Tumor proliferation and invasion are intrinsically coupled and unraveled through tunable spheroid and physics-based models.

Proliferation and invasion are two key drivers of tumor growth that are traditionally considered independent multicellular processes. However, these processes are intrinsically coupled through a maximum carrying capacity, i.e., the maximum spatial cell concentration supported by the tumor volume, total cell count, nutrient access, and mechanical properties of the tissue stroma. We explored this coupling of proliferation and invasion through in vitro and in silico methods where we modulated the mechanical properties of the tumor and the surrounding extracellular matrix. E-cadherin expression and stromal collagen concentration were manipulated in a tunable breast cancer spheroid to determine the overall impacts of these tumor variables on net tumor proliferation and continuum invasion. We integrated these results into a mixed-constitutive formulation to computationally delineate the influences of cellular and extracellular adhesion, stiffness, and mechanical properties of the extracellular matrix on net proliferation and continuum invasion. This framework integrates biological in vitro data into concise computational models of invasion and proliferation to provide more detailed physical insights into the coupling of these key tumor processes and tumor growth. STATEMENT OF SIGNIFICANCE: Tumor growth involves expansion into the collagen-rich stroma through intrinsic coupling of proliferation and invasion within the tumor continuum. These processes are regulated by a maximum carrying capacity that is determined by the total cell count, tumor volume, nutrient access, and mechanical properties of the surrounding stroma. The influences of biomechanical parameters (i.e., stiffness, cell elongation, net proliferation rate and cell-ECM friction) on tumor proliferation or invasion cannot be unraveled using experimental methods alone. By pairing a tunable spheroid system with computational modeling, we delineated the interdependencies of each system parameter on tumor proliferation and continuum invasion, and established a concise computational framework for studying tumor mechanobiology.

Precision-engineered biomimetics: the human fallopian tube.

The fallopian tube has an essential role in several physiological and pathological processes from pregnancy to ovarian cancer. However, there are no biologically relevant models to study its pathophysiology. The state-of-the-art organoid model has been compared to two-dimensional tissue sections and molecularly assessed providing only cursory analyses of the model's accuracy. We developed a novel multi-compartment organoid model of the human fallopian tube that was meticulously tuned to reflect the compartmentalization and heterogeneity of the tissue's composition. We validated this organoid's molecular expression patterns, cilia-driven transport function, and structural accuracy through a highly iterative platform wherein organoids are compared to a three-dimensional, single-cell resolution reference map of a healthy, transplantation-quality human fallopian tube. This organoid model was precision-engineered to match the human microanatomy. One sentence summary: Tunable organoid modeling and CODA architectural quantification in tandem help design a tissue-validated organoid model.

miR-142: A Master Regulator in Hematological Malignancies and Therapeutic Opportunities.

MicroRNAs (miRNAs) are a type of non-coding RNA whose dysregulation is frequently associated with the onset and progression of human cancers. miR-142, an ultra-conserved miRNA with both active -3p and -5p mature strands and wide-ranging physiological targets, has been the subject of countless studies over the years. Due to its preferential expression in hematopoietic cells, miR-142 has been found to be associated with numerous types of lymphomas and leukemias. This review elucidates the multifaceted role of miR-142 in human physiology, its influence on hematopoiesis and hematopoietic cells, and its intriguing involvement in exosome-mediated miR-142 transport. Moreover, we offer a comprehensive exploration of the genetic and molecular landscape of the miR-142 genomic locus, highlighting its mutations and dysregulation within hematological malignancies. Finally, we discuss potential avenues for harnessing the therapeutic potential of miR-142 in the context of hematological malignancies.

Performance of the 2017 European Alliance of Associations for Rheumatology/American College of Rheumatology Classification Criteria for Idiopathic Inflammatory Myopathies in Patients With Myositis-Specific Autoantibodies.

OBJECTIVE: We undertook this study to 1) determine the sensitivity of the European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) classification criteria for idiopathic inflammatory myopathies (IIMs) to properly classify myositis-specific autoantibody (MSA)-positive myositis patients, 2) describe the phenotype and muscle involvement over time in different MSA-positive patients, and 3) compare MSA subgroups to EULAR/ACR criteria-defined myositis subgroups for their capacity to predict clinical phenotypes in patients with IIMs. METHODS: The study included 524 MSA-positive myositis patients from the Johns Hopkins Myositis Center. Each patient was classified using the EULAR/ACR classification criteria. Patient phenotypes were summarized using factor analysis of mixed data (FAMD). We compared the ability of MSAs to that of the EULAR/ACR classification subgroups to predict the phenotype of patients by applying the Akaike information criterion (AIC) and the Bayesian information criteria (BIC) to the linear regression models. RESULTS: Overall, 91% of MSA-positive patients met the EULAR/ACR criteria to be classified as having myositis. However, 20% of patients with anti-hydroxymethylglutaryl-coenzyme A reductase (anti-HMGCR) and 50% of patients with anti-PL-7 were incorrectly classified as not having myositis. Furthermore, ~10% of patients with anti-signal recognition particle (anti-SRP) and patients with anti-HMGCR were misclassified as having inclusion body myositis. FAMD demonstrated that patients within each MSA-defined subgroup had similar phenotypes. Application of both the AIC and BIC to the linear regression models revealed that MSAs were better predictors of myositis phenotypes than the subgroups defined by the EULAR/ACR criteria. CONCLUSION: Although the EULAR/ACR criteria successfully classified 91% of MSA-positive myositis patients, certain MSA-defined subgroups, including those with autoantibodies against HMGCR, SRP, and PL-7, are frequently misclassified. In myositis patients with MSAs, autoantibodies outperform the EULAR/ACR-defined myositis subgroups in predicting the clinical phenotypes of patients. These findings underscore the need to include MSAs in a revised myositis classification scheme.

Targeting conserved N-glycosylation blocks SARS-CoV-2 variant infection in vitro.

BACKGROUND: Despite clinical success with anti-spike vaccines, the effectiveness of neutralizing antibodies and vaccines has been compromised by rapidly spreading SARS-CoV-2 variants. Viruses can hijack the glycosylation machinery of host cells to shield themselves from the host's immune response and attenuate antibody efficiency. However, it remains unclear if targeting glycosylation on viral spike protein can impair infectivity of SARS-CoV-2 and its variants. METHODS: We adopted flow cytometry, ELISA, and BioLayer interferometry approaches to assess binding of glycosylated or deglycosylated spike with ACE2. Viral entry was determined by luciferase, immunoblotting, and immunofluorescence assays. Genome-wide association study (GWAS) revealed a significant relationship between STT3A and COVID-19 severity. NF-κB/STT3A-regulated N-glycosylation was investigated by gene knockdown, chromatin immunoprecipitation, and promoter assay. We developed an antibody-drug conjugate (ADC) that couples non-neutralization anti-spike antibody with NGI-1 (4G10-ADC) to specifically target SARS-CoV-2-infected cells. FINDINGS: The receptor binding domain and three distinct SARS-CoV-2 surface N-glycosylation sites among 57,311 spike proteins retrieved from the NCBI-Virus-database are highly evolutionarily conserved (99.67%) and are involved in ACE2 interaction. STT3A is a key glycosyltransferase catalyzing spike glycosylation and is positively correlated with COVID-19 severity. We found that inhibiting STT3A using N-linked glycosylation inhibitor-1 (NGI-1) impaired SARS-CoV-2 infectivity and that of its variants [Alpha (B.1.1.7) and Beta (B.1.351)]. Most importantly, 4G10-ADC enters SARS-CoV-2-infected cells and NGI-1 is subsequently released to deglycosylate spike protein, thereby reinforcing the neutralizing abilities of antibodies, vaccines, or convalescent sera and reducing SARS-CoV-2 variant infectivity. INTERPRETATION: Our results indicate that targeting evolutionarily-conserved STT3A-mediated glycosylation via an ADC can exert profound impacts on SARS-CoV-2 variant infectivity. Thus, we have identified a novel deglycosylation method suitable for eradicating SARS-CoV-2 variant infection in vitro. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

BROAD PECTUS EXCAVATUM TREATMENT: LONG TERM RESULTS OF A BRAZILIAN TECHNIQUE.

OBJECTIVE: This study aims the treatment results of broad pectus excavatum after a long-term follow-up and skeletal maturity. METHODS: Eighty-four children and adolescents with broad-type pectus excavatum were selected for evaluation after treatment with a dynamic orthosis that applies compression to the lower rib projections and prescription of exercises. The broad pectus excavatum was defined as a deformity that the depressed area was greater and covered the area above and below the nipple line. All patients were evaluated for more than 1 year after the end of treatment and skeletal maturity. Post-treatment results were categorized as mild, moderate and severe. Statistic correlations between results and deformity flexibility, deformity severity, and adherence to treatment were assessed. RESULTS: The mean age at the beginning of treatment was 13.3 years, and the follow-up duration was 25.7 months after suspension of orthosis use. Forty-eight percent of patients showed good results. With regular use of orthoses and performance of exercises, this rate increased to 70% (p < 0,001). Mild cases showed more success than severe cases (p = 0,007). Initial flexibility didn't influence the results (p = 0,63). CONCLUSION: Treatment of broad pectus excavatum with orthoses and exercises led to good definitive results in most resilient patients, especially in those with mild deformities. Level of Evidence V, Expert Opinion.

OBJETIVO: Estudar os resultados de longo prazo e com seguimento até a maturidade esquelética do tratamento do pectus excavatum amplo. MÉTODOS: 84 crianças e adolescentes foram tratados com uma órtese que aplicacompressão nas saliências costais inferiores, associada a exercícios específicos. A deformidade foi classificada como ampla quando a depressão tem maior extensão e abrange uma área acima e abaixo da linha mamilar. Os resultados foram categorizados em ruim, regular ou bom, sendo correlacionados estatisticamente com a flexibilidade, a gravidade da deformidade e a adesão ao tratamento, com avaliação um ano após o fim do tratamento e na maturidade esquelética. RESULTADOS: A idade média no início do tratamento foi de 13,7 anos e o seguimento médio foi de 25.7 meses após a suspensão do uso da órtese. 48% dos casos apresentaram sucesso com o tratamento, mas quando os exercícios e o uso da órtese foram regulares, esta taxa aumentou para 70% (p < 0,001). Os casos mais leves tiveram maior sucesso que os de maior gravidade (p = 0,007), mas a flexibilidade inicial não influenciou os resultados (p = 0,63). CONCLUSÃO: O tratamento do pectus excavatum amplo com o uso de órtese e exercícios apresentou bons resultados definitivos na maioria dos pacientes resilientes, em especial nos casos mais leves. Nível de Evidência V, Opinião do Especialista.

Localized pectus excavatum treated with brace and exercise: long term results of a brazilian technique / Tratamento do pectus excavatum localizado com órtese e exercícios: resultados de longo prazo de uma técnica brasileira

ABSTRACT Objective: Pectus excavatum is a deformity that affects aesthetics and causes emotional disorders. Surgical correction is well established, but conservative treatment is less common. We investigated the long-term results of using a brace and performing specific physical exercises to treat localized pectus excavatum, a type of deformity in which the depressed area is restricted to the midline region along the nipple line. Methods: We selected 115 patients (mean age 12.8 years), with a minimum follow-up of 36 months, who were evaluated more than one year after the end of treatment and skeletal maturity. Results were correlated with deformity flexibility, severity, regular use of the device, and performance of specific exercises. The chi-square (χ2) and the Cochran-Mantel-Haenszel tests were used for statistical analysis. Results: Treatment was successful in 58% of patients, however, when exercises were performed and the brace was used regularly by patients with flexible deformities, the rate increased to 83% (p = 0.005). Severity and adherence to treatment greatly impacted successful treatment (p = 0.009 and < 0.001, respectively). Conclusion: The proposed treatment method was effective for correction or partial correction of the deformity in motivated patients followed up until skeletal maturity, especially when started early in milder and more flexible deformities. Level of Evidence V, Expert opinion.

RESUMO Objetivo: O pectus excavatum é uma deformidade importante por comprometer a estética e causar distúrbios emocionais. A sua correção cirúrgica é bem estabelecida, mas o tratamento conservador é menos familiar. Investigamos os resultados de longo prazo do tratamento do pectus excavatum localizado (deformidade restrita a linha média e na linha mamilar) com uso de órtese e exercícios físicos específicos. Métodos: Selecionamos 115 pacientes (média de 12,8 anos) com seguimento mínimo de 36 meses, sendo avaliados mais de um ano após o término do tratamento e maturidade esquelética. Os resultados foram relacionados estatisticamente (qui-quadrado e Cochran-Mantel-Haenszel) com a flexibilidade da deformidade, a gravidade, o uso regular da órtese e a realização de exercícios específicos. Resultados: O tratamento foi bem-sucedido em 58% dos pacientes, mas quando o uso da órtese e os exercícios foram regulares em pacientes com deformidades flexíveis, essa taxa aumentou para 83% (p = 0,005). A gravidade e a adesão ao tratamento tiveram grande impacto no sucesso do tratamento (p = 0,009 e <0,001, respectivamente). Conclusão: O método de tratamento proposto foi eficaz para correção total ou parcial da deformidade em pacientes motivados acompanhados até a maturidade esquelética, principalmente quando a terapêutica foi iniciada precocemente em deformidades mais leves e flexíveis. Nível de Evidência V, Opinião do especialista.

Broad pectus excavatum treatment: long term results of a brazilian technique / Tratamento do pectus excavatum amplo: resultados a longo prazo de uma técnica brasileira

ABSTRACT Objective: This study aims the treatment results of broad pectus excavatum after a long-term follow-up and skeletal maturity. Methods: Eighty-four children and adolescents with broad-type pectus excavatum were selected for evaluation after treatment with a dynamic orthosis that applies compression to the lower rib projections and prescription of exercises. The broad pectus excavatum was defined as a deformity that the depressed area was greater and covered the area above and below the nipple line. All patients were evaluated for more than 1 year after the end of treatment and skeletal maturity. Post-treatment results were categorized as mild, moderate and severe. Statistic correlations between results and deformity flexibility, deformity severity, and adherence to treatment were assessed. Results: The mean age at the beginning of treatment was 13.3 years, and the follow-up duration was 25.7 months after suspension of orthosis use. Forty-eight percent of patients showed good results. With regular use of orthoses and performance of exercises, this rate increased to 70% (p < 0,001). Mild cases showed more success than severe cases (p = 0,007). Initial flexibility didn't influence the results (p = 0,63). Conclusion: Treatment of broad pectus excavatum with orthoses and exercises led to good definitive results in most resilient patients, especially in those with mild deformities. Level of Evidence V, Expert Opinion.

RESUMO Objetivo: Estudar os resultados de longo prazo e com seguimento até a maturidade esquelética do tratamento do pectus excavatum amplo. Métodos: 84 crianças e adolescentes foram tratados com uma órtese que aplicacompressão nas saliências costais inferiores, associada a exercícios específicos. A deformidade foi classificada como ampla quando a depressão tem maior extensão e abrange uma área acima e abaixo da linha mamilar. Os resultados foram categorizados em ruim, regular ou bom, sendo correlacionados estatisticamente com a flexibilidade, a gravidade da deformidade e a adesão ao tratamento, com avaliação um ano após o fim do tratamento e na maturidade esquelética. Resultados: A idade média no início do tratamento foi de 13,7 anos e o seguimento médio foi de 25.7 meses após a suspensão do uso da órtese. 48% dos casos apresentaram sucesso com o tratamento, mas quando os exercícios e o uso da órtese foram regulares, esta taxa aumentou para 70% (p < 0,001). Os casos mais leves tiveram maior sucesso que os de maior gravidade (p = 0,007), mas a flexibilidade inicial não influenciou os resultados (p = 0,63). Conclusão: O tratamento do pectus excavatum amplo com o uso de órtese e exercícios apresentou bons resultados definitivos na maioria dos pacientes resilientes, em especial nos casos mais leves. Nível de Evidência V, Opinião do Especialista.

LOCALIZED PECTUS EXCAVATUM TREATED WITH BRACE AND EXERCISE: LONG TERM RESULTS OF A BRAZILIAN TECHNIQUE.

OBJECTIVE: Pectus excavatum is a deformity that affects aesthetics and causes emotional disorders. Surgical correction is well established, but conservative treatment is less common. We investigated the long-term results of using a brace and performing specific physical exercises to treat localized pectus excavatum, a type of deformity in which the depressed area is restricted to the midline region along the nipple line. METHODS: We selected 115 patients (mean age 12.8 years), with a minimum follow-up of 36 months, who were evaluated more than one year after the end of treatment and skeletal maturity. Results were correlated with deformity flexibility, severity, regular use of the device, and performance of specific exercises. The chi-square (χ2) and the Cochran-Mantel-Haenszel tests were used for statistical analysis. RESULTS: Treatment was successful in 58% of patients, however, when exercises were performed and the brace was used regularly by patients with flexible deformities, the rate increased to 83% (p = 0.005). Severity and adherence to treatment greatly impacted successful treatment (p = 0.009 and < 0.001, respectively). CONCLUSION: The proposed treatment method was effective for correction or partial correction of the deformity in motivated patients followed up until skeletal maturity, especially when started early in milder and more flexible deformities. Level of Evidence V, Expert opinion.

OBJETIVO: O pectus excavatum é uma deformidade importante por comprometer a estética e causar distúrbios emocionais. A sua correção cirúrgica é bem estabelecida, mas o tratamento conservador é menos familiar. Investigamos os resultados de longo prazo do tratamento do pectus excavatum localizado (deformidade restrita a linha média e na linha mamilar) com uso de órtese e exercícios físicos específicos. Métodos: Selecionamos 115 pacientes (média de 12,8 anos) com seguimento mínimo de 36 meses, sendo avaliados mais de um ano após o término do tratamento e maturidade esquelética. Os resultados foram relacionados estatisticamente (qui-quadrado e Cochran-Mantel-Haenszel) com a flexibilidade da deformidade, a gravidade, o uso regular da órtese e a realização de exercícios específicos. RESULTADOS: O tratamento foi bem-sucedido em 58% dos pacientes, mas quando o uso da órtese e os exercícios foram regulares em pacientes com deformidades flexíveis, essa taxa aumentou para 83% (p = 0,005). A gravidade e a adesão ao tratamento tiveram grande impacto no sucesso do tratamento (p = 0,009 e <0,001, respectivamente). CONCLUSÃO: O método de tratamento proposto foi eficaz para correção total ou parcial da deformidade em pacientes motivados acompanhados até a maturidade esquelética, principalmente quando a terapêutica foi iniciada precocemente em deformidades mais leves e flexíveis. Nível de Evidência V, Opinião do especialista.

Trim33 (Tif1γ) is not required for skeletal muscle development or regeneration but suppresses cholecystokinin expression.

The expression of Trim33 (Tif1γ) increases in skeletal muscles during regeneration and decreases upon maturation. Although Trim33 is required for the normal development of other tissues, its role in skeletal muscle is unknown. The current study aimed to define the role of Trim33 in muscle development and regeneration. We generated mice with muscle-specific conditional knockout of Trim33 by combining floxed Trim33 and Cre recombinase under the Pax7 promoter. Muscle regeneration was induced by injuring mouse muscles with cardiotoxin. We studied the consequences of Trim33 knockdown on viability, body weight, skeletal muscle histology, muscle regeneration, and gene expression. We also studied the effect of Trim33 silencing in satellite cells and the C2C12 mouse muscle cell line. Although Trim33 knockdown mice weighed less than control mice, their skeletal muscles were histologically unremarkable and regenerated normally following injury. Unexpectedly, RNAseq analysis revealed dramatically increased expression of cholecystokinin (CCK) in regenerating muscle from Trim33 knockout mice, satellite cells from Trim33 knockout mice, and C2C12 cells treated with Trim33 siRNA. Trim33 knockdown had no demonstrable effect on muscle differentiation or regeneration. However, Trim33 knockdown induced CCK expression in muscle, suggesting that suppression of CCK expression requires Trim33.

More prominent muscle involvement in patients with dermatomyositis with anti-Mi2 autoantibodies.

OBJECTIVE: To define the clinical phenotype of dermatomyositis (DM) with anti-Mi2 autoantibodies. METHODS: In this longitudinal cohort study, the prevalence and severity of clinical features at disease onset and during follow-up in patients with anti-Mi2-positive DM were compared to patients with anti-Mi2-negative DM, antisynthetase syndrome (AS), and immune-mediated necrotizing myopathy (IMNM). Longitudinal anti-Mi2 autoantibody titers were assessed. RESULTS: A total of 58 patients with anti-Mi2-positive DM, 143 patients with anti-Mi2-negative DM, 162 patients with AS, and 170 patients with IMNM were included. Among patients with anti-Mi2-positive DM, muscle weakness was present in 60% at disease onset and occurred in 98% during longitudinal follow-up; fewer patients with anti-Mi2-negative DM developed weakness (85%; p = 0.008). Patients with anti-Mi2-positive DM were weaker and had higher creatine kinase (CK) levels than patients with anti-Mi2-negative DM or patients with AS. Muscle biopsies from patients with anti-Mi2-positive DM had prominent necrosis. Anti-Mi2 autoantibody levels correlated with CK levels and strength (p < 0.001). With treatment, most patients with anti-Mi2-positive DM had improved strength and CK levels; among 10 with multiple serum samples collected over 4 or more years, anti-Mi2 autoantibody titers declined in all and normalized in 3, 2 of whom stopped immunosuppressant treatment and never relapsed. Patients with anti-Mi2-positive DM had less calcinosis (9% vs 28%; p = 0.003), interstitial lung disease (5% vs 16%; p = 0.04), and fever (7% vs 21%; p = 0.02) than did patients with anti-Mi2-negative DM. CONCLUSIONS: Patients with anti-Mi2-positive DM have more severe muscle disease than patients with anti-Mi2-negative DM or patients with AS. Anti-Mi2 autoantibody levels correlate with disease severity and may normalize in patients who enter remission.

Stimulation of Hair Growth by Small Molecules that Activate Autophagy.

Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide, but methods that can be used to regrow hair are lacking. We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, which impinge on mTOR and AMPK signaling. Stimulation of hair growth by these agents is blocked by specific autophagy inhibitors, suggesting a mechanistic link between autophagy and hair regeneration. Consistently, increased autophagy is detected upon anagen entry during the natural hair follicle cycle, and oral α-KB prevents hair loss in aged mice. Our finding that anagen can be pharmacologically activated in telogen skin when natural anagen-inducing signal(s) are absent has implications for the treatment of hair loss patients.

Muscular and extramuscular clinical features of patients with anti-PM/Scl autoantibodies.

OBJECTIVE: To define the clinical features of myositis patients with anti-PM/Scl-75 and/or anti-PM/Scl-100 autoantibodies at disease onset and during the course of disease and compare them to patients with other forms of myositis. METHODS: In this longitudinal cohort study, the prevalence and severity of clinical features at disease onset and during follow-up were compared between anti-PM/Scl-positive patients and those with the antisynthetase syndrome (AS), dermatomyositis (DM), and immune-mediated necrotizing myopathy (IMNM). RESULTS: Forty-one anti-PM/Scl-positive, 132 AS, 178 DM, and 135 IMNM patients were included. Although muscle weakness was a presenting feature in just 37% of anti-PM/Scl-positive patients, 93% eventually developed weakness. Unlike the other groups, anti-PM-Scl-positive patients had more severe weakness in arm abductors than hip flexors. Interstitial lung disease was a presenting feature in just 10% of anti-PM/Scl-positive patients, but occurred in 61% during follow-up; fewer patients with DM (13%, p < 0.001) and IMNM (6%, p < 0.001) and more patients with AS (80%, p < 0.05) developed interstitial lung disease during the course of disease. Mechanic's hands (80%), Raynaud syndrome (78%), sclerodactyly (66%), telangiectasias (66%), esophageal reflux disease (61%), subcutaneous edema (46%), puffy hands (39%), and calcinosis (39%) occurred more frequently in anti-PM/Scl-positive patients than in the other groups. Although 30% of anti-PM/Scl-positive patients met criteria for systemic sclerosis, less than 5% had renal crisis or finger ulcerations. No differences were found between patients with only anti-PM/Scl-100 or only anti-PM/Scl-75 autoantibodies. CONCLUSIONS: Unlike patients with DM, AS, or IMNM, anti-PM/Scl-positive patients have weaker arm abductors than hip flexors. Anti-PM/Scl-positive patients also have the most extensive extramuscular features.

Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy.

Transverse (T)-tubules make-up a specialized network of tubulated muscle cell membranes involved in excitation-contraction coupling for power of contraction. Little is known about how T-tubules maintain highly organized structures and contacts throughout the contractile system despite the ongoing muscle remodeling that occurs with muscle atrophy, damage and aging. We uncovered an essential role for autophagy in T-tubule remodeling with genetic screens of a developmentally regulated remodeling program in Drosophila abdominal muscles. Here, we show that autophagy is both upregulated with and required for progression through T-tubule disassembly stages. Along with known mediators of autophagosome-lysosome fusion, our screens uncovered an unexpected shared role for Rab2 with a broadly conserved function in autophagic clearance. Rab2 localizes to autophagosomes and binds to HOPS complex members, suggesting a direct role in autophagosome tethering/fusion. Together, the high membrane flux with muscle remodeling permits unprecedented analysis both of T-tubule dynamics and fundamental trafficking mechanisms.

Antinuclear Matrix Protein 2 Autoantibodies and Edema, Muscle Disease, and Malignancy Risk in Dermatomyositis Patients.

OBJECTIVE: Dermatomyositis (DM) patients typically present with proximal weakness and autoantibodies that are associated with distinct clinical phenotypes. We observed that DM patients with autoantibodies recognizing the nuclear matrix protein NXP-2 often presented with especially severe weakness. The aim of this study was to characterize the clinical features associated with anti-NXP-2 autoantibodies. METHODS: There were 235 DM patients who underwent testing for anti-NXP-2 autoantibodies. Patient characteristics, including muscle strength, were compared between those with and without these autoantibodies. The number of cancer cases observed in anti-NXP-2-positive subjects was compared with the number expected in the general population. RESULTS: Of the DM patients, 56 (23.8%) were anti-NXP-2-positive. There was no significant difference in the prevalence of proximal extremity weakness in patients with and without anti-NXP-2. In contrast, anti-NXP-2-positive patients had more prevalent weakness in the distal arms (35% versus 20%; P = 0.02), distal legs (25% versus 8%; P < 0.001), and neck (48% versus 23%; P < 0.001). Anti-NXP-2-positive subjects were also more likely to have dysphagia (62% versus 35%; P < 0.001), myalgia (46% versus 25%; P = 0.002), calcinosis (30% versus 17%; P = 0.02), and subcutaneous edema (36% versus 19%; P = 0.01) than anti-NXP-2-negative patients. Five anti-NXP-2-positive subjects (9%) had cancer-associated myositis, representing a 3.68-fold increased risk (95% confidence interval 1.2-8.6) compared to the expected prevalence in the general population. CONCLUSION: In DM, anti-NXP-2 autoantibodies are associated with subcutaneous edema, calcinosis, and a muscle phenotype characterized by myalgia, proximal and distal weakness, and dysphagia. As anti-NXP-2-positive patients have an increased risk of cancer, we suggest that they undergo comprehensive cancer screening.

17-hydroxyprogesterone caproate for preterm rupture of the membranes: a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Preterm rupture of membranes (PROM) is associated with an increased risk of preterm birth and neonatal morbidity. Prophylactic 17-hydroxyprogesterone caproate (17OHP-C) reduces the risk of preterm birth in some women who are at risk for preterm birth. We sought to test whether 17OHP-C would prolong pregnancy or improve perinatal outcome when given to mothers with preterm rupture of the membranes. STUDY DESIGN: This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. The study included singleton pregnancies with gestational ages from 23(0/7) to 30(6/7) weeks at enrollment, documented PROM, and no contraindication to expectant management. Consenting women were assigned randomly to receive weekly intramuscular injections of 17OHP-C (250 mg) or placebo. The primary outcome was continuation of pregnancy until a favorable gestational age, which was defined as either 34(0/7) weeks of gestation or documentation of fetal lung maturity at 32(0/7) to 33(6/7) weeks of gestation. The 2 prespecified secondary outcomes were interval from randomization to delivery and composite adverse perinatal outcome. The planned sample size was 222 total women. RESULTS: From October 2011 to April 2014, 152 women were enrolled; 74 women were allocated randomly to 17OHP-C, and 78 were allocated randomly to placebo. The trial was stopped when results of a planned interim analysis suggested that continuation was futile. The primary outcome was achieved in 3% of the 17OHP-C group and 8% of the placebo group (P = .18). There was no significant between-group difference in the prespecified secondary outcomes, randomization-to-delivery interval (17.1 ± 16.1 vs 17.0 ± 15.8 days, respectively; P = .76) or composite adverse perinatal outcome (63% vs 61%, respectively; P = .93). No significant differences were found in other outcomes, which included rates of chorioamnionitis, postpartum endometritis, cesarean delivery, individual components of the composite outcome, or prolonged neonatal length of stay. CONCLUSION: Compared with placebo, weekly 17OHP-C injections did not prolong pregnancy or reduce perinatal morbidity in patients with PROM in this trial.

Levofloxacin decreased chest wall mechanical inhomogeneities and airway and vascular remodeling in rats with induced hepatopulmonary syndrome.

The administration of antibiotics decreases bacterial translocation, reduces the activity of nitric oxide synthase and improves the gas exchange of hepatopulmonary syndrome (HPS) in rats. We hypothesized that levofloxacin could reduce HPS-induced respiratory mechanical inhomogeneities and airway and pulmonary vascular remodeling. We assessed the respiratory mechanical properties and lung tissue structure in 24 rats assigned to the control, HPS (eHPS) and HPS+levofloxacin (eHPS+L) groups. The administration of levofloxacin reduced the HPS-induced chest wall but not the lung mechanical inhomogeneities. The eHPS airway proportion of elastic fibers increased 20% but was similar between the control and eHPS+L groups. The eHPS vascular collagen increased 25% in eHPS but was similar between the control and eHPS+L groups. Compared to the control group, the vascular proportion of elastic fibers of the eHPS and eHPS+L groups increased by 60% and 16%, respectively. The administration of levofloxacin decreased the HPS-induced chest wall mechanical inhomogeneities and airway and vascular remodeling.

Implementation of a laborist program and evaluation of the effect upon cesarean delivery.

OBJECTIVE: Laborist programs have expanded throughout the United States in the last decade. Meanwhile, there has been no published research examining their effect on patient outcomes. Cesarean delivery is a key performance metric with maternal health implications and significant financial impact. Our hypothesis is that the initiation of a full-time dedicated laborist staff decreases cesarean delivery. STUDY DESIGN: In a tertiary hospital staffed with private practice physicians, data were retrospectively reviewed for 3 time periods from 2006 through 2011. The first period (16 months) there were no laborists (traditional model), followed by 14 months of continuous in-hospital laborist coverage provided by community staff (community laborist), and finally a 24-month period with full-time laborists providing continuous in-hospital coverage. The primary hypothesis was that full-time laborists would decrease cesarean delivery rates. RESULTS: Data from 6206 term nulliparous patients were retrospectively reviewed. The cesarean delivery rate for no laborist care was 39.2%, for community physician laborist care was 38.7%, and for full-time laborists was 33.2%. With adjustment via logistic regression, full-time laborist presence was associated with a significant reduction in cesarean delivery when contrasted with no laborist (odds ratio, 0.73; 95% confidence interval, 0.64-0.83; P < .0001) or community laborist care (odds ratio, 0.77; 95% confidence interval, 0.67-0.87; P < .001). The community laborist model was not associated with an effect upon cesarean delivery. CONCLUSION: A dedicated full-time laborist staff model is associated with lower rates of cesarean delivery. These findings may be used as part of a strategy to reduce cesarean delivery, lower maternal morbidity and mortality, and decrease health care costs.

A prospective randomized controlled trial that compared misoprostol, Foley catheter, and combination misoprostol-Foley catheter for labor induction.

OBJECTIVE: The purpose of this study was to determine the efficacy of combination intravaginal misoprostol and intracervical Foley catheter for prelabor cervical ripening. STUDY DESIGN: A prospective, randomized controlled trial was conducted. Women who were undergoing labor induction, with a singleton gestation >or=28 weeks and an unfavorable cervix (Bishop score

Abnormal first-trimester fetal nuchal translucency and Cornelia De Lange syndrome.

BACKGROUND: Cornelia de Lange syndrome is a genetic disorder associated with delayed growth and characteristic facial features. There is no definitive biochemical or chromosomal marker for the prenatal diagnosis of this syndrome. We describe a case of Cornelia de Lange syndrome associated with an increased nuchal translucency in the first trimester. CASE: A large nuchal translucency was identified in a fetus during a first trimester ultrasound. Subsequent second- and third-trimester sonograms demonstrated severe fetal growth restriction, limb shortening, and abnormal facial features, despite normal fetal karyotype per chorionic villus sampling. Neonatal evaluation confirmed the diagnosis of Cornelia de Lange syndrome. CONCLUSION: Sonographic finding of an increased nuchal translucency in early pregnancy is associated with fetal aneuploidy and various structural and genetic abnormalities. Increased nuchal translucency may identify fetuses that require vigilant assessment, especially when found in association with other abnormalities.