This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus ...cyclophosphamide, doxorubicin, vincristine, and prednisone R-CHOP or rituximab plus cyclophosphamide, vincristine, and prednisone R-CVP) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI 0.88 margin). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.
•The complete response rate for first-line bendamustine/rituximab was statistically noninferior to R-CHOP or R-CVP in indolent NHL or MCL.•The safety profile of bendamustine/rituximab is distinct from that of R-CHOP/R-CVP.
Connecting membranes to the actin cytoskeleton Wang, Pengwei; Hawkins, Tim J; Hussey, Patrick J
Current opinion in plant biology,
December 2017, 2017-12-00, 20171201, Volume:
40
Journal Article
Peer reviewed
•Membrane structures are linked to the actin cytoskeleton in plants.•Membrane–actin interactions are essential for various subcellular events in plants.•Membrane–cytoskeleton adapter proteins have ...been identified in recent studies.•Examples of the molecular mechanism of such interactions are discussed here.
In plants, the actin cytoskeleton plays a major role in organelle movement, cargo transport, maintaining cell polarity and controlling the morphogenesis of endomembrane systems. All of these events require a direct connection between membrane structures and the cytoskeleton. Our knowledge in this field has been greatly advanced by a few recent discoveries including the identification of the plant specific NETWORKED family of proteins, which can mediate such linkages. Other proteins that are known to regulate actin nucleation and polymerization are also likely to be involved, but many key questions still remain unanswered. In this paper, we will focus on recent research on the interfaces between the actin cytoskeleton and membranes of the endoplasmic reticulum, the vacuole and autophagosomes.
Thioglycolate is a potent depilatory agent. In addition, it has been proposed to be useful as a penetration enhancer for transepidermal drug delivery. However, the effects on hair structure and ...stress responses it elicits in epidermal keratinocytes have not been fully characterised. We have used label‐free confocal and fluorescence lifetime imaging supported by electron microscopy to demonstrate how thioglycolate damages hair cuticle cells by generating breakages along the endocuticle and leading to swelling of cortex cells. Maleimide staining of free SH‐groups and a decrease in the average fluorescence lifetime of endogenous fluorophores demonstrate a specific change in protein structure in both hair cuticle and cortex. We found that the thioglycolate damages cornified envelopes isolated from the stratum corneum of the epidermis. However, thioglycolate‐treated epidermal equivalent cultures recover within 48 hours, which highlights the reversibility of the damage. HaCaT keratinocytes respond to thioglycolate by increased proliferation, onset of differentiation and expression of the chaperone protein Hsp 70, but not Hsp 27. Up‐regulation of involucrin can be blocked by an application of c‐Jun N–terminal kinase (JNK) inhibitor, but the up‐regulation of Hsp 70 takes place regardless of the presence of the JNK inhibitor.
Evidence is accumulating for molecular microcompartments formed when proteins interact in localized domains with the cytoskeleton, organelle surfaces, and intracellular membranes. To understand the ...potential functional significance of protein microcompartmentation in plants, we studied the interaction of the glycolytic enzyme fructose bisphosphate aldolase with actin in Arabidopsis thaliana. Homology modelling of a major cytosolic isozyme of aldolase, FBA8, suggested that the tetrameric holoenzyme has two actin binding sites and could therefore act as an actin-bundling protein, as was reported for animal aldolases. This was confirmed by in vitro measurements of an increase in viscosity of F-actin polymerized in the presence of recombinant FBA8. Simultaneously, interaction with F-actin caused non-competitive inhibition of aldolase activity. We did not detect co-localization of an FBA8–RFP fusion protein, expressed in an fba8-knockout background, with the actin cytoskeleton using confocal laser-scanning microscopy. However, we did find evidence for a low level of interaction using FRET-FLIM analysis of FBA8–RFP co-expressed with the actinbinding protein GFP–Lifeact. Furthermore, knockout of FBA8 caused minor alterations of guard cell actin cytoskeleton morphology and resulted in a reduced rate of stomatal closure in response to decreased humidity. We conclude that cytosolic aldolase can be microcompartmented in vivo by interaction with the actin cytoskeleton and may subtly modulate guard cell behaviour as a result.
Comparative chemotherapy-related quality of life data are lacking. Bendamustine-rituximab (BR) demonstrated noninferiority to R-CHOP ...(rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone)/R-CVP (rituximab/cyclophosphamide/vincristine/prednisone) in first-line advanced indolent non-Hodgkin and mantle cell lymphomas. Patients receiving BR reported improvement across many domains, with a few exceptions, of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30.
We previously reported results of the phase III, randomized, noninferiority trial comparing bendamustine-rituximab (BR) with standard R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone)/R-CVP (rituximab/cyclophosphamide/vincristine/prednisone) in previously untreated advanced indolent non-Hodgkin and mantle cell lymphomas. Here we report health-related quality of life (HRQOL) results from the trial.
HRQOL, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), was a secondary end point. Differences between group means in global health status (GHS), 5-item functioning, and 9 symptoms/single-item measures at week 1 of cycle 1 and end-of- cycles 3 and 6 were examined using the screening (baseline) score as a covariate in analysis of covariance.
Overall EORTC QLQ-C30 compliance was 75.2%, 89.5%, and 89.9% at week 1 of cycle 1 and end-of-cycles 3 and 6, respectively. Patients treated with BR reported improvements in Cognitive Functioning, Physical Functioning, Social Functioning, Emotional Functioning, and GHS as well as reduction in dyspnea, constipation, and fatigue at some, but not all, time points. Patients treated with standard therapy reported less nausea/vomiting at one time point.
Compared with patients treated with standard therapy, patients treated with BR reported better quality of life in several areas.
The BRIGHT study ( ClinicalTrials.gov identifier: NCT00877006) was initiated to compare the efficacy and safety of bendamustine plus rituximab (BR) with either rituximab plus cyclophosphamide, ...doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) for treatment-naive patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma. This publication provides long-term follow-up data.
Patients were monitored for a minimum of 5 years after completion of study treatment for the time-to-event end points of progression-free survival (PFS), event-free survival, duration of response, and overall survival per investigator assessment. Data on the number of patients who received second-line anticancer treatment and the occurrence of other malignancies were also collected.
The medians were not reached for any of the time-to event end points for either the BR or R-CHOP/R-CVP study treatment groups by study completion. PFS rates at 5 years were 65.5% in the BR treatment group and 55.8% in the R-CHOP/R-CVP group. The difference in PFS was considered significant with a hazard ratio of 0.61 (95% CI, 0.45 to 0.85;
= .0025). The hazard ratio for event-free survival and duration of response (
= .0020 and .0134, respectively) also favored the BR regimen over R-CHOP/R-CVP. However, no significant difference in overall survival was observed. The overall safety profiles of BR, R-CHOP, and R-CVP were as expected; no new safety data were collected during long-term follow-up. A higher number of secondary malignancies was noted in the BR treatment group.
Overall, BR demonstrated better long-term disease control than R-CHOP/R-CVP and should be considered as a first-line treatment option for patients with indolent and mantle-cell lymphoma.
Purpose This paper aims to derive a model that explores how the interplay between knowledge integration capability and innovation impacts strategic orientation, leading to the attainment of ...sustainable competitive advantage. The study considers the constituents of strategic orientation, namely, customer orientation, competitor orientation and technology orientation, as the basis for achieving sustainable competitive advantage. The study suggests that the firm’s capacity for integrating external and internal knowledge shapes how strategic orientation influences sustainable competitive advantage through service innovation. Design/methodology/approach This empirical research relies on qualitative and quantitative data gathered from telecom professionals to assess how knowledge integration and service innovation influence sustained competitive advantage. Structured equation modeling is used to examine the model and its interrelationships. Findings The research establishes significant relationships between strategic orientations, knowledge integration capability, service innovation and sustainable competitive advantage. Knowledge integration capability and service innovation are found to mediate the relationship between strategic orientations and the achievement of sustainable competitive advantage. Practical implications The study highlights the significant contribution of a firm’s knowledge integration capability in driving service innovation, especially in technology-intensive service industries facing hypercompetition. It also advocates prioritizing technology orientation and integrating knowledge from internal and external sources for competitive advantage. Originality/value To the best of the authors’ knowledge, this study is the first to model the effect of knowledge integration capability and service innovation on strategic orientation-led sustainable competitive advantage.
ABSTRACT
Annexin 6 is one of a widely expressed family of calcium‐binding proteins found in most mammalian tissues, including the heart. Several studies have implicated annexin 6 in the regulation of ...intracellular Ca2+ signaling, and it has been shown in vitro to act as a modulator of the sarcoplasmic reticulum Ca2+‐release channel, cardiac L‐type calcium channel, and Na+/Ca2+ exchanger. To investigate the role of annexin 6 in intact cardiomyocytes, we used mice containing a targeted disruption of the annexin 6 gene. Compared with controls, the myocytes of annexin 6 null‐mutant mice demonstrated a significant increase in the rates of shortening and relengthening. Intracellular Ca2+ transients in fura‐2‐loaded cardiomyocytes induced by caffeine showed a normal baseline and amplitude, whereas the rate of decay was doubled in annexin 6/‐myocytes compared with control mice. These results show that annexin 6 knockout in the mouse leads to an increase in myocyte contractility and faster diastolic Ca2+ removal from the cytoplasm. In light of published findings showing annexin 6 to be down‐regulated in end‐stage heart failure, these results are consistent with a role for annexin 6 as a negative inotropic factor in the regulation of cardiomyocyte mechanics.
C. elegans is a well-characterized and relatively simple model organism, making it attractive for studying nuclear pore complex proteins in cell and developmental biology. C. elegans is transparent ...and highly amendable to genetic manipulation. Therefore, it is possible to generate fluorescently tagged proteins and combine this with various light microscopy techniques to study protein behavior in space and time. Here, we provide protocols to prepare both fixed and live C. elegans for confocal and light sheet microscopy. This enables the analysis of nuclear pore complex proteins from embryonic stages to the aging adult.
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