Skeletal muscle mechanics, energetics and plasticity Lieber, Richard L; Roberts, Thomas J; Blemker, Silvia S ...
Journal of neuroengineering and rehabilitation,
10/2017, Letnik:
14, Številka:
1
Journal Article
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The following papers by Richard Lieber (Skeletal Muscle as an Actuator), Thomas Roberts (Elastic Mechanisms and Muscle Function), Silvia Blemker (Skeletal Muscle has a Mind of its Own: a ...Computational Framework to Model the Complex Process of Muscle Adaptation) and Sabrina Lee (Muscle Properties of Spastic Muscle (Stroke and CP) are summaries of their representative contributions for the session on skeletal muscle mechanics, energetics and plasticity at the 2016 Biomechanics and Neural Control of Movement Conference (BANCOM 2016). Dr. Lieber revisits the topic of sarcomere length as a fundamental property of skeletal muscle contraction. Specifically, problems associated with sarcomere length non-uniformity and the role of sarcomerogenesis in diseases such as cerebral palsy are critically discussed. Dr. Roberts then makes us aware of the (often neglected) role of the passive tissues in muscles and discusses the properties of parallel elasticity and series elasticity, and their role in muscle function. Specifically, he identifies the merits of analyzing muscle deformations in three dimensions (rather than just two), because of the potential decoupling of the parallel elastic element length from the contractile element length, and reviews the associated implications for the architectural gear ratio of skeletal muscle contraction. Dr. Blemker then tackles muscle adaptation using a novel way of looking at adaptive processes and what might drive adaptation. She argues that cells do not have pre-programmed behaviors that are controlled by the nervous system. Rather, the adaptive responses of muscle fibers are determined by sub-cellular signaling pathways that are affected by mechanical and biochemical stimuli; an exciting framework with lots of potential. Finally, Dr. Lee takes on the challenging task of determining human muscle properties in vivo. She identifies the dilemma of how we can demonstrate the effectiveness of a treatment, specifically in cases of muscle spasticity following stroke or in children with cerebral palsy. She then discusses the merits of ultrasound based elastography, and the clinical possibilities this technique might hold. Overall, we are treated to a vast array of basic and clinical problems in skeletal muscle mechanics and physiology, with some solutions, and many suggestions for future research.
Farletuzumab is a humanized monoclonal antibody that binds to folate receptor-α, which is highly expressed in ovarian carcinoma and largely absent from normal tissue. Farletuzumab was investigated in ...a double-blind, randomized phase III study in platinum-sensitive ovarian cancer.
Eligible patients had first recurrent ovarian cancer 6-24 months following completion of platinum-taxane chemotherapy. All patients received carboplatin plus paclitaxel or docetaxel (for six cycles combined with randomly assigned test products in a 1:1:1 ratio: farletuzumab 1.25 mg/kg, farletuzumab 2.5 mg/kg, or placebo). The single-agent test product was continued weekly until disease progression. The primary end point was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors. Additional analyses not outlined in the original protocol were prespecified in the final statistical analysis plan, including a subgroup analysis by baseline CA-125 and farletuzumab exposure levels.
A total of 1,100 women were randomly assigned to treatment dose or placebo. PFS from the primary analysis was 9.0, 9.5, and 9.7 months for the placebo, farletuzumab 1.25 mg/kg, and farletuzumab 2.5 mg/kg groups, respectively. Neither farletuzumab group was statistically different from the placebo group (hazard ratio HR, 0.99 95% CI, 0.81 to 1.21 and 0.86 95% CI, 0.70 to 1.06 for farletuzumab 1.25 mg/kg and 2.5 mg/kg group v placebo, respectively). In the prespecified subgroup, baseline CA-125 levels not more than three times the upper limit of normal (ULN) correlated with longer PFS (HR, 0.49; P = .0028) and overall survival (OS) (HR, 0.44; P = .0108) for farletuzumab 2.5 mg/kg versus placebo. Subgroup analysis of farletuzumab exposure above the median, regardless of dose, showed significantly better PFS versus placebo. The most common adverse events were those associated with chemotherapy.
Neither farletuzumab dose met the study's primary PFS end point. Prespecified subgroup analyses demonstrated that patients with CA-125 levels not more than three times the ULN and patients with higher farletuzumab exposure showed superior PFS and OS compared with placebo.
Autophagy is an intracellular catabolic system. It delivers cellular components to lysosomes for degradation and supplies nutrients that promote cell survival under stress conditions. Although much ...is known regarding starvation-induced autophagy, the regulation of autophagy by cellular energy level is less clear. BRUCE is an ubiquitin conjugase and ligase with multi-functionality. It has been reported that depletion of BRUCE inhibits starvation-induced autophagy by blockage of the fusion step. Herein we report a new function for BRUCE in the dual regulation of autophagy and cellular energy. Depletion of BRUCE alone (without starvation) in human osteosarcoma U2OS cells elevated autophagic activity as indicted by the increased LC3B-II protein and its autophagic puncta as well as further increase of both by chloroquine treatment. Such elevation results from enhanced induction of autophagy since the numbers of both autophagosomes and autolysosomes were increased, and recruitment of ATG16L onto the initiating membrane structure phagophores was increased. This concept is further supported by elevated lysosomal enzyme activities. In contrast to starvation-induced autophagy, BRUCE depletion did not block fusion of autophagosomes with lysosomes as indicated by increased lysosomal cleavage of the GFP-LC3 fusion protein. Mechanistically, BRUCE depletion lowered the cellular energy level as indicated by both a higher ratio of AMP/ATP and the subsequent activation of the cellular energy sensor AMPK (pThr-172). The lower energy status co-occurred with AMPK-specific phosphorylation and activation of the autophagy initiating kinase ULK1 (pSer-555). Interestingly, the higher autophagic activity by BRUCE depletion is coupled with enhanced cisplatin resistance in human ovarian cancer PEO4 cells. Taken together, BRUCE depletion promotes induction of autophagy by lowering cellular energy and activating the AMPK-ULK1-autophagy axis, which could contribute to ovarian cancer chemo-resistance. This study establishes a BRUCE-AMPK-ULK1 axis in the regulation of energy metabolism and autophagy, as well as provides insights into cancer chemo-resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In the mammalian suprachiasmatic nucleus (SCN), noisy cellular oscillators communicate within a neuronal network to generate precise system-wide circadian rhythms. Although the intracellular genetic ...oscillator and intercellular biochemical coupling mechanisms have been examined previously, the network topology driving synchronization of the SCN has not been elucidated. This network has been particularly challenging to probe, due to its oscillatory components and slow coupling timescale. In this work, we investigated the SCN network at a single-cell resolution through a chemically induced desynchronization. We then inferred functional connections in the SCN by applying the maximal information coefficient statistic to bioluminescence reporter data from individual neurons while they resynchronized their circadian cycling. Our results demonstrate that the functional network of circadian cells associated with resynchronization has small-world characteristics, with a node degree distribution that is exponential. We show that hubs of this small-world network are preferentially located in the central SCN, with sparsely connected shells surrounding these cores. Finally, we used two computational models of circadian neurons to validate our predictions of network structure.
Epithelial ovarian cancer (EOC) is responsible for more cancer-related deaths than any other malignancy of the female reproductive system. The standard of care for advanced EOC involves a combination ...of cytoreductive surgery and platinum-based chemotherapy. Although a majority of patients respond to a platinum-containing regimen, many fail to respond to first-line treatment (platinum-refractory disease) or experience disease progression within 6 months of completing treatment (platinum-resistant disease). Even in patients who initially respond to platinum-based therapy, secondary development of platinum resistance is common. Many chemotherapeutic regimens with comparable efficacy and toxicities are available, leaving the determination of optimal therapy to the physician's discretion. There have been many efforts over the years to develop accurate predictors of outcomes in patients treated with chemotherapy to help inform treatment decisions. Predictive treatment markers are particularly relevant in a disease such as EOC, where a large number of similarly efficacious chemotherapy regimens are available. Chemosensitivity and resistance assays (CSRAs) are attractive approaches to interrogate the efficacy and complex biology of EOC. Some early predictive cellular tests, such as the early clonogenic assays, were limited by technical and logistical issues. Over time, changes in these assays have improved their prognostic and predictive value, but there is still a lack of widespread adoption due to methodological difficulties or limited clinical validation. Herein, we provide an overview of the evolution of CSRAs used to predict outcomes in patients treated with chemotherapy that have been evaluated for use in EOC, with a focus on the latest generation chemoresponse assay.
To perform an econometric analysis to examine the influence of procedure volume, variation in hospital accounting methodology, and use of various analytic methodologies on cost of robotically ...assisted hysterectomy for benign gynecologic disease and endometrial cancer.
A national sample was used to identify women who underwent laparoscopic or robotically assisted hysterectomy for benign indications or endometrial cancer from 2006 to 2012. Surgeon and hospital volume were classified as the number of procedures performed before the index surgery. Total costs as well as fixed and variable costs were modeled using multivariable quantile regression methodology.
A total of 180,230 women, including 169,324 women who underwent minimally invasive hysterectomy for benign indications and 10,906 patients whose hysterectomy was performed for endometrial cancer, were identified. The unadjusted median cost of robotically assisted hysterectomy for benign indications was $8,152 (interquartile range IQR $6,011-10,932) compared with $6,535 (IQR $5,127-8,357) for laparoscopic hysterectomy (P<.001). The cost differential decreased with increasing surgeon and hospital volume. The unadjusted median cost of robotically assisted hysterectomy for endometrial cancer was $9,691 (IQR $7,591-12,428) compared with $8,237 (IQR $6,400-10,807) for laparoscopic hysterectomy (P<.001). The cost differential decreased with increasing hospital volume from $2,471 for the first 5 to 15 cases to $924 for more than 50 cases. Based on surgeon volume, robotically assisted hysterectomy for endometrial cancer was $1,761 more expensive than laparoscopy for those who had performed fewer than five cases; the differential declined to $688 for more than 50 procedures compared with laparoscopic hysterectomy.
The cost of robotic gynecologic surgery decreases with increased procedure volume. However, in all of the scenarios modeled, robotically assisted hysterectomy remained substantially more costly than laparoscopic hysterectomy.
Polyethylene terephthalate (PET) oligomers are ubiquitous in PET used in food contact applications. Consumer exposure by migration of PET oligomers into food and beverages is documented. However, no ...specific risk assessment framework or guidance for the safety evaluating of PET oligomers exist to date.
The aim of this systematic evidence map (SEM) is to identify and organize existing knowledge clusters and associated gaps in hazard and exposure information of PET oligomers. Research needs will be identified as an input for chemical risk assessment, and to support future toxicity testing strategies of PET oligomers and regulatory decision-making.
Multiple bibliographic databases (incl. Embase, Medline, Scopus, and Web of Science Core Collection), chemistry databases (SciFinder-n, Reaxys), and gray literature sources will be searched, and the search results will be supplemented by backward and forward citation tracking on eligible records. The search will be based on a single-concept PET oligomer-focused strategy to ensure sensitive and unbiased coverage of all evidence related to hazard and exposure in a data-poor environment. A scoping exercise conducted during planning identified 34 relevant PET oligomers. Eligible work of any study type must include primary research data on at least one relevant PET oligomer with regard to exposure, health, or toxicological outcomes.
For indexed scientific literature, title and abstract screening will be performed by one reviewer. Selected studies will be screened in full-text by two independent reviewers. Gray literature will be screened by two independent reviewers for inclusion and exclusion.
Risk of bias analysis will not be conducted as part of this SEM.
Will be performed by one reviewer and peer-checked by a second reviewer for indexed scientific literature or by two independent reviewers for gray literature.
The extracted and coded information will be synthesized in different formats, including narrative synthesis, tables, and heat maps.
Zenodo: https://doi.org/10.5281/zenodo.6224302.
Objective We performed a population-based analysis to compare the clinical characteristics of women with mucinous tumors with women with other epithelial tumors. Study Design The Surveillance, ...Epidemiology, and End Results database was queried to identify all women with epithelial ovarian cancer diagnosed from 1988 to 2007. The natural history, clinical characteristics, and survival of women with serous tumors were compared with women with mucinous carcinomas. Results A total of 40,571 women including 4811 with mucinous carcinomas (11.9%) were identified. Among women with stage I neoplasms, the presence of mucinous histology had no effect on either cancer-specific survival (hazard ratio, 0.87; 95% confidence interval, 0.74–1.04). Survival was inferior in patients with advanced-stage mucinous compared with serous tumors. The hazard ratio for cancer-specific survival for women with stage III mucinous tumors was 1.55 (95% confidence interval, 1.43–1.96). Conclusion Although survival for early-stage mucinous and serous tumors is similar, survival for advanced-stage mucinous neoplasms is inferior to that of serous carcinomas.
Gemogenovatucel-T is an autologous tumour cell vaccine manufactured from harvested tumour tissue, which specifically reduces expression of furin and downstream TGF-β1 and TGF-β2. The aim of this ...study was to determine the safety and efficacy of gemogenovatucel-T in front-line ovarian cancer maintenance.
This randomised, double-blind, placebo-controlled, phase 2b trial involved 25 hospitals in the USA. Women aged 18 years and older with stage III/IV high-grade serous, endometrioid, or clear cell ovarian cancer in clinical complete response after a combination of surgery and five to eight cycles of chemotherapy involving carboplatin and paclitaxel, and an Eastern Cooperative Oncology Group status of 0 or 1 were eligible for inclusion in the study. Patients were randomly assigned (1:1) to gemogenovatucel-T or placebo by an independent third party interactive response system after successful screening using randomly permuted block sizes of two and four and stratified by extent of surgical cytoreduction and neoadjuvant versus adjuvant chemotherapy. Gemogenovatucel-T (1 × 107 cells per injection) or placebo was administered intradermally (one per month) for a minimum of four and up to 12 doses. Patients, investigators, and clinical staff were masked to patient allocation until after statistical analysis. The primary endpoint was recurrence-free survival, analysed in the per-protocol population. All patients who received at least one dose of gemogenovatucel-T were included in the safety analysis. The study is registered with ClinicalTrials.gov, NCT02346747.
Between Feb 11, 2015, and March 2, 2017, 310 patients consented to the study at 22 sites. 217 were excluded. 91 patients received gemogenovatucel-T (n=47) or placebo (n=44) and were analysed for safety and efficacy. The median follow-up from first dose of gemogenovatucel-T was 40·0 months (IQR 35·0–44·8) and from first dose of placebo was 39·8 months (35·5–44·6). Recurrence-free survival was 11·5 months (95% CI 7·5–not reached) for patients assigned to gemogenovatucel-T versus 8·4 months (7·9–15·5) for patients assigned to placebo (HR 0·69, 90% CI 0·44–1·07; one-sided p=0·078). Gemogenovatucel-T resulted in no grade 3 or 4 toxic effects. Two patients in the placebo group had five grade 3 toxic events, including arthralgia, bone pain, generalised muscle weakness, syncope, and dyspnea. Seven patients (four in the placebo group and three in the gemogenovatucel-T group) had 11 serious adverse events. No treatment-related deaths were reported in either of the groups.
Front-line use of gemogenovatucel-T immunotherapy as maintenance was well tolerated but the primary endpoint was not met. Further investigation of gemogenovatucel-T in patients stratified by BRCA mutation status is warranted.
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