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1.
J Clin Oncol ; : JCO2301655, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38531001

ABSTRACT

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

2.
Hum Vaccin Immunother ; 19(2): 2230760, 2023 08 01.
Article in English | MEDLINE | ID: mdl-37428653

ABSTRACT

This post-hoc analysis compared the receptor-binding domain (RBD)-specific and pseudovirus neutralizing antibodies against the wild-type SARS-CoV-2 strain elicited by one or two doses (56-d interval) of Ad5-nCoV vaccine regimen (NCT04341389 and NCT04566770). Both trials had low-dose and high-dose groups. Propensity score matching was used to adjust the baseline between one- and two-dose regimens. To predict the decrease in antibody titers 1 y after vaccination, half-lives of RBD-binding antibodies and pseudovirus neutralizing antibodies were computed. We obtained 34 and 29 pairs of participants in the low- and high-dose groups based on the propensity score matching. The two-dose regimen of Ad5-nCoV increased the peaking level of neutralizing antibodies compared to the one-dose regimen at day 28, but the responses of the neutralizing antibodies were not consistent with those of the RBD antibodies. Half-lives of the RBD-binding antibodies in the two-dose Ad5-nCoV regimen (202-209 days) were longer than those in the one-dose regimen (136-137 d); half-lives of the pseudovirus neutralizing antibody in the one-dose Ad5-nCoV regimen (177 d) were longer than those in the two-dose regimen (116-131 d). The predicted positive rates of RBD-binding antibodies in the one-dose regimen (34.1%-38.3%) would be lower than those in the two-dose Ad5-nCoV regimen (67.0%-84.0%), while the positive rates of pseudovirus neutralizing antibodies in the one-dose regimen (65.4%-66.7%) would be higher than those in the two-dose regimen (48.3%-58.0%). The two-dose Ad5-nCoV regimen with a 56-d interval had no effect on the persistence of neutralizing antibodies but slowed decay trend of RBD-binding antibodies.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , SARS-CoV-2 , Clinical Trials as Topic
3.
Lancet Respir Med ; 11(7): 613-623, 2023 07.
Article in English | MEDLINE | ID: mdl-36898400

ABSTRACT

BACKGROUND: Aerosolised Ad5-nCoV is the first approved mucosal respiratory COVID-19 vaccine to be used as a booster after the primary immunisation with COVID-19 vaccines. This study aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster. METHODS: This is an open-label, parallel-controlled, phase 4 randomised trial enrolling healthy adult participants (≥18 years) who had completed a two-dose primary immunisation and a booster immunisation with inactivated COVID-19 vaccines (CoronaVac only) at least 6 months before, in Lianshui and Donghai counties, Jiangsu Province, China. We recruited eligible participants from previous trials in China (NCT04892459, NCT04952727, and NCT05043259) as cohort 1 (with the serum before and after the first booster dose available), and from eligible volunteers in Lianshui and Donghai counties, Jiangsu Province, as cohort 2. Participants were randomly assigned at a ratio of 1:1:1, using a web-based interactive response randomisation system, to receive the fourth dose (second booster) of aerosolised Ad5-nCoV (0·1 mL of 1·0 × 1011 viral particles per mL), intramuscular Ad5-nCoV (0·5 mL of 1·0 × 1011 viral particles per mL), or inactivated COVID-19 vaccine CoronaVac (0·5 mL), respectively. The co-primary outcomes were safety and immunogenicity of geometric mean titres (GMTs) of serum neutralising antibodies against prototype live SARS-CoV-2 virus 28 days after the vaccination, assessed on a per-protocol basis. Non-inferiority or superiority was achieved when the lower limit of the 95% CI of the GMT ratio (heterologous group vs homologous group) exceeded 0·67 or 1·0, respectively. This study was registered with ClinicalTrials.gov, NCT05303584 and is ongoing. FINDINGS: Between April 23 and May 23, 2022, from 367 volunteers screened for eligibility, 356 participants met eligibility criteria and received a dose of aerosolised Ad5-nCoV (n=117), intramuscular Ad5-nCoV (n=120), or CoronaVac (n=119). Within 28 days of booster vaccination, participants in the intramuscular Ad5-nCoV group reported a significantly higher frequency of adverse reactions than those in the aerosolised Ad5-nCoV and intramuscular CoronaVac groups (30% vs 9% and 14%, respectively; p<0·0001). No serious adverse events related to the vaccination were reported. The heterologous boosting with aerosolised Ad5-nCoV triggered a GMT of 672·4 (95% CI 539·7-837·7) and intramuscular Ad5-nCoV triggered a serum neutralising antibody GMT of 582·6 (505·0-672·2) 28 days after the booster dose, both of which were significantly higher than the GMT in the CoronaVac group (58·5 [48·0-71·4]; p<0·0001). INTERPRETATION: A heterologous fourth dose (second booster) with either aerosolised Ad5-nCoV or intramuscular Ad5-nCoV was safe and highly immunogenic in healthy adults who had been immunised with three doses of CoronaVac. FUNDING: National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan.


Subject(s)
COVID-19 Vaccines , COVID-19 , Adult , Humans , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , SARS-CoV-2 , Vaccines, Inactivated
4.
Curr Oncol Rep ; 24(11): 1477-1488, 2022 11.
Article in English | MEDLINE | ID: mdl-35696020

ABSTRACT

PURPOSE OF REVIEW: Checkpoint inhibitors (CPIs) targeting PD1 are highly active in relapsed/refractory classical Hodgkin lymphoma. A plethora of recent studies, often small and non-randomised, have raised many questions about how to optimally integrate these into clinical practice. We aim to discuss the use of CPIs in different relapsed/refractory settings in an effort to better define their role and highlight areas of research. RECENT FINDINGS: CPIs have shown efficacy at first relapse, as salvage pre- and post-autologous (ASCT) and allogeneic stem cell transplant (alloSCT) and as maintenance post-ASCT. Immune-related adverse events require careful attention, especially when used peri-alloSCT, where it is associated with hyperacute graft-versus-host disease. Newer PD1 inhibitors, as well as strategies to overcome CPI resistance, are being tested. CPIs are increasingly deployed at earlier points in the classical Hodgkin lymphoma pathway. Whilst progress is clearly being made, randomised studies are required to more clearly define the optimal positioning of these agents.


Subject(s)
Hematopoietic Stem Cell Transplantation , Hodgkin Disease , Humans , Hodgkin Disease/drug therapy , Hodgkin Disease/pathology , Neoplasm Recurrence, Local/drug therapy , Salvage Therapy , Transplantation, Autologous
5.
Lancet Respir Med ; 10(8): 739-748, 2022 08.
Article in English | MEDLINE | ID: mdl-35605625

ABSTRACT

BACKGROUND: Due to waning immunity and protection against infection with SARS-CoV-2, a third dose of a homologous or heterologous COVID-19 vaccine has been proposed by health agencies for individuals who were previously primed with two doses of an inactivated COVID-19 vaccine. METHODS: We did a randomised, open-label, controlled trial to evaluate the safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in Chinese adults (≥18 years old) who had previously received two doses of an inactivated SARS-CoV-2 vaccine-Sinovac CoronaVac. Eligible participants were randomly assigned (1:1:1) to receive a heterologous booster vaccination with a low dose (1·0 × 1011 viral particles per mL; 0·1 mL; low dose group), or a high dose (1·0 × 1011 viral particles per mL; 0·2 mL; high dose group) aerosolised Ad5-nCoV, or a homologous intramuscular vaccination with CoronaVac (0·5 mL). Only laboratory staff were masked to group assignment. The primary endpoint for safety was the incidence of adverse reactions within 14 days after the booster dose. The primary endpoint for immunogenicity was the geometric mean titres (GMTs) of serum neutralising antibodies (NAbs) against live SARS-CoV-2 virus 14 days after the booster dose. This study was registered with ClinicalTrials.gov, NCT05043259. FINDINGS: Between Sept 14 and 16, 2021, 420 participants were enrolled: 140 (33%) participants per group. Adverse reactions were reported by 26 (19%) participants in the low dose group and 33 (24%) in the high dose group within 14 days after the booster vaccination, significantly less than the 54 (39%) participants in the CoronaVac group (p<0·0001). The low dose group had a serum NAb GMT of 744·4 (95% CI 520·1-1065·6) and the high dose group had a GMT of 714·1 (479·4-1063·7) 14 days after booster dose, significantly higher than the GMT in the CoronaVac group (78·5 [60·5-101·7]; p<0·0001). INTERPRETATION: We found that a heterologous booster vaccine with an orally administered aerosolised Ad5-nCoV is safe and highly immunogenic in adults who have previously received two doses of CoronaVac as the primary series vaccination. FUNDING: National Natural Science Foundation of China and Jiangsu Provincial Key Research and Development Program.


Subject(s)
COVID-19 Vaccines , COVID-19 , Adolescent , Adult , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Research , SARS-CoV-2 , Vaccination
6.
Br J Haematol ; 194(3): 508-517, 2021 08.
Article in English | MEDLINE | ID: mdl-33618434

ABSTRACT

Twenty-five to thirty per cent of diffuse large B-cell lymphoma (DLBCL) presents as limited stage (I-II). Prognosis is generally excellent with four to six cycles of R-CHOP alone (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisolone) or combined-modality therapy with three or four cycles and involved-site radiotherapy (RT). There is growing interest in optimising algorithms to retain disease control whilst minimising long-term toxicity, with several recent studies focusing on the safety of abbreviating chemotherapy and omitting RT in low-risk patients and the utility of PET-based response-adapted approaches. As these studies are limited to younger patients without risk factors, application of similar approaches in elderly or higher-risk patients is hampered by a lack of evidence. Whilst there has been a move away from using RT in low-risk patients, it remains a useful adjunct in specific situations. Current evidence cannot exclude a clinically meaningful benefit from RT even in low-risk patients and, given the low expected toxicity from modern RT techniques, a risk-benefit assessment should be individualised and considered in a multidisciplinary fashion. The optimal approach for extranodal limited-stage DLBCL (~40% of cases) varies according to site of origin. Herein we discuss the latest clinical trial evidence and how this can be applied in routine practice.


Subject(s)
Lymphoma, Large B-Cell, Diffuse/therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy/adverse effects , Chemoradiotherapy/methods , Clinical Trials as Topic , Cyclophosphamide/adverse effects , Cyclophosphamide/therapeutic use , Disease Management , Doxorubicin/adverse effects , Doxorubicin/therapeutic use , Humans , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/radiotherapy , Prednisone/adverse effects , Prednisone/therapeutic use , Rituximab/adverse effects , Rituximab/therapeutic use , Treatment Outcome , Vincristine/adverse effects , Vincristine/therapeutic use
7.
J Clin Oncol ; 39(10): 1129-1138, 2021 04 01.
Article in English | MEDLINE | ID: mdl-33502927

ABSTRACT

PURPOSE: Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. METHODS: We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. RESULTS: In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. CONCLUSION: The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Burkitt Lymphoma/drug therapy , Outcome Assessment, Health Care/statistics & numerical data , Adult , Australia , Canada , Cohort Studies , Europe , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Outcome Assessment, Health Care/methods , Prognosis , Rituximab/administration & dosage , United States
8.
Cochrane Database Syst Rev ; 9: CD010054, 2020 09 05.
Article in English | MEDLINE | ID: mdl-32888198

ABSTRACT

BACKGROUND: Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the day. This review focuses on the subclass of beta-blockers with partial agonist activity (BBPAA). OBJECTIVES: To assess the degree of variation in hourly BP lowering efficacy of BBPAA over a 24-hour period in adults with essential hypertension. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for relevant studies up to June 2020: the Cochrane Hypertension Specialised Register; CENTRAL; 2020, Issue 5; MEDLINE Ovid; Embase Ovid; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We sought to include all randomised and non-randomised trials that assessed the hourly effect of BBPAA by ambulatory monitoring, with a minimum follow-up of three weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the included trials and extracted the data. We assessed the certainty of the evidence using the GRADE approach. Outcomes included in the review were end-point hourly systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR), measured using a 24-hour ambulatory BP monitoring (ABPM) device. MAIN RESULTS: Fourteen non-randomised baseline controlled trials of BBPAA met our inclusion criteria, but only seven studies, involving 121 participants, reported hourly ambulatory BP data that could be included in the meta-analysis. Beta-blockers studied included acebutalol, pindolol and bopindolol. We judged most studies at high or unclear risk of bias for selection bias, attrition bias, and reporting bias. We judged the overall certainty of the evidence to be very low for all outcomes. We analysed and presented data by each hour post-dose. Very low-certainty evidence showed that hourly mean reduction in BP and HR visually showed an attenuation over time. Over the 24-hour period, the magnitude of SBP lowering at each hour ranged from -3.68 mmHg to -17.74 mmHg (7 studies, 121 participants), DBP lowering at each hour ranged from -2.27 mmHg to -9.34 mmHg (7 studies, 121 participants), and HR lowering at each hour ranged from -0.29 beats/min to -10.29 beats/min (4 studies, 71 participants). When comparing between three 8-hourly time intervals that correspond to day, evening, and night time hours, BBPAA was less effective at lowering BP and HR at night, than during the day and evening. However, because we judged that these outcomes were supported by very low-certainty evidence, further research is likely to have an important impact on the estimate of effect and may change the conclusion. AUTHORS' CONCLUSIONS: There is insufficient evidence to draw general conclusions about the degree of variation in hourly BP-lowering efficacy of BBPAA over a 24-hour period, in adults with essential hypertension. Very low-certainty evidence showed that BBPAA acebutalol, pindolol, and bopindolol lowered BP more during the day and evening than at night. However, the number of studies and participants included in this review was very small, further limiting the certainty of the evidence. We need further and larger trials, with accurate recording of time of drug intake, and with reporting of standard deviation of BP and HR at each hour.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Circadian Rhythm/physiology , Hypertension/drug therapy , Acebutolol/therapeutic use , Adrenergic beta-Agonists/therapeutic use , Adult , Bias , Blood Pressure/physiology , Controlled Clinical Trials as Topic , Female , Heart Rate/drug effects , Humans , Hypertension/physiopathology , Male , Middle Aged , Pindolol/analogs & derivatives , Pindolol/therapeutic use , Time Factors
9.
J Cell Sci ; 129(24): 4449-4454, 2016 12 15.
Article in English | MEDLINE | ID: mdl-27872153

ABSTRACT

As time passes, mutations accumulate in the genomes of all living organisms. These changes promote genetic diversity, but also precipitate ageing and the initiation of cancer. Food is a common source of mutagens, but little is known about how nutritional factors cause lasting genetic changes in the consuming organism. Here, we describe an unusual genetic interaction between DNA repair in the unicellular amoeba Dictyostelium discoideum and its natural bacterial food source. We found that Dictyostelium deficient in the DNA repair nuclease Xpf (xpf-) display a severe and specific growth defect when feeding on bacteria. Despite being proficient in the phagocytosis and digestion of bacteria, over time, xpf- Dictyostelium feeding on bacteria cease to grow and in many instances die. The Xpf nuclease activity is required for sustained growth using a bacterial food source. Furthermore, the ingestion of this food source leads to a striking accumulation of mutations in the genome of xpf- Dictyostelium This work therefore establishes Dictyostelium as a model genetic system to dissect nutritional genotoxicity, providing insight into how phagocytosis can induce mutagenesis and compromise survival fitness.


Subject(s)
Dictyostelium/metabolism , Mutagenesis , Phagocytosis , Protozoan Proteins/metabolism , Amino Acid Sequence , DNA Repair/genetics , Dictyostelium/cytology , Dictyostelium/growth & development , Phagocytosis/genetics , Protozoan Proteins/chemistry , Protozoan Proteins/genetics
10.
BMJ Case Rep ; 20162016 Feb 02.
Article in English | MEDLINE | ID: mdl-26838300

ABSTRACT

Histological features of Epstein-Barr virus (EBV) can rarely mimic lymphoma. A 25-year-old presented with a spontaneous splenic rupture following a short illness. Histopathology assessment of the splenic and marrow tissue was highly suggestive of peripheral T-cell lymphoma not-otherwise-specified (PTCL-NOS). T-cell receptor (TCR) PCR clonality studies revealed a monoclonal T-cell population expressing for both TCRß and γ, strongly suggestive of a T-cell clonal disease. EBV IgM was positive and IgG negative. EBV PCR was positive (7.02 ×10(4)/mL). Despite the strong suggestion of PTCL-NOS from histopathology and clonality studies, the decision was made to observe the patient and not start multiagent chemotherapy. The patient remained well, with no signs of PTCL and subsequently seroconverted to IgG+ EBV. We highlight the potential pitfall of acute EBV masquerading as PTCL and show the critical role of the multidisciplinary integration of histopathological, serology, molecular and clinical features to avoid misdiagnosis.


Subject(s)
Epstein-Barr Virus Infections/diagnosis , Lymphoma, T-Cell, Peripheral/diagnosis , Adult , Antibodies, Monoclonal/blood , Diagnosis, Differential , Epstein-Barr Virus Infections/blood , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/immunology , Humans , Male , Receptors, Complement 3d/blood
12.
Guang Pu Xue Yu Guang Pu Fen Xi ; 30(1): 58-61, 2010 Jan.
Article in Chinese | MEDLINE | ID: mdl-20302081

ABSTRACT

The objective of the present study is to assess the cerebral saturation under driver fatigue based on the near infrared spectroscopy (NIRS) signals. Twenty healthy male subjects were randomly divided into two groups: A-group (study group) and B-group (control group). All subjects were required to be well rested before the experiment. In A-group the subjects were required to perform the simulated driving task for 3 hours. Cerebral oxygenation signal was monitored for 20 minutes prior to and after the prescribed task period from the left frontal lobe. The results show that cerebral oxygen saturation was found to be significantly lower following 3-hour driving in the task group compared to that in the control group (F = 15.92, p < 0.001). Also a significant difference in selective reaction time was observed between the task group and control group during the post task period (p = 0.021). These findings showed that the cerebral blood oxygen saturation was closely related to the driver fatigue. The decline of the cerebral oxygen saturation might indicate a reduced cerebral oxygen delivery. This suggests that NIRS could provide a non-invasive method to detect driver fatigue.


Subject(s)
Automobile Driving , Cerebrum/metabolism , Fatigue , Oxygen Consumption , Spectroscopy, Near-Infrared , Case-Control Studies , Humans , Male , Oximetry , Oxygen/blood
13.
PLoS Genet ; 5(9): e1000645, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19763158

ABSTRACT

Organisms like Dictyostelium discoideum, often referred to as DNA damage "extremophiles", can survive exposure to extremely high doses of radiation and DNA crosslinking agents. These agents form highly toxic DNA crosslinks that cause extensive DNA damage. However, little is known about how Dictyostelium and the other "extremophiles" can tolerate and repair such large numbers of DNA crosslinks. Here we describe a comprehensive genetic analysis of crosslink repair in Dictyostelium discoideum. We analyse three gene groups that are crucial for a replication-coupled repair process that removes DNA crosslinks in higher eukarya: The Fanconi anaemia pathway (FA), translesion synthesis (TLS), and nucleotide excision repair. Gene disruption studies unexpectedly reveal that the FA genes and the TLS enzyme Rev3 play minor roles in tolerance to crosslinks in Dictyostelium. However, disruption of the Xpf nuclease subcomponent results in striking hypersensitivity to crosslinks. Genetic interaction studies reveal that although Xpf functions with FA and TLS gene products, most Xpf mediated repair is independent of these two gene groups. These results suggest that Dictyostelium utilises a distinct Xpf nuclease-mediated repair process to remove crosslinked DNA. Other DNA damage-resistant organisms and chemoresistant cancer cells might adopt a similar strategy to develop resistance to DNA crosslinking agents.


Subject(s)
Cisplatin/pharmacology , DNA-Binding Proteins/metabolism , DNA-Directed DNA Polymerase/metabolism , Dictyostelium/drug effects , Dictyostelium/enzymology , Drug Resistance/drug effects , Fanconi Anemia Complementation Group Proteins/metabolism , Animals , Cross-Linking Reagents/pharmacology , DNA Repair/drug effects , Dictyostelium/genetics , Fanconi Anemia Complementation Group D2 Protein/metabolism , Gene Targeting , Genes, Protozoan , Models, Biological , Mutation/genetics , Ubiquitin/metabolism , Ubiquitination/drug effects
14.
Mol Endocrinol ; 23(6): 881-92, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19246514

ABSTRACT

Collectrin is a downstream target of the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha), which is mutated in maturity-onset diabetes of the young subtype 3 (MODY3). Evidence from transgenic mouse models with collectrin overexpression in pancreatic islets suggests divergent roles for collectrin in influencing beta-cell mass and insulin exocytosis. To clarify the function of collectrin in the pancreas, we used a mouse line with targeted deletion of the gene. We examined pancreas morphology, glucose homeostasis by ip glucose tolerance testing (IPGTT) and insulin tolerance testing (IPITT), and pancreas function by in vivo acute-phase insulin response determination and glucose-stimulated insulin secretion from isolated islets. We find no difference in either pancreas morphology or function between wild-type and collectrin-deficient animals (Tmem27(-/y)). However, we note that by 6 months of age, Tmem27(-/y) mice exhibit increased insulin sensitivity by IPITT and decreased adiposity by dual-energy x-ray absorptiometry scanning compared with wild-type. We have previously reported that Tmem27(-/y) mice exhibit profound aminoaciduria due to failed renal recovery. We now demonstrate that Tmem27(-/y) animals also display inappropriate excretion of some short-chain acylcarnitines derived from amino acid and fatty acid oxidation. We provide further evidence for compensatory up-regulation of oxidative metabolism in Tmem27(-/y) mice, along with enhanced protein turnover associated with preserved lean mass even out to 1.5 yr of age. Our studies suggest that collectrin-deficient mice activate a number of adaptive mechanisms to defend energy homeostasis in the setting of ongoing nutrient losses.


Subject(s)
Hepatocyte Nuclear Factor 1-alpha/metabolism , Insulin/metabolism , Membrane Glycoproteins/deficiency , Acute-Phase Reaction/metabolism , Adiposity/drug effects , Amino Acids/blood , Animals , Body Weight/drug effects , Cell Proliferation/drug effects , Fasting/blood , Food , Glucose/pharmacology , Glucose Tolerance Test , Insulin Resistance , Insulin Secretion , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Islets of Langerhans/pathology , Membrane Glycoproteins/metabolism , Mice , Phenotype , Protein Processing, Post-Translational/drug effects , Thinness/blood , Thinness/metabolism , Time Factors
15.
Carcinogenesis ; 27(11): 2341-53, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16973673

ABSTRACT

Following integration of human papillomavirus (HPV) into the host genome, overexpression of the viral oncogenes E6 and E7 requires loss of the transcriptional repressor functions of E2. A key step in HPV-related carcinogenesis is therefore clearance of residual viral episomes, which encode E2. As spontaneous loss of HPV-16 episomes in vitro is associated with increased expression of antiviral genes inducible by type I interferon (IFN), we used the W12 model to examine the effects of exogenous IFN-beta on cervical keratinocytes containing HPV-16 episomes as a result of 'natural' infection in vivo. In contrast to studies of cells transfected with HPV-31 or bovine papillomavirus, IFN-beta caused rapid reduction in numbers of HPV-16 episomes. This was associated with the emergence of cells bearing previously latent integrants, in which there was increased expression of E6 and E7. Our data indicate that integrated HPV-16 can exist in a minority of cells in a mixed population without exerting a selective advantage until episome numbers are reduced. The kinetics of cell death and changes in viral transcription and translation that we observed support a model where integrants are initially present in cells also containing episomes, with generalized episome clearance by IFN-beta resulting in integrant de-repression. We conclude that IFN-beta can hasten the transition from episomal to integrated HPV-16 in naturally infected cervical keratinocytes. Greater emphasis should be placed on episome loss in models of HPV-related carcinogenesis. We provide the strongest evidence to date that treating HPV-16 lesions by inducing an IFN response may cause clinical progression.


Subject(s)
Cervix Uteri/drug effects , Cervix Uteri/virology , Gene Expression Regulation, Viral , Human papillomavirus 16/metabolism , Interferon-beta/pharmacology , Keratinocytes/drug effects , Keratinocytes/virology , Papillomavirus Infections/drug therapy , Animals , Apoptosis , Cell Proliferation , Cervix Uteri/cytology , Disease Progression , Female , Flow Cytometry , Humans , Mice , Papillomavirus Infections/metabolism , Time Factors , Transfection
16.
Shanghai Kou Qiang Yi Xue ; 14(5): 525-7, 2005 Oct.
Article in Chinese | MEDLINE | ID: mdl-16288336

ABSTRACT

PURPOSE: To reduce the cost of the fabrication of the magnetic retentor,and meet the clinical requirements, nonprecious alloy such as Co-Cr alloy was used to fabricate the magnetic retentor in overdenture , instead of the precious alloy. METHODS: A mandibular canine was chosen for root canal preparation in vitro. Thirty two resin posts were made in the same root canal with self-curing resin. The 32 resin posts were randomly divided into 4 groups. Among them,2 groups were fabricated with soft Co-Cr alloy, gold alloy(55.6%Au) respectively in vitro. Another 2 groups were fabricated with Co-Cr alloy, and the surface of the root casting post with keeper were treated with gold deposit and gold coating technique. After that, test of dislodgment force was done and one-way ANOVA was performed with SAS 6.2 software package. RESULTS: The dislodgment force of the root casting posts with keeper which were fabricated with the Co-Cr, Ni-Cr, and gold alloy had significant difference(P<0.01). While after surface treatment by gold deposit and gold coating technique on root casting posts with keeper that were fabricated with Co-Cr and Ni-Cr alloy, there was no significant difference in dislodgment force, compared with that of gold alloy. CONCLUSIONS: After surface treatment of the root casting posts with keeper which were fabricated with the Co-Cr and Ni-Cr alloy, the same clinical retentive effect can be obtained as the one that was fabricated with gold alloy.


Subject(s)
Chromium Alloys/therapeutic use , Denture, Overlay , Gold Alloys/therapeutic use , Root Canal Preparation/instrumentation , Root Canal Preparation/methods , Humans , Magnetic Phenomena
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