Mammalian orthoreovirus capsid protein σ3 antagonizes RLR-mediated antiviral responses by degrading MAVS.

Mammalian orthoreovirus (MRV) outer capsid protein σ3 is a multifunctional protein containing a double-stranded RNA-binding domain, which facilitates viral entry and assembly. We reasoned that σ3 has an innate immune evasion function. Here, we show that σ3 protein localizes in the mitochondria and interacts with mitochondrial antiviral signaling protein (MAVS) to activate the intrinsic mitochondria-mediated apoptotic pathway. Consequently, σ3 protein promotes the degradation of MAVS through the intrinsic caspase-9/caspase-3 apoptotic pathway. Moreover, σ3 protein can also inhibit the expression of the components of the RNA-sensing retinoic acid-inducible gene (RIG)-like receptor (RLR) signaling pathway to block antiviral type I interferon responses. Mechanistically, σ3 inhibits RIG-I and melanoma differentiation-associated gene 5 expression is independent of its inhibitory effect on MAVS. Overall, we demonstrate that the MRV σ3 protein plays a vital role in negatively regulating the RLR signaling pathway to inhibit antiviral responses. This enables MRV to evade host defenses to facilitate its own replication providing a target for the development of effective antiviral drugs against MRV. IMPORTANCE: Mammalian orthoreovirus (MRV) is an important zoonotic pathogen, but the regulatory role of its viral proteins in retinoic acid-inducible gene-like receptor (RLR)-mediated antiviral responses is still poorly understood. Herein, we show that MRV σ3 protein co-localizes with mitochondrial antiviral signaling protein (MAVS) in the mitochondria and promotes the mitochondria-mediated intrinsic apoptotic pathway to cleave and consequently degrade MAVS. Furthermore, tryptophan at position 133 of σ3 protein plays a key role in the degradation of MAVS. Importantly, we show that MRV outer capsid protein σ3 is a key factor in antagonizing RLR-mediated antiviral responses, providing evidence to better unravel the infection and transmission mechanisms of MRV.

Mammalian reovirus µ1 protein attenuates RIG-I and MDA5-mediated signaling transduction by blocking IRF3 phosphorylation and nuclear translocation.

Mammalian reovirus (MRV) is a non-enveloped, gene segmented double-stranded RNA (dsRNA) virus. It is an important zoonotic pathogen that infects many mammals and vertebrates that act as natural hosts and causes respiratory and digestive tract diseases. Studies have reported that RIG-I and MDA5 in the innate immune cytoplasmic RNA-sensing RIG-like receptor (RLR) signaling pathway can recognize dsRNA from MRV and promote antiviral type I interferon (IFN) responses. However, the mechanism by which many MRV-encoded proteins evade the host innate immune response remains unclear. Here, we show that exogenous µ1 protein promoted the proliferation of MRV in vitro, while knockdown of MRV µ1 protein expression by shRNA could impair MRV proliferation. Specifically, µ1 protein inhibited MRV or poly(I:C)-induced IFN-ß expression, and attenuated RIG-I/MDA5-mediated signaling axis transduction during MRV infection. Importantly, we found that µ1 protein significantly decreased IFN-ß mRNA expression induced by MDA5, RIG-I, MAVS, TBK1, IRF3(5D), and degraded the protein expression of exogenous MDA5, RIG-I, MAVS, TBK1 and IRF3 via the proteasomal and lysosomal pathways. Additionally, we show that µ1 protein can physically interact with MDA5, RIG-I, MAVS, TBK1, and IRF3 and attenuate the RIG-I/MDA5-mediated signaling cascades by blocking the phosphorylation and nuclear translocation of IRF3. In conclusion, our findings reveal that MRV outer capsid protein µ1 is a key factor in antagonizing RLRs signaling cascades and provide new strategies for effective prevention and treatment of MRV infection.

Histone H1.2 Inhibited EMCV Replication through Enhancing MDA5-Mediated IFN-ß Signaling Pathway.

Histone H1.2 is a member of the linker histone family, which plays extensive and crucial roles not only in the regulation of chromatin dynamics, cell cycle, and cell apoptosis, but also in viral diseases and innate immunity response. Recently, it was discovered that H1.2 regulates interferon-ß and inhibits influenza virus replication, whereas its role in other viral infections is poorly reported. Here, we first found the up-regulation of H1.2 during Encephalomyocarditis virus (EMCV) infection, implying that H1.2 was involved in EMCV infection. Overexpression of H1.2 inhibited EMCV proliferation, whereas knockdown of H1.2 showed a significant promotion of virus infection in HEK293T cells. Moreover, we demonstrated that overexpression of H1.2 remarkably enhanced the production of EMCV-induced type I interferon, which may be the crucial factor for H1.2 proliferation-inhibitory effects. We further found that H1.2 up-regulated the expression of the proteins of the MDA5 signaling pathway and interacted with MDA5 and IRF3 in EMCV infection. Further, we demonstrated that H1.2 facilitated EMCV-induced phosphorylation and nuclear translocation of IRF3. Briefly, our research uncovers the mechanism of H1.2 negatively regulating EMCV replication and provides new insight into antiviral targets for EMCV.

Prognostic and immune infiltration features of disulfidptosis-related subtypes in breast cancer.

Breast cancer (BC) is a prominent cause of cancer incidence and mortality around the world. Disulfidptosis, a type of cell death, can induce tumor cell death. The purpose of this study was to analyze the potential impact of disulfidptosis-related genes (DRGs) on the prognosis and immune infiltration features of BC. Based on DRGs, we conducted an unsupervised clustering analysis on gene expression data of BC in TCGA-BRCA dataset and identified two BC subtypes, cluster1 and cluster2, with cluster1 showing a higher likelihood of favorable survival. Through immune analysis, we found that cluster1 had lower proportions of infiltration in immune-related cells, including aDCs, DCs, NK_cells, Th2_cells, and Treg. Based on the immunophenoscore (IPS) results, we inferred that cluster1 might benefit more from immune checkpoint inhibitors targeting CTLA-4 and PD1. Targeted small molecule prediction results showed that patients with cluster2 BC might respond better to antagonistic small molecule compounds, including clofazimine, lenalidomide, and epigallocatechin. Differentially expressed genes between the two subtypes were found to be enriched in signaling pathways related to steroid hormone biosynthesis, ovarian steroidogenesis, and neutrophil extracellular trap formation, according to enrichment analyses. In conclusion, this study identified BC subtypes based on DRGs so as to help predict patient prognosis and provide valuable tools for guiding clinical management and precise treatment of BC patients.

Targeting POLRMT by a first-in-class inhibitor IMT1 inhibits osteosarcoma cell growth in vitro and in vivo.

Osteosarcoma (OS) is a highly aggressive form of bone cancer that predominantly affects adolescents and young adults. In this study, we have undertaken an investigation into the potential anti-OS cell activity of IMT1 (inhibitor of mitochondrial transcription 1), a first-in-class inhibitor of RNA polymerase mitochondrial (POLRMT). IMT1 exhibited a profound inhibitory effect on cell survival, proliferation, cell cycle progression, and migration in primary and immortalized OS cells. Furthermore, this POLRMT inhibitor elicited apoptosis in the OS cells, without, however, inducing cytotoxicity in human osteoblasts or osteoblastic cells. IMT1 disrupted mitochondrial functions in OS cells, resulting in mitochondrial depolarization, oxidative injury, lipid peroxidation, and ATP reduction in OS cells. Silencing POLRMT using targeted shRNA closely mimicked the actions of IMT1 and exerted potent anti-OS cell activity. Importantly, IMT1's effectiveness was diminished in POLRMT-silenced OS cells. Subsequent investigations revealed that IMT1 suppressed the activation of the Akt-mammalian target of rapamycin (mTOR) cascade in OS cells. IMT1 treatment or POLRMT silencing in primary OS cells led to a significant reduction in Akt1-S6K-S6 phosphorylation. Conversely, it was enhanced upon POLRMT overexpression. The restoration of Akt-mTOR activation through the introduction of a constitutively active S473D mutant Akt1 (caAkt1) mitigated IMT1-induced cytotoxicity in OS cells. In vivo, oral administration of IMT1 robustly curtailed the growth of OS xenografts in nude mice. Furthermore, IMT1 suppressed POLRMT activity, impaired mitochondrial function, repressed Akt-mTOR activation, and induced apoptosis within xenograft tissues. Collectively, these findings underscore the potent growth-inhibitory effects attributed to IMT1 via targeted POLRMT inhibition. The utilization of this POLRMT inhibitor carries substantial therapeutic promise in the context of OS treatment.

Comparative study on the interaction between transferrin and flavonols: Experimental and computational modeling approaches.

Transferrin is the indispensable component in the body fluids and has been explored as a potential drug carrier for target drugs to cancer cells. Flavonols are widely distributed in plants and shown a wide range of biological activities. In the present study, the interaction between flavonols (including galangin, kaempferol, quercetin, and myricetin) and transferrin under physiological conditions was investigated by using experimental as well as computational approaches. Fluorescence data reveal that the fluorescence quenching mechanism of transferrin by flavonols is static quenching. Transferrin has moderate affinity with flavonols, and the binding constants (Ka) are 103-104 L/mol. In addition, there are two different binding sites for the interaction between kaempferol and transferrin. Thermodynamic parameter analysis shows that the interaction of flavonols and transferrin is synergistically driven by enthalpy and entropy. Hydrophobic interaction, electrostatic force and hydrogen bonds are the main force types. Synchronous fluorescence spectroscopy shows that flavonols decrease the hydrophobicity of the microenvironment around tryptophan (Trp) and have no effect on the microenvironment around tyrosine (Tyr). UV-vis and CD spectra show that the interaction between transferrin and flavonols leads to the loosening and unfolding of transferrin backbone. The increase of ß-sheet is accompanied by the decrease of α-helix and ß-turn. The specific binding sites of flavonols to transferrin are confirmed by molecular docking. Molecular dynamic simulation suggests that the transferrin-flavonols docked complex is stable throughout the simulation trajectory.

Numerical study on the wall-impinging diesel spray soot generation and oxidation in the cylinder under cold-start conditions of a diesel engine.

The combustion of wall-impinging diesel spray of heavy-duty diesel engines deteriorates combustion quality under cold-start conditions, making it difficult to control soot emissions. To investigate the causes of soot increase in the combustion of wall-impinging spray at low temperature and low speed starting conditions, the effect of the starting fuel mass on the soot formation and oxidation process was analyzed using a multidimensional computational fluid dynamics (CFD) model. The results show that the diesel spray is guided by the piston wall and the limited space, the spray impinged on the wall and the vapor-phase fuel flowed in the spray interaction zone. Thus, the soot mainly accumulates in the spray interaction zone, the region near the cylinder head and the bowl wall in the combustion chamber bowl. The soot from the vapor of deposited fuel film in the piston bowl wall and near wall region accumulates continuously in the after combustion stage, becoming the main source of soot emissions at the time of exhaust valve opening (EVO). Increasing the mass of starting fuel raises the mass of the rich mixture and wall-impinging fuel, which enhances the mismatch between fuel and air, resulting in higher soot generation, while soot is more difficult to be completely oxidized by OH radicals, and ultimately soot emissions increase significantly. It can be deduced that the engine-optimized injection strategy may mitigate the increase in soot emissions at high start-up fuel injection conditions.

Effect of wall parameters on impinging combustion and soot emission characteristics of heavy-duty diesel engine at low temperature.

The effect of wall parameters on combustion and soot emission characteristics remains to be revealed so far, especially in the case of spray impingement at low temperatures. Therefore, the visualization experiments are carried out in a constant volume combustion chamber using the Mie scattering and direct photography techniques, and the two-color method was used to extract the flame temperature and soot volume. The results show that increased wall distance and wall angle contribute to fast and stable ignition, but result in more soot production. In addition, the lower the ambient temperature, the more prominent the above characteristics are. At Tamb = 820 K, as the wall distance increases from 40 mm to 60 mm, the liquid spray impingement changes to the vapor impingement, so the ignition delay shortens, and the flame area and natural luminance increase significantly. At lower Tamb = 770 K, a complete misfire is observed at Lw = 40 mm but the ignition remains stable at Lw = 60 mm. The variation of the ignition characteristic parameters with the wall angle is similar to that of the wall distance. Under Pinj = 40 MPa, as the wall angle increases from 0° to 70°, the time to reach luminance saturation advances from 0.60 ms to 0.27 ms. Under higher Pinj = 100 MPa, a complete misfire occurs at θ =0° but bright flames are observed at θ =30-70°. With the increase of wall distance, the mean flame temperature increases due to reduced wall cooling. Coupled with the expanded flame area and combustion duration, the high-temperature region (>1800K) of soot distribution and KL factor increase significantly, especially in the range of Lw = 40-50 mm.

HSP27 Protein Dampens Encephalomyocarditis Virus Replication by Stabilizing Melanoma Differentiation-Associated Gene 5.

Heat shock proteins (HSPs) are a protein family that respond to physiological stress, such as heat, starvation, and infection. As cellular protein chaperones, they play an important role in protein folding, assembly, and degradation. Though it is well known that HSP27 is involved in a range of viral infections, its role during an encephalomyocarditis virus (EMCV) infection is not known. Here, we report that EMCV degrades HSP27 and that EMCV proteins 2Cpro and 3Apro are primarily responsible for its degradation. Consequently, loss of cellular HSP27 augmented EMCV proliferation, an effect that could be reversed upon HSP27 overexpression. Importantly, we found that HSP27 positively regulated EMCV-triggered type I interferon (IFN) production. Moreover, overexpression of 2Cpro and 3Apro significantly blocked type I IFN production. We also found for the first time that HSP27, as a molecular chaperone, can specifically interact with MDA5 and stabilize the expression of MDA5. Collectively, this study shows that HSP27 dampens EMCV infectivity by positively regulating EMCV-triggered retinoic acid-inducible gene (RIG)-I-like receptor (RLR)/melanoma differentiation-associated gene 5 (MDA5) signal pathway, while EMCV proteins 2Cpro and 3Apro interact with HSP27 and degrade HSP27 protein expression to allow EMCV proliferation. Our findings provide further mechanistic evidence for EMCV partaking in immune escape mechanisms, and that 2Cpro and 3Apro could serve as potential antiviral targets.

Comparative study on the interaction between flavonoids with different core structures and hyaluronidase.

Hyaluronidase (HAase) is an important enzyme involved in a promoting inflammation pathway. Flavonoids are a group of major polyphenols including flavonols (such as myricetin and rutin), dihydroflavones (such as naringin and hesperidin), and isoflavones (such as genistein and puerarin), which have been proved to possess anti-inflammatory effects. In this study, the binding of the six flavonoids to HAase was investigated by steady state and time-resolved fluorescence, circular dichroism (CD) spectroscopy and molecular docking methods. Fluorescence data reveal that the fluorescence quenching mechanism of HAase by flavonoids is all static quenching procedure regardless of their core structure. The binding affinity is strongest for rutin and ranks in the order rutin > hesperidin > myricetin > puerarin > genistein > naringin. The thermodynamic analysis implies that hydrophobic interaction, electrostatic force and hydrogen bonding are the main interaction forces. Synchronous fluorescence spectroscopy and CD spectroscopy indicate that flavonoids have the same core structure and have similar effects on the microenvironment around Trp and Tyr residues and the secondary structure of HAase. The results of molecular docking show that the binding of flavonoids with the catalytic amino acid residues of HAase may lead to the decrease of enzyme activity.

Myristoylation-mediated phase separation of EZH2 compartmentalizes STAT3 to promote lung cancer growth.

N-myristoylation is a crucial signaling and pathogenic modification process that confers hydrophobicity to cytosolic proteins. Although different large-scale approaches have been applied, a large proportion of myristoylated proteins remain to be identified. EZH2 is overexpressed in lung cancer cells and exerts oncogenic effects via its intrinsic methyltransferase activity. Using a well-established click chemistry approach, we found that EZH2 can be modified by myristoylation at its N-terminal glycine in lung cancer cells. Hydrophobic interaction is one of the main forces driving or stabilizing liquid-liquid phase separation (LLPS), raising the possibility that myristoylation can modulate LLPS by mediating hydrophobic interactions. Indeed, myristoylation facilitates EZH2 to form phase-separated liquid droplets in lung cancer cells and in vitro. Furthermore, we provide evidence that myristoylation-mediated LLPS of EZH2 compartmentalizes its non-canonical substrate, STAT3, and activates STAT3 signaling, ultimately resulting in accelerated lung cancer cell growth. Thus, targeting EZH2 myristoylation may have significant therapeutic efficacy in the treatment of lung cancer. Altogether, these observations not only extend the list of myristoylated proteins, but also indicate that hydrophobic lipidation may serve as a novel incentive to induce or maintain LLPS.

Acetylation-dependent glutamate receptor GluR signalosome formation for STAT3 activation in both transcriptional and metabolism regulation.

Besides their original regulating roles in the brain, spinal cord, retina, and peripheral nervous system for mediating fast excitatory synaptic transmission, glutamate receptors consisting of metabotropic glutamate receptors (GluRs) and ionotropic glutamate receptors (iGluRs) have emerged to have a critical role in the biology of cancer initiation, progression, and metastasis. However, the precise mechanism underpinning the signal transduction mediated by ligand-bound GluRs is not clearly elucidated. Here, we show that iGluRs, GluR1 and GluR2, are acetylated by acetyltransferase CREB-binding protein upon glutamate stimulation of cells, and are targeted by lysyl oxidase-like 2 for deacetylation. Acetylated GluR1/2 recruit ß-arrestin1/2 and signal transducer and activator of transcription 3 (STAT3) to form a protein complex. Both ß-arrestin1/2 and STAT3 are subsequently acetylated and activated. Simultaneously, activated STAT3 acetylated at lysine 685 translocates to mitochondria to upregulate energy metabolism-related gene transcription. Our results reveal that acetylation-dependent formation of GluR1/2-ß-arrestin1/2-STAT3 signalosome is critical for glutamate-induced cell proliferation.

Encephalomyocarditis Virus Abrogates the Interferon Beta Signaling Pathway via Its Structural Protein VP2.

Type I interferon (IFN)-mediated antiviral responses are critical for modulating host-virus responses, and indeed, viruses have evolved strategies to antagonize this pathway. Encephalomyocarditis virus (EMCV) is an important zoonotic pathogen, which causes myocarditis, encephalitis, neurological disease, reproductive disorders, and diabetes in pigs. This study aims to understand how EMCV interacts with the IFN pathway. EMCV circumvents the type I IFN response by expressing proteins that antagonize cellular innate immunity. Here, we show that EMCV VP2 is a negative regulator of the IFN-ß pathway. This occurs via the degradation of the MDA5-mediated cytoplasmic double-stranded RNA (dsRNA) antiviral sensing RIG-I-like receptor (RLR) pathway. We show that structural protein VP2 of EMCV interacts with MDA5, MAVS, and TBK1 through its C terminus. In addition, we found that EMCV VP2 could significantly degrade RLRs by the proteasomal and lysosomal pathways. For the first time, EMCV VP2 was shown to play an important role in EMCV evasion of the type I IFN signaling pathway. This study expands our understanding that EMCV utilizes its capsid protein VP2 to evade the host antiviral response.IMPORTANCE Encephalomyocarditis virus is an important pathogen that can cause encephalitis, myocarditis, neurological diseases, and reproductive disorders. It also causes huge economic losses for the swine industry worldwide. Innate immunity plays an important role in defending the host from pathogen infection. Understanding pathogen microorganisms evading the host immune system is of great importance. Currently, whether EMCV evades cytosolic RNA sensing and signaling is still poorly understood. In the present study, we found that viral protein VP2 antagonized the RLR signaling pathway by degrading MDA5, MAVS, and TBK1 protein expression to facilitate viral replication in HEK293 cells. The findings in this study identify a new mechanism for EMCV evading the host's innate immune response, which provide new insights into the virus-host interaction and help develop new antiviral approaches against EMCV.

Alteration of liver immunity by increasing inflammatory response during co-administration of methamphetamine and atazanavir.

Objective: Use of methamphetamine (METH) is prevalent among HIV-infected individuals. Previous research has shown that both METH and HIV protease inhibitors exert influences on mitochondrial respiratory metabolism and hepatic nervous system. This study aims to study the joint effect of METH and HIV protease inhibitors on hepatic immune function.Materials and methods: Based on the differentially expressed genes obtained from RNA-seq of the liver from mouse model, the expression levels of CD48 and Macrophage Receptor with Collagenous Structure (MARCO) were examined using qRT-PCR and flow cytometry, and the expression and secretion of cytokines IL-1ß, IL-6, IL-8, IL-10, IFN-γ, IFN-ß, and TNF-α were determined using qRT-PCR and ELISA in THP-1-derived macrophages.Results: Our results indicated that compared with the control group, CD48 molecules were significantly down-regulated by METH-atazanavir co-treatment, and the expression level of CD48 decreased as METH concentration increases. MARCO molecules were increased, especially at larger doses of METH and atazanavir treatment. In addition, in the presence of METH-atazanavir, the expression and secretion of a series of pro-inflammatory cytokines TNF-α, IL-1ß, IL-6, and IL-8 increased while the expression and secretion of anti-inflammatory cytokine IL-10 decreased.Conclusion: These results demonstrated that METH and atazanavir had a combined impact on the liver immunity, suggesting that the co-treatment could enhance inflammatory response and suppress NK cell activation via CD48.

Enhanced production of questin by marine-derived Aspergillus flavipes HN4-13.

Questin has favorable applications. Fractional factorial design, Box-Behnken design, and response surface methodology were adopted to optimize the fermentation conditions of the marine-derived fungus, Aspergillus flavipes HN4-13, thereby enhancing questin production. Optimal fermentation conditions in a 500-mL conical flask with 200 mL of medium were 4% soluble starch, 0.9% beef extract, 4% NaCl, 0.05% Na2HPO4, pH 6, 2% inoculum size, and shaking at 28 â„ƒ and 160 rpm/min for 7 days. The production of questin can achieve 64.93 ± 4.55 mg/L, with no significant difference from the predicted value (66.27 mg/L). Thus, this optimized process of questin production is feasible. Such production is 17-fold higher than that of the basal Sabouraud's dextrose medium. Results indicate the potential of A. flavipes HN4-13 in the large-scale production of questin through fermentation.

Risk factors and control of seizures in 778 Chinese patients undergoing initial resection of supratentorial meningiomas.

This retrospective study explored the risk factors for the occurrence of seizures in the pre- and postoperative period in patients undergoing supratentorial meningiomas surgery to investigate those who are likely to benefit from prophylactic antiepileptic drugs (AEDs). We reviewed the medical records of 778 supratentorial meningiomas patients who were operated at our institution between 2011 and 2012. A total of 100 (12.9%) patients experienced preoperative seizures; 41 patients (5.3%) experienced postoperative in-hospital seizures, and 91 (13.5%, n = 673) patients experienced postoperative seizures after discharge. Multivariate analysis revealed that motor cortex involvement (odds ratio [OR] 3.243, P < 0.001) and peritumoral edema ≥ 1 cm (OR 3.936, P < 0.001) were significant risk factors of preoperative seizures. Whereas presenting with headache (OR 0.259, P < 0.001) and age ≥ 55 years at surgery (OR 0.514, P = 0.009) showed decreased incidence of preoperative seizures. The involvement of motor cortex (OR 3.290, P = 0.003), postoperative Karnofsky Performance Scale (KPS) ≤ 70 (OR 5.389, P < 0.001), preoperative seizure (OR 4.003, P < 0.001), and occurrence of any medical/surgical complication (OR 3.925, P = 0.001) were significant risk factors for postoperative in-hospital seizures. Postoperative seizures after discharge were associated with tumor maximal diameter ≥ 3.5 cm (OR 1.903, P = 0.022), preoperative seizures (OR 4.350, P < 0.001), postoperative in-hospital seizures (OR 6.385, P < 0.001), and tumor recurrence/progression (OR 7.642, P < 0.001). The probability of seizure freedom in the 5-year follow-up was roughly 59% among patients with preoperative seizures, and 87% among patients without preoperative seizures. Cox regression analysis showed that tumor recurrence/progression (relative risk 2.987, 95% CI 1.517, 5.879, P = 0.002) was the only predictor of postoperative seizures in patients without a history of preoperative epilepsy. The use of postoperative prophylactic antiepileptic drug (AED) did not reduce the incidence of seizures in our analysis. Understanding the risk factors for seizures might help clinicians to predict their occurrence and develop effective anti-epileptic treatment strategies. Further prospective randomized controlled trials are needed to determine the risk factors for seizures and the efficacy of AED prophylaxis.

The role of iron in Parkinson's disease monkeys assessed by susceptibility weighted imaging and inductively coupled plasma mass spectrometry.

Mounting evidences indicated that elevated iron levels in the substantia nigra (SN) have been concerned as the underlying mechanisms of neurodegenerative diseases, including Parkinson's disease (PD). The present study used the 1-Methyl-4-phenyl-1, 2, 3, 6 -tetrahydropyridine (MPTP)-treated cynomolgus monkeys for PD to evaluate the usability of SWI for assessing iron deposition in the cerebral nuclei of PD. The results showed that susceptibility-weighted imaging (SWI) phase values of the ipsilateral (MPTP-lesion side) SN of MPTP-treated monkeys were lower than those in the contralateral SN of MPTP-treated monkeys and the same side of Control monkeys, suggesting that iron deposition were elevated in the affected side SN of MPTP-treated monkeys. Whereas MPTP has not effects on the SWI phase values in other detected brain regions of monkeys, including red nucleus (RN), putamen (PUT) and caudate nucleus (CA). Furthermore, ICP-MS results showed that MPTP increased the iron levels in MPTP injection side, but no in the ipsilateral striatum. Additionally, MPTP treatment did not affect the calcium and manganese levels in the detected brain regions of monkeys. However, Pearson correlation analysis results indicated that there were not relationship between SWI phase values in MPTP-lesion side of SN with the behavioral score, tyrosine hydroxylase (TH)-positive cells number and iron levels in the MPTP-lesion side of midbrain. Taken together, the results confirm the involvement of SN iron accumulations in the MPTP-treated monkey models for PD, and indirectly verify the usability of SWI for the measurement of iron deposition in the cerebral nuclei of PD.

Clinical characteristics of and treatment protocol for trapped temporal horn following resection of lateral ventricular trigone meningioma: a single-center experience.

OBJECTIVE: Trapped temporal horn (TTH) is a rare subtype of loculated hydrocephalus that is often managed surgically. The natural history of TTH is not well understood, and there are few data on the outcomes of conservative management of this condition. The aim of this study was to analyze the clinical features and outcomes of conservatively and surgically managed cases of TTH. METHODS: The authors retrospectively reviewed the clinical data for 19 consecutive cases of TTH that developed after microsurgical resection of lateral ventricular trigone meningioma between 2011 and 2015. RESULTS: The 19 cases involved 6 male and 13 female patients (mean age [± SD] 39.9 ± 13.8 years). The mean time interval from tumor resection to onset of TTH was 3.2 ± 3.0 months (range 3 days-10 months). Symptoms of intracranial hypertension were the most common complaints at presentation. The mean Karnofsky Performance Scale (KPS) score at onset was 52.1 ± 33.3 (range 10-90). Midline shift was observed in 15 cases (78.9%), and the mean amount of midline shift was 6.0 ± 4.8 mm (range 0-15 mm). Eleven cases (57.9%) were managed with surgical intervention, while 8 cases (42.1%) were managed conservatively. All patients (100%) showed improved clinical status over the course of 4.8 ± 1.0 years (range 2.8-6.3 years) of follow-up. The mean KPS score at last follow-up was 87.9 ± 11.3 (range 60-100). Eighteen patients (94.7%) showed signs of radiographic improvement, and 1 patient (5.3%) exhibited stable size of the temporal horn. Significant differences were observed between the surgical and nonsurgical cohorts for the following variables: KPS score at onset, presence of intracranial hypertension, and midline shift. The mean KPS score at onset was greater (better) in the nonsurgical group than in the surgical group (82.5 ± 8.9 vs 30 ± 25.7, p = 0.001). A greater proportion of patients in the surgical group presented with symptoms of intracranial hypertension (81.8% vs 0%, p = 0.001). The extent of midline shift was greater in the surgical group than in the nonsurgical group (9.0 ± 3.8 mm vs 2.0 ± 2.4 mm, p = 0.001). CONCLUSIONS: The majority of patients with TTH presented in a delayed fashion. TTH is not always a surgical entity. Spontaneous resolution of TTH may be under-reported. Conservative management with clinical and radiological follow-up is effective in selected patients.

Characteristic features and proposed classification in 69 cases of intracranial microcystic meningiomas.

Microcystic meningioma (MM) is a rare subtype of intracranial meningiomas, with clinical and radiologic features not well characterized in the literature. Based on our experience, we propose a classification system of intracranial MMs. We reviewed the medical records, radiographic studies, and operative notes of a group of consecutive patients with intracranial MM. The mean age of the 69 patients was 46.8 ± 10.6 years (range, 21-75 years). Three types of intracranial MMs could be identified. Type 1 MMs presented as a solid lesion, hypointense or isointense on T1WI, hyperintense on T2WI, and homogeneous or heterogeneous enhancement, and were found in 43 patients (67.2%). Type 2 MMs represented signals similar to CSF both on T1WI and T2WI, and faint reticular enhancement with marginal enhancement, and these were found in 7 patients (10.9%). Type 3 MMs consisted of cystic-solid or cystic lesion and were found in 14 patients (21.9%). Significant differences were observed among the different types of MMs for the following variables: sex, presence of severe peritumoral brain edema (PTBE), and extent of tumor resection. Females were found in all of patients with type 2 MMs, but were only 35.7% of those with type 3 MMs (P = 0.018). Severe PTBEs were more common among patients with type 1 MMs (55.8%) than among those with type 2 (14.3%) and type 3 MMs (14.3%) (P = 0.007). Type 1 MMs (97.7%) were associated with a significantly higher rate of gross total resection compared with the other two types (71.4 and 78.6%) (P = 0.019). Total length of hospital stay after craniotomy ranged from 4 to 30 days (median, 8 days). There were no significant differences in progression-free survival among the three types of MMs (P = 0.788). The current classification identifies three distinct types of intracranial MM based on their radiological findings and growth patterns. The type 1 MMs are more commonly associated with severe PTBE. Type 2 and Type 3 MMs have a higher predilection towards parasaggital location with venous involvement and therefore have a lower rate of gross total resection.

Risk of cancer death by comorbidity severity and use of adjuvant chemotherapy among women with locoregional breast cancer.

OBJECTIVES: To examine the associations of comorbidity and chemotherapy with breast cancer- and non-breast cancer-related death. MATERIALS AND METHODS: Included were women with invasive locoregional breast cancer diagnosed in 2004 from seven population-based cancer registries. Data were abstracted from medical records and verified with treating physicians when there were inconsistencies and missing information on cancer treatment. Comorbidity severity was quantified using the Adult Comorbidity Evaluation 27. Treatment guideline concordance was determined by comparing treatment received with the National Comprehensive Cancer Network guidelines. Kaplan-Meier method and multivariable Cox proportional hazards regressions were employed for statistical analyses. RESULTS: Of 5852 patients, 76% were under 70years old and 69% received guideline concordant adjuvant chemotherapy. Comorbidity was more prevalent in women age 70 and older (79% vs. 51%; p<0.001). After adjusting for tumor characteristics and treatment, severe comorbidity burden was associated with significantly higher cancer-related mortality in older patients (Hazard Ratio [HR]=2.38, 95% CI 1.08-5.24), but not in younger patients (HR=1.78, 95% CI 0.87-3.64). Among patients receiving guideline adjuvant chemotherapy, cancer-related mortality was significantly higher in older patients (HR=2.35, 95% CI 1.52-3.62), and those with severe comorbidity (HR=3.79, 95% CI 1.72-8.33). CONCLUSIONS: Findings suggest that, compared to women with no comorbidity, patients with breast cancer age 70 and older with severe comorbidity are at increased risk of dying from breast cancer, even after adjustment for adjuvant chemotherapy and other tumor and treatment differences. This information adds to risk-benefit discussions and emphasizes the need for further study of the role for adjuvant chemotherapy in these patient groups.