Muscone inhibits angiotensin II-induced cardiac hypertrophy through the STAT3, MAPK and TGF-ß/SMAD signaling pathways.

BACKGROUND: Muscone is a chemical monomer derived from musk. Although many studies have confirmed the cardioprotective effects of muscone, the effects of muscone on cardiac hypertrophy and its potential mechanisms are unclear.The aim of the present study was to investigate the effect of muscone on angiotensin (Ang) II-induced cardiac hypertrophy. METHODS AND RESULTS: In the present study, we found for the first time that muscone exerted inhibitory effects on Ang II-induced cardiac hypertrophy and cardiac injury in mice. Cardiac function was analyzed by echocardiography measurement, and the degree of cardiac fibrosis was determined by the quantitative real-time polymerase chain reaction (qRT-PCR), Masson trichrome staining and western blot assay. Secondly, qRT-PCR experiment showed that muscone attenuated cardiac injury by reducing the secretion of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Moreover, western blot analysis found that muscone exerted cardio-protective effects by inhibiting phosphorylation of key proteins in the STAT3, MAPK and TGF-ß/SMAD pathways. In addition, CCK-8 and determination of serum biochemical indexes showed that no significant toxicity or side effects of muscone on normal cells and organs. CONCLUSIONS: Muscone could attenuate Ang II-induced cardiac hypertrophy, in part, by inhibiting the STAT3, MAPK, and TGF-ß/SMAD signaling pathways.

Closure intracranial pressure as a determinant of surgical decompression adequacy in spontaneous supratentorial intracerebral haematoma: a multicentre observational study.

PURPOSE: Despite significant advances, the literature on the optimal surgical treatment for spontaneous supratentorial intracerebral haematoma (ICH) remains lacking. Intraoperative ICP measured on closure (closure ICP) was reported to be a potential marker of adequate decompression in various neurosurgical conditions. We hypothesize that closure ICP also correlates with outcomes in ICH. METHODS: A multicentre retrospective study of 203 decompressive surgeries performed for ICHs was conducted (clot evacuation with either craniectomy or craniotomy). Receiver operating characteristic analysis on closure ICP was performed and an optimal threshold of 5 separated the patients into inadequate (iICP; ICP > 5 mmHg) and good decompression (gICP; ICP ≤ 5 mmHg). Postoperative ICP control, modified Rankin scale (mRS) and mortality were reported. RESULTS: There were 85 patients in the iICP and 118 patients in the gICP group respectively. The mean age, median preoperative Glasgow coma scale, ICH laterality, location, and volume were similar. After multivariable analysis, the need for (OR 2.55 [1.31-4.97]) and the duration of postoperative hyperosmolar therapy (iICP: 3 days, gICP: 1 day; p = 0.045), and repeat surgery for refractory ICP (OR 5.80 [1.53-22]) were more likely in the iICP group. The likelihood of mRS improvement at 1-year follow up was significantly worse in the iICP group (OR 0.38 [0.17-0.83], p = 0.015). CONCLUSION: Closure ICP is an objective and reproducible surgical target. When planning for surgical decompression, obtaining closure ICP of ≤ 5 mmHg is potentially able to improve postoperative ICP management and optimise functional recovery in a well selected patient population.

Rhein ameliorates transverse aortic constriction-induced cardiac hypertrophy via regulating STAT3 and p38 MAPK signaling pathways.

The progression from compensatory hypertrophy to heart failure is difficult to reverse, in part due to extracellular matrix fibrosis and continuous activation of abnormal signaling pathways. Although the anthraquinone rhein has been examined for its many biological properties, it is not clear whether it has therapeutic value in the treatment of cardiac hypertrophy and heart failure. In this study, we report for the first time that rhein can ameliorate transverse aortic constriction (TAC)-induced cardiac hypertrophy and other cardiac damage in vivo and in vitro. In addition, rhein can reduce cardiac hypertrophy by attenuating atrial natriuretic peptide, brain natriuretic peptide, and ß-MHC expression; cardiac fibrosis; and ERK phosphorylation and transport into the nucleus. Furthermore, the inhibitory effect of rhein on myocardial hypertrophy was similar to that of specific inhibitors of STAT3 and ERK signaling. In addition, rhein at therapeutic doses had no significant adverse effects or toxicity on liver and kidney function. We conclude that rhein reduces TAC-induced cardiac hypertrophy via targeted inhibition of the molecular function of ERK and downregulates STAT3 and p38 MAPK signaling. Therefore, rhein might be a novel and effective agent for treating cardiac hypertrophy and other cardiovascular diseases.

Stereotactic Neurosurgical Robotics With Real-Time Patient Tracking: A Cadaveric Study.

BACKGROUND: Robotic neurosurgery may improve the accuracy, speed, and availability of stereotactic procedures. We recently developed a computer vision and artificial intelligence-driven frameless stereotaxy for nonimmobilized patients, creating an opportunity to develop accurate and rapidly deployable robots for bedside cranial intervention. OBJECTIVE: To validate a portable stereotactic surgical robot capable of frameless registration, real-time tracking, and accurate bedside catheter placement. METHODS: Four human cadavers were used to evaluate the robot's ability to maintain low surface registration and targeting error for 72 intracranial targets during head motion, ie, without rigid cranial fixation. Twenty-four intracranial catheters were placed robotically at predetermined targets. Placement accuracy was verified by computed tomography imaging. RESULTS: Robotic tracking of the moving cadaver heads occurred with a program runtime of 0.111 ± 0.013 seconds, and the movement command latency was only 0.002 ± 0.003 seconds. For surface error tracking, the robot sustained a 0.588 ± 0.105 mm registration accuracy during dynamic head motions (velocity of 6.647 ± 2.360 cm/s). For the 24 robotic-assisted intracranial catheter placements, the target registration error was 0.848 ± 0.590 mm, providing a user error of 0.339 ± 0.179 mm. CONCLUSION: Robotic-assisted stereotactic procedures on mobile subjects were feasible with this robot and computer vision image guidance technology. Frameless robotic neurosurgery potentiates surgery on nonimmobilized and awake patients both in the operating room and at the bedside. It can affect the field through improving the safety and ability to perform procedures such as ventriculostomy, stereo electroencephalography, biopsy, and potentially other novel procedures. If we envision catheter misplacement as a "never event," robotics can facilitate that reality.

Closure intracranial pressure is an objective intraoperative determinant of the adequacy of surgical decompression in traumatic acute subdural haematoma: a multicentre observational study.

PURPOSE: Acute subdural haematoma (ASDH) is associated with severe traumatic brain injury and poor outcomes. Although guidelines exist for the decompression of ASDH, the question of adequate decompression remains unanswered. The authors examined the relationship of intracranial pressure (ICP) on closure with outcomes to determine its utility in the determination of adequate ASDH decompression. METHODS: A multicentre retrospective review of 105 consecutive patients with ASDH who underwent decompressive surgery was performed. Receiver operating characteristic (ROC) analysis with internal validation was performed to determine an ICP threshold for the division of patients into the inadequate and good ICP groups. Multivariable analyses were performed for both inpatient and long-term outcomes. RESULTS: An ICP threshold of 10 mmHg was identified with a 91.5% specificity, 45.7% sensitivity, and a positive and negative predictive value of 80.8% and 68.4%. There were 26 patients (24.8%) and 79 patients (75.2%) in the inadequate and good ICP groups, respectively. After adjustment, the inadequate ICP group was associated with increased postoperative usage of mannitol (OR 14.2, p < 0.001) and barbiturates (OR 150, p = 0.001). Inadequate ICP was also associated with increased inpatient mortality (OR 24.9, p < 0.001), and a lower rate of favourable MRS at 1 year (OR 0.08, p = 0.008). The complication rate was similar amongst the groups. CONCLUSIONS: Closure ICP is a novel, objective, and actionable intraoperative biomarker that correlates with inpatient and long-term outcomes in ASDH. Various surgical manoeuvres can be undertaken to achieve this target safely. Large-scale prospective studies should be performed to validate this ICP threshold.

Inhibition of GSDMD Activates Poly(ADP-ribosyl)ation and Promotes Myocardial Ischemia-Reperfusion Injury.

The precise control of cardiomyocyte viability is imperative to combat myocardial ischemia-reperfusion injury (I/R), in which apoptosis and pyroptosis putatively contribute to the process. Recent researches indicated that GSDMD is involved in I/R as an executive protein of pyroptosis. However, its effect on other forms of cell death is unclear. We identified that GSDMD and GSDMD-N levels were significantly upregulated in the I/R myocardium of mice. Knockout of GSDMD conferred the resistance of the hearts to reperfusion injury in the acute phase of I/R but aggravated reperfusion injury in the chronic phase of I/R. Mechanistically, GSDMD deficiency induced the activation of PARylation and the consumption of NAD+ and ATP, leading to cardiomyocyte apoptosis. Moreover, PJ34, a putative PARP-1 inhibitor, reduced the myocardial injury caused by GSDMD deficiency. Our results reveal a novel action modality of GSDMD in the regulation of cardiomyocyte death; inhibition of GSDMD activates PARylation, suggesting the multidirectional role of GSDMD in I/R and providing a new theory for clinical treatment.

Intracranial Pressure as an Objective Biomarker of Decompression Adequacy in Large Territory Infarction: A Multicenter Observational Study.

Background: Decompressive craniectomy (DC) improves the survival and functional outcomes in patients with malignant cerebral infarction. Currently, there are no objective intraoperative markers that indicates adequate decompression. We hypothesise that closure intracranial pressure (ICP) correlates with postoperative outcomes. Methods: This is a multicentre retrospective review of all 75 DCs performed for malignant cerebral infarction. The patients were divided into inadequate ICP (iICP) and good ICP (gICP) groups based on a suitable ICP threshold determined with tiered receiver operating characteristic and association analysis. Multivariable logistic regression was performed for various postoperative outcomes. Results: An ICP threshold of 7 mmHg was determined, with 36 patients (48.0%) and 39 patients (52.0%) in the iICP and gICP group, respectively. After adjustment, postoperative osmotherapy usage was more likely in the iICP group (OR 6.32, p = 0.003), and when given, was given for a longer median duration (iICP, 4 days; gICP, 1 day, p = 0.003). There was no difference in complications amongst both groups. When an ICP threshold of 11 mmHg was applied, there was significant difference in the duration on ventilator (ICP ≥11 mmHg, 3-9 days, ICP <11 mmHg, 3-5 days, p = 0.023). Conclusion: Surgical decompression works complementarily with postoperative medical therapy to manage progressive cerebral edema in malignant cerebral infarctions. This is a retrospective study which showed that closure ICP, a novel objective intraoperative biomarker, is able to guide the adequacy of DC in this condition. Various surgical manoeuvres can be performed to ensure that this surgical aim is accomplished.

Relevance of presenting risks of frailty, sarcopaenia and osteopaenia to outcomes from aneurysmal subarachnoid haemorrhage.

INTRODUCTION: Aneurysmal subarachnoid haemorrhage (aSAH) is a condition with significant morbidity and mortality. Traditional markers of aSAH have established their utility in the prediction of aSAH outcomes while frailty markers have been validated in other surgical specialties. We aimed to compare the predictive value of frailty indices and markers of sarcopaenia and osteopaenia, against the traditional markers for aSAH outcomes. METHODS: An observational study in a tertiary neurosurgical unit on 51 consecutive patients with ruptured aSAH was performed. The best performing marker in predicting the modified Rankin scale (mRS) on discharge was selected and an appropriate threshold for the definition of frail and non-frail was derived. We compared various frailty indices (modified frailty index 11, and 5, and the National Surgical Quality Improvement Program score [NSQIP]) and markers of sarcopaenia and osteopaenia (temporalis [TMT] and zygoma thickness), against traditional markers (age, World Federation of Neurological Surgery and modified Fisher scale [MFS]) for aSAH outcomes. Univariable and multivariable analysis was then performed for various inpatient and long-term outcomes. RESULTS: TMT was the best performing marker in our cohort with an AUC of 0.82, Somers' D statistic of 0.63 and Tau statistic 0.25. Of the frailty scores, the NSQIP performed the best (AUC 0.69), at levels comparable to traditional markers of aSAH, such as MFS (AUC 0.68). The threshold of 5.5 mm in TMT thickness was found to have a specificity of 0.93, sensitivity of 0.51, positive predictive value of 0.95 and negative predictive value of 0.42. After multivariate analysis, patients with TMT ≥ 5.5 mm (defined as non-frail), were less likely to experience delayed cerebral ischaemia (OR 0.11 [0.01 - 0.93], p = 0.042), any complications (OR 0.20 [0.06 - 0.069], p = 0.011), and had a larger proportion of favourable mRS on discharge (95.0% vs. 58.1%, p = 0.024) and at 3-months (95.0% vs. 64.5%, p = 0.048). However, the gap between unfavourable and favourable mRS was insignificant at the comparison of 1-year outcomes. CONCLUSION: TMT, as a marker of sarcopaenia, correlated well with the presenting status, and outcomes of aSAH. Frailty, as defined by NSQIP, performed at levels equivalent to aSAH scores of clinical relevance, suggesting that, in patients presenting with acute brain injury, both non-neurological and neurological factors were complementary in the determination of eventual clinical outcomes. Further validation of these markers, in addition to exploration of other relevant frailty indices, may help to better prognosticate aSAH outcomes and allow for a precision medicine approach to decision making and optimization of best outcomes.

Discovery and characterization of a monoclonal antibody targeting a conformational epitope of IL-6/IL-6Rα to inhibit IL-6/ IL-6Rα/gp130 hexameric signaling complex formation.

The functional interleukin 6 (IL-6) signaling complex is a hexameric structure composed of IL-6, IL-6Rα, and the signaling receptor gp130. There are three different modes of IL-6 signaling, classic signaling, trans-signaling, and trans-presentation, which are not functionally redundant and mediate pleiotropic effects on both physiological and pathophysiological states. Monoclonal antibodies against IL-6 or IL-6Rα have been successfully developed for clinical application. However, designing therapeutic interventions that block specific modes of IL-6 signaling in a pathologically relevant manner remains a great challenge. Here, we constructed a fusion protein Hyper-IL-6 (HyIL-6) composed of human IL-6 and IL-6Rα to develop specific blocking antibodies against the IL-6/IL-6Rα complex. We successfully screened the monoclonal antibody C14mab, which can bind to HyIL-6 with the binding constant 2.86 × 10-10 and significantly inhibit IL-6/IL-6Rα/gp130 complex formation. In vitro, C14mab effectively inhibited HyIL-6-stimulated signal transducer and activator of transcription 3 (STAT3) activation and related vascular endothelial growth factor (VEGF) induction. Moreover, C14mab efficaciously suppressed HyIL-6-induced acute phase response in vivo. Our data from hydrogen-deuterium exchange mass spectrometry demonstrate that C14mab mainly binds to site IIIa of IL-6 and blocks the final step in the interaction between gp130 and IL-6/IL-6Rα complex. Additionally, data from enzyme-linked immunosorbent assays and kinetics assays indicate that C14mab interacts simultaneously with IL-6 and IL-6Rα, while it does not interact with IL-6Rα alone. The unique features of C14mab may offer a novel alternative for IL-6 blockade and illuminate a better therapeutic intervention targeting IL-6.

Endoscopic excision of an aqueduct of Sylvius cavernoma causing obstructive hydrocephalus: technical note.

BACKGROUND AND IMPORTANCE: Acquired lesions within the aqueduct of Sylvius are rare and their surgical management is challenging. Open transcranial approaches require dissection and manipulation of surrounding eloquent structures. Use of an endoscope can avoid potential morbidity from traversing and handling eloquent structures during open approaches whilst providing better visualisation of an intraventricular lesion. CLINICAL PRESENTATION: A 62-year-old female presented with insidious onset short-term memory loss, unsteady gait, urinary incontinence and left-sided dysaesthesia. Magnetic resonance imaging (MRI) revealed hydrocephalus from an obstructive haemorrhagic lesion consistent with a cavernoma at the central midbrain within the aqueduct of Sylvius. An endoscopic approach was selected to provide optimal visualisation of the lesion. As only a single instrument could be accommodated, rotational movements were employed to tease out the lesion. Gross total resection was achieved. Her symptoms improved immediately postoperatively and she made a complete recovery by 2 months. Post-operative MRI showed resolution of hydrocephalus and no evidence of residual/recurrence of the lesion. Unfortunately, she developed hydrocephalus 3 months post-op and required placement of a ventriculoperitoneal shunt. CONCLUSIONS: Endoscopic resection is safe and feasible for selected periaqueductal lesions as it provides direct access while minimising disruption of the surrounding anatomical structures. The limitation of only having a single instrument can be overcome by employing rotational movements.

Frameless neuronavigation with computer vision and real-time tracking for bedside external ventricular drain placement: a cadaveric study.

OBJECTIVE: A major obstacle to improving bedside neurosurgical procedure safety and accuracy with image guidance technologies is the lack of a rapidly deployable, real-time registration and tracking system for a moving patient. This deficiency explains the persistence of freehand placement of external ventricular drains, which has an inherent risk of inaccurate positioning, multiple passes, tract hemorrhage, and injury to adjacent brain parenchyma. Here, the authors introduce and validate a novel image registration and real-time tracking system for frameless stereotactic neuronavigation and catheter placement in the nonimmobilized patient. METHODS: Computer vision technology was used to develop an algorithm that performed near-continuous, automatic, and marker-less image registration. The program fuses a subject's preprocedure CT scans to live 3D camera images (Snap-Surface), and patient movement is incorporated by artificial intelligence-driven recalibration (Real-Track). The surface registration error (SRE) and target registration error (TRE) were calculated for 5 cadaveric heads that underwent serial movements (fast and slow velocity roll, pitch, and yaw motions) and several test conditions, such as surgical draping with limited anatomical exposure and differential subject lighting. Six catheters were placed in each cadaveric head (30 total placements) with a simulated sterile technique. Postprocedure CT scans allowed comparison of planned and actual catheter positions for user error calculation. RESULTS: Registration was successful for all 5 cadaveric specimens, with an overall mean (± standard deviation) SRE of 0.429 ± 0.108 mm for the catheter placements. Accuracy of TRE was maintained under 1.2 mm throughout specimen movements of low and high velocities of roll, pitch, and yaw, with the slowest recalibration time of 0.23 seconds. There were no statistically significant differences in SRE when the specimens were draped or fully undraped (p = 0.336). Performing registration in a bright versus a dimly lit environment had no statistically significant effect on SRE (p = 0.742 and 0.859, respectively). For the catheter placements, mean TRE was 0.862 ± 0.322 mm and mean user error (difference between target and actual catheter tip) was 1.674 ± 1.195 mm. CONCLUSIONS: This computer vision-based registration system provided real-time tracking of cadaveric heads with a recalibration time of less than one-quarter of a second with submillimetric accuracy and enabled catheter placements with millimetric accuracy. Using this approach to guide bedside ventriculostomy could reduce complications, improve safety, and be extrapolated to other frameless stereotactic applications in awake, nonimmobilized patients.

Loganin Inhibits Angiotensin II-Induced Cardiac Hypertrophy Through the JAK2/STAT3 and NF-κB Signaling Pathways.

Loganin is an iridoid glycoside extracted from Cornus officinalis, which is a traditional oriental medicine, and many biological properties of loganin have been reported. Nevertheless, it is not clear whether loganin has therapeutic effect on cardiovascular diseases. Hence, the aim of the present study was to investigate the effect of loganin on Ang II-induced cardiac hypertrophy. In the present study, we reported for the first time that loganin inhibits Ang II-provoked cardiac hypertrophy and cardiac damages in H9C2 cells and in mice. Furthermore, loganin can achieve cardioprotective effects through attenuating cardiac fibrosis, decreasing pro-inflammatory cytokine secretion, and suppressing the phosphorylation of critical proteins such as JAK2, STAT3, p65, and IκBα. Besides, the outstanding findings of the present study were to prove that loganin has no significant toxicity or side effects on normal cells and organs. Based on these results, we conclude that loganin mitigates Ang II-induced cardiac hypertrophy at least partially through inhibiting the JAK2/STAT3 and NF-κB signaling pathways. Accordingly, the natural product, loganin, might be a novel effective agent for the treatment of cardiac hypertrophy and heart failure.

Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122.

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers, which is the second most lethal tumor worldwide. Epigenetic deregulation is a common trait observed in HCC. Recently, increasing evidence suggested that the G9a histone methyltransferase might be a novel regulator of HCC development. However, several HCC cell lines were recently noted to have HeLa cell contamination or to have been derived from non-hepatocellular origin, suggesting that functional validation of G9a in proper HCC models is still required. Herein, we first confirmed that higher G9a messenger RNA and protein expression levels were correlated with poor overall survival (OS) and disease-free survival (DFS) rates of HCC patients from The Cancer Genome Atlas (TCGA) dataset and our recruited HCC cohort. In an in vitro functional evaluation of HCC cells, HCC36 (hepatitis B virus-positive (HBV+) and Mahlavu (HBV-)) cells showed that G9a participated in promoting cell proliferation, colony formation, and migration/invasion abilities. Moreover, orthotopic inoculation of G9a-depleted Mahlavu cells in NOD-SCID mice also resulted in a significantly decreased tumor burden compared to the control group. Furthermore, after surveying microRNA (miRNA; miR) prediction databases, we identified the liver-specific miR-122 as a G9a-targeting miRNA. In various HCC cell lines, we observed that miR-122 expression levels tended to be inversely correlated to G9a expression levels. In clinical HCC specimens, a significant inverse correlation of miR-122 and G9a mRNA expression levels was also observed. Functionally, the colony formation and invasive ability were attenuated in miR-122-overexpressing HCC cells. HCC patients with low miR-122 and high G9a expression levels had the worst OS and DFS rates compared to others. Together, our results confirmed the importance of altered G9a expression during HCC progression and discovered that a novel liver-specific miR-122-G9a regulatory axis exists.

Aqueductal Compression by Dilated Virchow-Robin Spaces in the Mesencephalic-Pontine Region Presenting with Symptoms Mimicking Normal Pressure Hydrocephalus: A Case Report and Review of Literature.

BACKGROUND: Dilatation of Virchow-Robin spaces (dVRS) have been described in the development of hydrocephalic syndromes. We report an unusual case of a type III dVRS presenting as a mimic of normal pressure hydrocephalus (NPH), due to distortion at the level of the cerebral aqueduct. CASE DESCRIPTION: A 59-year-old woman presented with mild traumatic brain injury and possible NPH, due to a history of progressive gait disturbance, recurrent falls, and cognitive decline over a year, in the context of ventriculomegaly. Detailed structural imaging of the brain revealed multiple dilated cystic lesions consistent with dVRS causing distortion at the level of the cerebral aqueduct. Cerebrospinal fluid examination was negative for infection. The patient was treated with endoscopic third ventriculostomy; at 12 months postoperatively, she demonstrated a sustained improvement in gait and stabilization of cognitive decline. CONCLUSIONS: This is an illustrative case of a subacute obstructive hydrocephalus due to a collection of periaqueductal dVRS, leading to an insidious clinical presentation mimicking NPH. We reviewed the literature for key clinical presentations and describe neuroanatomical considerations as well as primary treatment strategies. Various hydrocephalic syndromes may present with classic symptoms from Hakim's triad; such symptoms are not specific to idiopathic NPH. Both endoscopic third ventriculostomy and shunting may be efficacious. In our case, dVRS may serve as both a cause of and compensatory mechanism in a subacute obstructive hydrocephalus of unknown etiology. Our case highlights the need to understand the neuroanatomy of aberrant cerebrospinal fluid spaces in hydrocephalic syndromes. Further studies of dVRS would provide valuable insights into the pathogenesis of hydrocephalus.

The National Neuroscience Institute External Ventricular Drain Study: A Pragmatic Multisite Risk-Stratification Pathway to Reduce Ventriculostomy-Related Infection.

OBJECTIVE: Ventriculostomy-related infection (VRI) is associated with potential serious morbidity, extended hospitalization duration, increased health care costs, and mortality. We assessed the effectiveness of a pragmatic risk-stratification pathway for external ventricular drain (EVD) management, allowing for surgical decision making, in reducing the rate of VRIs. METHODS: Two studies were performed concurrently. A retrospective audit of EVD infection rates and outcomes in our unit across 3 hospitals was conducted from January to December 2014. The second prospective study compared the same variables during the implementation of the EVD pathway across the 3 sites from January 2015 to December 2016. RESULTS: The number of patients requiring EVDs increased from 2014 to 2016 (165 vs. 189 vs. 197 patients, respectively), with a significant increase in patients with intraventricular hemorrhage (P = 0.009). Despite increasing risk, overall EVD infections decreased during the implementation period, from 4.8% (8/165) in 2014 to 3.7% in 2015 (7/189) and 2.0% in 2016 (4/197, P = 0.33). In 2 sites (site 1, 2.0% vs. 2.1% vs. 1.9%, and site 2, 4.7% vs. 5.0% vs. 5.3%), transition to the EVD risk-stratification pathway maintained already low infection rates; in site 3, EVD infections decreased from 6.8% (5/73) to 3.9% (4/102) and 0% (0/86, P = 0.06). CONCLUSIONS: The introduction of a pragmatic evidence-based risk-stratification pathway, in which different options for EVD management are incorporated, results in low EVD infection rates across a multisite institutional practice. Our results are comparable to published protocols involving the implementation of standard care bundles and/or antibacterial EVDs alone, in reducing VRIs.

The STAT3-miRNA-92-Wnt Signaling Pathway Regulates Spheroid Formation and Malignant Progression in Ovarian Cancer.

Ovarian cancer spheroids constitute a metastatic niche for transcoelomic spread that also engenders drug resistance. Spheroid-forming cells express active STAT3 signaling and display stem cell-like properties that may contribute to ovarian tumor progression. In this study, we show that STAT3 is hyperactivated in ovarian cancer spheroids and that STAT3 disruption in this setting is sufficient to relieve chemoresistance. In an NSG murine model of human ovarian cancer, STAT3 signaling regulated spheroid formation and self-renewal properties, whereas STAT3 attenuation reduced tumorigenicity. Mechanistic investigations revealed that Wnt signaling was required for STAT3-mediated spheroid formation. Notably, the Wnt antagonist DKK1 was the most strikingly upregulated gene in response to STAT3 attenuation in ovarian cancer cells. STAT3 signaling maintained stemness and interconnected Wnt/ß-catenin signaling via the miR-92a/DKK1-regulatory pathways. Targeting STAT3 in combination with paclitaxel synergistically reduced peritoneal seeding and prolonged survival in a murine model of intraperitoneal ovarian cancer. Overall, our findings define a STAT3-miR-92a-DKK1 pathway in the generation of cancer stem-like cells in ovarian tumors, with potential therapeutic applications in blocking their progression. Cancer Res; 77(8); 1955-67. ©2017 AACR.

Glutaminase 2 stabilizes Dicer to repress Snail and metastasis in hepatocellular carcinoma cells.

Glutaminolysis that catabolizes glutamine to glutamate plays a critical role in cancer progression. Glutaminase 2 (GLS2) has been reported as a tumor suppressor. Recent studies implied that GLS2 may display its multifunction besides classical metabolic feature by different localizations and potential protein binding domains. Here, we showed that GLS2 expression correlates inversely with stage, vascular invasion, tumor size and poor prognosis in human hepatocellular carcinoma (HCC) tissues. We found that GLS2 significantly represses cell migration, invasion and metastasis of HCC through downregulation of Snail in vitro and in vivo. Moreover, our results demonstrated that GLS2 interacts with Dicer and stabilizes Dicer protein to facilitate miR-34a maturation and subsequently represses Snail expression in a glutaminase activity independent manner. Our findings indicate that non-glutaminolysis function of GLS2 inhibits migration and invasion of HCC cells by repressing the epithelial-mesenchymal transition via the Dicer-miR-34a-Snail axis.