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BACKGROUND: Accurate and precise templating is paramount for anatomic total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (RSA) to enhance preoperative planning, streamline surgery, and improve implant positioning. We aimed to evaluate the predictive potential of readily available patient demographic data in TSA and RSA implant sizing, independent of implant design. METHODS: A total of 578 consecutive, primary, noncemented shoulder arthroplasty cases were retrospectively reviewed. Demographic variables and implant characteristics were recorded. Multivariate linear regressions were conducted to predict implant sizes using patient demographic variables. RESULTS: Linear models accurately predict TSA implant sizes within 2 millimeters of humerus stem sizes 75.3% of the time, head diameter 82.1%, head height 82.1%, and RSA glenosphere diameter 77.6% of the time. Linear models predict glenoid implant sizes accurately 68.2% and polyethylene thickness 76.6% of the time and within one size 100% and 95.7% of the time, respectively. CONCLUSION: Linear models accurately predict shoulder arthroplasty implant sizes from demographic data. No significant statistical differences were observed between linear models and machine learning algorithms, although the analysis was underpowered. Future sufficiently powered studies are required for more robust assessment of machine learning models in predicting primary shoulder arthroplasty implant sizes based on patient demographics.
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Artroplastia do Ombro , Aprendizado de Máquina , Humanos , Estudos Retrospectivos , Feminino , Masculino , Idoso , Prótese de Ombro , Pessoa de Meia-Idade , Desenho de Prótese , Modelos Lineares , Inteligência Artificial , Algoritmos , Idoso de 80 Anos ou mais , Articulação do Ombro/cirurgia , Articulação do Ombro/anatomia & histologiaRESUMO
Background: Managed populations of the alfalfa leafcutting bee (ALCB), Megachile rotundata (F.), are often not sustainable. In addition to numerous mortality factors that contribute to this, the dense bee populations used to maximize alfalfa pollination quickly deplete floral resources available to bees later in the summer. Providing alternative floral resources as alfalfa declines may help to improve ALCB reproduction. Methods: We examined the relationship between floral resource availability and ALCB reproduction and offspring condition via (1) a field study using alfalfa plots with and without late-blooming wildflower strips to supply food beyond alfalfa bloom, and (2) a field-cage study in which we provided bees with alfalfa, wildflowers, or both as food resources. Results: In the field study, bee cell production closely followed alfalfa floral density with an initial peak followed by large declines prior to wildflower bloom. Few bees visited wildflower strips, whose presence or absence was not associated with any measure of bee reproduction. However, we found that female offspring from cells provisioned earlier in the season, when alfalfa predominated as a source of provisions, eclosed with greater body sizes and proportion body lipids relative to total body mass. For bees restricted to cages, the proportion of offspring that survived to adults was highest on pure alfalfa diets. Adding wildflowers to cages with alfalfa did not affect adult offspring production or female offspring body size and lipid content. Furthermore, although similar numbers of adults were produced on wildflowers alone as with alfalfa alone, females eclosed with smaller body sizes and lower proportion body lipids on wildflowers despite the higher protein content we estimated for wildflower pollen. We found no evidence that adding the late-season wildflower species that we chose to plant enhanced ALCB offspring numbers. Our results highlight the importance of considering multiple measures of reproductive success, including offspring body size and lipid stores, when designing and evaluating floral resource management strategies for agroecosystems.
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Flores , Medicago sativa , Polinização , Reprodução , Estações do Ano , Animais , Abelhas/fisiologia , Reprodução/fisiologia , FemininoRESUMO
Clinical predictive models that include race as a predictor have the potential to exacerbate disparities in healthcare. Such models can be respecified to exclude race or optimized to reduce racial bias. We investigated the impact of such respecifications in a predictive model - UTICalc - which was designed to reduce catheterizations in young children with suspected urinary tract infections. To reduce racial bias, race was removed from the UTICalc logistic regression model and replaced with two new features. We compared the two versions of UTICalc using fairness and predictive performance metrics to understand the effects on racial bias. In addition, we derived three new models for UTICalc to specifically improve racial fairness. Our results show that, as predicted by previously described impossibility results, fairness cannot be simultaneously improved on all fairness metrics, and model respecification may improve racial fairness but decrease overall predictive performance.
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Objective: Statistical and artificial intelligence algorithms are increasingly being developed for use in healthcare. These algorithms may reflect biases that magnify disparities in clinical care, and there is a growing need for understanding how algorithmic biases can be mitigated in pursuit of algorithmic fairness. Individual fairness in algorithms constrains algorithms to the notion that "similar individuals should be treated similarly." We conducted a scoping review on algorithmic individual fairness to understand the current state of research in the metrics and methods developed to achieve individual fairness and its applications in healthcare. Methods: We searched three databases, PubMed, ACM Digital Library, and IEEE Xplore, for algorithmic individual fairness metrics, algorithmic bias mitigation, and healthcare applications. Our search was restricted to articles published between January 2013 and September 2023. We identified 1,886 articles through database searches and manually identified one article from which we included 30 articles in the review. Data from the selected articles were extracted, and the findings were synthesized. Results: Based on the 30 articles in the review, we identified several themes, including philosophical underpinnings of fairness, individual fairness metrics, mitigation methods for achieving individual fairness, implications of achieving individual fairness on group fairness and vice versa, fairness metrics that combined individual fairness and group fairness, software for measuring and optimizing individual fairness, and applications of individual fairness in healthcare. Conclusion: While there has been significant work on algorithmic individual fairness in recent years, the definition, use, and study of individual fairness remain in their infancy, especially in healthcare. Future research is needed to apply and evaluate individual fairness in healthcare comprehensively.
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We describe the analytical validation of NeXT Personal®, an ultra-sensitive, tumor-informed circulating tumor DNA (ctDNA) assay for detecting residual disease, monitoring therapy response, and detecting recurrence in patients diagnosed with solid tumor cancers. NeXT Personal uses whole genome sequencing of tumor and matched normal samples combined with advanced analytics to accurately identify up to ~1,800 somatic variants specific to the patient's tumor. A personalized panel is created, targeting these variants and then used to sequence cell-free DNA extracted from patient plasma samples for ultra-sensitive detection of ctDNA. The NeXT Personal analytical validation is based on panels designed from tumor and matched normal samples from two cell lines, and from 123 patients across nine cancer types. Analytical measurements demonstrated a detection threshold of 1.67 parts per million (PPM) with a limit of detection at 95% (LOD95) of 3.45 PPM. NeXT Personal showed linearity over a range of 0.8 to 300,000 PPM (Pearson correlation coefficient = 0.9998). Precision varied from a coefficient of variation of 12.8% to 3.6% over a range of 25 to 25,000 PPM. The assay targets 99.9% specificity, with this validation study measuring 100% specificity and in silico methods giving us a confidence interval of 99.92 to 100%. In summary, this study demonstrates NeXT Personal as an ultra-sensitive, highly quantitative and robust ctDNA assay that can be used to detect residual disease, monitor treatment response, and detect recurrence in patients.
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DNA Tumoral Circulante , Neoplasias , Humanos , DNA Tumoral Circulante/genética , Mutação , Neoplasias/diagnóstico , Neoplasias/genética , DNA de Neoplasias/genética , Bioensaio , Biomarcadores Tumorais/genéticaRESUMO
A primigravida woman in her 30s with severe pulmonary hypertension, tricuspid regurgitation and depressed right ventricular function presented for therapeutic termination of pregnancy at 7 weeks gestation after referral and multidisciplinary recommendation. A slowly titrated lumbar epidural was chosen for the primary anaesthetic. Under standard American Society of Anesthesiologists (ASA) monitoring, invasive blood pressure monitoring and continuous transthoracic echocardiography, the patient's right ventricular systolic function was monitored throughout the case using qualitative and quantitative metrics and was notable for a right ventricular systolic pressure of 102.4 mm Hg. Milrinone, started prior to epidural titration, was used for inotropic support. Vasopressin was used in conjunction to sustain systemic vascular resistance while having little effect on the pulmonary vascular resistance. The patient experienced no complications or exacerbation of her pulmonary hypertension and was discharged home the following day.
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Anestésicos , Hipertensão Pulmonar , Insuficiência da Valva Tricúspide , Disfunção Ventricular Direita , Feminino , Humanos , Gravidez , Curetagem , Dilatação , Hipertensão Pulmonar/complicações , Insuficiência da Valva Tricúspide/complicações , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Insuficiência da Valva Tricúspide/cirurgia , Disfunção Ventricular Direita/complicações , AdultoRESUMO
Clinical predictive models that include race as a predictor have the potential to exacerbate disparities in healthcare. Such models can be respecified to exclude race or optimized to reduce racial bias. We investigated the impact of such respecifications in a predictive model - UTICalc - which was designed to reduce catheterizations in young children with suspected urinary tract infections. To reduce racial bias, race was removed from the UTICalc logistic regression model and replaced with two new features. We compared the two versions of UTICalc using fairness and predictive performance metrics to understand the effects on racial bias. In addition, we derived three new models for UTICalc to specifically improve racial fairness. Our results show that, as predicted by previously described impossibility results, fairness cannot be simultaneously improved on all fairness metrics, and model respecification may improve racial fairness but decrease overall predictive performance.
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Entropy compartmentalization provides new self-assembly routes to colloidal host-guest (HG) structures. Leveraging host particle shape to drive the assembly of HG structures has only recently been proposed and demonstrated. However, the extent to which the guest particles can dictate the structure of the porous network of host particles has not been explored. In this work, by modifying only the guest shape, we show athermal, binary mixtures of star-shaped host particles and convex polygon-shaped guest particles assemble as many as five distinct crystal structures, including rotator and discrete rotator guest crystals, two homoporous host crystals, and one heteroporous host crystal. Edge-to-edge alignment of neighboring stars results in the formation of three distinct pore motifs, whose preferential formation is controlled by the size and shape of the guest particles. Finally, we confirm, via free volume calculations, that assembly is driven by entropy compartmentalization, where the hosts and guests contribute differently to the free energy of the system; free volume calculations also explain differences in assembly based on guest shape. These results provide guest design rules for assembling colloidal HG structures, especially on surfaces and interfaces.
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Treatment for the deadly brain tumor glioblastoma (GBM) has been improved through the non-invasive addition of alternating electric fields, called tumor treating fields (TTFields). Improving both progression-free and overall survival, TTFields are currently approved for treatment of recurrent GBMs as a monotherapy and in the adjuvant setting alongside TMZ for newly diagnosed GBMs. These TTFields are known to inhibit mitosis, but the full molecular impact of TTFields remains undetermined. Therefore, we sought to understand the ability of TTFields to disrupt the growth patterns of and induce kinomic landscape shifts in TMZ-sensitive and -resistant GBM cells. We determined that TTFields significantly decreased the growth of TMZ-sensitive and -resistant cells. Kinomic profiling predicted kinases that were induced or repressed by TTFields, suggesting possible therapy-specific vulnerabilities. Serving as a potential pro-survival mechanism for TTFields, kinomics predicted the increased activity of platelet-derived growth-factor receptor alpha (PDGFRα). We demonstrated that the addition of the PDGFR inhibitor, crenolanib, to TTFields further reduced cell growth in comparison to either treatment alone. Collectively, our data suggest the efficacy of TTFields in vitro and identify common signaling responses to TTFields in TMZ-sensitive and -resistant populations, which may support more personalized medicine approaches.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/terapia , Neoplasias Encefálicas/terapia , Medicina de Precisão , Adjuvantes Imunológicos , Adjuvantes FarmacêuticosRESUMO
The scaphoid is the largest of the carpal bones, articulating with both proximal and distal carpal rows. If scaphoid fractures are not appropriately diagnosed and treated, there is a risk of nonunion, osteonecrosis and degenerative arthritis. Operative management of the scaphoid fracture is primarily determined by the fracture location and amount of displacement. There is increased momentum for dual screw fixation constructs, intended to provide greater stability and reduce the risk of nonunion. Our current practice is to utilize two screws without graft as a first-line treatment for scaphoid nonunion with or without humpback deformity and cyst formation. This review will discuss the management of acute scaphoid fractures and the treatment of nonunion.
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Fraturas Ósseas , Traumatismos da Mão , Osso Escafoide , Traumatismos do Punho , Humanos , Fraturas Ósseas/cirurgia , Osso Escafoide/cirurgia , Extremidade SuperiorRESUMO
We describe the analytic validation of NeXT Dx, a comprehensive genomic profiling assay to aid therapy and clinical trial selection for patients diagnosed with solid tumor cancers. Proprietary methods were utilized to perform whole exome and whole transcriptome sequencing for detection of single nucleotide variants (SNVs), insertions/deletions (indels), copy number alterations (CNAs), and gene fusions, and determination of tumor mutation burden and microsatellite instability. Variant calling is enhanced by sequencing a patient-specific normal sample from, for example, a blood specimen. This provides highly accurate somatic variant calls as well as the incidental reporting of pathogenic and likely pathogenic germline alterations. Fusion detection via RNA sequencing provides more extensive and accurate fusion calling compared to DNA-based tests. NeXT Dx features the proprietary Accuracy and Content Enhanced technology, developed to optimize sequencing and provide more uniform coverage across the exome. The exome was validated at a median sequencing depth of >500x. While variants from 401 cancer-associated genes are currently reported from the assay, the exome/transcriptome assay is broadly validated to enable reporting of additional variants as they become clinically relevant. NeXT Dx demonstrated analytic sensitivities as follows: SNVs (99.4%), indels (98.2%), CNAs (98.0%), and fusions (95.8%). The overall analytic specificity was >99.0%.
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Bioensaio , Exoma , Humanos , Exoma/genética , Fusão Gênica , Mutação INDEL , GenômicaRESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. To identify potential therapeutic targets, previous studies used genome-scale shRNA screens that implicated the neuregulin-1 receptor erb-B2 receptor tyrosine kinase 3 (erbB3) in MPNST proliferation and/or survival. The current study shows that erbB3 is commonly expressed in MPNSTs and MPNST cell lines and that erbB3 knockdown inhibits MPNST proliferation and survival. Kinomic and microarray analyses of Schwann and MPNST cells implicate Src- and erbB3-mediated calmodulin-regulated signaling as key pathways. Consistent with this, inhibition of upstream (canertinib, sapitinib, saracatinib, and calmodulin) and parallel (AZD1208) signaling pathways involving mitogen-activated protein kinase and mammalian target of rapamycin reduced MPNST proliferation and survival. ErbB inhibitors (canertinib and sapitinib) or erbB3 knockdown in combination with Src (saracatinib), calmodulin [trifluoperazine (TFP)], or proviral integration site of Moloney murine leukemia kinase (AZD1208) inhibition even more effectively reduces proliferation and survival. Drug inhibition enhances an unstudied calmodulin-dependent protein kinase IIα phosphorylation site in an Src-dependent manner. The Src family kinase inhibitor saracatinib reduces both basal and TFP-induced erbB3 and calmodulin-dependent protein kinase IIα phosphorylation. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events; and when combined with TFP, it even more effectively reduces proliferation and survival compared with monotherapy. These findings implicate erbB3, calmodulin, proviral integration site of Moloney murine leukemia kinases, and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective.
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Leucemia , Neoplasias de Bainha Neural , Neurofibrossarcoma , Humanos , Camundongos , Animais , Receptor ErbB-2/metabolismo , Receptor ErbB-2/uso terapêutico , Neoplasias de Bainha Neural/tratamento farmacológico , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/metabolismo , Calmodulina/metabolismo , Calmodulina/farmacologia , Calmodulina/uso terapêutico , Sirolimo/farmacologia , Proliferação de Células , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Linhagem Celular Tumoral , Mamíferos/metabolismoRESUMO
BACKGROUND: The International Statistical Classification of Diseases (ICD), 10th Revision Procedure Coding System (PCS) was created to increase the granularity of procedural coding. These codes are entered by hospital coders from information derived from the medical record. Concern exists that this increase in complexity could lead to inaccurate data. METHODS: Medical records and ICD-10-PCS codes were reviewed for operatively treated geriatric hip fractures from January 2016 through February 2019 at a tertiary referral medical center. Definitions for each of the 7-unit figures from the 2022 American Medical Association's ICD-10-PCS official codebook were compared to the medical, operative, and implant records. RESULTS: There were 56% (135 of 241) of PCS codes that had ambiguous, partially incorrect, or frankly incorrect figures within the code. One or more inaccurate figures were noted in 72% (72 of 100) of fractures treated with arthroplasty compared to 44.7% (63 of 141) treated with fixation (P < .01). There was at least 1 frankly incorrect figure contained in 9.5% (23 of 241) of codes. Approach was coded ambiguously for 24.8% (29 of 117) of pertrochanteric fractures. Device/implant codes were partially incorrect in 34.9% (84 of 241) of all hip fracture PCS codes. Hemi and total hip arthroplasties were partially incorrect in 78.4% (58 of 74) and 30.8% (8/26) of device/implant codes, respectively. Significantly more femoral neck (69.4%, 86 of 124) than pertrochanteric fractures (41.9%, 49 of 117) had 1 or more incorrect or partially correct figures (P < .01). CONCLUSION: Despite the increased granularity of ICD-10-PCS codes, the application of this system is inconsistent and often incorrect when applied to hip fracture treatments. The definitions in the PCS system are difficult to be utilized by coders and do not reflect the operation performed.
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Artroplastia de Quadril , Fraturas do Fêmur , Fraturas do Quadril , Estados Unidos , Humanos , Idoso , Classificação Internacional de Doenças , Fraturas do Quadril/cirurgia , Centros de Atenção TerciáriaRESUMO
BACKGROUND: Extensor mechanism disruption (EMD) following total knee arthroplasty (TKA) is a devastating problem commonly treated with allograft or synthetic reconstruction. Understanding of reconstruction success rates and patient recorded outcomes is lacking. METHODS: Patients who have an EMD after TKA undergoing mesh or whole-extensor allograft reconstruction between 2011 and 2019, with minimum 2-year follow-up were reviewed at two tertiary care centers. Functional failure was defined as extensor lag >30 degrees, amputation, or fusion, as well as revision extensor mechanism reconstruction (EMR). Survivorship was assessed using Kaplan-Meier curves, and factors for success were determined with logistic regressions. RESULTS: Of fifty-six EMRs (49 patients), 50.0% (28/56) were functionally successful at 3.2 years of mean follow-up (range, 0.2 to 7.4). In situ survivorship of the reconstructions at 36 months was 75.0% (42 of 58). There were 50.0% (14 of 28) of functionally failed EMRs that retained their reconstruction at last follow-up. Mean extensor lag among successes and failures was 5.4 and 71.0° (P = .01), respectively. Mean Knee Injury and Osteoarthritis Outcome Score, Joint Replacement scores were 67.1 and 48.8 among successes and failures (P = .01). There were 64.0% (16 of 25) of successes and 1 of 19 failures that obtained a Knee Injury and Osteoarthritis Outcome Score, Joint Replacement score above the minimum patient-acceptable symptom state for TKA. Survivorship and success rates were similar between reconstruction methods (P = .86; P = .76). All-cause mortality was 8.2% (4 of 49), each with EMR failure prior to death. All-cause reoperation rate was 42.9% (24 of 56), with a 14.3% (8 of 56) rate of revision EMR and 10.7% (6 of 56) rate of above-knee-amputation or modular fusion. CONCLUSIONS: This multicenter investigation of mesh or allograft EMR demonstrated modest functional success at 3.2 years. Complication and reoperation rates were high, regardless of EMR technique. Therefore, EMD after TKA remains problematic.
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Artroplastia do Joelho , Traumatismos do Joelho , Osteoartrite , Humanos , Artroplastia do Joelho/efeitos adversos , Transplante Homólogo , Reoperação , Osteoartrite/cirurgia , Traumatismos do Joelho/cirurgia , Resultado do Tratamento , Articulação do Joelho/cirurgia , Estudos RetrospectivosRESUMO
There is converging evidence that readers monitor text coherence and consistency by immediate, nonstrategic processes of validation. The literature also offers numerous instances of deficient validation. A prominent example of the latter is that understanders tend to overlook discourse anomalies that are embedded in given (presupposed) sentence information. However, we previously documented reading time "consistency effects" (O'Brien & Albrecht, 1992) that exposed readers' sensitivity to both given and new text discrepancies in numerous declarative syntactic constructions (Singer et al., 2017; Singer & Spear, 2020). Five new experiments addressed these phenomena with reference to constructions regularly shown to mask discourse inconsistencies: namely, interrogatives. In striking contrast with declaratives, five interrogative conditions in four experiments yielded no significant consistency effect. Experiments 2-4 documented coincident consistency effects with declarative but not interrogative constructions. A fifth experiment denied that the interrogative-construction findings resulted from readers' lack of knowledge about critical concepts. The cognitive-scientific linguistic construct of verb resolutivity offers a possible basis for these outcomes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Idioma , Leitura , HumanosRESUMO
BACKGROUND: Vanilla is a globally important spice crop used in a variety of food, cosmetic, and pharmaceutical products. V. planifolia is the primary commercial species with V. x tahitensis also permissible for food use. Other aromatic species, including V. pompona, are used for food throughout Central and South America. Supply chain complexity hinders the vanilla bean industry and can lead to false claims of genetic and geographical origins to obtain higher prices. Beans of some species can be differentiated by experienced buyers, but hybrids and morphological differences caused by environmental variability or disease would best be resolved by diagnostic tests. METHODS AND RESULTS: Kompetitive Allele Specific Polymerase Chain Reaction is a widely used molecular marker that can genotype single nucleotide polymorphisms efficiently and inexpensively. Assays were designed to differentiate V. planifolia, V. x tahitensis, and V. pompona using publicly available vanilla genomics data. Ten KASP assays on chromosomes 1 through 7, the ITS region, and plastid-encoded rbcL gene successfully differentiated V. planifolia, V. odorata, and V. x tahitensis. Additional KASP assays on chromosomes 1 through 4, the ITS region, and rbcL gene successfully differentiated V. planifolia and V. pompona. Further, a method for extracting KASP-quality DNA from cured vanilla bean seeds was developed and successfully differentiated V. planifolia, V. odorata, V. x tahitensis, V. pompona, and their hybrids. CONCLUSION: The methods and results from this study can be used to identify interspecific hybrids, ensure the authenticity of cured vanilla beans, and reduce abuse within the vanilla supply chain.
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Vanilla , Vanilla/genética , Genômica , Sementes/genética , Folhas de Planta/genética , Reação em Cadeia da PolimeraseRESUMO
In the Southern Great Plains, wheat cultivars have been selected for a combination of outstanding yield and drought tolerance as a long-term breeding goal. To understand the underlying genetic mechanisms, this study aimed to dissect the quantitative trait loci (QTL) associated with yield components and kernel traits in two wheat cultivars `TAM 112' and `Duster' under both irrigated and dryland environments. A set of 182 recombined inbred lines (RIL) derived from the cross of TAM 112/Duster were planted in 13 diverse environments for evaluation of 18 yield and kernel related traits. High-density genetic linkage map was constructed using 5,081 single nucleotide polymorphisms (SNPs) from genotyping-by-sequencing (GBS). QTL mapping analysis detected 134 QTL regions on all 21 wheat chromosomes, including 30 pleiotropic QTL regions and 21 consistent QTL regions, with 10 QTL regions in common. Three major pleiotropic QTL on the short arms of chromosomes 2B (57.5 - 61.6 Mbps), 2D (37.1 - 38.7 Mbps), and 7D (66.0 - 69.2 Mbps) colocalized with genes Ppd-B1, Ppd-D1, and FT-D1, respectively. And four consistent QTL associated with kernel length (KLEN), thousand kernel weight (TKW), plot grain yield (YLD), and kernel spike-1 (KPS) (Qklen.tamu.1A.325, Qtkw.tamu.2B.137, Qyld.tamu.2D.3, and Qkps.tamu.6A.113) explained more than 5% of the phenotypic variation. QTL Qklen.tamu.1A.325 is a novel QTL with consistent effects under all tested environments. Marker haplotype analysis indicated the QTL combinations significantly increased yield and kernel traits. QTL and the linked markers identified in this study will facilitate future marker-assisted selection (MAS) for pyramiding the favorable alleles and QTL map-based cloning.
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BACKGROUND: Heart failure is the leading cause of mortality, morbidity, and health care expenditures worldwide. Numerous studies have implicated GSK-3 (glycogen synthase kinase-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms seem to play overlapping, unique and even opposing functions in the heart. Previously, we have shown that of the 2 isoforms of GSK-3, cardiac fibroblast GSK-3ß acts as a negative regulator of myocardial fibrosis in the ischemic heart. However, the role of cardiac fibroblast-GSK-3α in the pathogenesis of cardiac diseases is completely unknown. METHODS: To define the role of cardiac fibroblast-GSK-3α in myocardial fibrosis and heart failure, GSK-3α was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or Postn-promoter-driven Cre recombinase. Control and GSK-3α KO mice were subjected to cardiac injury and heart parameters were evaluated. The fibroblast kinome mapping was carried out to delineate molecular mechanism followed by in vivo and in vitro analysis. RESULTS: Fibroblast-specific GSK-3α deletion restricted fibrotic remodeling and preserved function of the injured heart. We observed reductions in cell migration, collagen gel contraction, α-SMA protein levels, and expression of ECM genes in TGFß1-treated KO fibroblasts, indicating that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion did not affect SMAD3 activation, suggesting the profibrotic role of GSK-3α is SMAD3 independent. The molecular studies confirmed decreased ERK signaling in GSK-3α-KO CFs. Conversely, adenovirus-mediated expression of a constitutively active form of GSK-3α (Ad-GSK-3αS21A) in fibroblasts increased ERK activation and expression of fibrogenic proteins. Importantly, this effect was abolished by ERK inhibition. CONCLUSIONS: GSK-3α-mediated MEK-ERK activation is a critical profibrotic signaling circuit in the injured heart, which operates independently of the canonical TGF-ß1-SMAD3 pathway. Therefore, strategies to inhibit the GSK-3α-MEK-ERK signaling circuit could prevent adverse fibrosis in diseased hearts.