USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration.

BACKGROUND: Breast cancer (BC) is the most frequent tumor entity in women worldwide with a high chance of therapeutic response in early- and non-metastatic disease stages. Among all BC subtypes, triple-negative BC (TNBC) is the most challenging cancer subtype lacking effective molecular targets due to the particular enrichment of cancer stem cells (CSCs), frequently leading to a chemoresistant phenotype and metastasis. The Ubiquitin Specific Peptidase 22 (USP22) is a deubiquitinase that has been frequently associated with a CSC-promoting function and intimately implicated in resistance to conventional therapies, tumor relapse, metastasis and overall poor survival in a broad range of cancer entities, including BC. To date, though, the role of USP22 in TNBC has been only superficially addressed. METHODS: The current study utilized the MMTV-cre, Usp22fl/fl transgenic mouse model to study the involvement of USP22 in the stem cell-like properties of the growing mammary tissue. Additionally, we combined high-throughput transcriptomic analyses with publicly available patient transcriptomic data and utilized TNBC culture models to decipher the functional role of USP22 in the CSC characteristics of this disease. RESULTS: Interestingly, we identified that USP22 promotes CSC properties and drug tolerance by supporting the oxidative phosphorylation program, known to be largely responsible for the poor response to conventional therapies in this particularly aggressive BC subtype. CONCLUSIONS: This study suggests a novel tumor-supportive role of USP22 in sustaining cellular respiration to facilitate the drug-tolerant behavior of HER2+-BC and TNBC cells. Therefore, we posit USP22 as a promising therapeutic target to optimize standard therapies and combat the aggressiveness of these malignancies. Video Abstract.

Loss of CASK Accelerates Heart Failure Development.

[Figure: see text].

Intramuscular blood flow in Duchenne and Becker Muscular Dystrophy: Quantitative power Doppler sonography relates to disease severity.

OBJECTIVE: Absent or truncated dystrophin in Duchenne (DMD) and Becker (BMD) muscular dystrophies results in impaired vasodilatory pathways and exercise induced muscle ischemia. Here, we used power Doppler sonography to quantify changes in intramuscular blood flow immediately following exercise in boys with D/BMD. METHOD: We quantified changes in intramuscular blood flow following exercise using power Doppler sonography in 14 boys with D/BMD and compared changes in muscle blood flow to disease severity and to historic controls. RESULT: Post exercise blood flow change in the anterior forearm muscles is lower in (1) DMD (median 0.25%; range -0.47 to 2.19%) than BMD (2.46%; 2.02-3.38%, p < 0.05) and historical controls (6.59%; 2.16-12.40%, p < 0.01); (2) in non-ambulatory (0.04%; -0.47 to 0.10%) than ambulatory DMD boys (0.71%; 0.07-2.19%, p < 0.05); and (3) in muscle with higher echointensity (rs = -0.7253, p = 0.005). The tibialis anterior showed similar findings. We estimate that a single sample clinical trial would require 19 subjects to detect a doubling of blood flow to the anterior forearm after the intervention. CONCLUSION: Post-exercise blood flow is reduced in D/BMD and relates to disease severity. SIGNIFICANCE: Our protocol for quantifying post-exercise intramuscular blood flow is feasible for clinical trials in D/BMD.

Reliability of bedside ultrasound of limb and diaphragm muscle thickness in critically ill children.

INTRODUCTION: We evaluated the reliability of measuring muscle thickness with ultrasound in limbs and diaphragms of critically ill children and determined the sensitivity of these measures to quantitate muscle atrophy over time. METHODS: An expert and trained novice sonographers prospectively measured limb and diaphragm muscle thickness in 33 critically ill children. RESULTS: Expert and novice intrarater and interrater reliability were similar. Intraclass correlations (ICC) and coefficients of variation (CoV) were better in limbs (ICC > 0.9; CoV 3.57%-5.40%) than in diaphragm (ICC > 0.8; CoV novice 11.88%, expert, 12.28%). Mean relative difference in all muscles was small (1%-8%). Limits of agreement of the relative difference were smaller in limb (<13%-18%) than in diaphragm (<38%) muscles. DISCUSSION: Muscle thickness is reliably measured with ultrasound by trained examiners in critically ill children. Our approach detects atrophy >13% in limb and >38% in diaphragm muscles. The smaller detectable change in limb muscles is likely due to their greater thickness. Muscle Nerve 59:88-94, 2019.

Muscle atrophy in mechanically-ventilated critically ill children.

IMPORTANCE: ICU-acquired muscle atrophy occurs commonly and worsens outcomes in adults. The incidence and severity of muscle atrophy in critically ill children are poorly characterized. OBJECTIVE: To determine incidence, severity and risk factors for muscle atrophy in critically ill children. DESIGN, SETTING AND PARTICIPANTS: A single-center, prospective cohort study of 34 children receiving invasive mechanical ventilation for ≥48 hours. Patients 1 week- 18 years old with respiratory failure and without preexisting neuromuscular disease or skeletal trauma were recruited from a tertiary Pediatric Intensive Care Unit (PICU) between June 2015 and May 2016. We used serial bedside ultrasound to assess thickness of the diaphragm, biceps brachii/brachialis, quadriceps femoris and tibialis anterior. Serial electrical impedance myography (EIM) was assessed in children >1 year old. Medical records were abstracted from an electronic database. EXPOSURES: Respiratory failure requiring endotracheal intubation for ≥48 hours. MAIN OUTCOME AND MEASURES: The primary outcome was percent change in muscle thickness. Secondary outcomes were changes in EIM-derived fat percentage and "quality". RESULTS: Of 34 enrolled patients, 30 completed ≥2 ultrasound assessments with a median interval of 6 (IQR 6-7) days. Mean age was 5.42 years, with 12 infants <1 year (40%) and 18 children >1 year old (60%). In the entire cohort, diaphragm thickness decreased 11.1% (95%CI, -19.7% to -2.52%) between the first two assessments or 2.2%/day. Quadriceps thickness decreased 8.62% (95%CI, -15.7% to -1.54%) or 1.5%/day. Biceps (-1.71%; 95%CI, -8.15% to 4.73%) and tibialis (0.52%; 95%CI, -5.81% to 3.40%) thicknesses did not change. Among the entire cohort, 47% (14/30) experienced diaphragm atrophy (defined a priori as ≥10% decrease in thickness). Eighty three percent of patients (25/30) experienced atrophy in ≥1 muscle group, and 47% (14/30)-in ≥2 muscle groups. On multivariate linear regression, increasing age and traumatic brain injury (TBI) were associated with greater muscle loss. EIM revealed increased fat percentage and decreased muscle "quality". CONCLUSIONS AND RELEVANCE: In children receiving invasive mechanical ventilation, diaphragm and other skeletal muscle atrophy is common and rapid. Increasing age and TBI may increase severity of limb muscle atrophy. Prospective studies are required to link muscle atrophy to functional outcomes in critically ill children.

Clinical Problem-Solving: Fever and Rapidly Progressive Weakness in an Immunocompromised Patient.

Here we report the challenging case of a 41-year-old man with HIV complicated by AIDS and a history of prior neurologic injury from progressive multifocal leukoencephalopathy who presented with headache, fevers, lower extremity weakness, hyperreflexic upper extremities, and diminished lower extremity reflexes. We review the clinical decision-making and differential diagnosis for this presentation as the physical examination evolved and diagnostic testing changed over time.

Nerve ultrasound reliability of upper limbs: Effects of examiner training.

INTRODUCTION: Duration of training to reliably measure nerve cross-sectional area with ultrasound is unknown. METHODS: A retrospective review was performed of ultrasound data, acquired and recorded by 2 examiners-an expert and either a trainee with 2 months (novice) or a trainee with 12 months (experienced) of experience. Data on median, ulnar, and radial nerves were reviewed for 42 patients. RESULTS: Interrater reliability was good and varied most with nerve site but little with experience. Coefficient of variation (CoV) range was 9.33%-22.5%. Intraclass correlation coefficient (ICC) was good to excellent (0.65-95) except ulnar nerve-wrist/forearm and radial nerve-humerus (ICC = 0.39-0.59). Interrater differences did not vary with nerve size or body mass index. Expert-novice and expert-experienced interrater differences and CoV were similar. The ulnar nerve-wrist expert-novice interrater difference decreased with time (rs = -0.68, P = 0.001). DISCUSSION: A trainee with at least 2 months of experience can reliably measure upper limb nerves. Reliability varies by nerve and location and slightly improves with time. Muscle Nerve 57: 189-192, 2018.

The Role of Surface Viscosity in the Escape Mechanism of the Stenus Beetle.

Beetles of the species Stenus comma live and hunt close to ponds and rivers, where they occasionally fall on the water surface. To escape this jeopardized state, the beetle developed a strategy relying on the excretion of a secretion containing the substances stenusine and norstenusine. They reduce surface tension and propel the bug to the saving river bank. These substances were synthesized and analyzed with respect to their equilibrium and dynamic adsorption properties at the air-water interface (pH 7, 23 ± 1 °C). The surface dilatational rheological characteristics in a frequency range from 2 to 500 Hz at molar bulk concentrations of 20.6 mmol L(-1) were studied using the oscillating bubble technique. Both alkaloids formed surface viscoelastic adsorption layers. The frequency dependence of the surface dilatational modulus E could successfully be described by the extended Lucassen-van den Tempel model accounting for a nonzero intrinsic surface viscosity κ. The findings confirmed a dual purpose of the spreading alkaloids in the escape mechanism of the Stenus beetle. Next to generating a surface pressure, a transition to surface viscoelastic behavior of the adsorbed layers was observed.

Nerve ultrasound identifies abnormalities in the posterior interosseous nerve in patients with proximal radial neuropathies.

INTRODUCTION: The radial nerve and posterior interosseous nerve (PIN) are prone to injury at multiple sites. Electrodiagnostic (EDx) studies may only identify the most proximal lesion. Nerve ultrasound could augment EDx by visualizing additional pathology. METHODS: This investigation was a retrospective examination of ultrasound and EDx from 26 patients evaluated for posterior cord/radial/PIN lesions. RESULTS: Eighteen of 26 patients had abnormalities on EDx (15 radial, 2 PIN, 1 posterior cord). Ultrasound identified 15 of 18 (83%) of the EDx abnormalities and provided additional diagnostic information. In 6 of 15 (40%) patients with EDx evidence of radial neuropathy, ultrasound identified both radial nerve enlargement and additional, unsuspected PIN enlargement (53% to 339% enlarged vs. unaffected side). Ultrasound also identified: nerve (dis)continuity at the trauma site (n = 8); and nerve tumor (n = 2; 1 with normal EDx). CONCLUSION: In radial neuropathy, ultrasound often augments EDx studies and identifies a second lesion in the PIN. Further studies are required to determine the etiology and significance of this additional distal pathology.

Risk of breast cancer in families with cleft lip and palate.

PURPOSE: To test whether female subjects in families with cleft lip and/or palate (CL/P) have an increased risk of breast cancer. METHODS: By using the Danish Facial Cleft Registry, we identified female subjects with CL/P, mothers of children with CL/P, and sisters to CL/P cases for the Danish birth cohorts 1911-1975. These subjects were compared with a 5% random sample of these cohorts regarding the incidence and age of onset for breast cancer registered in the Danish Hospital Discharge Register 1977-2005. RESULTS: Examining 48,404 person-years for 1809 female CL/P cases (49 breast cancer cases) and 212,795 person-years for 7935 female relatives (188 breast cancer cases), we found no increased breast cancer risk for either CL/P cases (hazard ratio [HR], 1.23; 95% confidence interval (CI), 0.92-1.63), mothers of children with CL/P (HR, 0.93; 95% CI, 0.80-1.08), or sisters of CL/P cases (HR, 0.94; 95% CI, 0.55-1.60), nor was there any significant differences in age of onset. CONCLUSION: Both epidemiological and genetic studies have suggested common etiological factors for breast cancer and CL/P. However, in this population-based study we were not able to confirm a general increase in the risk of breast cancer among female subjects in families with CL/P.