Overexpression of ABCB4 contributes to acquired doxorubicin resistance in breast cancer cells in vitro

Abstract

Purpose

Doxorubicin is one of the most active agents in the first-line therapy for metastatic breast cancer, but its utility is partially limited by the frequent emergence of doxorubicin resistance. In this study, we aimed to investigate the role of ATP-binding cassette sub-family B, member 4 (ABCB4) in acquired doxorubicin resistance in breast cancer cells, as well as its potential mechanism.

Methods

In doxorubicin-sensitive and -resistant breast cancer cell lines MCF-7 and MDA-MB-231, the expression levels of ABCB4 were detected using real-time quantitative PCR and Western blot analysis, the DNA methylation and histone acetylation status of ABCB4 gene were investigated by bisulfite-sequencing PCR (BSP) and chromatin immunoprecipitation (ChIP) assays, and the doxorubicin sensitivity and intracellular doxorubicin accumulation were observed using cell cytotoxicity assay and flow cytometry. In Madin–Darby Canine Kidney (MDCKII) cells, In vitro transport assay was used to assess the ABCB4-mediated transport of doxorubicin.

Results

ABCB4 was overexpressed in doxorubicin-resistant breast cancer cells compared to their doxorubicin-sensitive counterparts, which was associated with reduced DNA methylation as well as increased histone acetylation at the ABCB4 promoter. ABCB4 could actively pump doxorubicin out of the cells, and knockdown of ABCB4 increased doxorubicin sensitivity and intracellular accumulation in doxorubicin-resistant breast cancer cells.

Conclusions

Our results indicate that ABCB4 is overexpressed in breast cancer cells with acquired doxorubicin resistance, which could be attributed, at least partially, to the epigenetic modifications of ABCB4 gene. ABCB4 mediates the efflux transport of doxorubicin, and contributes to the acquired resistance of doxorubicin in breast cancer cells.

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Association of anterior and posterior occlusal planes with different Angle and skeletal classes in permanent dentitions

Abstract

Objectives

Malocclusions affect about two-thirds of the population and orthodontic treatment is justified in 65% of these. However, the associations between anterior and posterior occlusal plane (AOP, POP) inclinations and Angle classification are lacking.

Patients and methods

In a retrospective study, lateral cephalometric radiograph tracings of 230 previously untreated Caucasians, aged 13 to 49 years, yielded inclines of the bisector occlusal plane, AOP, and POP. All inclinations were referenced to the Sella-Nasion line and the Frankfort horizontal and were assigned to the Angle classification as well as skeletal groups (retrognathic, neutral, prognathic). Quantile regressions were calculated.

Results

In the skeletal groups the angles between Sella-Nasion line and both AOP and POP were significantly different between the groups (p < 0.01), showing steep inclines in skeletal class II and flat inclines in skeletal class III. The angles Frankfort horizontal-to-POP and Frankfort horizontal-to-AOP showed the same trends but only the latter differed significantly between the groups (p = 0.02). Among the Angle groups, AOP inclinations did not differ significantly for both reference planes whereas POP inclinations were significantly different (p = 0.01 to Frankfort horizontal, p = 0.02 to Sella-Nasion). Angle class I patients showed the flattest POP.

Conclusion

Occlusal plane inclines, measured to Sella-Nasion, were more consistent than those referenced to Frankfort horizontal. Sella-Nasion related anterior and posterior occlusal plane inclinations were steep in skeletal class II and flat in skeletal class III patients over all quantiles. Using the Angle classification, anterior and posterior occlusal plane inclinations did not follow this principle.

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Home-Based, Therapist-Assisted, Therapy for Young Children with Primary Complex Motor Stereotypies

Publication date: Available online 18 May 2018
Source:Pediatric Neurology
Author(s): Harvey S. Singer, Shreenath Rajendran, H. Richard Waranch, E. Mark Mahone
BackgroundComplex motor stereotypies (CMS) typically begin before 3 years, and include rhythmic, repetitive, fixed movements, that last for seconds-minutes, and stop with distraction.ObjectiveTo evaluate the effectiveness of a home-based, parent-provided therapy accompanied by scheduled telephone calls with a therapist, in 5-7 year-olds with primary CMS.MethodsEligible families received an instructional DVD, written instructions, and scheduled telephone contacts with a therapist at baseline (DVD receipt), 1, 3, and 8 weeks later. At each call, parents completed outcome measures and received feedback. Outcome scales (Stereotypy Severity Scale (SSS) Motor and Impairment scales and a Stereotypy Linear Analogue Scale (SLAS) were also completed via the internet (REDCap) - at screening, 1 and 2 months post baseline call. At study conclusion, participants were divided into an Intent-to-Treat (ITT; had at least one call) or a Lost-to-Follow-up (LTF) group.Results38 children (m=6 years ± 11 months) were enrolled. The LTF (n=14) had significantly higher scores, than the ITT (n=24) group, on all ADHD ratings (p<0.01), but not stereotypy severity. Primary outcome scores, acquired by telephone and REDCap, showed a significant reduction in SSS Motor and Impairment scores between the initial and the last completed evaluation (p≤0.001). Calculated change ratios were SSS Motor -0.23/-0.30 (call/REDCap); SSS Impairment -0.31/-0.32; and SLAS -0.54 (REDCap). Clinical improvement was further supported by results from a parent improvement scale and end of study questionnaires.ConclusionHome-based, parent-administered behavioral therapy supplemented by telephone contact with a therapist is effective in reducing complex motor stereotypies in children.



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Optimal doses of H1 antihistamines do not increase susceptibility to febrile convulsions in children

Publication date: Available online 18 May 2018
Source:Pediatric Neurology
Author(s): Kosuke Yonemoto, Kazuo Okanari, Hiroshi Koga
BackgroundThe purpose of this study was to elucidate whether H1 antihistamine administration increases susceptibility to febrile convulsions in children.MethodsA single-center, retrospective observational study was conducted in Japan. The study included 380 children with febrile convulsions between the ages of 6 months and 5 years transported via ambulance from 2011 through 2016. They were divided into the pre-seizure H1 antagonist "use group" and the "non-use group." The former consisted of children who took H1 antagonists within 24 hours prior to the seizure onset. The primary outcome (seizure duration) and the secondary outcome (interval from fever to seizure onset) were compared between the two groups.ResultsOf the 380 study patients, 70 (18%) were identified as the use group. None of the patients were taking excessive doses of H1 antagonists. The prevalence of seizures lasting 15 minutes or longer was not different between the use group and the non-use group (11% vs. 8%, prevalence ratio 1.47 [95% confidence interval (CI), 0.63 – 3.42], P=0.37). The prevalence of fever to seizure onset <6 hours was significantly lower in the use group (26% vs. 52%, prevalence ratio 0.33 [95%CI 0.19 – 0.60], P<0.001). Similar results were obtained when analyses were conducted separately by different generations (first and second) of H1 antagonists.ConclusionsProlonged seizure duration and shortened interval from fever to seizure were not observed in children who received H1 antagonists. This study provides evidence that H1 antagonists at optimal doses could be safely used in febrile children with allergic symptoms.



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Cockayne Syndrome Complicated by Moyamoya Vasculopathy and Stroke

Publication date: Available online 18 May 2018
Source:Pediatric Neurology
Author(s): Robert C. Stowe, Andres Jimenez-Gomez, Alfred Balasa, Gary D. Clark




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Sedation and Analgesia Influence EEG Monitoring in Pediatric Neurocritical Care,

Publication date: Available online 18 May 2018
Source:Pediatric Neurology
Author(s): Giulia M. Benedetti, Faye S. Silverstein, Stephanie M. Rau, Shannon G. Lester, Marco H. Benedetti, Renée A. Shellhaas
ObjectivesTo assess neuroactive medication use in critically-ill children who require neurologic consultation and to evaluate the associations between administration of these medications and continuous electroencephalography (cEEG) utilization and seizure frequency.MethodsWe evaluated exposure to sedatives, analgesics, anesthetics, and paralytics in consecutive patients (0 days to 18 years) for whom neurological consultation was requested in 3 intensive care units (ICUs) [neonatal (NICU), pediatric (PICU), and cardiothoracic (PCTU)] at one children's hospital. We assessed cEEG usage and seizure incidence in relation to drug exposure.ResultsFrom November 2015-November 2016, 300 consecutive patients were evaluated (93 NICU, 139 PICU, 68 PCTU). Ninety-seven (32%) were receiving ≥1 sedative infusion at the time of consultation [NICU 7(8%), PICU 50(36%), PCTU 40(58%)]; 91(30%) received ≥1 paralytic agent within the preceding 24 hours. cEEG was performed more often for patients treated with sedative infusions (81/97 vs 133/203, p=0.001) and paralytic medications (80/91 vs 134/209, p<0.001) within 24 hours preceding consultation than those who were not. 68/214 (32%) had electrographic seizures (65/68 within initial 24 hours of monitoring); seizures were less common among patients who had received sedative infusions (18/81 vs 51/133, p=0.014). In multivariable analysis of seizure likelihood, only younger age was associated with increased risk (p=0.037).ConclusionsCritically-ill infants and children are frequently treated with sedatives, anesthetics, analgesics, and paralytics. Neuroactive medications limit bedside neurologic assessments and, in this cohort, were associated with increased cEEG usage. Our data underscore the need to study the impact of these medications on clinical care and long-term outcomes.



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Evaluation of Responsiveness to Reduced-dose Rituximab in Corticotropin/IVIg/Rituximab Combination Immunotherapy for Opsoclonus-Myoclonus Syndrome

Publication date: Available online 18 May 2018
Source:Pediatric Neurology
Author(s): Michael R. Pranzatelli, Elizabeth D. Tate, Nathan R. McGee, Craig A. MacArthur
BACKGROUNDRituximab (anti-CD20) has been used as B cell-targeted intervention to treat opsoclonus-myoclonus syndrome (OMS). Due to isolated reports of chronic hypogammaglobulinemia and B lymphopenia following rituximab in several disorders, and rapid B cell depletion after a few doses, we reduced the dosage 20% in our clinical practice.METHODSIn this IRB-approved retrospective study, 32 children with OMS and cerebrospinal fluid (CSF) B cell expansion had received front-loaded adrenocorticotropic hormone (ACTH1-39), intravenous immunoglobulin (IVIg), and rituximab combination immunotherapy ("FLAIR-CI") for de novo OMS. Parametric statistical analysis compared 10 children receiving 1200 mg/m² of rituximab (300 mg/m² x 4) and 22 receiving 1500 mg/m² (375 mg/m² x 4). Clinical response had been video-documented and scored by a blinded observer.RESULTSIn both groups, motor severity (total score) lessened by ≥ 76% and CSF B cells were similarly depleted (≥ 95%) 6 months after treatment. None of the treated patients remained unable to walk independently. Serum IgM depletion was analogous in the 1200 mg/m² (-73%) and 1500 mg/m² group (-64%). The relapse frequency was similar in both groups. Side effects were principally steroidal, tolerable, and transient. Circulating B cell repopulation was comparable.CONCLUSIONSThe reduced-dose of rituximab in FLAIR-CI was as effective and well- tolerated as the standard dose, and provided rapid, early therapeutic intervention in OMS. Pending a long-term prospective study, these are proof-of-concept data in support of challenging the dose of rituximab in various disorders, which may have different dose requirements.



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