Background:
Stem cell therapy is emerging as a potential treatment of osteoarthritis (OA) and chondral defects (CDs). However, there is a great deal of heterogeneity in the literature. The ...indications for stem cell use, the ideal tissue source, and the preferred outcome measures for stem cell–based treatments have yet to be determined.
Purpose:
To provide clinicians with a comprehensive overview of the entire body of the current human literature investigating the safety and efficacy of intra-articular mesenchymal stem cell (MSC) therapy in all joints.
Methods:
To provide a comprehensive overview of the current literature, all clinical studies investigating the safety and efficacy of intra-articular MSC therapy were included. PubMed, MEDLINE, and Cochrane Library databases were searched for published human clinical trials involving the use of MSCs for the treatment of OA and CDs in all joints. A total of 3867 publications were screened.
Results:
Twenty-eight studies met the criteria to be included in this review. Fourteen studies treating osteoarthritis and 14 studies treating focal chondral defects were included. MSCs originating from bone marrow (13), adipose tissue (12), synovial tissue (2), or peripheral blood (2) were administered to 584 distinct individuals. MSCs were administered into the knee (523 knees), foot/ankle (61), and hip (5). The mean follow-up time was 24.4 months after MSC therapy. All studies reported improvement from baseline in at least 1 clinical outcome measure, and no study reported major adverse events attributable to MSC therapy.
Discussion:
The studies included in this review suggest that intra-articular MSC therapy is safe. While clinical and, in some cases, radiological improvements were reported for both OA and CD trials, the overall quality of the literature was poor, and heterogeneity and lack of reproducibility limit firm conclusions regarding the efficacy of these treatments.
Conclusion:
This review provides strong evidence that autologous intra-articular MSC therapy is safe, with generally positive clinical outcomes.
Intra-articular drug delivery has a number of advantages over systemic administration; however, for the past 20 years, intra-articular treatment options for the management of knee osteoarthritis (OA) ...have been limited to analgesics, glucocorticoids, hyaluronic acid (HA) and a small number of unproven alternative therapies. Although HA and glucocorticoids can provide clinically meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of other factors, including the placebo effect. Biologic drugs that target inflammatory processes are used to manage rheumatoid arthritis, but have not translated well into use in OA. A lack of high-level evidence and methodological limitations hinder our understanding of so-called 'stem' cell therapies and, although the off-label administration of intra-articular cell therapies (such as platelet-rich plasma and bone marrow aspirate concentrate) is common, high-quality clinical data are needed before these treatments can be recommended. A number of promising intra-articular treatments are currently in clinical development in the United States, including small-molecule and biologic therapies, devices and gene therapies. Although the prospect of new, non-surgical treatments for OA is exciting, the benefits of new treatments must be carefully weighed against their costs and potential risks.
Background:
There has been a surge in high-level studies investigating platelet-rich plasma (PRP) for tendon and ligament injuries. A number of meta-analyses have been published, but few studies have ...focused exclusively on tendon and ligament injuries.
Purpose:
To perform a meta-analysis assessing the ability of PRP to reduce pain in patients with tendon and ligament injuries.
Study Design:
Systematic review and meta-analysis.
Methods:
This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive search of the literature was carried out in April 2017 using electronic databases PubMed, MEDLINE, and the Cochrane Library. Only level 1 studies were included. Platelet and leukocyte count, injection volume, kit used, participant age/sex, comparator, and activating agent used were recorded. The short-term and long-term efficacy of PRP was assessed using the visual analog scale (VAS) to measure pain intensity. Injury subgroups (rotator cuff, tendinopathy, anterior cruciate ligament, and lateral epicondylitis) were evaluated. Funnel plots and the Egger test were used to screen for publication bias, and sensitivity analysis was performed to evaluate the effect of potential outliers by removing studies one at a time.
Results:
Thirty-seven articles were included in this review, 21 (1031 participants) of which could be included in the quantitative analysis. The majority of studies published investigated rotator cuff injuries (38.1%) or lateral epicondylitis (38.1%). Seventeen studies (844 participants) reported short-term VAS data, and 14 studies (771 participants) reported long-term VAS data. Overall, long-term follow-up results showed significantly less pain in the PRP group compared with the control group (weighted mean difference WMD, –0.84; 95% CI, –1.23 to –0.44; P < .01). Patients treated with PRP for rotator cuff injuries (WMD, –0.53; 95% CI, –0.98 to –0.09; P = .02) and lateral epicondylitis (WMD, –1.39; 95% CI, –2.49 to –0.29; P = .01) reported significantly less pain in the long term. Substantial heterogeneity was reported at baseline (I2 = 72.0%; P < .01), short-term follow-up (I2 = 72.5%; P < .01), long-term follow-up (I2 = 76.1%; P < .01), and overall (I2 = 75.8%; P < .01). The funnel plot appeared to be asymmetric, with some missingness at the lower right portion of the plot suggesting possible publication bias.
Conclusion:
This review shows that PRP may reduce pain associated with lateral epicondylitis and rotator cuff injuries.
Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support ...glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.
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•Tumor cell metabolic flexibility enables glucose-independent cell proliferation•PCK2 helps generate glycolytic intermediates under low-glucose conditions•PCK2 expression is regulated by glucose and required for in vivo tumor growth•PCK2 expression is elevated in non-small-cell lung carcinoma (NSCLC)
Cancer cells adapt metabolically to maintain proliferation under nutrient limitation. Vincent et al. demonstrate that cancer cells can engage the early steps of gluconeogenesis—a process regulated by mitochondrial PEPCK (PCK2)—to generate biosynthetic intermediates required for tumor cell proliferation.
Background:
Many clinical trials have investigated the use of platelet-rich plasma (PRP) to treat rotator cuff–related abnormalities. Several meta-analyses have been published, but none have focused ...exclusively on level 1 randomized controlled trials.
Purpose:
To assess the efficacy of PRP for rotator cuff–related abnormalities and evaluate how specific tendon involvement, the inclusion of leukocytes, and the use of gel/nongel formulations affect pain and functional outcomes.
Study Design:
Systematic review and meta-analysis.
Methods:
The literature was screened following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Baseline, short-term, and long-term data were extracted for the Constant score, University of California, Los Angeles (UCLA) score, visual analog scale (VAS) for pain, retear rate, Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) score. The 100-point modified Coleman Methodology Score (CMS) was used to assess methodological quality. Funnel plots and the Egger test were used to screen for publication bias, and sensitivity analysis was performed to evaluate the effect of potential outliers.
Results:
A total of 18 level 1 studies were included in this review, 17 (1116 patients) of which could be included in quantitative analysis. The mean modified CMS was 79.4 ± 10.39. The Constant scores of patients who received PRP were significantly better short term (weighted mean difference WMD, 2.89 95% CI, 0.89-4.90; P < .01) and long term (WMD, 2.66 95% CI, 1.13-4.19; P < .01). The VAS scores were significantly improved short term (WMD, –0.45 95% CI, –0.75 to −0.15; P < .01). Sugaya grade IV and V retears in PRP-treated patients were significantly reduced long term (odds ratio OR, 0.34 95% CI, 0.20-0.57; P < .01). In PRP-treated patients with multiple tendons torn, there were reduced odds of retears (OR, 0.28 95% CI, 0.13-0.60; P < .01). Patients who received leukocyte-rich PRP had significantly better Constant scores compared with the leukocyte-poor PRP group, but there was no difference in VAS scores. Patients receiving PRP gel reported higher Constant scores compared with the controls, whereas those receiving nongel PRP treatments did not, although there was no difference in VAS scores. Long-term odds of retears were decreased, regardless of leukocyte content (leukocyte-poor PRP: OR, 0.36 95% CI, 0.16-0.82; leukocyte-rich PRP: OR, 0.32 95% CI, 0.16-0.65; all P < .05) or usage of gel (nongel: OR, 0.42 95% CI, 0.23-0.76; gel: OR, 0.17 95% CI, 0.05-0.51; all P < .01).
Conclusion:
Long-term retear rates were significantly decreased in patients with rotator cuff–related abnormalities who received PRP. Significant improvements in PRP-treated patients were noted for multiple functional outcomes, but none reached their respective minimal clinically important differences. Overall, our results suggest that PRP may positively affect clinical outcomes, but limited data, study heterogeneity, and poor methodological quality hinder firm conclusions.
Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism ...and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.
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•T cells display metabolic flexibility in response to nutrient limitation•AMPK couples nutrient availability to T cell effector function•T cell metabolic adaptation is AMPKα1-dependent•AMPKα1 is required for primary T cell responses and cellular bioenergetics in vivo
T cells undergo metabolic reprogramming upon activation to fuel T cell growth, proliferation, and effector function. Jones and colleagues show effector T cells adapt their metabolic programs in response to reduced glucose availability, which is regulated by the energy sensor AMPK.
The minimal clinically important difference (MCID) is used when interpreting the importance of outcome data. However, a consensus regarding the MCID for commonly used patient-reported outcomes in ...shoulder surgery has not been established. The purpose of this systematic review was to evaluate the available literature on shoulder MCID to improve clinical interpretation of shoulder outcome data.
A systematic review of the literature was conducted to identify studies reporting anchor-based MCID values for the patient-reported outcomes recommended by the American Shoulder and Elbow Surgeons (ASES): Veterans Rand 12 score, ASES score, Single Assessment Numeric Evaluation (SANE) score, Western Ontario Rotator Cuff (WORC) score, Western Ontario Osteoarthritis Score (WOOS), Western Ontario Shoulder Instability Index (WOSI), Pennsylvania Shoulder Score, and Oxford Shoulder Score (OSS).
A total of 14 articles reporting anchor-based MCID values were included in the final analysis. No studies reporting the Western Ontario Osteoarthritis Score (WOOS) were identified. The ASES score (6 studies), OSS (4 studies), and WORC score (2 studies) were the only instruments investigated in more than 1 study. The average reported MCID values for the ASES, OSS, and WORC scores were 15.5 (15% total difference), 275.7 (13% total difference), and 6 (13% total difference), respectively. The vast majority of studies failed to report information necessary to validate the credibility of these MCID values.
The current utility of the MCID for patient-report shoulder outcome instruments is limited by poor study methodology, inadequate reporting, and a lack of data. Further research is needed to more clearly define the MCID values for commonly used patient-reported outcomes in shoulder surgery.
Reactive oxygen species (ROS) are continuously produced as a by-product of mitochondrial metabolism and eliminated via antioxidant systems. Regulation of mitochondrially produced ROS is required for ...proper cellular function, adaptation to metabolic stress, and bypassing cellular senescence. Here, we report non-canonical regulation of the cellular energy sensor AMP-activated protein kinase (AMPK) by mitochondrial ROS (mROS) that functions to maintain cellular metabolic homeostasis. We demonstrate that mitochondrial ROS are a physiological activator of AMPK and that AMPK activation triggers a PGC-1α-dependent antioxidant response that limits mitochondrial ROS production. Cells lacking AMPK activity display increased mitochondrial ROS levels and undergo premature senescence. Finally, we show that AMPK-PGC-1α-dependent control of mitochondrial ROS regulates HIF-1α stabilization and that mitochondrial ROS promote the Warburg effect in cells lacking AMPK signaling. These data highlight a key function for AMPK in sensing and resolving mitochondrial ROS for stress resistance and maintaining cellular metabolic balance.
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•Mitochondrial ROS (mROS) are a non-canonical activator of AMPK•AMPK-deficient cells have elevated mROS and undergo premature senescence•AMPK activation promotes a PGC-1α-dependent antioxidant response•AMPK-PGC-1α control of mROS regulates Warburg metabolism
AMP-activated protein kinase (AMPK) regulates cellular metabolic balance in response to energy stress. This work by Rabinovitch et al. demonstrates that mitochondrial reactive oxygen species (mROS) are a physiological activator of AMPK and that AMPK couples mROS to an antioxidant program that regulates mitochondrial homeostasis and cellular metabolic balance.
Development of new treatments for drug addiction will depend on high-throughput screening in animal models. However, an addiction biomarker fit for rapid testing, and useful in both humans and ...animals, is not currently available. Economic models are promising candidates. They offer a structured quantitative approach to modeling behavior that is mathematically identical across species, and accruing evidence indicates economic-based descriptors of human behavior may be particularly useful biomarkers of addiction severity. However, economic demand has not yet been established as a biomarker of addiction-like behavior in animals, an essential final step in linking animal and human studies of addiction through economic models. We recently developed a mathematical approach for rapidly modeling economic demand in rats trained to self-administer cocaine. We show here that economic demand, as both a spontaneous trait and induced state, predicts addiction-like behavior, including relapse propensity, drug seeking in abstinence, and compulsive (punished) drug taking. These findings confirm economic demand as a biomarker of addiction-like behavior in rats. They also support the view that excessive motivation plays an important role in addiction while extending the idea that drug dependence represents a shift from initially recreational to compulsive drug use. Finally, we found that economic demand for cocaine predicted the efficacy of a promising pharmacotherapy (oxytocin) in attenuating cocaine-seeking behaviors across individuals, demonstrating that economic measures may be used to rapidly identify the clinical utility of prospective addiction treatments.
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