Simultaneous screening of overexpressed genes in breast cancer for oncogenic drivers and tumor dependencies.

There are hundreds of genes typically overexpressed in breast cancer cells and it's often assumed that their overexpression contributes to cancer progression. However, the precise proportion of these overexpressed genes contributing to tumorigenicity remains unclear. To address this gap, we undertook a comprehensive screening of a diverse set of seventy-two genes overexpressed in breast cancer. This systematic screening evaluated their potential for inducing malignant transformation and, concurrently, assessed their impact on breast cancer cell proliferation and viability. Select genes including ALDH3B1, CEACAM5, IL8, PYGO2, and WWTR1, exhibited pronounced activity in promoting tumor formation and establishing gene dependencies critical for tumorigenicity. Subsequent investigations revealed that CEACAM5 overexpression triggered the activation of signaling pathways involving ß-catenin, Cdk4, and mTOR. Additionally, it conferred a growth advantage independent of exogenous insulin in defined medium and facilitated spheroid expansion by inducing multiple layers of epithelial cells while preserving a hollow lumen. Furthermore, the silencing of CEACAM5 expression synergized with tamoxifen-induced growth inhibition in breast cancer cells. These findings underscore the potential of screening overexpressed genes for both oncogenic drivers and tumor dependencies to expand the repertoire of therapeutic targets for breast cancer treatment.

Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development. Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression. See related article by Belle et al., p. 1324.

Induction of Multiple Alternative Mitogenic Signaling Pathways Accompanies the Emergence of Drug-Tolerant Cancer Cells.

Drug resistance can evolve from a subpopulation of cancer cells that initially survive drug treatment and then gradually form a pool of drug-tolerant cells. Several studies have pinpointed the activation of a specific bypass pathway that appears to provide the critical therapeutic target for preventing drug tolerance. Here, we take a systems-biology approach, using proteomics and genomics to examine the development of drug tolerance to EGFR inhibitors in EGFR-mutant lung adenocarcinoma cells and BRAF inhibitors in BRAF-mutant melanoma cells. We found that there are numerous alternative mitogenic pathways that become activated in both cases, including YAP, STAT3, IGFR1, and phospholipase C (PLC)/protein kinase C (PKC) pathways. Our results suggest that an effective therapeutic strategy to prevent drug tolerance will need to take multiple alternative mitogenic pathways into account rather than focusing on one specific pathway.

Coordinated single-cell tumor microenvironment dynamics reinforce pancreatic cancer subtype.

Bulk analyses of pancreatic ductal adenocarcinoma (PDAC) samples are complicated by the tumor microenvironment (TME), i.e. signals from fibroblasts, endocrine, exocrine, and immune cells. Despite this, we and others have established tumor and stroma subtypes with prognostic significance. However, understanding of underlying signals driving distinct immune and stromal landscapes is still incomplete. Here we integrate 92 single cell RNA-seq samples from seven independent studies to build a reproducible PDAC atlas with a focus on tumor-TME interdependence. Patients with activated stroma are synonymous with higher myofibroblastic and immunogenic fibroblasts, and furthermore show increased M2-like macrophages and regulatory T-cells. Contrastingly, patients with 'normal' stroma show M1-like recruitment, elevated effector and exhausted T-cells. To aid interoperability of future studies, we provide a pretrained cell type classifier and an atlas of subtype-based signaling factors that we also validate in mouse data. Ultimately, this work leverages the heterogeneity among single-cell studies to create a comprehensive view of the orchestra of signaling interactions governing PDAC.

Exercise-Induced Antisenescence and Autophagy Restoration Mitigate Metabolic Disorder-Induced Cardiac Disruption in Mice.

INTRODUCTION: Metabolic disorder promotes premature senescence and poses more severe cardiac dysfunction in females than males. Although endurance exercise (EXE) has been known to confer cardioprotection against metabolic diseases, whether EXE-induced cardioprotection is associated with mitigating senescence in females remains unknown. Thus, the aim of the present study was to examine metabolic disorder-induced cardiac anomalies (cellular senescence, metabolic signaling, and autophagy) using a mouse model of obese/type 2 diabetes induced by a high-fat/high-fructose (HFD/HF) diet. METHODS: Female C57BL/6 mice (10 wk old) were assigned to three groups ( n = 11/group): normal diet group (CON), HFD/HF group, and HFD/HF diet + endurance exercise (HFD/HF + EXE) group. Upon confirmation of hyperglycemia and overweight after 12 wk of HFD/HF diet, mice assigned to HFD/HF + EXE group started treadmill running exercise (60 min·d -1 , 5 d·wk -1 for 12 wk), with HFD/HF diet continued. RESULTS: EXE ameliorated HFD/HF-induced body weight gain and hyperglycemia, improved insulin signaling and glucose transporter 4 (GLUT4) levels, and counteracted cardiac disruption. EXE reversed HFD/HF-induced myocyte premature senescence (e.g., prevention of p53, p21, p16, and lipofuscin accumulation), resulting in suppression of a senescence-associated secretory phenotype such as inflammation (tumor necrosis factor α and interleukin-1ß) and oxidative stress (protein carbonylation). Moreover, EXE restored HFD/HF-induced autophagy flux deficiency, evidenced by increased LC3-II concomitant with p62 reduction and restoration of lysosome function-related proteins (LAMP2, CATHEPSIN L, TFEB, and SIRT1). More importantly, EXE retrieved HFD/HF-induced apoptosis arrest (e.g., increased cleaved CASPASE3, PARP, and TUNEL-positive cells). CONCLUSIONS: Our study demonstrated that EXE-induced antisenescence phenotypes, autophagy restoration, and promotion of propitiatory cell removal by apoptosis play a crucial role in cardiac protection against metabolic distress-induced cardiac disruption.

Structural lung disease in preschool children with cystic fibrosis: An 18 month natural history study.

BACKGROUND: This study was performed to describe the natural history of CF lung disease in young children over an 18 month period to assess the use of CT scanning as an outcome measure for intervention trials. METHODS: Chest CT scans were obtained at baseline and after 18 months in 42 two- to six-year-old children with CF. CT scans were scored by 2 experienced radiologists for the presence and severity of bronchiectasis, mucous plugging, and air trapping. RESULTS: Mean age at baseline 3.5 (1.3) (mean, sd) years. One or more findings of CF lung disease was seen on the first CT in 27 (64%) and at 18 months in 30 (75%). From baseline to 18 months bronchiectasis, mucous plugging, and air trapping increased from 50% to 53%, 14% to 28%, and 48% to 58% respectively. There was marked variability in the rate of progression, with subjects commonly showing improvement in lung disease. Bronchiectasis worsened in 14 (33%) and improved in 13 (31%). Single subjects with F508del/class III and F508del/class V demonstrated greater worsening and improvement respectively than F508del homozygous and class I genotypes. CONCLUSIONS: The natural history of CF lung disease over 18 months varies widely between subjects. Factors including genotype may affect natural history as well as the effectiveness of mediators and could be an important confounder if not recognized. These findings suggest that the use of CT scanning as an outcome surrogate for CF lung disease in young children may be more challenging than has been previously recognized.

Combinatorial CRISPR/Cas9 Screening Reveals Epistatic Networks of Interacting Tumor Suppressor Genes and Therapeutic Targets in Human Breast Cancer.

The majority of cancers are driven by multiple genetic alterations, but how these changes collaborate during tumorigenesis remains largely unknown. To gain mechanistic insights into tumor-promoting genetic interactions among tumor suppressor genes (TSG), we conducted combinatorial CRISPR screening coupled with single-cell transcriptomic profiling in human mammary epithelial cells. As expected, different driver gene alterations in mammary epithelial cells influenced the repertoire of tumor suppressor alterations capable of inducing tumor formation. More surprisingly, TSG interaction networks were comprised of numerous cliques-sets of three or four genes such that each TSG within the clique showed oncogenic cooperation with all other genes in the clique. Genetic interaction profiling indicated that the predominant cooperating TSGs shared overlapping functions rather than distinct or complementary functions. Single-cell transcriptomic profiling of CRISPR double knockouts revealed that cooperating TSGs that synergized in promoting tumorigenesis and growth factor independence showed transcriptional epistasis, whereas noncooperating TSGs did not. These epistatic transcriptional changes, both buffering and synergistic, affected expression of oncogenic mediators and therapeutic targets, including CDK4, SRPK1, and DNMT1. Importantly, the epistatic expression alterations caused by dual inactivation of TSGs in this system, such as PTEN and TP53, were also observed in patient tumors, establishing the relevance of these findings to human breast cancer. An estimated 50% of differentially expressed genes in breast cancer are controlled by epistatic interactions. Overall, our study indicates that transcriptional epistasis is a central aspect of multigenic breast cancer progression and outlines methodologies to uncover driver gene epistatic networks in other human cancers. SIGNIFICANCE: This study provides a roadmap for moving beyond discovery and development of therapeutic strategies based on single driver gene analysis to discovery based on interactions between multiple driver genes.See related commentary by Fong et al., p. 6078.

Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity.

Skeletal muscle is the most abundant tissue in the body and is required for numerous vital functions, including breathing and locomotion. Notably, deterioration of skeletal muscle mass is also highly correlated to mortality in patients suffering from chronic diseases (e.g., cancer). Numerous conditions can promote skeletal muscle wasting, including several chronic diseases, cancer chemotherapy, aging, and prolonged inactivity. Although the mechanisms responsible for this loss of muscle mass is multifactorial, mitochondrial dysfunction is predicted to be a major contributor to muscle wasting in various conditions. This systematic review will highlight the biochemical pathways that have been shown to link mitochondrial dysfunction to skeletal muscle wasting. Importantly, we will discuss the experimental evidence that connects mitochondrial dysfunction to muscle wasting in specific diseases (i.e., cancer and sepsis), aging, cancer chemotherapy, and prolonged muscle inactivity (e.g., limb immobilization). Finally, in hopes of stimulating future research, we conclude with a discussion of important future directions for research in the field of muscle wasting.

Angiotensin 1-7 protects against ventilator-induced diaphragm dysfunction.

Mechanical ventilation (MV) is a life-saving instrument used to provide ventilatory support for critically ill patients and patients undergoing surgery. Unfortunately, an unintended consequence of prolonged MV is the development of inspiratory weakness due to both diaphragmatic atrophy and contractile dysfunction; this syndrome is labeled ventilator-induced diaphragm dysfunction (VIDD). VIDD is clinically important because diaphragmatic weakness is an important contributor to problems in weaning patients from MV. Investigations into the pathogenesis of VIDD reveal that oxidative stress is essential for the rapid development of VIDD as redox disturbances in diaphragm fibers promote accelerated proteolysis. Currently, no standard treatment exists to prevent VIDD and, therefore, developing a strategy to avert VIDD is vital. Guided by evidence indicating that activation of the classical axis of the renin-angiotensin system (RAS) in diaphragm fibers promotes oxidative stress and VIDD, we hypothesized that activation of the nonclassical RAS signaling pathway via angiotensin 1-7 (Ang1-7) will protect against VIDD. Using an established animal model of prolonged MV, our results disclose that infusion of Ang1-7 protects the diaphragm against MV-induced contractile dysfunction and fiber atrophy in both fast and slow muscle fibers. Further, Ang1-7 shielded diaphragm fibers against MV-induced mitochondrial damage, oxidative stress, and protease activation. Collectively, these results reveal that treatment with Ang1-7 protects against VIDD, in part, due to diminishing oxidative stress and protease activation. These important findings provide robust evidence that Ang1-7 has the therapeutic potential to protect against VIDD by preventing MV-induced contractile dysfunction and atrophy of both slow and fast muscle fibers.

KRAS drives immune evasion in a genetic model of pancreatic cancer.

Immune evasion is a hallmark of KRAS-driven cancers, but the underlying causes remain unresolved. Here, we use a mouse model of pancreatic ductal adenocarcinoma to inactivate KRAS by CRISPR-mediated genome editing. We demonstrate that at an advanced tumor stage, dependence on KRAS for tumor growth is reduced and is manifested in the suppression of antitumor immunity. KRAS-deficient cells retain the ability to form tumors in immunodeficient mice. However, they fail to evade the host immune system in syngeneic wild-type mice, triggering strong antitumor response. We uncover changes both in tumor cells and host immune cells attributable to oncogenic KRAS expression. We identify BRAF and MYC as key mediators of KRAS-driven tumor immune suppression and show that loss of BRAF effectively blocks tumor growth in mice. Applying our results to human PDAC we show that lowering KRAS activity is likewise associated with a more vigorous immune environment.

The Role of Calpains in Skeletal Muscle Remodeling with Exercise and Inactivity-induced Atrophy.

Calpains are cysteine proteases expressed in skeletal muscle fibers and other cells. Although calpain was first reported to act as a kinase activating factor in skeletal muscle, the consensus is now that calpains play a canonical role in protein turnover. However, recent evidence reveals new and exciting roles for calpains in skeletal muscle. This review will discuss the functions of calpains in skeletal muscle remodeling in response to both exercise and inactivity-induced muscle atrophy. Calpains participate in protein turnover and muscle remodeling by selectively cleaving target proteins and creating fragmented proteins that can be further degraded by other proteolytic systems. Nonetheless, an often overlooked function of calpains is that calpain-mediated cleavage of proteins can result in fragmented proteins that are biologically active and have the potential to actively influence cell signaling. In this manner, calpains function beyond their roles in protein turnover and influence downstream signaling effects. This review will highlight both the canonical and noncanonical roles that calpains play in skeletal muscle remodeling including sarcomere transformation, membrane repair, triad junction formation, regulation of excitation-contraction coupling, protein turnover, cell signaling, and mitochondrial function. We conclude with a discussion of key unanswered questions regarding the roles that calpains play in skeletal muscle.

Comparative single-cell RNA sequencing (scRNA-seq) reveals liver metastasis-specific targets in a patient with small intestinal neuroendocrine cancer.

Genomic analysis of a patient's tumor is the cornerstone of precision oncology, but it does not address whether metastases should be treated differently. Here we tested whether comparative single-cell RNA sequencing (scRNA-seq) of a primary small intestinal neuroendocrine tumor to a matched liver metastasis could guide the treatment of a patient's metastatic disease. Following surgery, the patient was put on maintenance treatment with a somatostatin analog. However, the scRNA-seq analysis revealed that the neuroendocrine epithelial cells in the liver metastasis were less differentiated and expressed relatively little SSTR2, the predominant somatostatin receptor. There were also differences in the tumor microenvironments. RNA expression of vascular endothelial growth factors was higher in the primary tumor cells, reflected by an increased number of endothelial cells. Interestingly, vascular expression of the major VEGF receptors was considerably higher in the liver metastasis, indicating that the metastatic vasculature may be primed for expansion and susceptible to treatment with angiogenesis inhibitors. The patient eventually progressed on Sandostatin, and although consideration was given to adding an angiogenesis inhibitor to her regimen, her disease progression involved non-liver metastases that had not been characterized. Although in this specific case comparative scRNA-seq did not alter treatment, its potential to help guide therapy of metastatic disease was clearly demonstrated.

The COVID-19 pandemic and physical activity.

The SARS-CoV-2-caused COVID-19 pandemic has resulted in a devastating threat to human society in terms of health, economy, and lifestyle. Although the virus usually first invades and infects the lung and respiratory track tissue, in extreme cases, almost all major organs in the body are now known to be negatively impacted often leading to severe systemic failure in some people. Unfortunately, there is currently no effective treatment for this disease. Pre-existing pathological conditions or comorbidities such as age are a major reason for premature death and increased morbidity and mortality. The immobilization due to hospitalization and bed rest and the physical inactivity due to sustained quarantine and social distancing can downregulate the ability of organs systems to resist to viral infection and increase the risk of damage to the immune, respiratory, cardiovascular, musculoskeletal systems and the brain. The cellular mechanisms and danger of this "second wave" effect of COVID-19 to the human body, along with the effects of aging, proper nutrition, and regular physical activity, are reviewed in this article.

Identification of targetable BRAF ΔN486_P490 variant by whole-genome sequencing leading to dabrafenib-induced remission of a BRAF-mutant pancreatic adenocarcinoma.

The tumor genome of a patient with advanced pancreatic cancer was sequenced to identify potential therapeutic targetable mutations after standard of care failed to produce any significant overall response. Matched tumor-normal whole-genome sequencing revealed somatic mutations in BRAF, TP53, CDKN2A, and a focal deletion of SMAD4 The BRAF variant was an in-frame deletion mutation (ΔN486_P490), which had been previously demonstrated to be a kinase-activating alteration in the BRAF kinase domain. Working with the Novartis patient assistance program allowed us to treat the patient with the BRAF inhibitor, dabrafenib. The patient's overall clinical condition improved dramatically with dabrafenib. Levels of serum tumor marker dropped immediately after treatment, and a subsequent CT scan revealed a significant decrease in the size of both primary and metastatic lesions. The dabrafenib-induced remission lasted for 6 mo. Preclinical studies published concurrently with the patient's treatment showed that the BRAF in-frame mutation (ΔNVTAP) induces oncogenic activation by a mechanism distinct from that induced by V600E, and that this difference dictates the responsiveness to different BRAF inhibitors. This study describes a dramatic instance of how high-level genomic technology and analysis was necessary and sufficient to identify a clinically logical treatment option that was then utilized and shown to be of clinical value for this individual.

Screening Family and Psychosocial Risk in Pediatric Migraine and Tension-Type Headache: Validation of the Psychosocial Assessment Tool (PAT).

OBJECTIVE: To present data on psychometric properties of the Psychosocial Assessment Tool 2.0_General (PAT), a brief screener for psychosocial risk in families of youth with medical conditions, in youth with headache. BACKGROUND: Emotional and behavioral disturbances, parent distress, and poor family functioning are common among youth with recurrent migraine and tension-type headache; however, tools to comprehensively screen family and psychosocial risk in youth with headache are not currently available. The PAT could address an important gap by facilitating identification of psychosocial treatment needs among youth with headache. DESIGN AND METHODS: Youth with recurrent migraine (with and without aura; chronic migraine) or tension-type headache (episodic and chronic) completed the PAT and validated measures of adolescent emotional and behavioral functioning, parent emotional functioning, and family functioning at baseline (n = 239; 157 from neurology clinic, 82 from the community) and 6-month follow-up (n = 221; 146 from neurology clinic, 75 from the community). RESULTS: Internal consistency for the PAT Total score was strong (α = .88). At baseline, the PAT Total score was significantly associated in the expected direction with established measures of child emotional and behavioral functioning (r = .62), parent anxiety and depressive symptoms (r = .49; r = .53, respectively), and family functioning (r = .21). Predictive validity was demonstrated by a significant association between PAT Total scores at baseline with child emotional and behavioral functioning (r = .64), parent anxiety (r = .37), parent depression (r = .42), and family functioning (r = .26) at 6-month follow-up. CONCLUSIONS: The PAT is a promising tool for screening psychosocial risk that could facilitate identification of psychosocial treatment needs among youth with recurrent headache at risk for poor outcomes.

Effects of exercise preconditioning and HSP72 on diaphragm muscle function during mechanical ventilation.

BACKGROUND: Mechanical ventilation (MV) is a life-saving measure for patients in respiratory failure. However, prolonged MV results in significant diaphragm atrophy and contractile dysfunction, a condition referred to as ventilator-induced diaphragm dysfunction (VIDD). While there are currently no clinically approved countermeasures to prevent VIDD, increased expression of heat shock protein 72 (HSP72) has been demonstrated to attenuate inactivity-induced muscle wasting. HSP72 elicits cytoprotection via inhibition of NF-κB and FoxO transcriptional activity, which contribute to VIDD. In addition, exercise-induced prevention of VIDD is characterized by an increase in the concentration of HSP72 in the diaphragm. Therefore, we tested the hypothesis that increased HSP72 expression is required for the exercise-induced prevention of VIDD. We also determined whether increasing the abundance of HSP72 in the diaphragm, independent of exercise, is sufficient to prevent VIDD. METHODS: Cause and effect was determined by inhibiting the endurance exercise-induced increase in HSP72 in the diaphragm of exercise trained animals exposed to prolonged MV via administration of an antisense oligonucleotide targeting HSP72. Additional experiments were performed to determine if increasing HSP72 in the diaphragm via genetic (rAAV-HSP72) or pharmacological (BGP-15) overexpression is sufficient to prevent VIDD. RESULTS: Our results demonstrate that the exercise-induced increase in HSP72 protein abundance is required for the protective effects of exercise against VIDD. Moreover, both rAAV-HSP72 and BGP-15-induced overexpression of HSP72 were sufficient to prevent VIDD. In addition, modification of HSP72 in the diaphragm is inversely related to the expression of NF-κB and FoxO target genes. CONCLUSIONS: HSP72 overexpression in the diaphragm is an effective intervention to prevent MV-induced oxidative stress and the transcriptional activity of NF-κB and FoxO. Therefore, overexpression of HSP72 in the diaphragm is a potential therapeutic target to protect against VIDD.

Challenges in Ras therapeutics in pancreatic cancer.

Pancreatic cancer is considered among the most aggressive and the least curable of all human malignancies. It is usually characterized by multiple aberrations in tumor suppressor genes and oncogenes, most notably activating mutations in KRAS. This review examines the various attempts that have been made to inhibit Kras and its downstream signaling pathways in pancreatic cancer with an emphasis on challenges related to clinical trials. Attempts include preventing the localization of Ras protein to the plasma membrane, inhibiting downstream oncogenic signaling by targeting Kras effectors such as MEK1/2, Erk1/2 or Akt singly or in combination, and directly inhibiting Kras protein. Most clinical trials have focused on inhibiting downstream effector pathways and clinical benefit has been limited due to compensatory mechanisms and toxicity associated with small therapeutic windows. Additionally, genetic screens have been conducted to identify gene or genes that could provide therapeutic vulnerabilities in mutant KRAS cells and provide a way to target mutant Kras protein only. We also discuss how potentially transforming clinical trials have failed in the past and what new strategies are on-going in clinical trials for pancreas cancer. For long-term success in targeting Kras, future efforts should focus on combinatorial strategies to more effectively block Kras pathways at multiple points, and improve translational application of pre-clinical data to the clinic.

Evaluating disease prediction models using a cohort whose covariate distribution differs from that of the target population.

Personal predictive models for disease development play important roles in chronic disease prevention. The performance of these models is evaluated by applying them to the baseline covariates of participants in external cohort studies, with model predictions compared to subjects' subsequent disease incidence. However, the covariate distribution among participants in a validation cohort may differ from that of the population for which the model will be used. Since estimates of predictive model performance depend on the distribution of covariates among the subjects to which it is applied, such differences can cause misleading estimates of model performance in the target population. We propose a method for addressing this problem by weighting the cohort subjects to make their covariate distribution better match that of the target population. Simulations show that the method provides accurate estimates of model performance in the target population, while un-weighted estimates may not. We illustrate the method by applying it to evaluate an ovarian cancer prediction model targeted to US women, using cohort data from participants in the California Teachers Study. The methods can be implemented using open-source code for public use as the R-package RMAP (Risk Model Assessment Package) available at http://stanford.edu/~ggong/rmap/ .

Endurance exercise protects skeletal muscle against both doxorubicin-induced and inactivity-induced muscle wasting.

Repeated bouts of endurance exercise promotes numerous biochemical adaptations in skeletal muscle fibers resulting in a muscle phenotype that is protected against a variety of homeostatic challenges; these exercise-induced changes in muscle phenotype are often referred to as "exercise preconditioning." Importantly, exercise preconditioning provides protection against several threats to skeletal muscle health including cancer chemotherapy (e.g., doxorubicin) and prolonged muscle inactivity. This review summarizes our current understanding of the mechanisms responsible for exercise-induced protection of skeletal muscle fibers against both doxorubicin-induced muscle wasting and a unique form of inactivity-induced muscle atrophy (i.e., ventilator-induced diaphragm atrophy). Specifically, the first section of this article will highlight the potential mechanisms responsible for exercise-induced protection of skeletal muscle fibers against doxorubicin-induced fiber atrophy. The second segment will discuss the biochemical changes that are responsible for endurance exercise-mediated protection of diaphragm muscle against ventilator-induced diaphragm wasting. In each section, we highlight gaps in our knowledge in hopes of stimulating future research in this evolving field of investigation.

Long-term outcomes of adolescents with juvenile-onset fibromyalgia into adulthood and impact of depressive symptoms on functioning over time.

Juvenile-onset fibromyalgia (JFM) is typically diagnosed in adolescence and characterized by widespread pain and marked functional impairment. The long-term impact of JFM into adulthood is poorly understood. The objectives of this study were to describe physical and psychosocial outcomes of youth diagnosed with JFM in early adulthood (∼8-year follow-up), examine longitudinal trajectories of pain and depressive symptoms from adolescence to young adulthood, and examine the impact of pain and depressive symptoms on physical functioning over time. Participants were 97 youth with JFM enrolled in a prospective longitudinal study in which pain symptoms, and physical and psychosocial functioning were assessed at 4 time points over approximately 8 years. At the time 4 follow-up (Mage = 24.2 years), the majority continued to suffer from pain and impairment in physical, social, and psychological domains. However, trajectories of pain and emotional symptoms showed varying patterns. Longitudinal analysis using growth mixture modeling revealed 2 pain trajectories (Steady Improvement and Rapid Rebounding Improvement), whereas depressive symptoms followed 3 distinct trajectories (Low-Stable, Improving, and Worsening). Membership in the Worsening Depressive symptoms group was associated with poorer physical functioning over time (P < 0.001) compared with the Low-Stable and Improving groups. This study offers evidence that although JFM symptoms persist for most individuals, pain severity tends to decrease over time. However, depressive symptoms follow distinct trajectories that indicate subgroups of JFM. In particular, JFM patients with worsening depressive symptoms showed decreasing physical functioning and may require more intensive and consistent intervention to prevent long-term disability.