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.

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.

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.

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.

Leukocyte cell-derived chemotaxin 2 antagonizes MET receptor activation to suppress hepatocellular carcinoma vascular invasion by protein tyrosine phosphatase 1B recruitment.

UNLABELLED: Leukocyte cell-derived chemotoxin 2 (LECT2) has been shown to act as a tumor suppressor in hepatocellular carcinoma (HCC). However, the underlying mechanism has not yet been completely defined. Here, we employ a LECT2-affinity column plus liquid chromatography coupled with tandem mass spectrometry to identify LECT2-binding proteins and found that MET receptor strongly interacted with LECT2 protein. Despite the presence of hepatocyte growth factor, the LECT2 binding causes an antagonistic effect to MET receptor activation through recruitment of protein tyrosine phosphatase 1B. The antagonistic effect of LECT2 on MET activation also mainly contributes to the blockage of vascular invasion and metastasis of HCC. Furthermore, serial deletions and mutations of LECT2 showed that the HxGxD motif is primarily responsible for MET receptor binding and its antagonistic effects. CONCLUSION: These findings reveal a novel, specific inhibitory function of LECT2 in HCC by the direct binding and inactivation of MET, opening a potential avenue for treating MET-related liver cancer.

The H3K9 Methyltransferase G9a Represses E-cadherin and is Associated with Myometrial Invasion in Endometrial Cancer.

BACKGROUND: Emerging evidence suggests that G9a, a histone methyltransferase, is involved in tumor progression and metastasis. However, the functional significance of G9a in endometrial carcinogenesis has not been defined. METHODS: The differential expression of G9a in cancer and normal tissues was assessed using an array of 28 paired samples. Tissue specimens from 94 patients with endometrial cancer who underwent primary surgery were immunohistochemically evaluated for G9a and E-cadherin expression. To assess the biologic role of G9a in endometrial cancer, G9a was either stably knocked down or knocked down using a tetracycline-controllable system in endometrial cancer cells, followed by functional assays. RESULTS: Increased G9a expression was identified in endometrial cancer tissues, and its expression was specifically correlated with deep myometrial invasion. Cell invasiveness was inhibited by an RNAi-mediated knockdown of G9a in invasive endometrial cancer cells in vitro and in vivo. An important mediator of G9a-induced tumor invasion is the epigenetic silencing of E-cadherin. Knockdown of G9a restored E-cadherin expression by reducing H3K9me2 levels and decreasing CDH1 promoter DNA methyltransferase recruitment. Knockdown of RNAi-mediated E-cadherin substantially relieved the invasion suppression imposed by G9a suppression. A significant negative correlation between G9a and E-cadherin expression was observed in endometrial cancer (Spearman's rho, -0.27; P = 0.02). CONCLUSIONS: This study provides the first clear evidence that G9a contributes to endometrial cancer progression. Mechanistic investigations suggest that E-cadherin repression mediates the effects of G9a. Targeting G9a-mediated epigenetic pathway dysregulation may be a therapeutic strategy for endometrial cancers.

The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis.

BACKGROUND: Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer-related deaths in women with limited therapeutic options available for treating it and poor prognosis, as the underlying mechanism is not fully understood. METHOD: The clinicopathological correlation of G9a expression was assessed in tumor specimens of ovarian cancer patients. Knockdown or overexpression of G9a in ovarian cancer cell lines was analysed with regard to its effect on adhesion, migration, invasion and anoikis-resistance. In vivo biological functions of G9a were tested by i.p. xenograft ovarian cancer models. Microarray and quantitative RT-PCR were used to analyze G9a-regulated downstream target genes. RESULTS: We found that the expression of histone methyltransferase G9a was highly correlated with late stage, high grade, and serous-type OCa. Higher G9a expression predicted a shorter survival in ovarian cancer patients. Furthermore, G9a expression was higher in metastatic lesions compared with their corresponding ovarian primary tumors. Knockdown of G9a expression suppressed prometastatic cellular activities including adhesion, migration, invasion and anoikis-resistance of ovarian cancer cell lines, while G9a over-expression promoted these cellular properties. G9a depletion significantly attenuated the development of ascites and tumor nodules in a peritoneal dissemination model. Importantly, microarray and quantitative RT-PCR analysis revealed that G9a regulates a cohort of tumor suppressor genes including CDH1, DUSP5, SPRY4, and PPP1R15A in ovarian cancer. Expression of these genes was also inversely correlated with G9a expression in OCa specimens. CONCLUSION: We propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease.

Arsenic trioxide inhibits CXCR4-mediated metastasis by interfering miR-520h/PP2A/NF-κB signaling in cervical cancer.

BACKGROUND: Arsenic apparently affects numerous intracellular signal transduction pathways and causes many alterations leading to apoptosis and differentiation in malignant cells. We and others have demonstrated that arsenic inhibits the metastatic capacity of cancer cells. Here we present additional mechanistic studies to elucidate the potential of arsenic as a promising therapeutic inhibitor of metastasis. METHODS: The effects of arsenic trioxide (ATO) on human cervical cancer cell lines migration and invasion were observed by transwell assays. In experimental metastasis assays, cancer cells were injected into tail veins of severe combined immunodeficient mice for modeling metastasis. The mechanisms involved in ATO regulation of CXCR4 were analyzed by immunoblot, real-time polymerase chain reaction, and luciferase reporter assays. Immunohistochemistry was utilized to identify PP2A/C and CXCR4 protein expressions in human cervical cancer tissues. RESULTS: ATO inhibited CXCR4-mediated cervical cancer cell invasion in vitro and distant metastasis in vivo. We determined that ATO modulates the pivotal nuclear factor-kappa B (NF-κB)/CXCR4 signaling pathway that contributes to cancer metastasis. Substantiating our findings, we demonstrated that ATO activates PP2A/C activity by downregulating miR-520h, which results in IKK inactivation, IκB-dephosphorylation, NF-κB inactivation, and, subsequently, a reduction in CXCR4 expression. Furthermore, PP2A/C was reduced during cervical carcinogenesis, and the loss of PP2A/C expression was closely associated with the nodal status of cervical cancer patients. CONCLUSIONS: Our results indicate a functional link between ATO-mediated PP2A/C regulation, CXCR4 expression, and tumor-suppressing ability. This information will be critical in realizing the potential for synergy between ATO and other anti-cancer agents, thus providing enhanced benefit in cancer therapy.

Immersive virtual reality as a surgical training tool: A cohort study.

Background: Few studies have studied the efficacy of using immersive virtual reality (iVR) to teach surgical skills, especially by using real-world iVR recordings rather than simulations. This study aimed to investigate whether viewing 360° iVR instructional recordings produces greater improvements in basic suturing skills of students without prior medical training, beyond traditional methods like reading written manuals or watching 2D instructional videos. Materials and methods: This was a partially blinded randomized cohort study. 44 pre-university students (aged 17) were randomized equally to either the written instruction manual, 2D instructional video, or iVR recordings. All students first watched a silent 2D demonstration video of the suturing task, before attempting to place three simple interrupted sutures on a piece of meat as a baseline. The time taken for the first attempt was recorded. Students were then given an hour to train using their allocated modality. They attempted the suturing task again, and timings were re-recorded. Four blinded surgically-trained judges independently assessed the quality of the stitches placed both pre and post-intervention. One-way analysis of variance tests (ANOVAs) and independent two-sample t-tests were used to determine the effect of training modality on improvements in suturing scores and time taken to complete suturing from pre to post-training. Results: For suturing scores, the iVR group showed significantly larger score improvements than the Written Manual group (p = 0.031, Cohen's D = 0.92), while this iVR advantage was less pronounced when compared with the 2D Video group (p = 0.16, Cohen's D = 0.65). Similarly for time taken to complete suturing, the iVR group had significantly larger time improvements than the Written Manual group (p = 0.045), although this difference was less robust compared to the 2D Instructional Video group (p = 0.34). Conclusion: This study demonstrates that iVR training using real-world 360° instructional recordings produced significantly greater training gains in suturing scores and efficiency compared to reading written text. iVR training also led to larger training gains in both outcome measures than viewing 2D instructional videos, although the differences between them did not reach statistical significance.

CD164 regulates the tumorigenesis of ovarian surface epithelial cells through the SDF-1α/CXCR4 axis.

BACKGROUND: CD164 (endolyn), a sialomucin, has been reported to play a role in the proliferation, adhesion, and differentiation of hematopoietic stem cells. The potential association of CD164 with tumorigenicity remains unclear. METHODS: The clinicopathological correlation of ovarian cancer with CD164 was assessed in a 97-patient tumor tissue microarray. Overexpression or silence CD164 was to analyze the effect of CD164 on the proliferation, colony formation and apoptosis via a mouse xenograft and western blotting analysis. The subcellular localization of CD164 was collected in the immunohistochemical and confocal analysis. RESULTS: Our data demonstrated that higher expression levels of CD164 were identified in malignant ovarian cancer cell lines, such as SKOV3 and HeyA8. The clinicopathological correlation analysis showed that the upregulation of CD164 protein was significantly associated with tumor grade and metastasis. The overexpression of CD164 in human ovarian epithelial surface cells promoted cellular proliferation and colony formation and suppressed apoptosis. These tumorigenicity effects of CD164 were reconfirmed in a mouse xenograft model. We also found that the overexpression of CD164 proteins increased the amounts of CXCR4 and SDF-1α and activated the SDF-1α/CXCR4 axis, inducing colony and sphere formation. Finally, we identified the subcellular localization of CD164 in the nucleus and cytosol and found that nuclear CD164 might be involved in the regulation of the activity of the CXCR4 promoter. CONCLUSIONS: Our findings suggest that the increased expression of CD164 is involved in ovarian cancer progression via the SDF-1α/CXCR4 axis, which promotes tumorigenicity. Thus, targeting CD164 may serve as a potential ovarian cancer biomarker, and targeting CD164 may serve as a therapeutic modality in the management of high-grade ovarian tumors.

Curcumin attenuates cyclooxygenase-2 expression via inhibition of the NF-κB pathway in lipopolysaccharide-stimulated human gingival fibroblasts.

Porphyromonas gingivalis lipopolysaccharide (LPS) induces the expression of the cyclooxygenase-2 (COX-2), which contributes to the process of periodontitis. Curcumin, a constituent of turmeric, exhibits anti-inflammatory properties. We have investigated the anti-inflammatory effect of curcumin in human gingival fibroblasts (HGFs) stimulated by P. gingivalis LPS and its mechanism of action. HGFs pretreated with curcumin were stimulated by P. gingivalis LPS. COX-2 mRNA and protein expressions were analysed by real-time PCR and Western blot analysis. Activation of nuclear factor kappa B (NF-κB) was analysed by the NF-κB-dependent luciferase activity and electrophoretic mobility-shift assay (EMSA). Curcumin inhibited COX-2 mRNA and protein synthesis in LPS-stimulated HGFs in a dose-dependent manner. P. gingivalis LPS activated NF-κB-dependent transcription in HGFs, which were also downregulated by pretreatment with curcumin. Therefore, curcumin can inhibit P. gingivalis LPS-induced COX-2 expression, which may be due to the inhibition of the NF-κB pathway.

Human umbilical cord mesenchymal stem cells suppress breast cancer tumourigenesis through direct cell-cell contact and internalization.

The purpose of this study was to investigate how human umbilical cord mesenchymal stem cells (HUMSCs) affect breast cancer tumourigenesis. To observe the influence of HUMSCs on tumourigenesis in vitro, we performed a co-culture of MDA MB-231 breast cancer cells with HUMSCs, and a result of HUMSCs on tumourigenesis in vivo was achieved by injection of HUMSCs into nonobese diabetic/severe combined immunodeficient mice following tumour establishment with MDA-MB231. During the co-culture, apoptosis of MDA-MB231 was noted, which was driven either by binding with HUMSC through direct cell-cell contact or by formation of a novel cell-in-cell phenomenon after internalization of HUMSC. Also, treatment with HUMSC injection was efficacious in both in situ and metastatic breast cancers in the animal models. Since HUMSCs were proved to efficaciously suppress breast cancer tumourigenesis both in vitro and in vivo, it is our expectation that treatment with HUMSCs can be a viable therapy for breast cancer in the near future. In addition, we share a new point of view on the role of HUMSCs in foetal development during pregnancy.

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.

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.

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.

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.

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.