 50 Gy in 20 fractions (n = 6), 55 Gy in 20 fractions (n = 8), 60 Gy in 20 fractions (n = 42), and 60 Gy in 25 fractions (n = 4). All patients were treated once daily. The median follow-up was 27 months (range: 4-94 months). The os rates at 2 and 5 years were 61% [95% confidence interval (ci): 50% to 75%] and 19% (95% ci: 10% to 34%) respectively. The css rates at 2 and 5 years were 79% (95% ci: 68% to 91%) and 39% (95% ci: 24% to 63%) respectively. The cumulative incidence of local failure was 20% at 5 years. The cumulative incidence of distant failure was 28% at 5 years. No patients experienced grade 3 or greater pneumonitis or esophagitis. CONCLUSIONS: Accelerated hypofractionated regimens are well tolerated and provide good local control in medically inoperable patients with stage i nsclc. Such regimens may be a reasonable treatment alternative when stereotactic body radiation therapy is not feasible.

7.
Clin Oncol (R Coll Radiol) ; 23(5): 359-63, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21194908

ABSTRACT

The early response of lung tumours to stereotactic radiotherapy was prospectively evaluated with 18F-fluorodeoxyglucose positron emission tomography-computed tomography. Three months after treatment, the maximum standardised uptake value and the tumour diameter fell by 64 and 30%, respectively. This imaging strategy therefore remains under ongoing evaluation with the aim of identifying predictive and prognostic factors.


Subject(s)
Lung Neoplasms/surgery , Positron-Emission Tomography/methods , Radiosurgery , Tomography, X-Ray Computed/methods , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/surgery , Female , Fluorodeoxyglucose F18 , Humans , Lung Neoplasms/diagnostic imaging , Male , Middle Aged , Pilot Projects , Radiopharmaceuticals
8.
J Biol Chem ; 275(26): 20127-35, 2000 Jun 30.
Article in English | MEDLINE | ID: mdl-10777512

ABSTRACT

The p53 tumor suppressor gene and members of the transforming growth factor-beta (TGF-beta) superfamily play central roles in signaling cell cycle arrest and apoptosis (programmed cell death) in normal development and differentiation, as well as in carcinogenesis. Here we describe a distantly related member of the TGF-beta superfamily, designated placental TGF-beta (PTGF-beta), that is up-regulated in response to both p53-dependent and -independent apoptotic signaling events arising from DNA damage in human breast cancer cells. PTGF-beta is normally expressed in placenta and at lower levels in kidney, lung, pancreas, and muscle but could not be detected in any tumor cell line studied. The PTGF-beta promoter is activated by p53 and contains two p53 binding site motifs. Functional studies demonstrated that one of these p53 binding sites is essential for p53-mediated PTGF-beta promoter induction and specifically binds recombinant p53 in gel mobility shift assays. PTGF-beta overexpression from a recombinant adenoviral vector (AdPTGF-beta) led to an 80% reduction in MDA-MB-468 breast cancer cell viability and a 50-60% reduction in other human breast cancer cell lines studied, including MCF-7 cells, which are resistant to growth inhibition by recombinant wild-type p53. Like p53, PTGF-beta overexpression was seen to induce both G(1) cell cycle arrest and apoptosis in breast tumor cells. These results provide the first evidence for a direct functional link between p53 and the TGF-beta superfamily and implicate PTGF-beta as an important intercellular mediator of p53 function and the cytostatic effects of radiation and chemotherapeutic cancer agents.


Subject(s)
Apoptosis , DNA Damage , Growth Substances/metabolism , Pregnancy Proteins/metabolism , Tumor Suppressor Protein p53/biosynthesis , Adenoviridae/metabolism , Blotting, Northern , Breast Neoplasms/metabolism , Cell Cycle/drug effects , Cell Division , Cell Survival/drug effects , DNA, Complementary/metabolism , Genes, p53/genetics , Genetic Vectors/metabolism , Humans , RNA, Messenger/metabolism , Sequence Analysis, DNA , Time Factors , Tissue Distribution , Transcriptional Activation , Tumor Cells, Cultured , Up-Regulation/drug effects , Up-Regulation/radiation effects
9.
Cancer Gene Ther ; 7(12): 1566-74, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11228535

ABSTRACT

Targeting therapeutic gene expression to tumor cells represents a major challenge for cancer gene therapy. The strong transcriptional response exhibited by heat shock genes, along with the beneficial therapeutic effects of hyperthermia have led us to develop a heat-directed gene-targeting strategy for cancer treatment. Heat shock gene expression is mediated in large part by the interaction of heat shock factor 1 with specific binding sites (heat shock elements; HSE) found in the promoters of heat-inducible genes. Here we present a quantitative analysis of heat-inducible gene expression mediated by the wild-type hsp70b gene promoter, as well as a modified hsp70b promoter containing additional HSE sequences. Beta-galactosidase (beta-gal) expression was induced between 50- and 800-fold in a panel of human breast cancer cell lines infected with an adenoviral vector containing the wild-type hsp70b promoter (Ad.70b.betag) following treatment at 43 degrees C for 30 minutes. Infection with an adenoviral vector containing the modified hsp70b promoter (Ad.HSE.70b.betag) resulted in a 200- to 950-fold increase in beta-gal expression under the same conditions, and also provided a 1-2 degrees C decrease in the threshold of activation. Significant increases in the heat responsiveness of the Ad.HSE.70b.betag construct were observed in five of six tumor cell lines tested, as well as under thermotolerant conditions. Finally, we demonstrate that localized heating of a HeLa cell xenograft can effectively target beta-gal gene expression following intratumoral injection of Ad.70b.betag. Adenoviral vectors incorporating heat-inducible therapeutic genes may provide useful adjuncts for clinical hyperthermia.


Subject(s)
Adenoviridae/genetics , Gene Targeting/methods , Genetic Therapy/methods , Genetic Vectors , Hyperthermia, Induced , Tumor Cells, Cultured/metabolism , Animals , Female , Gene Expression , Genes, Reporter , HSP70 Heat-Shock Proteins/genetics , Humans , Interleukin-12/genetics , Mice , Mice, SCID , Transfection , beta-Galactosidase/metabolism
10.
Cancer Gene Ther ; 6(2): 179-90, 1999.
Article in English | MEDLINE | ID: mdl-10195885

ABSTRACT

The development of resistance to radiation and chemotherapeutic agents that cause DNA damage is a major problem for the treatment of breast and other cancers. The p53 tumor suppressor gene plays a direct role in the signaling of cell cycle arrest and apoptosis in response to DNA damage, and p53 gene mutations have been correlated with increased resistance to DNA-damaging agents. Herpes simplex virus thymidine kinase (HSV-tk) gene transfer followed by ganciclovir (GCV) treatment is a novel tumor ablation strategy that has shown good success in a variety of experimental tumor models. However, GCV cytotoxicity is believed to be mediated by DNA damage-induced apoptosis, and the relationship between p53 gene status, p53-mediated apoptosis, and the sensitivity of human tumors to HSV-tk/GCV treatment has not been firmly established. To address this issue, we compared the therapeutic efficacy of adenovirus-mediated HSV-tk gene transfer and GCV treatment in two human breast cancer cell lines: MCF-7 cells, which express wild-type p53, and MDA-MB-468 cells, which express high levels of a mutant p53 (273 Arg-His). Treating MCF-7 cells with AdHSV-tk/GCV led to the predicted increase in endogenous p53 and p21WAF1/CIP1 protein levels, and apoptosis was observed in a significant proportion of the target cell population. However, treating MDA-MB-468 cells under the same conditions resulted in a much stronger apoptotic response in the absence of induction in p21WAF1/CIP1 protein levels. This latter result suggested that HSV-tk/GCV treatment can activate a strong p53-independent apoptotic response in tumor cells that lack functional p53. To confirm this observation, four additional human breast cancer cell lines expressing mutant p53 were examined. Although a significant degree of variability in GCV chemosensitivity was observed in these cell lines, all displayed a greater reduction in cell viability than MCF-7 or normal mammary cells treated under the same conditions. These results suggest that endogenous p53 status does not correlate with chemosensitivity to HSV-tk/GCV treatment. Furthermore, evidence for a p53-independent apoptotic response serves to extend the potential of this therapeutic strategy to tumors that express mutant p53 and that may have developed resistance to conventional genotoxic agents.


Subject(s)
Breast Neoplasms/therapy , Ganciclovir/therapeutic use , Genetic Therapy , Simplexvirus/genetics , Thymidine Kinase/genetics , Acridine Orange/metabolism , Adenoviridae/metabolism , Apoptosis , Blotting, Northern , Blotting, Western , Cell Survival , DNA Fragmentation , Ethidium/metabolism , Fluorescent Dyes/metabolism , Humans , Proto-Oncogene Proteins c-bcl-2/metabolism , Sensitivity and Specificity , Thymidine Kinase/administration & dosage , Time Factors , Transduction, Genetic , Tumor Cells, Cultured , Tumor Suppressor Protein p53/drug effects , Tumor Suppressor Protein p53/metabolism
11.
Glia ; 18(1): 11-26, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8891688

ABSTRACT

In neonatal mice, an acute injury produced by a stab wound to the cortex results in minimal astrocyte reactivity, as has been observed by others. However, if the source of the stab wound, a piece of nitrocellulose (NC) membrane, were now implanted in the cortex for a period of time (chronic NC implant injury), then extensive astroglial reactivity in the neonatal brain ensues. The astrogliosis is manifested by increased mRNA, protein content, and immunoreactivity for GFAP, and by ultrastructural changes. Given the previous reports that inflammatory cytokines are possible mediators of astrocyte reactivity (e.g., Balasingam et al: J Neurosci 14:846, 1994), we examined the brain parenchyma of neonatal mice following an NC stab or implant injury, with minimal or extensive astrogliosis, respectively, for a possible differential representation of inflammatory cells. A significant correlation (r = 0.87, P < 0.05) was observed between the occurrence of astrogliosis and the presence of reactive microglia/macrophages; no other inflammatory cell type was detected in the brain parenchyma of neonatal mice following NC implant injury. We suggest that reactive microglia/macrophages are required for the evolution of cells into reactive astrocytes following insults to the neonatal brain.


Subject(s)
Animals, Newborn/physiology , Astrocytes/physiology , Macrophages/physiology , Microglia/physiology , Aging/metabolism , Animals , Astrocytes/ultrastructure , Brain/cytology , Brain/growth & development , Brain Injuries/pathology , Female , Glial Fibrillary Acidic Protein/biosynthesis , Immunohistochemistry , Macrophage-1 Antigen/metabolism , Male , Mice , Mice, Inbred Strains , RNA, Messenger/biosynthesis
12.
Dan Medicinhist Arbog ; : 180-93, 1996.
Article in Danish | MEDLINE | ID: mdl-11625141

ABSTRACT

In 1875 A.P. Møller, a bookseller on "Gammelmønt" in Copenhagen published a little book on "aquavit" as a universal medicament written by an old shepherd from Schlesien. The idea behind the book is discussed and several additions to aquavit are mentioned. The adding of salt is especially recommended for many ailments. The Danes have generally prefered to add other substances, which is shown by comparing the shepherds list with a danish investigation.


Subject(s)
History of Pharmacy , Medicine, Traditional/history , Nostrums/history , Books/history , Denmark , History, 19th Century , Humans
13.
Dan Medicinhist Arbog ; : 228-99, 1995.
Article in Danish | MEDLINE | ID: mdl-11625133

ABSTRACT

By his contemporaries Niels Ryberg Finsen (1860-1904) has been described as a highly dynamic personality and characterised as a sympathetic, kind, confidence-inspiring, conscientious, reliable, intellectual, mysterious and genious doctor, who took care of his patients' illness as well as their social and economic conditions. But he was known too as sharp, critical and able to defend his scientific viewpoints with a deep commitment. Niels Finsen introduced the universal light bath, but his great achievement was the local light treatment of lupus vulgaris for which he got the Nobel Prize in 1903. In the article the history of lupus vulgaris, its treatment and its social consequenses for the patients as individuals are described as an introduction to an analysis of Niels Finsen's scientific methods, his treatment and results and the reactions from the contemporary medical authorities, the public represented by the press and the patients themselves. Finally the discussions after Niels Finsen's death are researched.


Subject(s)
Lupus Vulgaris/history , Skin Diseases/history , Tuberculosis/history , Denmark , History, 19th Century , History, 20th Century , Humans
14.
Z Orthop Ihre Grenzgeb ; 132(5): 424-31, 1994.
Article in German | MEDLINE | ID: mdl-7985404

ABSTRACT

A pronounced valgization or varization of the lower extremity leads to changes in skeletal muscle which are histologically and morphometrically demonstrable in biopsies of Mm. vastus lateralis et medialis of patients with chronically anomalous stressing of the knee joint. During chronic over-stressing, increased thickness in type I and type II muscle fibers can be observed in both Mm. vastus medialis and lateralis, whereas type II fibers demonstrate a greater variability and there is a greater occurrence in type I fibers. Our investigations show that a chronic anomalous stressing influences both the size and energy metabolism of a skeletal muscle cell in a manner which can be interpreted as a functional adaptation.


Subject(s)
Knee Joint , Muscles/pathology , Osteoarthritis/pathology , Aged , Biopsy , Female , Histocytochemistry , Humans , Joint Deformities, Acquired/etiology , Knee Prosthesis , Male , Middle Aged , Muscles/ultrastructure , Osteoarthritis/complications , Osteotomy
15.
J Biol Chem ; 269(1): 556-66, 1994 Jan 07.
Article in English | MEDLINE | ID: mdl-8276851

ABSTRACT

PAY genes are required for peroxisome assembly in the yeast Yarrowia lipolytica. Here we characterize one mutant, pay4, and describe the cloning and sequencing of the PAY4 gene. The pay4 mutant shows no identifiable peroxisomes by biochemical and morphological criteria. The complementing PAY4 gene encodes a polypeptide, Pay4p, 1025 amino acids in length and having a predicted molecular mass of 112,258 Da. The predicted Pay4p sequence contains two putative ATP-binding domains and shows structural relationships to other potential ATP-binding proteins involved in biological processes as diverse as peroxisome biogenesis, vesicle-mediated protein transport, cell cycle control, and transcriptional regulation. These proteins all share a highly conserved stretch of approximately 175 amino acids that contains a consensus sequence for ATP binding. Pay4p shows sequence conservation with Pas1p and Pas5p, putative ATPases required for peroxisomal assembly in the yeasts Saccharomyces cerevisiae and Pichia pastoris, respectively. Pay4p, Pas1p, and Pas5p are presumably related members of a family of putative ATPases involved in peroxisome biogenesis. Pay4p is synthesized in low amounts in Y. lipolytica cells grown in glucose, and there is a rapid and pronounced increase in the levels of Pay4p upon transfer of the cells to a medium containing oleic acid as the sole carbon source.


Subject(s)
Adenosine Triphosphatases/genetics , Fungal Proteins/genetics , Microbodies , Saccharomycetales/enzymology , ATPases Associated with Diverse Cellular Activities , Adenosine Triphosphatases/metabolism , Amino Acid Sequence , Base Sequence , Cloning, Molecular , Cytoplasm/metabolism , DNA, Fungal , Fungal Proteins/metabolism , Genes, Fungal , Immunohistochemistry , Microscopy, Electron , Molecular Sequence Data , Mutation , Protein Sorting Signals/metabolism , Saccharomycetales/ultrastructure , Sequence Homology, Amino Acid
16.
Mol Microbiol ; 6(23): 3455-60, 1992 Dec.
Article in English | MEDLINE | ID: mdl-1474890

ABSTRACT

Eukaryotic cells have evolved a complex set of intracellular organelles, each of which possesses a specific complement of enzymes and performs unique metabolic functions. This compartmentalization of cellular functions provides a level of metabolic control not available to prokaryotes. However, it presents the eukaryotic cell with the problem of targeting proteins to their specific location(s). Proteins must be efficiently transported from their site of synthesis in the cytosol to their specific organelle(s). Such a process may require translocation across one or more hydrophobic membrane barriers and/or asymmetric integration into specific membranes. Proteins carry cis-acting amino acid sequences that serve to act as recognition motifs for protein sorting and for the cellular translocation machinery. Sequences that target proteins to the endoplasmic reticulum/secretory pathway, mitochondria, and chloroplasts are often present as cleavable amino-terminal extensions. In contrast, most peroxisomal proteins are synthesized at their mature size and are translocated to the organelle without any post-translational modification. This review will summarize what is known about how yeast solve the problem of specifically importing proteins into peroxisomes and will suggest future directions for investigations into peroxisome biogenesis in yeast.


Subject(s)
Microbodies/ultrastructure , Saccharomyces cerevisiae/ultrastructure , Amino Acid Sequence , Biological Transport , Cell Compartmentation , Fungal Proteins/metabolism , Microbodies/metabolism , Molecular Sequence Data , Morphogenesis
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