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PubMed2003

Role of Pin2/TRF1 in telomere maintenance and cell cycle control.

Telomeres are specialized structures found at the extreme ends of chromosomes, which have many functions, including preserving genomic stability, maintaining cell proliferative capacity, and blocking the activation of DNA-damage cell cycle checkpoints. Deregulation of telomere length has been implicated in cancer and ageing. Telomere maintenance is tightly regulated by telomerase and many other telomere-associated proteins and is also closely linked to cell cycle control, especially mitotic regulation. However, little is known about the identity and function of the signaling molecules connecting telomere maintenance and cell cycle control. Pin2/TRF1 was originally identified as a protein bound to telomeric DNA (TRF1) and as a protein involved in mitotic regulation (Pin2). Pin2/TRF1 negatively regulates telomere length and importantly, its function is tightly regulated during the cell cycle, acting as an important regulator of mitosis. Recent identification of many Pin2/TRF1 upstream regulators and downstream targets has provided important clues to understanding the dual roles of Pin2/TRF1 in telomere maintenance and cell cycle control. These results have led us to propose that Pin2/TRF1 functions as a key molecule in connecting telomere maintenance and cell cycle control.

Amino Acid Sequence↗
PubMed1981

Combination chemoimmunotherapy with FAC-BCG for metastatic breast cancer: the impact of CMF maintenance chemotherapy.

In an attempt to prolong the durations of remission and survival of patients with advanced breast cancer treated with the FAC-BCG protocol, we modified the CMF maintenance combination by increasing the dose of all three drugs and administering them intravenously. Eighty-five evaluable patients treated with this new regimen were compared with a recent historical control group of 105 evaluable patients treated with FAC-BCG and a lower-dose, oral CMF maintenance program. The overall (70% and 76%) and complete (16% and 19%) response rates were identical in these two groups. The median times to progression for all patients entered were similar too (13 months for both groups.). The durations of response were 17 months (PO-CMF) and 14 months (IV-CMF), not significantly different (P = .16). The durations of survival of the two treated groups were also very similar. After the administration of intensive FAC induction therapy, a high-dose, intravenous CMF maintenance program appears no better than a low-dose oral regimen. Other drug combinations consisting entirely of drugs not used in the induction regimen might be better choices for maintenance treatment

Administration, Oral↗
PubMed1976

Immunocompetence and prognosis in children with acute lymphoblastic leukemia: combination of two different maintenance therapies.

Intensive chemotherapy in patients with leukemia produced immunosuppression. The level of immunocompetence correlates with prognosis. The immunological function of 29 children with acute lymphoblastic leukemia (ALL) in complete remission and on 2 different maintenance therapies was evaluated and compared with 16 normal children (Group A). Sixteen children (Group B) with ALL received 6 mercaptopurine (6MP) daily and methotrexate (MTX) twice a week, and 13 children (Group C) received 6MP and MTX weekly for maintenance. There was depression of both cellular immunity, measured by the number of T cells and skin tests, and humoral immunity, measured by number of B cells, primary antibody production to typhoid vaccine, and levels of immunoglobulins. However, continuous maintenance therapy (Group B) produced significantly more severe immunosuppression of cellular immunity than the intermittent therapy (Group C). Humoral immunity was equally depressed in both groups of leukemia patients, but was less altered than cellular immunity. Concomitantly, patients with intermittent maintenance chemotherapy had less hematologic depression, fewer episodes of infection, and fewer died in complete remission. Patients of both groups with higher levels of immunocompetence had better prognosis with longer duration of complete remission than patients with severe immunosuppression. Out of 6 patients with "favorable immunocompetence" only 1 relapsed at 7 months and the other 5 remain in complete remission from 8 to 31 months. Among 23 leukemic patients with "unfavorable immunocompetence," 15 relapsed and 8 remain in complete remission from 9 to 26 months.

Acute Disease↗
PubMed2005

Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy.

BACKGROUND: 6-Thioguanine (TG) was recently studied to determine whether TG in maintenance therapy achieves better event free survival than 6-mercaptopurine (MP) for standard risk acute lymphoblastic leukemia (ALL) on the clinical trial, CCG-1952 (5/1996-1/2000). Veno-occlusive disease was previously recognized as a complication of TG on CCG-1952. We report a newly recognized pediatric complication of TG: splenomegaly and portal hypertension (PH) developing during maintenance or after completion of therapy. PROCEDURE: Twelve patients (3-10 years) had been randomized to receive a targeted dose of 50 mg/m(2)/day of TG during maintenance phases. Actual TG dose ranged from 25 to 77 mg/m(2)/day (median 34 mg/m(2)/day). RESULTS: The initial patient, a boy who had marked thrombocytopenia and intermittent splenomegaly during maintenance therapy, was evaluated for persistent pancytopenia and progressive splenomegaly 3 months after completion of therapy. Dilated splenic vein and collaterals consistent with PH were documented by MRI/MRA. Esophagogastroduodenoscopy found esophageal varices. Liver biopsy showed periportal fibrosis and marked dilatation of veins and venules. Of the other 12 patients, 9 patients studied had abnormal MRI/MRAs with evidence of varices in 4. Eight patients had splenomegaly on physical examination. Liver biopsies in a girl after 3.3 courses of TG and a boy after 4.6 courses of TG showed periportal fibrosis and dilatation of venules and sinusoids and minimal focal fatty changes. Subsequent MRI/MRAs have been stable or improved. CONCLUSIONS: The evaluations of these 12 patients suggest that treatment with TG causes injury to the liver leading to PH and that thrombocytopenia and splenomegaly are clinical hallmarks of this toxicity.

Administration, Oral↗
PubMed1998

Defect in the maintenance of the apical ectodermal ridge in the Dactylaplasia mouse.

During vertebrate limb development the distal apex of the limb bud ectoderm is induced to form the apical ectodermal ridge (AER). The presence of the AER is required for the continued outgrowth of the limb bud. Classical embryological studies have led to the hypothesis that a secreted mesenchymal factor is required to maintain the AER. We have undertaken a detailed analysis of Dactylaplasia (Dac) mice, a semidominant mutant which displays missing central digits in the fore- and hindlimbs of heterozygous animals and monodactyly in homozygous animals. Our data show that Dac mice have a defect in the maintenance of the AER. At E10.5, the mutant AER is found to be morphologically normal. However, by E11.5 the central aspect of the AER degenerates leaving the anterior and posterior AER intact. In homozygous mice both the central and anterior AER degenerate, while the posterior extremity of the AER is unaffected. Analysis of BrdU incorporation reveals that degeneration of the AER is due to a lack of cell proliferation in the mutant AER. The loss of the AER leads to a reduction in cell proliferation in the subridge mesenchyme at E11.5. The data represent direct genetic evidence for the existence of an AER maintenance activity that is distinct from AER induction and differentiation. Moreover, the data suggest that the role of the AER maintenance factor is to promote cell proliferation in the ridge. Based on our findings, we propose a model for AER maintenance in the vertebrate limb.

Animals↗
PubMed2002

Maintenance and manipulation in spatial working memory: dissociations in the prefrontal cortex.

Two experiments were conducted to compare thec ries of the functional organization of spatial working memory within the human prefrontal cortex. In Experiment I, memory set size for locations was parametrically varied, allowing for the assessment of BOLD signal across maintenance requirements. In the sec ond experiment, manipulation of spatial information held in working memory was contrasted with simple maintenance of that information. Both experiment evoked significant activity in a distributed spatia working memory network. Although dorsolateral prefrontal activation increased monotonically with memory set size, this region was differentially engaged in task conditions involving explicit manipulation of in ternal representations. Activation in the superior frontal sulcal region was associated with maintenance of spatial information, increasing with memory se size. In contrast, ventrolateral prefrontal activation was present only at the highest memory set size, possibly due to the differential use of organizational strategies with more complex stimuli. These results sup port claims that the dorsolateral prefrontal cortex is involved in the manipulation of internal representa tions and that the superior frontal sulcal region is involved in the maintenance of spatial information but they suggest a complex role for the ventrolatera prefrontal region.

Algorithms↗
PubMed1977

An effect of F-like plasmids on the maintenance of Flac in a dnaC mutant of Salmonella typhimurium.

Flac maintenance was aberrant at permissive temperature in a temperature-sensitive dnaC mutant of Salmonella typhimurium when the normally resident pLT2 plasmid was present. Flac was, however, efficiently transferred into the dnaC pLT2+ strain and the resulting Flac derivative was almost as efficient in transferring Flac as was dnaC+ pLT2+ Flac strains indicating that aberrant Flac maintenance was not associated with appreciable inhibition of transfer replication. A range of F-like plasmids behaved like pLT2 in causing aberrant Flac maintenance when present in the dnaC pLT2- strain. Flac was, however, stably maintained in the dnaC strain in the absence of other plasmids. Although the F-like plasmids destabilized Flac, each was stably maintained when introduced into strain 11G dnaC pLT2+ and pLT2 was also apparently stable under these conditions. The destabilizing effect of pLT2 and other fi+ plasmids was not consequent upon their inhibiting the formation of a repressible F transfer component needed for Flac replication in the dnaC strain. Incompatibility between Flac and the other plasmids induced by the dnaC lesion also appeared unlikely to be a cause of the aberrant Flac maintenance. The possibility is discussed that the initiation of Flac replication differs from that of pLT2 and the F-like plasmids with F competing less effectively than the others for the DnaC gene product.

Conjugation, Genetic↗
PubMed1986

Maintenance chemotherapy for anaplastic small cell carcinoma of the bronchus: a randomised, controlled trial.

Since March 1980, 309 patients with anaplastic small cell carcinoma of the bronchus (ASCB) have received remission induction therapy prior to randomisation to maintenance (M) or no maintenance (NM) chemotherapy. Induction therapy consisted of six courses of vincristine, doxorubicin and cyclophosphamide (VAC) given IV every 3 weeks. Those with limited disease also received mediastinal irradiation. Consenting patients with no unequivocal residual disease were randomised to have no further treatment until relapse or a further eight courses of VAC, at a lower dosage, every 4 weeks. Patients failing to achieve randomisation status received palliative treatment only. The median survival for all patients with limited disease (LD) is 363 days and that for patients with extensive disease (ED) is 272 days (P less than 0.00001). Sixty-one patients with ED were randomised. Those having maintenance chemotherapy lived significantly longer (median 372 days) than those who did not continue therapy (median 259 days) (P = 0.006). An imbalance in the proportion of 'complete remitters' randomised to maintenance therapy does not account for this difference. There is no significant difference between the M and NM groups in the 32 randomised LD patients. Continuing treatment during remission with agents used to induce the remission can prolong survival in patients with extensive stage ASCB.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Maintenance with low-dose cytarabine for acute myeloid leukemia in complete remission.

Thirty-four patients with acute myeloid leukemia (AML) in complete remission (CR), 30 of them aged over 60, received maintenance therapy scheduling four courses of low-dose cytarabine (LDA) 20 mg/m2/day in two subcutaneous injections for 3 weeks every 6 weeks. Each course was stopped when hematologic toxicity occurred, and doses of LDA were subsequently reduced by 50% for the following courses. During the first course of LDA, 15 patients needed blood and four patients platelet transfusions. Overall, 28 patients received four courses of LDA: 11 did not require any dose reduction, while 14 required one dose reduction and three needed two successive dose reductions. Two patients were hospitalized during maintenance. Median disease-free survival (DFS) is 308 days, with 16% of patients surviving at 5 years. Seven patients relapsed during the 168 days of maintenance, while ten of the 27 patients remaining at risk on day 169 relapsed during the 168 days following maintenance. We conclude that in AML in CR, the maximal dose of LDA tolerated by ambulatory patients is 10 mg/m2/day for 3 weeks. LDA seemed to delay relapse; however, precise assessment of the efficacy of this approach would require a randomized trial.

Acute Disease↗
PubMed1981

A prospective evaluation of chemohormonal therapy remission maintenance in advanced breast cancer.

From October 1973 to October 1977 the ECOG prospectively evaluated cyclophosphamide, methotrexate, and fluorouracil (CMF) versus CMF plus fluoxymesterone (CMFH) maintenance therapies in responders to 6 months of induction therapy which consisted of either CMF, CMF plus prednisone (CMFP), or adriamycin plus vincristine (AV). Following the maintenance randomization 12% of the patients converted from a PR to a CR status. The median time from randomization to treatment failure was 9.5 months for CMFH and 6.7 months for CMF (p = 0.03). This difference was observed only for partial responders (p = 0.01) and not for complete responders. Patients receiving CMFH tended to maintain higher hemoglobin, leukocyte, and platelet levels, and receive a higher dosage of each of the cytotoxic drugs. The results are taken as evidence that the addition of fluoxymesterone to a maintenance CMF regimen provides a therapeutic advantage. It is hypothesized that this effect is due at least in part to fluoxymesterone associated maintenance of improved marrow function resulting in greater myelosuppressive drug delivery.

Aged↗
PubMed1994

Successful treatment of recurrent cholangitis with antibiotic maintenance therapy.

The impact of antibiotic maintenance therapy on the incidence of biliary tract infection was evaluated in patients with recurrent cholangitis after resection of a malignancy at the hepatic confluence. Thirty-eight of 54 patients (70%) experienced episodes of cholangitis. In 14 of the 38 patients recurrent episodes of cholangitis caused a severe interruption of their daily life. These 14 were selected for antibiotic maintenance therapy. During maintenance therapy six patients experienced no further episodes of cholangitis and five patients a marked decrease in the frequency of episodes, while in three patients no improvement was seen. Antibiotic maintenance therapy can be highly successful in the treatment of recurrent cholangitis after resection of a malignancy at the hepatic hilum.

Adolescent↗
PubMed1996

Enhancement of cocaine's abuse liability in methadone maintenance patients.

The present study was conducted to determine whether methadone maintenance alters the pharmacodynamic effects of single doses of cocaine. Twenty-two current users of IV cocaine who were not seeking treatment for their illicit cocaine use participated while living on a research unit. Eleven were maintained on methadone 50 mg PO daily as treatment for their opioid abuse; 11 were opioid abusers who were not physically dependent on opioids and who provided opioid-free urines throughout the study. Each subject received acute cocaine challenge doses of 0, 12.5, 25, and 50 mg intravenously in random order under double-blind conditions in separate test sessions. Physiologic and subject-rated responses were measured before injection and for 2 h after. In the methadone maintenance group, cocaine challenge sessions occurred 15.5 h after the daily methadone dose. There were significant differences between the methadone-dependent and nondependent groups: 1) baseline differences related to chronic methadone administration and not associated with cocaine administration (lower respiration rates and pupil diameter; higher skin temperature) and 2) differences in response to cocaine administration; cocaine-induced increases in subject ratings of Drug Effect, Rush, Good Effects, Liking, and Desire for Cocaine and in heart rate were greater in the methadone maintenance patients compared to the non-dependent group. These results indicate that the positive subjective effects and some physiological effects of cocaine are enhanced in methadone-maintained individuals, suggesting a pharmacological basis for the high rates of cocaine abuse among methadone maintenance patients.

Adult↗
PubMedDate not supplied

Retention in publicly funded methadone maintenance treatment in two Western States.

This study examined individual and system characteristics associated with retention in methadone maintenance treatment among Medicaid-eligible adults in treatment for opiate use in Oregon and Washington. Logistic regression was used to examine the contributions of predisposing, need, and enabling characteristics on 365 day retention in methadone maintenance treatment. Older patients, patients with a history of methadone maintenance treatment, and persons with stable Medicaid eligibility had higher rates of retention than did patients with disabilities, polysubstance users, and those with an arrest record. In Oregon, which delivers methadone maintenance treatment through managed care, retention rose sharply from 28% to 51% between 1994 and 1998 and then leveled off. During the same time period, retention in Washington State grew from 28% to 34%. The higher rates of retention in Oregon, in part, can be explained by differences in service delivery influenced by financing. Faced with long waiting lists, Washington providers were more than twice as likely to administratively discharge patients for rule violations as their Oregon counterparts. Given the importance of retention, policies and practices that influence retention should be carefully considered. Because Medicaid eligibility has a dramatic impact on retention, policies that help extend eligibility or stabilize eligibility among individuals actively engaged in treatment should be carefully considered.

Adult↗
PubMed2001

Survival and sinus rhythm maintenance after modified Cox/maze procedure and mitral valve operation in patients with chronic atrial fibrillation.

OBJECTIVE: Sinus rhythm gained after the Cox/maze procedure concomitant with mitral valve operation has demonstrated long-term attrition during the follow-up, no information exists on whether the type of mitral valve operation--(repair vs. replacement)--affects this sinus rhythm maintenance rate. We retrospectively studied patients undergoing concomitant mitral valve operation and Cox/maze procedure to answer this question. METHODS: Between April 1993 and August 1995, 87 consecutive patients--35 men and 52 women (mean age: 59.3 years)--with chronic atrial fibrillation and mitral valve disease underwent the modified Cox/maze procedure and concomitant mitral valve operation, with 56 having mitral valve repair (repair group) and 31 mitral valve replacement (replacement group). Patients were followed up and changes in rhythm studied retrospectively. RESULTS: Follow-up for a mean 51.3 +/- 11.6 months was completed in 82 of 83 long-term survivors (99%). Repair group surgery survival was 98.1 +/- 1.9% at 1 year and 94.2 +/- 3.2% at 5 based on the Kaplan-Meier method. Replacement group surgery survival was 85.7 +/- 5.9% at 1 year and 82.9 +/- 6.4% at 5. Probability in sinus rhythm maintenance for the repair group at 1 year was 88.6 +/- 5.4% and at 5 years was 67.6 +/- 9.1%. Probability in sinus rhythm maintenance for the replacement group at 1 year was 95.7 +/- 4.3% and at 5 years was 65.0 +/- 11.1%. CONCLUSIONS: Medium-term results after the Cox/maze III procedure concomitant with mitral valve operation are good. The attrition of sinus rhythm maintenance appears similar by the completion of 5-year follow-up.

Atrial Fibrillation↗
PubMed1993

Maintenance therapy for peptic ulcer--who needs it?

Until recently, peptic ulcer disease implied lifelong susceptibility to symptomatic, asymptomatic or complicated ulcer recurrences. Only about 50% of the ulcers seen endoscopically ever become symptomatic. Asymptomatic ulcers appear clinically unimportant, except in the setting of aspirin (ASA) or NSAID use, where they may lead without warning to fatal complications. Until recently, ulcer disease could not be cured medically: no drug has been shown to prevent ulcer complications occurring in patients taking ASA/NSAIDs. Low-dose maintenance therapy with H2-antagonists reduces recurrences and complications, but is expensive and requires indefinite use. Other anti-ulcer drugs have not been studied enough to conclude with confidence that they are similarly effective. Over 80% of recurrences are infrequent and can be treated when they occur n 20% of ulcer patients have 3 recurrences/yr, ulcer complications, or such poor health that recurrence might prove fatal. Ulcers recurring during maintenance therapy rarely complicate and heal with increasing and maintaining dosage. Eradication of H. Pylori (HP) infection, while difficult, abolishes most recurrences without maintenance therapy. Maintenance therapy is therefore indicated principally when HP can not be eradicated. Surgery is rarely required for uncomplicated disease.

Adult↗
PubMedDate not supplied

The role of interferon as maintenance therapy in malignant lymphoma.

Interferon (IFN) is a biologic response modifier that has been employed in the treatment of malignant lymphomas with various degrees of success. In patients with low-grade lymphomas, IFN alone induced complete remissions in 17-62% of the patients. When used in combination with chemotherapy, prolongation of remission duration and survival has been reported. The best results have been reported when IFN was used as maintenance therapy in patients with minimal residual disease or complete remission. When used as maintenance treatment toxicity was mild with less than 5% of the patients discontinuing IFN treatment, and late side-effects have not been reported. The results obtained with IFN in patients with intermediate and high-grade lymphomas are disappointing. Complete remissions were observed in less than 10% of the patients and duration of remission and survival did not exceed 12 months. In contrast, promising results have been reported when IFN was used as maintenance treatment following bone marrow transplantation. In conclusion, IFN should be considered as part of the therapeutic process in patients with low-grade lymphomas, and in particular as a maintenance treatment following induction chemotherapy.

Humans↗
PubMed2003

[Electroconvulsive therapy as maintenance therapy and for prevention of recurrence in psychiatric disorders and Parkinson disease].

Electroconvulsive therapy is a reliable and safe option for patients with psychiatric disorders who are resistant or intolerant to medication as these patients usually respond quickly to this form of treatment. For clinicians, the management of these often severely ill patients is an important challenge given the high rate of relapse of these disorders. Maintenance electroconvulsive therapy is an interesting treatment option for these patients. Until now, only few controlled studies exist about the long-term outcome of this treatment in depressive disorders and other psychiatric disorders. Altogether, this form of outpatient prophylactic therapy has been found to be safe, well tolerated, and efficacious in relapse prevention. Moreover, it has been found to reduce hospitalization rates. Particularly in the elderly, and in patients who have been shown to be refractory to medication regimens, maintenance electroconvulsive therapy should be seriously considered as a means to reduce the risk of recurrence of illness. In Parkinson's disease maintenance electroconvulsive therapy is not widely established although its usefulness has been documented in numerous studies. First-line evidence data on incidence, dimensions and outcome of cognitive side effects under maintenance electroconvulsive therapy is still warranted.

Electroconvulsive Therapy↗
PubMed2003

Weight changes after renal transplantation: a comparison between patients on 5-mg maintenance steroid therapy and those on steroid-free immunosuppressive therapy.

After renal transplantation (RTx), an increase in body weight (BW) is usually observed, in which corticosteroids may play an important role. However, the effects of a low maintenance dosage of corticosteroids on BW have not been studied longitudinally in RTx patients. The aim of this study was to compare changes in BW after RTx in patients on steroid- or steroid-free immunosuppressive therapy and to assess the relationship between post-transplant weight changes and other potentially important factors. The charts of 123 RTx patients (72 male, 51 female) were retrospectively examined for BW changes in the first 5 years after RTx. Sixty-six patients were on 5-mg maintenance steroid dose and 57 patients underwent steroid-free immunosuppression. Mean post-transplant BW gain was 3.0+/-5.3 kg after 6 months, 3.9+/-6.2 kg after 1 year and 6.2+/-8.6 kg after 5 years. Weight gain in the first year after RTx was related neither to maintenance- nor to cumulative steroid dose, age, gender, occurrence of rejection, or renal function. Weight gain was, however, significantly related to pre-transplant BMI and dialysis modality. After the first year, weight gain was significantly and positively related only to the cumulative steroid dose. The course of weight gain in the first year after RTx turned out to be independent from factors such as maintenance- or cumulative steroid dose, age, gender, occurrence of rejection, and renal function; weight gain was, however, dependent on pre-transplant BMI and dialysis modality. After the first year, the weight course was significantly affected by cumulative steroid dose.

Acute Disease↗