Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation.

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor clinical outcomes. Emerging data suggest that mitochondrial oxidative phosphorylation (mtOXPHOS) plays a significant role in AML tumorigenesis, progression, and resistance to chemotherapies. However, how the mtOXPHOS is regulated in AML cells is not well understood. In this study, we investigated the oncogenic functions of ERRα in AML by combining in silico, in vitro, and in vivo analyses and showed ERRα is a key regulator of mtOXPHOS in AML cells. The increased ERRα level was associated with worse clinical outcomes of AML patients. Single cell RNA-Seq analysis of human primary AML cells indicated that ERRα-expressing cancer cells had significantly higher mtOXPHOS enrichment scores. Blockade of ERRα by pharmacologic inhibitor (XCT-790) or gene silencing suppressed mtOXPHOS and increased anti-leukemic effects in vitro and in xenograft mouse models.

Mycobacterial acyl carrier protein suppresses TFEB activation and upregulates miR-155 to inhibit host defense.

Mycobacterial acyl carrier protein (AcpM; Rv2244), a key protein involved in Mycobacterium tuberculosis (Mtb) mycolic acid production, has been shown to suppress host cell death during mycobacterial infection. This study reports that mycobacterial AcpM works as an effector to subvert host defense and promote bacterial growth by increasing microRNA (miRNA)-155-5p expression. In murine bone marrow-derived macrophages (BMDMs), AcpM protein prevented transcription factor EB (TFEB) from translocating to the nucleus in BMDMs, which likely inhibited transcriptional activation of several autophagy and lysosomal genes. Although AcpM did not suppress autophagic flux in BMDMs, AcpM reduced Mtb and LAMP1 co-localization indicating that AcpM inhibits phagolysosomal fusion during Mtb infection. Mechanistically, AcpM boosted the Akt-mTOR pathway in BMDMs by upregulating miRNA-155-5p, a SHIP1-targeting miRNA. When miRNA-155-5p expression was inhibited in BMDMs, AcpM-induced increased intracellular survival of Mtb was suppressed. In addition, AcpM overexpression significantly reduced mycobacterial clearance in C3HeB/FeJ mice infected with recombinant M. smegmatis strains. Collectively, our findings point to AcpM as a novel mycobacterial effector to regulate antimicrobial host defense and a potential new therapeutic target for Mtb infection.

Quantifying neonatal patient effort using non-invasive model-based methods.

Patient-specific spontaneous breathing effort (SB) is common in invasively mechanically ventilated (MV) adult patients, and especially common in preterm neonates who are not typically sedated. However, there is no proven, ethically feasible and non-invasive method to quantify SB effort in neonates, creating the potential for model-based measures. Lung mechanics and SB effort are segregated using a basis function model to identify passive lung mechanics, and an additional time-varying elastance model to identify patient-specific SB effort and asynchrony as negative and positive added elastances, respectively. Data from ten preterm neonates on standard MV care in the neonatal intensive care unit (NICU) are used to assess this model-based approach, using area under the curve (AUC) for positive (asynchrony) and negative (SB effort) time-varying elastance. Median [interquartile-range (IQR)] of passive pulmonary lung elastance was 3.82 [2.09-5.80] cmH2O/ml. Median [IQR] AUC quantified SB effort was -0.32 [-0.43--0.12]cmH2O/ml. AUC quantified asynchrony was 0.00 [0.00-0.01]cmH2O/ml, and affected 28% of the 25,287 total breaths. This proof of concept model-based approach provides a non-invasive, computationally straightforward, and thus clinically feasible means to quantify patient-specific spontaneous breathing effort and asynchrony.

Model-based estimation of negative inspiratory driving pressure in patients receiving invasive NAVA mechanical ventilation.

BACKGROUND: Optimisation of mechanical ventilation (MV) and weaning requires insight into underlying patient breathing effort. Current identifiable models effectively describe lung mechanics, such as elastance (E) and resistance (R) at the bedside in sedated patients, but are less effective when spontaneous breathing is present. This research derives and regularises a single compartment model to identify patient-specific inspiratory effort. METHODS: Constrained second-order b-spline basis functions (knot width 0.05 s) are used to describe negative inspiratory drive (Pp, cmH2O) as a function of time. Breath-breath Pp are identified with single E and R values over inspiration and expiration from n = 20 breaths for N = 22 patients on NAVA ventilation. Pp is compared to measured electrical activity of the diaphragm (Eadi) and published results. RESULTS: Average per-patient root-mean-squared model fit error was (median [interquartile range, IQR]) 0.9 [0.6-1.3] cmH2O, and average per-patient median Pp was -3.9 [-4.5- -3.0] cmH2O, with range -7.9 - -1.9 cmH2O. Per-patient E and R were 16.4 [13.6-21.8] cmH2O/L and 9.2 [6.4-13.1] cmH2O.s/L, respectively. Most patients showed an inspiratory volume threshold beyond which Pp started to return to baseline, and Pp at peak Eadi (end-inspiration) was often strongly correlated with peak Eadi (R2=0.25-0.86). Similarly, average transpulmonary pressure was consistent breath-breath in most patients, despite differences in peak Eadi and thus peak airway pressure. CONCLUSIONS: The model-based inspiratory effort aligns with electrical muscle activity and published studies showing neuro-muscular decoupling as a function of pressure and/or volume. Consistency in coupling/dynamics were patient-specific. Quantification of patient and ventilator work of breathing contributions may aid optimisation of MV modes and weaning.

Model-based PEEP titration versus standard practice in mechanical ventilation: a randomised controlled trial.

BACKGROUND: Positive end-expiratory pressure (PEEP) at minimum respiratory elastance during mechanical ventilation (MV) in patients with acute respiratory distress syndrome (ARDS) may improve patient care and outcome. The Clinical utilisation of respiratory elastance (CURE) trial is a two-arm, randomised controlled trial (RCT) investigating the performance of PEEP selected at an objective, model-based minimal respiratory system elastance in patients with ARDS. METHODS AND DESIGN: The CURE RCT compares two groups of patients requiring invasive MV with a partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio ≤ 200; one criterion of the Berlin consensus definition of moderate (≤ 200) or severe (≤ 100) ARDS. All patients are ventilated using pressure controlled (bi-level) ventilation with tidal volume = 6-8 ml/kg. Patients randomised to the control group will have PEEP selected per standard practice (SPV). Patients randomised to the intervention will have PEEP selected based on a minimal elastance using a model-based computerised method. The CURE RCT is a single-centre trial in the intensive care unit (ICU) of Christchurch hospital, New Zealand, with a target sample size of 320 patients over a maximum of 3 years. The primary outcome is the area under the curve (AUC) ratio of arterial blood oxygenation to the fraction of inspired oxygen over time. Secondary outcomes include length of time of MV, ventilator-free days (VFD) up to 28 days, ICU and hospital length of stay, AUC of oxygen saturation (SpO2)/FiO2 during MV, number of desaturation events (SpO2 < 88%), changes in respiratory mechanics and chest x-ray index scores, rescue therapies (prone positioning, nitric oxide use, extracorporeal membrane oxygenation) and hospital and 90-day mortality. DISCUSSION: The CURE RCT is the first trial comparing significant clinical outcomes in patients with ARDS in whom PEEP is selected at minimum elastance using an objective model-based method able to quantify and consider both inter-patient and intra-patient variability. CURE aims to demonstrate the hypothesized benefit of patient-specific PEEP and attest to the significance of real-time monitoring and decision-support for MV in the critical care environment. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, ACTRN12614001069640. Registered on 22 September 2014. (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366838&isReview=true) The CURE RCT clinical protocol and data usage has been granted by the New Zealand South Regional Ethics Committee (Reference number: 14/STH/132).

Mechanically ventilated premature babies have sex differences in specific elastance: A pilot study.

OBJECTIVES: A pilot study to compare pulmonary mechanics in a neonatal intensive care unit (NICU) cohort, specifically, comparing lung elastance between male and female infants in the NICU. HYPOTHESIS: Anecdotally, male infants are harder to ventilate than females. We hypothesize that males have higher model-based elastance (converse: lower specific compliance) compared to females, reflecting underlying stiffer lungs. STUDY DESIGN: A clinically validated, single-compartment model is used to identify specific elastance (inverse of specific compliance) and resistance for each breath. Specific elastance accounts for weight differences when comparing male and female infants. Relative percent breath-to-breath variability (%ΔE) in specific elastance is also compared. Level of asynchrony was also determined. PATIENT-SUBJECT SELECTION: Ten invasively mechanically ventilated patients from Christchurch Women's Hospital. METHODOLOGY: Airway pressure and flow data from 10 invasive mechanical ventilation (MV) infants from Christchurch Women's Hospital Neonatal Intensive Care Unit, New Zealand was prospectively recorded under standard MV care. Model-based specific elastance and resistance are identified for each breath, as well as relative percent breath-to-breath variability (%ΔE) in specific elastance. RESULTS: Male infants overall had higher specific elastance compared to females infants (P ≤ .01), with median (interquartile range) for males of 1.91 (1.33-2.48) cmH2 O·kg/mL compared to 1.31 (0.86-2.02) cmH2 O·kg/mL in females. Male infants had lower variability with %ΔE of -0.03 (-7.56 to 8.01)% vs female infants of -0.59 (12.56-12.86)%. Males had 14.75% asynchronous breaths whereas females had 17.54%. CONCLUSION: Overall, males had higher specific elastance and correspondingly lower breath-to-breath variability. These results indicate male and female infants may require different MV settings, mode, and monitoring.

General review of titanium toxicity.

BACKGROUND: Titanium is a commonly used inert bio-implant material within the medical and dental fields. Although the use of titanium is thought to be safe with a high success rate, in some cases, there are rare reports of problems caused by titanium. In most of these problematic reports, only individual reports are dominant and comprehensive reporting has not been performed. This comprehensive article has been prepared to review the toxicity of titanium materials within the medical and dental fields. METHODS: We used online searching tools including MEDLINE (PubMed), Embase, Cochrane Library, and Google Scholar by combining keywords such as "titanium implant toxicity," "titanium implant corrosion," "titanium implant allergy," and "yellow nail syndrome." Recently updated data has been collected and compiled into one of four categories: "the toxicity of titanium," "the toxicity of titanium alloys," "the toxicity of titanium implants," and "diseases related to titanium." RESULTS: Recent studies with regard to titanium toxicity have been increasing and have now expanded to the medical field in addition to the fields of environmental research and basic science. Problems that may arise in titanium-based dental implants include the generation of titanium and titanium alloy particles and ions deposited into surrounding tissues due to the corrosion and wear of implants, resulting in bone loss due to inflammatory reactions, which may lead to osseointegration failure of the dental implant. These titanium ions and particles are systemically deposited and can lead to toxic reactions in other tissues such as yellow nail syndrome. Additionally, implant failure and allergic reactions can occur due to hypersensitivity reactions. Zirconia implants can be considered as an alternative; however, limitations still exist due to a lack of long-term clinical data. CONCLUSIONS: Clinicians should pay attention to the use of titanium dental implants and need to be aware of the problems that may arise from the use of titanium implants and should be able to diagnose them, in spite of very rare occurrence. Within the limitation of this study, it was suggested that we should be aware the rare problems of titanium toxicity.

Anesthetic management of the emergency laparotomy for a patient with multiple sclerosis -A case report-.

A 33-year-old male patient with multiple sclerosis (MS) received an emergency laparotomy because of perforated appendicitis. He had been suffering from MS for 2 years and the symptoms of MS were paraplegia and urinary incontinence. Anesthesia was induced with propofol and remifentanil and maintained with nitrous oxide, sevoflurane and remifentanil. Rocuronium was used for tracheal intubation. Train of four ratio and bispectral index scale were also monitored for adequate muscle relaxation and anesthetic depth. The patient emerged from general anesthesia smoothly and was extubated without any complication. Postoperative exacerbation of MS symptoms did not appear. However, he was rehospitalized because deep vein thrombosis (DVT) occurred after discharge and he received heparinization immediately. Eventually, he was discharged after a full recovery from DVT. We report a safe anesthetic management of the patient with MS, with the use of sevoflurane and with no the aggravation of MS during postoperative period.