Showing papers by "Catholic University of the Sacred Heart published in 1999"

The Involvement of Cysteine Proteases and Protease Inhibitor Genes in the Regulation of Programmed Cell Death in Plants

Abstract: Programmed cell death (PCD) is a process by which cells in many organisms die. The basic morphological and biochemical features of PCD are conserved between the animal and plant kingdoms. Cysteine proteases have emerged as key enzymes in the regulation of animal PCD. Here, we show that in soybean cells, PCD-activating oxidative stress induced a set of cysteine proteases. The activation of one or more of the cysteine proteases was instrumental in the PCD of soybean cells. Inhibition of the cysteine proteases by ectopic expression of cystatin, an endogenous cysteine protease inhibitor gene, inhibited induced cysteine protease activity and blocked PCD triggered either by an avirulent strain of Pseudomonas syringae pv glycinea or directly by oxidative stress. Similar expression of serine protease inhibitors was ineffective. A glutathione S -transferase–cystatin fusion protein was used to purify and characterize the induced proteases. Taken together, our results suggest that plant PCD can be regulated by activity poised between the cysteine proteases and the cysteine protease inhibitors. We also propose a new role for proteinase inhibitor genes as modulators of PCD in plants.

Elevated Levels of C-Reactive Protein at Discharge in Patients With Unstable Angina Predict Recurrent Instability

Abstract: Background—In a group of patients admitted for unstable angina, we investigated whether C-reactive protein (CRP) plasma levels remain elevated at discharge and whether persistent elevation is associated with recurrence of instability. Methods and Results—We measured plasma levels of CRP, serum amyloid A protein (SAA), fibrinogen, total cholesterol, and Helicobacter pylori and Chlamydia pneumoniae antibody titers in 53 patients admitted to our coronary care unit for Braunwald class IIIB unstable angina. Blood samples were taken on admission, at discharge, and after 3 months. Patients were followed for 1 year. At discharge, CRP was elevated (>3 mg/L) in 49% of patients; of these, 42% had elevated levels on admission and at 3 months. Only 15% of patients with discharge levels of CRP <3 mg/L but 69% of those with elevated CRP (P<0.001) were readmitted because of recurrence of instability or new myocardial infarction. New phases of instability occurred in 13% of patients in the lower tertile of CRP (≤2.5 mg/L)...

Increasing Levels of Interleukin (IL)-1Ra and IL-6 During the First 2 Days of Hospitalization in Unstable Angina Are Associated With Increased Risk of In-Hospital Coronary Events

Abstract: Background—A growing body of evidence suggests a role for inflammation in acute coronary syndromes. The aim of this study was to assess the role of proinflammatory cytokines, their time course, and their association with prognosis in unstable angina. Methods and Results—We studied 43 patients aged 62±8 years admitted to our coronary care unit for Braunwald class IIIB unstable angina. In each patient, serum levels of interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6) (which represent sensitive markers of biologically active IL-1β and tumor necrosis factor-α levels, respectively), and troponin T were measured at entry and 48 hours after admission. Troponin T–positive patients were excluded. Patients were divided a posteriori into 2 groups according to their in-hospital outcome: group 1 comprised 17 patients with an uneventful course, and group 2 comprised 26 patients with a complicated in-hospital course. In group 1, mean IL-1Ra decreased at 48 hours by 12%, and IL-6 diminished at 48 hours by ...

The Risk of Recurrent Deep Venous Thrombosis among Heterozygous Carriers of Both Factor V Leiden and the G20210A Prothrombin Mutation

Abstract: Background Point mutations in the factor V gene (factor V Leiden) and the prothrombin gene (the substitution of A for G at position 20210) are the most common causes of inherited thrombophilia. Whether or not factor V Leiden increases the risk of recurrent deep venous thrombosis is controversial, and there is no information on the risk of recurrence among carriers of both mutations. Methods We studied a retrospective cohort of 624 patients who were referred for a first episode of deep venous thrombosis. After excluding 212 patients with other inherited or acquired causes of thrombophilia, we compared 112 patients who were heterozygous carriers of factor V Leiden with 17 patients who were heterozygous for both factor V Leiden and the prothrombin mutation and 283 patients who had neither mutation. The relative risk of recurrent deep venous thrombosis was calculated with use of a proportional-hazards model. Results Patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous t...

Binding of the G domains of laminin α1 and α2 chains and perlecan to heparin, sulfatides, α‐dystroglycan and several extracellular matrix proteins

Abstract: The C‐terminal G domain of the mouse laminin α2 chain consists of five lamin‐type G domain (LG) modules (α2LG1 to α2LG5) and was obtained as several recombinant fragments, corresponding to either individual modules or the tandem arrays α2LG1‐3 and α2LG4‐5. These fragments were compared with similar modules from the laminin α1 chain and from the C–terminal region of perlecan (PGV) in several binding studies. Major heparin‐binding sites were located on the two tandem fragments and the individual α2LG1, α2LG3 and α2LG5 modules. The binding epitope on α2LG5 could be localized to a cluster of lysines by site‐directed mutagenesis. In the α1 chain, however, strong heparin binding was found on α1LG4 and not on α1LG5. Binding to sulfatides correlated to heparin binding in most but not all cases. Fragments α2LG1–3 and α2LG4‐5 also bound to fibulin‐1, fibulin‐2 and nidogen‐2 with K d = 13–150 nM. Both tandem fragments, but not the individual modules, bound strongly to α‐dystroglycan and this interaction was abolished by EDTA but not by high concentrations of heparin and NaCl. The binding of perlecan fragment PGV to α‐dystroglycan was even stronger and was also not sensitive to heparin. This demonstrated similar binding repertoires for the LG modules of three basement membrane proteins involved in cell–matrix interactions and supramolecular assembly.

Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinson's disease.

Abstract: Objective: To reduce antiparkinsonian medication in parkinsonian patients with bilateral high frequency subthalamic nucleus (STN) stimulation. Background: Parkinsonian syndromes are characterized by hyperactivity of the STN. Preliminary data indicate that functional inactivation of the STN may reduce the requirement for dopaminergic therapy in PD. Methods: Bilateral quadripolar leads were implanted stereotactically in the STN of seven patients with advanced PD (mean age, 57.4 years; mean disease duration, 15.4 years). High-frequency stimulation was applied for 24 hours a day. Following implantation, antiparkinsonian medication was reduced to the minimum possible and stimulation was gradually increased. The patients were evaluated in the practically defined “off” and “on” conditions using the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Schwab & England scale. The average follow-up was 16.3 ± 7.6 months. A battery of neuropsychological tests was applied before and 9 months after the implant. Results: Parkinsonian features improved in all patients—the greatest change seen in rigidity, then tremor, followed by bradykinesia. Compared with the presurgical condition, off-drug UPDRS motor scores improved by 41.9% on the last visit ( p = 0.0002), UPDRS activities of daily living (ADL) scores improved by 52.2% ( p = 0.0002), and the Schwab & England scale score improved by 213% ( p = 0.0002). The levodopa-equivalent daily dose was reduced by 65%. Night sleep improved in all patients due to increased mobility at night, and in five patients insomnia was resolved. All patients gained weight after surgery and their appetite increased. The mean weight gain at the last follow-up was 13% compared with before surgery. During the last visit, the stimulation amplitude was 2.9 ± 0.5 V and the total energy delivered per patient averaged 2.7 ± 1.4 W × 10 −6 . The results of patient self-assessment scales indicated a marked improvement in five patients and a moderate improvement in the other two. The neuropsychological data showed no changes. Side effects were mild and tolerable. In all cases, a tradeoff between the optimal voltage and the severity of side effects made it possible to control parkinsonian signs effectively. The most marked side effects directly related to STN stimulation consisted of ballistic or choreic dyskinesias of the neck and the limbs elicited by contralateral STN stimulation above a given threshold voltage, which varied depending on the individual. Conclusions: Parkinsonian signs can be controlled by bilateral high-frequency STN stimulation. The procedure is well tolerated. On-state dyskinesias were greatly reduced, probably due to the reduction of total antiparkinsonian medication. Bilateral high-frequency STN stimulation compensated for drug reduction and elicited dyskinesias, which differ from those observed following dopaminergic medication. ADL improved significantly, suggesting that some motor tasks performed during everyday chores, and that are not taken into account in the UPDRS motor score, also improved.

Perturbation of the T-Cell Repertoire in Patients With Unstable Angina

Abstract: Background—Monocytes are constitutively activated in unstable angina (UA), resulting in the production of IL-6 and the upregulation of acute phase proteins. Underlying mechanisms are not understood. To explore whether the production of the potent monocyte activator IFN-γ is altered in UA, we compared cytokine production by T lymphocytes in patients with UA (Braunwald’s class IIIB) and with stable angina (SA). Methods and Results—Peripheral blood lymphocytes were collected at the time of hospitalization and after 2 and 12 weeks. Cytokine-producing CD4+ and CD8+ T cells were quantified by 3-color flow cytometry after stimulation with phorbol myristate acetate and ionomycin. UA was associated with an increased number of CD4+ and CD8+ T cells producing IFN-γ, whereas patients with SA had higher frequencies of IL-2+ and IL-4+ CD4+ T cells. Expansion of the IFN-γ + T-cell population in UA persisted for at least 3 months. Increased production of IFN-γ in UA could be attributed to the expansion of an unusual subs...

The incidence of secondary leukemias.

Abstract: BACKGROUND AND OBJECTIVE: The term secondary leukemia is usually employed to indicate both forms of acute myeloid leukemia (AML) evolving from previous myelodysplasia and forms of acute leukemia developing after exposure to environmental or therapeutic toxins or radiation (therapy related). Secondary leukemias account for 10-30% of all AML. The majority of secondary leukemias resulting from the use of cytotoxic drugs can be divided into two well defined groups depending on whether the patient has received 1) alkylating agents or 2) drugs binding to the enzyme DNA-topoisomerase II. Alkylating agents related leukemias are very similar to post MDS leukemias being characterized frequently by a preleukemic phase, tri-lineage dysplasia, frequent cytogenetic abnormalities involving chromosomes 5 and 7 and a poor prognosis. Secondary leukemias related to therapy with topoisomerase II inhibitors are not preceded by a preleukemic phase and show frequently balanced translocations involving chromosome 11q23. Among therapy-related leukemias, AML is generally a second neoplasm, thus a predisposition to malignancy, independently from previous chemotherapy, cannot be excluded. This review article examines the incidence of all secondary AMLs and the risk of therapy-related leukemia in relation to the different primary malignancies and treatments. INFORMATION SOURCES: The authors have been working in this field, both experimentally and at clinical level, contributing original papers for many years. In addition, the material examined in this review includes articles published in journals covered by MedLine, reviews in journals with high impact factor and recent reports presented at the Secondary Leukemia. An Update Symposium held in Rome in November 1998. STATE OF THE ART AND PERSPECTIVES: The incidence of secondary leukemias is increasing because of aging of the population (MDS is more frequent in elderly people) and widespread and successful use of chemoradiotherapy in cancer patients. In the GIMEMA archive of adult acute leukemia (2,964 AML pts from June 1992 to June 1996) an antecedent hematologic disorder (AHD) and/or MDS was found in 8% of all patients (10% of 2,118 patients aged more than 45 years and in 4% of 848 patients aged less than 45). In this series of patients, 6% of all myeloid leukemias were therapy-related leukemia. Therapy-related leukemias are a major problem in patients treated for Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, polycythemia, breast cancer, ovarian carcinoma, or testicular carcinoma. In the GIMEMA archive more than 50% of patients with secondary AML have breast cancer, NHL, and HD. Alkylating agents, nitrosureas and procarbazine appear to have the highest leukemogenic potential. Furthermore aggressive chemotherapy and radiotherapy followed or not by hematopoietic stem cell infusion will produce a more and more prolonged survival but also a greater incidence of secondary AML. Assessment of the risk of secondary leukemia should become part of any therapeutic plan for cancer patients. Avoidance of drugs with more leukemogenic potential will produce a marked reduction of secondary AML.

UV- and midwave-sensitive cone-driven retinal responses of the mouse: a possible phenotype for coexpression of cone photopigments.

Abstract: Molecular biological, histological and flicker electroretinographic results have established that mice have two cone photopigments, one peaking near 350 nm (UV-cone pigment) and a second near 510 nm [midwave (M)-cone pigment]. The goal of this investigation was to measure the action spectra and absolute sensitivities of the UV-cone- and M-cone-driven b-wave responses of C57BL/6 mice. To achieve this goal, we suppressed rod-driven signals with steady or flashed backgrounds and obtained intensity–response relations for cone-driven b-waves elicited by narrowband flashes between 340 and 600 nm. The derived cone action spectra can be described as retinal1pigments with peaks at 355 and 508 nm. The UV peak had an absolute sensitivity of ∼8 nV/(photon μm2) at the cornea, approximately fourfold higher than the M peak. In an attempt to isolate UV-cone-driven responses, it was discovered that an orange conditioning flash (λ > 530 nm) completely suppressed ERG signals driven by both M pigment- and UV pigment-containing cones. Analysis showed that the orange flash could not have produced a detectable response in the UV-cone pathway were their no linkage between M pigment- and UV pigment-generated signals. Because cones containing predominantly the UV and M pigments have been shown to be located largely in separate parts of the mouse retina ([Szel et al., 1992][1]), the most probable linkage is coexpression of M pigment in cones primarily expressing UV pigment. New histological evidence supports this interpretation ([Gloesman and Ahnelt, 1998][2]). Our data are consistent with an upper bound of ∼3% coexpression of M pigment in the cones that express mostly the UV pigment. [1]: #ref-47 [2]: #ref-15

Direct demonstration of interhemispheric inhibition of the human motor cortex produced by transcranial magnetic stimulation

Abstract: Electromyographic (EMG) responses evoked in hand muscles by a magnetic test stimulus over the motor cortex can be suppressed if a conditioning stimulus is applied to the opposite hemisphere 6-30 ms earlier. In order to define the mechanism and the site of action of this inhibitory phenomenon, we recorded descending volleys produced by the test stimulus through high cervical, epidural electrodes implanted for pain relief in three conscious subjects. These could be compared with simultaneously recorded EMG responses in hand muscles. When the test stimulus was given on its own it evoked three waves of activity (I-waves) in the spinal cord, and a small EMG response in the hand. A prior conditioning stimulus to the other hemisphere suppressed the size of both the descending spinal cord volleys and the EMG responses evoked by the test stimulus when the interstimulus interval was greater than 6 ms. In the spinal recordings, the effect was most marked for the last I-wave (I3), whereas the second I2-wave was only slightly inhibited, and the first I-wave (I1) was not inhibited at all. We conclude that transcranial stimulation over the lateral part of the motor cortex of one hemisphere can suppress the excitability of the contralateral motor cortex.

Ischemic Preconditioning in Humans Models, Mediators, and Clinical Relevance

Abstract: —Ischemic preconditioning, a powerful form of endogenous protection against myocardial infarction, has been demonstrated in several animal species and, recently, in isolated human cardiomyocytes. For both logistic and ethical reasons, no clinical study can meet the strict conditions of experimental studies on preconditioning with infarct size as the end-point. Nevertheless, the demonstration of adaptation to ischemia observed during in vitro studies on human atrial trabeculae, in patients in the setting of coronary bypass surgery, and in the setting of coronary angioplasty in the absence of collateral vessel recruitment strongly suggests that ischemic preconditioning occurs in humans. This notion is further supported by the observation that in these human models, the adaptation to ischemia is influenced by drugs acting on KATP channels and on purinergic and α-adrenergic receptors, similar to what is observed in accepted experimental models of ischemic preconditioning. This important form of myocar...

Body mass index and mortality among older people living in the community.

Abstract: OBJECTIVES: To determine if body mass index (BMI = weight/height2), predictive of mortality in seriously ill hospitalized and institutionalized patients, is also predictive of mortality in a longitudinal epidemiologic study. DESIGN: A prospective cohort study. SETTING: Rovereto, a town in northern Italy. PARTICIPANTS: A consecutive sample of 214 patients aged 81.2 ± 7.3 years receiving community care services. MAIN OUTCOME MEASURES: Malnutrition and mortality. RESULTS: According to logistic regression analysis, malnutrition status, expressed by a BMI 27 Kg/m2) was not significantly related to risk of mortality. CONCLUSIONS: Nutrition variables are a cardinal component of comprehensive geriatric assessment. Our results suggest that BMI, a simple anthropometric measure of nutritional status, is an important predictor of mortality among older people living in the community. Even when controlling for clinical and functional variables, a low BMI remained a significant and independent predictor of shortened survival. J Am Geriatr Soc 47:1072–1076, 1999.

Synergistic Effect of Histone Hyperacetylation and DNA Demethylation in the Reactivation of the FMR1 Gene

Abstract: Most fragile X syndrome patients have expansion of a (CGG) n sequence with >200 repeats (full mutation) in the FMR1 gene responsible for this condition. Hypermethylation of the expanded repeat and of the FMR1 promoter is almost always present and apparently suppresses transcription, resulting in absence of the FMR1 protein. We recently showed that transcriptional reactivation of FMR1 full mutations can be achieved by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC). The level of histone acetylation is another important factor in regulating gene expression; therefore, we treated lymphoblastoid cell lines of non-mosaic full mutation patients with three drugs capable of Inducing histone hyperacetylation. We observed a consistent, although modest, reactivation of the FMR1 gene with 4-phenylbutyrate, sodium butyrate and trichostatin A, as shown by RT-PCR. However, we report that combining these drugs with 5-azadC results in a 2- to 5-fold increase in FMR1 mRNA levels obtained with 5-azadC alone, thus showing a marked synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of FMR1 full mutations.

Frequency, phenomenology and anatomical-clinical correlates of major post-stroke depression

Abstract: BACKGROUND The meaning of post-stroke depression is controversial. AIMS To investigate the hypothesis that major post-stroke depression (PSD) may be due to organic factors (left frontal lesions) immediately after the stroke, but to psychosocial factors in later stages. METHOD We studied 153 consecutive stroke patients, categorised on the basis of time elapsed since stroke, lesion location and presence/absence of major PSD. Fifty-eight were examined in the first two months following the stroke, 52 between two and four months, and 43 after four months or more. The symptom profiles and anatomical-clinical correlates of major PSD were studied in each subgroup. A group of 30 patients affected by a functional form of major depression were also investigated. RESULTS The symptom profiles and anatomical-clinical correlates of major PSD were not different in the acute and more chronic stages. Clear symptom differences were, however, observed between major PSD and endogenous major depression. Motivated (reactive) symptoms prevailed in the former, whereas unmotivated symptoms prevailed in the latter. CONCLUSIONS Our data are more consistent with a psychological than with a neurological model of post-stroke depression.

Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X.

Abstract: The effects of a beta blocker (atenolol), a calcium antagonist (amlodipine), and a nitrate (isosorbide-5-mononitrate) on anginal symptoms in 10 patients with syndrome X were assessed in a crossover, double-blind, randomized trial. Only atenolol was found to significantly improve chest pain episodes, suggesting that it should be the preferred drug when starting pharmacologic treatment of patients with syndrome X.

Minimally invasive, totally gasless video-assisted thyroid lobectomy

Abstract: Background: Neck surgery is one of the newest fields of application of video-assisted surgery. We developed a technique for minimally invasive, totally gasless video-assisted thyroid lobectomy. Methods: The procedure was accepted by a patient with a follicular nodule of the left lobe of the thyroid. We performed a left thyroid lobectomy through a single 20-mm horizontal skin incision, just above the sternal notch, after inserting a 5-mm 30° laparoscope, by using both endoscopic and conventional instrumentation. Results: The recurrent laryngeal nerve and the parathyroid glands were easily identified and preserved. The operating time was 2.5 hours. No complication occurred. The postoperative stay was 2 days. The cosmetic result was excellent Conclusions: We concluded that our technique is feasible and safe. This makes us optimistic about the future of minimally invasive, video-assisted thyroid surgery.

Intracortical origin of the short latency facilitation produced by pairs of threshold magnetic stimuli applied to human motor cortex.

Abstract: Under certain conditions, EMG responses evoked by pairs of transcranial magnetic stimuli over the motor cortex are larger than the sum of the responses to each stimulus given alone. This occurs with interstimulus intervals of around 1.3, 2.5 and 4.3 ms and could be due to interaction between the responses to each stimulus at either the cortex or spinal cord. We recorded the descending volleys set up by such pairs of stimuli from the cervical epidural space of five patients implanted with chronic stimulators for pain control. Interstimulus intervals of 1, 1.2, 1.4 and 2 ms were used to investigate the first peak of facilitation. Enhanced EMG responses occurred after pairs of stimuli at 1, 1.2 and 1.4 ms, and these were accompanied by larger and more numerous descending volleys than expected from the sum of each stimulus alone. We conclude that facilitatory interaction between the stimuli can occur within the cerebral cortex. This may involve elements that produce repetitive I-wave activity in response to a single stimulus.

Multiperspective assessment of carpal tunnel syndrome A multicenter study

Abstract: Objective: To assess the clinical and neurophysiologic dissociation often observed in clinical practice, and to improve patient evaluation for diagnosis of carpal tunnel syndrome (CTS). Methods: The Italian CTS Study Group studied 1,123 idiopathic CTS hands with multiple measurements—clinical, neurophysiologic, and patient-oriented—of CTS. Results: Clinical and neurophysiologic relationships were very strong when the clinical picture was evaluated by the hand functional measurements, with an exponential increase in functional impairment as the classification of neurophysiologic severity progressed. Conversely, symptoms and pain did not increase as the classification of neurophysiologic severity progressed: 1) A large part of the CTS population complained of severe symptoms, although minimal functional impairment and minimal or no electrophysiologic abnormalities were observed; and 2) symptoms improved in the patients with more severe neurophysiologic and clinical examination scenarios. Conclusions: Multiperspective and multimeasurement assessment, even when using a validated patient-oriented tool, provided interesting information that confirmed and clarified the clinical neurophysiologic dissociation often observed in carpal tunnel syndrome (CTS) patients. Furthermore, CTS appeared to be an ideal model for evaluating the importance of patient-oriented measurement.

Networks within Industrial Districts: Organising Knowledge Creation and Transfer by Means of Moderate Hierarchies

Abstract: This paper furnishes evidence of innovative modes of organisationof inter-firm relationships and knowledge management within industrialdistricts. With the aid of a district firm, we first highlight the marked tendency among the largest companies to eschew an exclusively endogenous innovative process. Next, we analyse how the leading firm can play an active role within a network by assigning outside its boundaries tasks that were once undertaken in-house. This happens gradually with the moderate hierarchisation of originally destructured network relationships. In its attempt to organise innovative modes of design and manufacturing, without losing control and strategic legitimisation, the leading firm elects a coordinating agent withdirect responsibility over a selected team of specialist suppliers.

Characteristics of the SAGE database: a new resource for research on outcomes in long-term care. SAGE (Systematic Assessment of Geriatric drug use via Epidemiology) Study Group.

Abstract: Background Because there is a lack of databases specific to long-term care, standardized assessments of nursing home residents are seen as a potential new resource for studying an important but neglected population. We describe the design and principal population characteristics of the first integrated database combining detailed clinical information and administrative claims data. Methods We studied nearly 300,000 residents admitted between 1992 and 1994 to all Medicare/Medicaid certified nursing homes of five U.S. states (Kansas, Maine, Mississippi, New York, and South Dakota). The database crosslinks: (a) Resident Data: over 350 items (demographic, diagnostic, clinical, and treatments) collected with the Minimum Data Set; (b) Drug Data: brand name, dosage route, and frequency of administration for all drugs consumed by each resident; (c) Medicare Data: eligibility and inpatient hospital claims; (d) Facilities Data: structural and staffing information on nursing homes; and (e) Country Data: information on population, health professions and facility data, and economic parameters. Results Ninety-two percent of the residents were aged 65 years and older. Residents were predominantly white (85%) and female (72%). The average number of medical diagnoses was above three, and residents were receiving an average of six medications. Sixty-five percent of residents had at least one hospital claim following the initial assessment, most commonly related to cardiovascular diseases and metabolic disorders. Fifty-five percent of the facilities were for-profit and 33% were of small size. Quality indicators and staffing level varied significantly by state. Conclusions The SAGE (Systematic Assessment of Geriatric drug use via Epidemiology) database provides a unique resource to study the relation between treatments received and outcomes experienced, particularly functional and health services outcomes, that have not been possible before in very old, frail people.

Frequent loss of expression of the cyclin-dependent kinase inhibitor p27 in epithelial ovarian cancer.

Abstract: p27Kip1 is a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors and is a potential tumor suppressor gene. Low levels of p27 are associated with poor prognosis in a variety of tumors, including breast, colon, prostate, and lung carcinomas. In the present study, p27 protein expression was investigated by immunohistochemistry and Western blot analysis in a series of 82 epithelial ovarian tumors [16 classified as low malignant potential (LMP) and 66 classified as primary ovarian adenocarcinomas]. Immunohistochemical analysis revealed frequent loss of p27 expression in primary ovarian adenocarcinomas (33%), with respect to LMP tumors (6%; P = 0.0009). In addition to nuclear staining, cytoplasmic localization of p27 was noted in 45 (55%) of 82 cases. p27 levels inversely correlated with cdk2 kinase activity in a representative subset of tumors. When the clinical outcome of the patients was evaluated in relationship to p27 status, we observed a significant correlation between presence of p27 staining and a longer time to progression (P = 0.032 by log-rank test). These data indicate that loss of p27 is a frequent event in ovarian carcinomas as compared with LMP tumors, suggesting that these tumor types may have different pathogenesis. p27 levels may also represent a useful prognostic marker for predicting disease recurrence in primary ovarian carcinomas.