Small airway fibroblasts from patients with chronic obstructive pulmonary disease exhibit cellular senescence.

Small airway disease (SAD) is a key early-stage pathology of chronic obstructive pulmonary disease (COPD). COPD is associated with cellular senescence whereby cells undergo growth arrest and express the senescence-associated secretory phenotype (SASP) leading to chronic inflammation and tissue remodeling. Parenchymal-derived fibroblasts have been shown to display senescent properties in COPD, however small airway fibroblasts (SAFs) have not been investigated. Therefore, this study investigated the role of these cells in COPD and their potential contribution to SAD. To investigate the senescent and fibrotic phenotype of SAF in COPD, SAFs were isolated from nonsmoker, smoker, and COPD lung resection tissue (n = 9-17 donors). Senescence and fibrotic marker expressions were determined using iCELLigence (proliferation), qPCR, Seahorse assay, and ELISAs. COPD SAFs were further enriched for senescent cells using FACSAria Fusion based on cell size and autofluorescence (10% largest/autofluorescent vs. 10% smallest/nonautofluorescent). The phenotype of the senescence-enriched population was investigated using RNA sequencing and pathway analysis. Markers of senescence were observed in COPD SAFs, including senescence-associated ß-galactosidase, SASP release, and reduced proliferation. Because the pathways driving this phenotype were unclear, we used cell sorting to enrich senescent COPD SAFs. This population displayed increased p21CIP1 and p16INK4a expression and mitochondrial dysfunction. RNA sequencing suggested these senescent cells express genes involved in oxidative stress response, fibrosis, and mitochondrial dysfunction pathways. These data suggest COPD SAFs are senescent and may be associated with fibrotic properties and mitochondrial dysfunction. Further understanding of cellular senescence in SAFs may lead to potential therapies to limit SAD progression.NEW & NOTEWORTHY Fibroblasts and senescence are thought to play key roles in the pathogenesis of small airway disease and COPD; however, the characteristics of small airway-derived fibroblasts are not well explored. In this study we isolate and enrich the senescent small airway-derived fibroblast (SAF) population from COPD lungs and explore the pathways driving this phenotype using bulk RNA-seq.

Pan-antiviral effects of a PIKfyve inhibitor on respiratory virus infection in human nasal epithelium and mice.

Endocytosis, or internalization through endosomes, is a major cell entry mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a critical enzyme for the synthesis of phosphatidylinositol (3, 5)biphosphate (PtdIns (3, 5)P2) and has been implicated in virus trafficking via the endocytic pathway. In fact, antiviral effects of PIKfyve inhibitors against SARS-CoV-2 and Ebola have been reported, but there is little evidence regarding other respiratory viruses. In this study, we demonstrated the antiviral effects of PIKfyve inhibitors on influenza virus and respiratory syncytial virus in vitro and in vivo. PIKfyve inhibitors Apilimod mesylate (AM) and YM201636 concentration-dependently inhibited several influenza strains in an MDCK cell-cytopathic assay. AM also reduced the viral load and cytokine release, while improving the cell integrity of human nasal air-liquid interface cultured epithelium infected with influenza PR8. In PR8-infected mice, AM (2 mg/mL), when intranasally treated, exhibited a significant reduction of viral load and inflammation and inhibited weight loss caused by influenza infection, with effects being similar to oral oseltamivir (10 mg/kg). In addition, AM demonstrated antiviral effects in RSV A2-infected human nasal epithelium in vitro and mouse in vivo, with an equivalent effect to that of ribavirin. AM also showed antiviral effects against human rhinovirus and seasonal coronavirus in vitro. Thus, PIKfyve is found to be involved in influenza and RSV infection, and PIKfyve inhibitor is a promising molecule for a pan-viral approach against respiratory viruses.

Diagnostic efficacy of image-guided core needle biopsy of suspected malignant osseous lesions: a retrospective cohort study from a single academic institution.

OBJECTIVES: To evaluate diagnostic yield and accuracy of image-guided core needle biopsy (ICNB) of suspected malignant osseous lesions in a large cohort of adults, evaluate what factors influence these measures, and offer technical recommendations to optimize yield. METHODS: A retrospective analysis of 2321 ICNBs performed from 2010 to 2021 was completed. The diagnostic yield and accuracy of the biopsies as well as a series of patient, lesion-related, and technical factors were retrospectively analyzed. Multivariate statistical analysis was performed to evaluate what factors were associated with yield and accuracy. Different cutoff values of total core length and core number were then tested to determine threshold values in relation to increased diagnostic yield. RESULTS: Diagnostic yield was 98.2% (2279/2321) and accuracy was 97.6% (120/123). Increased total core length (odds ratio [OR] = 2.34, 95% confidence interval [CI] (1.41-3.90), p = 0.001), core number (OR = 1.51, 95% CI (1.06-2.16), p = 0.02) and presence of primary malignancy (OR = 2.81, 95% CI (1.40-5.62), p = 0.004) were associated with improved yield. Lesion location in an extremity (OR = 0.27, 95% CI (0.11-0.68), p = 0.006) and using fluoroscopic imaging guidance (OR = 0.33, 95% CI (0.12-0.90), p = 0.03) were associated with lower yield. Cutoff thresholds in relation to increased diagnostic yield were found to be 20 mm total core length (marginal OR = 4.16, 95% CI = (2.09-9.03), p < 0.001), and three total cores obtained (marginal OR = 2.78, 95% CI (1.34-6.54), p = 0.005). None of the analyzed factors influenced diagnostic accuracy. CONCLUSIONS: ICNB has a high rate of diagnostic yield and accuracy. Several factors influence diagnostic yield; 20 mm core length and three total cores optimize yield. CLINICAL RELEVANCE STATEMENT: Image-guided core needle biopsy of suspected malignant osseous lesions is a safe procedure with a very high rate of diagnostic yield and accuracy. Obtaining 20 mm total core length and three total cores optimizes diagnostic yield. KEY POINTS: • In a retrospective cohort study, image-guided core needle biopsy of suspected osseous malignant lesions in adults was found to have very high rates of diagnostic yield and accuracy. • Increased total core length and core number of biopsies were each associated with increased diagnostic yield, and these relationships reached thresholds at 20 mm total core length and three total cores obtained. • The presence of a known primary malignancy was also associated with increased yield while using fluoroscopic imaging guidance and lesion location in an extremity were associated with decreased yield.

Observed mechanisms activating the recent subpolar North Atlantic Warming since 2016.

The overturning circulation of the subpolar North Atlantic (SPNA) plays a fundamental role in Earth's climate variability and change. Here, we show from observations that the recent warming period since about 2016 in the eastern SPNA involves increased western boundary density at the intergyre boundary, likely due to enhanced buoyancy forcing as a response to the strong increase in the North Atlantic Oscillation since the early 2010s. As these deep positive density anomalies spread southward along the western boundary, they enhance the North Atlantic Current and associated meridional heat transport at the intergyre region, leading to increased influx of subtropical heat into the eastern SPNA. Based on the timing of this chain of events, we conclude that this recent warming phase since about 2016 is primarily associated with this observed mechanism of changes in deep western boundary density, an essential element in these interactions. This article is part of a discussion meeting issue 'Atlantic overturning: new observations and challenges'.

Shared Decision-Making Experiences of Couples with Inherited Cancer Risk Regarding Family Building.

Patients with hereditary cancer predisposition syndromes have a high likelihood of passing germline mutations to future offspring. Patients at risk for inherited cancer may not have started and/or completed building their families; thus, they must decide about having children and consider the possibility of passing on their germline mutation. Utilizing the Shared Decision Making (SDM) Model, this study explores family building decision-making communication processes in opposite-sex couples with inherited cancer risk (ICR). Fifteen couples completed two recorded, analogue discussions and dyadic interviews at two time points. Participants were recruited through social media and snowball sampling. The constant comparison method was utilized to thematically analyze the data. When couples discussed family building options (FBOs), several themes were identified: FBO risks, FBO considerations, genetic-related FBO logistics, and life FBOs logistics. When deliberating family building decisions, couples shared easy conversational topics (e.g. FBO options and potential child's cancer risk due to a genetic variant) and difficult/conflict-inducing topics (e.g. preparing for possibilities, parenting, emotions, finances, and timing). Last, couples self-reported primary and secondary FBOs. The findings of this study capture couples' decision-making communication process while considering their experiences. Clinicians and practitioners can utilize these findings to support couples' family building decisions considering their ICR.

Timing and structure of the Younger Dryas event and its underlying climate dynamics.

The Younger Dryas (YD), arguably the most widely studied millennial-scale extreme climate event, was characterized by diverse hydroclimate shifts globally and severe cooling at high northern latitudes that abruptly punctuated the warming trend from the last glacial to the present interglacial. To date, a precise understanding of its trigger, propagation, and termination remains elusive. Here, we present speleothem oxygen-isotope data that, in concert with other proxy records, allow us to quantify the timing of the YD onset and termination at an unprecedented subcentennial temporal precision across the North Atlantic, Asian Monsoon-Westerlies, and South American Monsoon regions. Our analysis suggests that the onsets of YD in the North Atlantic (12,870 ± 30 B.P.) and the Asian Monsoon-Westerlies region are essentially synchronous within a few decades and lead the onset in Antarctica, implying a north-to-south climate signal propagation via both atmospheric (decadal-time scale) and oceanic (centennial-time scale) processes, similar to the Dansgaard-Oeschger events during the last glacial period. In contrast, the YD termination may have started first in Antarctica at ∼11,900 B.P., or perhaps even earlier in the western tropical Pacific, followed by the North Atlantic between ∼11,700 ± 40 and 11,610 ± 40 B.P. These observations suggest that the initial YD termination might have originated in the Southern Hemisphere and/or the tropical Pacific, indicating a Southern Hemisphere/tropics to North Atlantic-Asian Monsoon-Westerlies directionality of climatic recovery.

How Individuals Use Metaphors to Negotiate Fertility Treatment Decision-Making with Their Romantic Partners.

Fertility problems, or the inability to conceive or carry a pregnancy to term for a period of over 12 months while engaging in unprotected sex, affects 12% of women and 9% of men of childbearing age. To answer calls for more research about individuals' fertility decision-making (DM) with their partners, we conducted in-depth, semi-structured interviews with 53 individuals who have experienced fertility decision-making with a romantic partner at some point in their lives. Our findings indicate at least three primary ways individuals and their partners navigated their decision-making communication in their infertility "journeys:" (1) the Driver-Navigator, (2) Driver-Passenger, and (3) Driver-Backseat Driver approaches. All decision-making communication approaches were viewed by individuals as collaborative (i.e. shared), but varied in degrees of "togetherness" (high, moderate, low) in how they communicated with each other about treatment decisions. Implications include helping couples and their clinicians to be aware of their DM approach(es) and offering alternative DM approaches based on understanding how and why certain approaches may (not) be effective in addressing goals, needs, and identities.

Making Sense of Memorable Messages About Infertility: Examining Message Valence by Theme and Sender.

Fertility problems, often called infertility, have been defined as the inability to conceive or maintain pregnancy throughout one year of trying (World Health Organization, 2020). Because fertility problems can present unique medical, emotional, relational, and identity challenges, they are often difficult to talk about, and even well-intentioned messages can be perceived negatively. This study uses Communicated Sense-Making (CSM; Kellas & Kranstuber Horstman, 2015), particularly its mechanism of memorable messages, to explore what types of support-related messages people experiencing infertility find memorable. Results from semi-structured interviews (N = 54) indicate five supra-themes of memorable messages: (a) communicating solidarity; (b) attempting to minimize participants' stress; (c) communicating investment or interest in the patient's experience; (d) sharing expertise; and (e) absolving the patient of responsibility; we identify several sub-themes within each. We also explore patterns between message types, senders, and message valence: message themes were perceived as either positive, negative, or neutral based on the combination of sender and perceived intention. Theoretical and practical implications are discussed.

An update on expanding HIV preexposure prophylaxis.

ABSTRACT: HIV continues to affect certain populations disproportionately, including sexual and gender minorities, racial/ethnic minorities, and populations with limited resources in southern US states. New CDC guidelines include a recommendation to discuss HIV preexposure prophylaxis (PrEP) with all sexually active patients, which is likely to expand use. The guidelines also include important changes in PrEP monitoring and address PrEP telehealth. The FDA approved the first non-oral PrEP, long-acting injectable cabotegravir, in late 2021. However, PrEP continues to be underused. This article describes how to better employ PrEP in light of these recent significant changes.

Xanthogranulomatous epithelial tumors and keratin-positive giant cell-rich soft tissue tumors: two aspects of a single entity with frequent HMGA2-NCOR2 fusions.

Xanthogranulomatous epithelial tumor (XGET) and keratin-positive giant cell-rich soft tissue tumor with HMGA2-NCOR2 fusion (KPGCT) are two recently described neoplasms with both distinct and overlapping clinical and histopathologic features. We hypothesized that XGET and KPGCT may be related and represent a histologic spectrum of a single entity. To test this, we sought to characterize the clinical, radiographic, immunohistochemical, ultrastructural and molecular features of additional tumors with features of XGET and/or KPGCT, which we refer to descriptively as keratin-positive xanthogranulomatous/giant cell-rich tumors (KPXG/GCT). The archives were searched for potential cases of KPXG/GCT. Clinical and imaging features were noted. Slides were assessed for histologic and immunohistochemical findings. Ultrastructural and next generation RNA sequencing-based analysis were also performed. Nine cases were identified arising in seven women and two men [median age of 33 years (range: 12-87)]. Median tumor size was 4 cm (range: 2.4-14.0 cm) and tumors presented in the thigh (2), buttock (1), forearm (2), groin (1), cranial fossa (1), ilium (1), and tibia (1). Morphologically, tumors were most frequently characterized by a fibrous capsule, with associated lymphoid reaction, enclosing a polymorphous proliferation of histiocytes, giant cells (Touton and osteoclast-types), mixed inflammatory infiltrate, hemorrhage and hemosiderin deposition, which imparted a variably xanthogranulomatous to giant cell tumor-like appearance. One case clearly showed mononuclear cells with eosinophilic cytoplasm characteristic of XGET. All cases expressed keratin and 7 of 9 were found to harbor HMGA2-NCOR2 fusions including cases with xanthogranulomatous appearance. One patient developed local recurrence and multifocal pulmonary lesions, which were radiographically suspicious for metastases. Shared clinical, histologic and immunohistochemical features, and the shared presence of HMGA2-NCOR2 fusions supports interpretation of KPXG/GCT as a single entity which includes XGET and KPGCT. Given limited clinical follow-up to date and rare cases with apparently aggressive findings, we provisionally regard these tumors as having uncertain biologic potential.

Autophagy in asthma and chronic obstructive pulmonary disease.

Autophagy (or macroautophagy) is a key cellular process that removes damaged molecules (particularly proteins) and subcellular organelles to maintain cellular homeostasis. There is growing evidence that abnormalities in autophagy may contribute to the pathogenesis of many chronic diseases, including asthma and chronic obstructive pulmonary disease (COPD). In asthma, increased autophagy plays a role in promoting type 2 immune responses and eosinophilic inflammation, whereas decreased autophagy may be important in neutrophilic asthma. Acute exposure to cigarette smoke may activate autophagy, resulting in ciliary dysfunction and death of airway epithelial cells, whereas in stable COPD most studies have demonstrated an impairment in autophagy, with reduced autophagic flux and accumulation of abnormal mitochondria (defective mitophagy) and linked to cellular senescence. Autophagy may be increased or decreased in different cell types and depending on the cellular environment, making it difficult to target autophagy therapeutically. Several existing drugs may activate autophagy, including rapamycin, metformin, carbamazepine, cardiac glycosides and statins, whereas others, such as chloroquine, inhibit this process. However, these drugs are nonspecific and more selective drugs are now in development, which may prove useful as novel agents to treat asthma and COPD in the future.

Hepcidin Is Essential for Alveolar Macrophage Function and Is Disrupted by Smoke in a Murine Chronic Obstructive Pulmonary Disease Model.

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease associated with cigarette smoking. Alterations in local lung and systemic iron regulation are associated with disease progression and pathogenesis. Hepcidin, an iron regulatory peptide hormone, is altered in subjects with COPD; however, the molecular role of hepcidin in COPD pathogenesis remains to be determined. In this study, using a murine model of smoke-induced COPD, we demonstrate that lung and circulating hepcidin levels are inhibited by cigarette smoke. We show that cigarette smoke exposure increases erythropoietin and bone marrow-derived erythroferrone and leads to expanded but inefficient erythropoiesis in murine bone marrow and an increase in ferroportin on alveolar macrophages (AMs). AMs from smokers and subjects with COPD display increased expression of ferroportin as well as hepcidin. Notably, murine AMs exposed to smoke fail to increase hepcidin in response to Gram-negative or Gram-positive infection. Loss of hepcidin in vivo results in blunted functional responses of AMs and exaggerated responses to Streptococcus pneumoniae infection.

Autotrophic lactate production from H2 + CO2 using recombinant and fluorescent FAST-tagged Acetobacterium woodii strains.

Lactate has various uses as industrial platform chemical, poly-lactic acid precursor or feedstock for anaerobic co-cultivations. The aim of this study was to construct and characterise Acetobacterium woodii strains capable of autotrophic lactate production. Therefore, the lctBCD genes, encoding the native Lct dehydrogenase complex, responsible for lactate consumption, were knocked out. Subsequently, a gene encoding a D-lactate dehydrogenase (LDHD) originating from Leuconostoc mesenteroides was expressed in A. woodii, either under the control of the anhydrotetracycline-inducible promoter Ptet or under the lactose-inducible promoter PbgaL. Moreover, LDHD was N-terminally fused to the oxygen-independent fluorescence-activating and absorption-shifting tag (FAST) and expressed in respective A. woodii strains. Cells that produced the LDHD fusion protein were capable of lactate production of up to 18.8 mM in autotrophic batch experiments using H2 + CO2 as energy and carbon source. Furthermore, cells showed a clear and bright fluorescence during exponential growth, as well as in the stationary phase after induction, mediated by the N-terminal FAST. Flow cytometry at the single-cell level revealed phenotypic heterogeneities for cells expressing the FAST-tagged LDHD fusion protein. This study shows that FAST provides a new reporter tool to quickly analyze gene expression over the course of growth experiments of A. woodii. Consequently, fluorescence-based reporters allow for faster and more targeted optimization of production strains.Key points •Autotrophic lactate production was achieved with A. woodii. •FAST functions as fluorescent marker protein in A. woodii. •Fluorescence measurements on single-cell level revealed population heterogeneity.

The pivot fracture: an unusual tibial plateau fracture found in association with acute ACL injury.

Tibial plateau fractures are common fractures which are often associated with concurrent soft tissue injury and for which accurate preoperative diagnosis is important for development of an appropriate treatment plan and outcome prediction. Here, we present an extreme manifestation of the pivot shift phenomenon with an unusual tibial plateau fracture with flipped component not described by any existing tibial plateau fracture classification system and never reported previously in conjunction with an anterior cruciate ligament injury. We describe the utilization of advanced imaging not typically utilized in the management of tibial plateau fractures in combination with clinical suspicion to diagnose the associated soft tissue injuries and develop an appropriate management plan.

Three-Column Classification System for Tibial Plateau Fractures: What the Orthopedic Surgeon Wants to Know.

Recent orthopedic surgical literature emphasizes a three-column approach to understand and guide the treatment of tibial plateau fractures. This three-column classification system published in 2010 relies on preoperative CT images to depict injuries to the medial, lateral, and posterior columns of the tibial plateau and improves surgical outcomes in complex tibial plateau fractures with coronal fracture planes and posterior plateau fracture fragments requiring dorsal plating. Tibial plateau fracture classification systems traditionally used by radiologists and orthopedic surgeons, including the Schatzker and the Arbeitsgemeinschaft für Osteosynthesefragen-Orthopedic Trauma Association (AO-OTA) classification systems, rely on findings at anteroposterior radiography and lack the terminology to accurately characterize fractures in the coronal plane involving the posterior tibial plateau. Incorporating elements from the contemporary three-column classification system into radiology reports will enhance radiologists' descriptions of these injuries. It is essential for radiologists to understand the role of clinical assessment and the pertinent imaging findings taken into consideration by orthopedic surgeons in their management of these injuries. This understanding includes familiarity with injury patterns and how they relate to mechanism of injury, patient demographics, and underlying pertinent comorbidities. Evaluating findings on initial radiographs is the basis of tibial plateau fracture diagnosis. Additional information provided by preoperative cross-sectional imaging, including two-dimensional and three-dimensional CT and MRI in specific circumstances, aids in the identification of specific soft-tissue injuries and fracture morphologies that influence surgical management. These specific fracture morphologies and soft-tissue injuries should be identified and communicated to orthopedic surgeons for optimal patient management. Online DICOM image stacks are available for this article. ©RSNA, 2020.

Implementation of multidisciplinary reflective rounds within a children's hospital before and during the COVID-19 pandemic.

AIM: Regular reflective practice within a large group setting has been shown to reduce levels of burnout in healthcare professionals. We describe how regular reflective rounds were designed and implemented within an existing educational program at a UK children's hospital and report on the feedback received from participants. METHODS: Eight face-to-face reflective rounds took place in Southampton Children's Hospital, UK, from September 2017 to February 2020 with a further virtual round in July 2020 during the COVID-19 pandemic. Each round was facilitated by a clinical psychologist and consultant. For each round, up to three volunteer panellists from different staff groups were invited to share their personal experiences on a pre-selected subject to the large group. The group would then contribute to the discussion by offering their own reflections. Feedback forms were distributed to attendees and collated. RESULTS: Eight rounds were held with mean attendance of 32 (range 19-47). Across the eight rounds, the total attendance was 256 staff members. The virtual round had 20 participants. Feedback was received from 202 participants. The majority (98%) would recommend the rounds to colleagues with 64 participants (32%) rating the rounds as 'exceptional' and 91 (45%) as 'excellent'. The virtual round received similar positive feedback. CONCLUSION: Large group reflective practice can be implemented within an existing regular educational program. Rounds have been well received by participants and are likely to be of relevance and value to other healthcare groups. The rounds can also be delivered effectively virtually, which may increase participation.

Ulnar shaft stress fractures in fast-pitch softball pitchers: a case series and proposed mechanism of injury.

BACKGROUND: Stress fractures of the upper extremities in athletes are important injuries for radiologists to appreciate despite being far less common than stress fractures of the lower extremities. Among upper extremity stress fractures, those involving the olecranon have been well described in overhead pitching athletes. Isolated stress fractures of the ulnar shaft however are less commonly reported in the literature and considered to be rare. We have observed a correlation between young patients with ulnar shaft stress fractures and the activity of fast-pitch softball pitching. CASE REPORTS: In this series, we present the imaging findings in four cases of ulnar shaft stress fractures in softball pitchers who presented with insidious onset forearm pain. Furthermore, a review of the literature focusing on softball pitching mechanics is provided to offer a potential underlying mechanism for the occurrence and location of these injuries. CONCLUSION: An awareness of the imaging appearance of ulnar shaft stress fractures along with an understanding of its proposed mechanism will facilitate accurate and timely imaging diagnosis of this injury by the radiologist.

The diagnostic performance of MRI signs to distinguish Pectoralis major tendon avulsions from Myotendinous injuries.

BACKGROUND: Management of pectoralis major (PM) injuries is largely determined by the anatomic location of the injury, with tendon avulsions from the humerus requiring surgery while myotendinous (MT) injuries are typically managed non-operatively. Because physical examination cannot reliably make this distinction, MRI is often used for staging. However, correct classification can also be difficult with MRI where there is extensive soft tissue edema and distorted anatomy. OBJECTIVE: To determine the diagnostic performance of primary and secondary MRI signs of PM injury for distinguishing tendon avulsions from MT injuries in a selected sample of patients that underwent surgical repair using a practical interpretation algorithm. METHODS: In this retrospective study, 3 blinded observers independently assessed the MRI findings of 17 patients with PM injury (including 12 acute injuries, 4 chronic, and 1 of uncertain age) where subsequent surgery documented tendon avulsion (11) and MT injuries (6) by applying the primary MRI criteria of absent tendon at the humerus, retracted tendon stump, epicenter of edema, and the secondary finding of soft tissue edema contacting the anterior humeral cortex. Operative findings were used as the reference standard. Sensitivity, specificity, and positive and negative predictive value were recorded for each finding. RESULTS: The primary MRI finding of lack of a visible tendon at the insertion (sensitivity 82-100%, specificity 100%) and the secondary finding of edema contacting the anterior humeral cortex (sensitivity 64-91%, specificity 67-100%) were both useful for the distinction of tendon avulsion from MT injury, particularly in acute injuries. The presence of a retracted tendon stump and the epicenter of edema were not reliable findings. The use of a decision tree including the secondary finding of humeral edema increased the sensitivity and specificity for 2 of the 3 observers. CONCLUSION: MRI assessment of PM injury focused on the humeral insertion of the PM tendon allows accurate distinction of tendon avulsion from MT injury. CLINICAL IMPACT: This study describes a practical approach to classifying PM injuries with MRI to distinguish injuries that require surgery from those that can potentially be managed conservatively.

MicroRNA-570 is a novel regulator of cellular senescence and inflammaging.

Diseases of accelerated aging often occur together (multimorbidity), and their prevalence is increasing, with high societal and health care costs. Chronic obstructive pulmonary disease (COPD) is one such condition, in which one half of patients exhibit ≥4 age-related diseases. Diseases of accelerated aging share common molecular pathways, which lead to the detrimental accumulation of senescent cells. These senescent cells no longer divide but release multiple inflammatory proteins, known as the senescence-associated secretory phenotype, which may perpetuate and speed disease. Here, we show that inhibiting miR-570-3p, which is increased in COPD cells, reverses cellular senescence by restoring the antiaging molecule sirtuin-1. MiR-570-3p is induced by oxidative stress in airway epithelial cells through p38 MAP kinase-c-Jun signaling and drives senescence by inhibiting sirtuin-1. Inhibition of elevated miR-570-3p in COPD small airway epithelial cells, using an antagomir, restores sirtuin-1 and suppresses markers of cellular senescence (p16INK4a, p21Waf1, and p27Kip1), thereby restoring cellular growth by allowing progression through the cell cycle. MiR-570-3p inhibition also suppresses the senescence-associated secretory phenotype (matrix metalloproteinases-2/9, C-X-C motif chemokine ligand 8, IL-1ß, and IL-6). Collectively, these data suggest that inhibiting miR-570-3p rejuvenates cells via restoration of sirtuin-1, reducing many of the abnormalities associated with cellular senescence.-Baker, J. R., Vuppusetty, C., Colley, T., Hassibi, S., Fenwick, P. S., Donnelly, L. E., Ito, K., Barnes, P. J. MicroRNA-570 is a novel regulator of cellular senescence and inflammaging.

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases.

Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16INK4a, respectively, leading to activation of p21CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype, leading to low-grade chronic inflammation, which further drives senescence. Loss of key antiaging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN (phosphatase tensin homolog), thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a (miR-34a), which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6, and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing senescence-associated secretory phenotype, and reversing cell cycle arrest in epithelial cells from peripheral airways of patients with COPD. miR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 mitogen-activated protein kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but also outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs, or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.