Publications by authors named "F Ida Hsu"

1,275 Publications

  • Page 1 of 1

Characteristics and overall survival in pediatric versus adult craniopharyngioma: a population-based study.

Childs Nerv Syst 2021 Feb 28. Epub 2021 Feb 28.

Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine, 101 The City Drive South, Orange, CA, 92868-3201, USA.

Purpose: This study uses a large-population national database to describe the presenting clinical, sociodemographic, treatment, and clinical outcome differences between pediatric and adult craniopharyngiomas.

Methods: This study utilized the 2004-2015 National Cancer Database and was queried for all cases of craniopharyngioma. Multivariate Cox proportional-hazards analysis was used to determine clinical and sociodemographic factors associated with mortality. Kaplan-Meier log-rank test determined differences in overall survival (OS) time.

Results: The cohort consisted of 3638 patients, with 816 (22.4%) pediatric (≤ 18 years) patients. Pediatric patients presented with significantly higher frequency of large tumors (> 3 cm, 54.1 vs. 31.8%, p < 0.001), lower frequency of papillary subtype (0.9 vs. 11.5%, p < 0.001), and were exclusively treated at academic centers (100 vs. 73.4%, p < 0.001). Pediatric patients had significantly higher rates of adjuvant radiation (34.3 vs. 22.3%; p < 0.001), and had significantly lower 90-day mortality (1.6 vs. 4.9%; p < 0.001); however, no significant differences in extent of resection (p = 0.93), length of hospital stay (p = 0.53), and 30-day readmissions (p = 0.06) were observed between pediatric and adult patients. On Kaplan-Meier log-rank test, there were no significant differences in OS in pediatric patients receiving gross total resection (GTR), subtotal resection (STR), or STR + adjuvant radiation (p = 0.68). Lastly, when comparing endoscopic and open surgical approaches in pediatric patients, there were no significant differences in extent of surgical resection (p = 0.81), length of hospital stay (p = 0.54), 30-day readmissions (p = 0.22), and 90-day mortality (p = 0.80).

Conclusion: Craniopharyngioma has improved OS in pediatric compared to adult patients. Pediatric craniopharyngioma patients are best managed within multidisciplinary teams at academic centers with an individualized approach.
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http://dx.doi.org/10.1007/s00381-021-05094-yDOI Listing
February 2021

Exfoliation of 2D materials by saponin in water: Aerogel adsorption / photodegradation organic dye.

Chemosphere 2021 Jan 27;274:129795. Epub 2021 Jan 27.

Department of Applied Science, National Taitung University, 369, Sec. 2, University Rd., Taitung City, 95092, Taiwan. Electronic address:

The biggest challenge for the paint industry is to clean the contaminated waste dye solution before it released into the water or to reuse it to create new paint and to protect the water from environmental pollution. Here in this work, exfoliating layered transition metal dichalcogenide materials prepare to the exfoliated 2D materials thin sheets in water with the assistance of natural saponin. Then, the three-dimensional (3D) MoS-aerogel composite was synthesized by using greenway exfoliated two-dimensional (2D) MoS thin sheets to form MoS-aerogel composite. The prepared 3D MoS-aerogel composite demonstrates excellent 94% methylene blue (MB) dye adsorption ability over 5 min. Moreover, the adsorbed MB of the MoS-aerogel shows ∼80% dye degradation activity in the presence of visible light. Therefore, these synthesized 3D MoS-aerogel composite could be an excellent candidate for photocatalytic applications in the future.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129795DOI Listing
January 2021

Exploring the Relationship Between Colorectal Cancer and Allopurinol: A Taiwanese Population-Based Propensity-Matched Case-Control Study.

J Clin Pharmacol 2021 Feb 12. Epub 2021 Feb 12.

Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan.

The role of allopurinol usage in colorectal cancer (CRC) has no definite conclusion. The aim of this study is to explore the correlation between allopurinol usage and CRC risk in Taiwan. Using the National Health Insurance Database, we conducted a case-control study of cases who were ≥20 years old and newly diagnosed CRC for the period from 2000 to 2013. The controls were matched to cases by age, sex, index year, comorbidities, and socio-economic status using propensity scores. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were measured by the conditional logistic regression model. We examined 4372 cases and 4372 matched controls. A statistically significant correlation was noted between allopurinol usage and CRC risk (OR 0.79, 95% CI 0.69-0.90). We used the cumulative-defined daily doses (cDDDs) in a further subgroup analysis, the ORs decreased from tertile 1 (T1, low dose, < 12 cDDDs), T2 (medium dose, 12-88.5 cDDDs), to T3 (high dose, > 88.5 cDDDs). These values were 0.85 (95% CI 0.69-1.06), 0.77 (95% CI 0.62-0.95), to 0.76 (95% CI 0.61-0.94). The results indicated a dose-response relationship between allopurinol usage and CRC risk (p for trend < 0.001). We thus inferred that patients with medium and high doses of allopurinol (≥12 cDDDs) had a statistically significantly decreased CRC risk. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jcph.1832DOI Listing
February 2021

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Drug Metab Dispos 2021 Feb 2. Epub 2021 Feb 2.

DMPK, Genentech, United States of America

Volume of distribution (V) is a primary pharmacokinetic parameter used to calculate the half-life and plasma concentration-time profile of drugs. Numerous models have been relatively successful in predicting V, but the model developed by Korzekwa and Nagar is of particular interest because it utilizes plasma protein binding and microsomal binding data, both of which are readily available parameters. Here, Korzekwa and Nagar's model was validated and expanded upon using external and internal datasets. Tissue binding, plasma protein binding, V, physiochemical, and physiological datasets were procured from literature and Genentech's internal database. First, we investigated the hypothesis that tissue binding is primarily governed by passive processes that depend on the lipid composition of the tissue type. The fraction unbound in tissues (fu)was very similar across human, rat, and mouse. In addition, we showed that dilution factors could be generated from non-linear regression so that one fu value could be used to estimate another one regardless of species. More importantly, results suggested that microsomes could serve as a surrogate for tissue binding. We applied the parameters from Korzekwa and Nagar's V model to two distinct liver microsomal datasets and found remarkably close statistical results. Brain and lung datasets also accurately predicted V, further validating the model. V prediction accuracy for compounds with LogD > 1 significantly outperformed that of more hydrophilic compounds. Finally, human V predictions from Korzekwa and Nagar's model appear to be as accurate as rat allometry and slightly less accurate than dog and cyno allometry. We showed that tissue binding is comparable in three tissues across species and the fraction unbound in tissue can be interconverted with a dilution factor. In addition, we applied internal and external datasets to the volume of distribution model developed by Korzekwa and Nagar and found comparable V prediction accuracy between the V model and allometry. Our findings could potentially accelerate the drug R&D process by reducing the amount of resources associated with binding and animal experiments.
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http://dx.doi.org/10.1124/dmd.120.000337DOI Listing
February 2021

THZ1, a covalent CDK7 inhibitor, enhances gemcitabine-induced cytotoxicity via suppression of Bcl-2 in urothelial carcinoma.

Am J Cancer Res 2021 1;11(1):171-180. Epub 2021 Jan 1.

Department of Urology, College of Medicine, National Taiwan University and National Taiwan University Hospital Taipei, Taiwan.

Chemotherapy with gemcitabine plus cisplatin remains the mainstay of treatment for metastatic urothelial carcinoma (UC); however, drug resistance occurs in most patients and eventually leads to treatment failure. In this study, we investigated the role of cyclin-dependent kinase 7 (CDK7) regulation in the treatment of human UCs. Moreover, we studied the effect of THZ1, a CDK7 inhibitor, alone and in combination with gemcitabine, on UCs and explored the underlying mechanism. Immunohistochemical staining showed that CDK7 expression was significantly higher in UC tumors than in counterpart urothelium. THZ1 elicited dose-dependent cytotoxicity and apoptosis in two high-grade UC cells (BFTC905 and T24). THZ1 co-treatment potentiated gemcitabine-induced cytotoxicity with suppression of B-cell lymphoma 2 (Bcl-2). Studies with a xenograft nude mouse model also confirmed that THZ1 enhanced the antitumor effect of gemcitabine on UC. These findings provide important pilot data to target CDK7 or Bcl-2 for the treatment of UCs and for overcoming chemoresistance in UCs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840706PMC
January 2021

Restoring Fertility for Novel Interspecific Hybrids between and Using Colchicine Treatment.

Plants (Basel) 2021 Jan 22;10(2). Epub 2021 Jan 22.

Department of Horticulture and Landscape Architecture, National Taiwan University, Taipei 10617, Taiwan.

Interspecific hybridization is an effective strategy in breeding programs for the introduction of new traits. Wild species within the genus are valuable genetic resources for providing new horticulture traits and to improve environmental adaptations. However, reproductive barriers associated with fertilization and hybrid sterility must be overcome to produce fertile hybrid progenies. To approach the breeding objectives for cut flower cultivars with long stem traits and adaptation to tropical/subtropical regions, a tropical species endemic to Taiwan, Kudo, was used as a parent to cross with other long stem species. Reciprocal crossing was effective in overcoming interspecific unilateral incompatibility in our crossed pairs. One superior hybrid, '103-1', produced capsules without seeds by selfing and backcrossing with pollens from either parent. Other than the seedless trait, failure of pollen releasing from anther, pollen aggregation and no pollen germination in '103-1' suggested its F sterility. Colchicine treatments on apical buds of '103-1' successfully overcame potential meiotic abnormalities by doubling ploidy. For the first time, fertile interspecific hybrids of and Engler were generated. The fertile hybrid has further produced progeny populations by crossing with or von Poelln, 'Ida'.
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http://dx.doi.org/10.3390/plants10020209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911985PMC
January 2021

Circulating Exosomal Integrin β3 Is Associated with Intracranial Failure and Survival in Lung Cancer Patients Receiving Cranial Irradiation for Brain Metastases: A Prospective Observational Study.

Cancers (Basel) 2021 Jan 20;13(3). Epub 2021 Jan 20.

Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei 100, Taiwan.

Brain metastasis (BM) is a major problem in patients with cancer. Exosomes or extracellular vesicles (EV) and integrins contribute to the development of BM, and exosomal integrins have been shown to determine organotropic metastasis. We hypothesized that circulating EV integrins are able to influence the failure patterns and outcomes in patients treated for BM. We prospectively enrolled 75 lung cancer patients with BM who received whole brain radiotherapy (WBRT). We isolated and quantified their circulating EV integrins, and analyzed the association of EV integrins with clinical factors, survival, and intracranial/extracranial failure. Circulating EV integrin levels were independent of age, sex, histology, number of BM, or graded prognostic assessment score. Age, histology, and graded prognostic assessment score correlated with survival. Patients with higher levels of circulating EV integrin β3 had worse overall survival (hazard ratio: 1.15 per 1 ng/mL increase; = 0.04) following WBRT. Multivariate regression analysis also showed a higher cumulative incidence of intracranial failure (subdistribution hazard ratio: 1.216 per 1 ng/mL increase; = 0.037). In conclusion, circulating EV integrin β3 levels correlated with survival and intracranial control of patients with lung cancer after WBRT for BM. This supports that EV integrin β3 mediates a brain-tropic metastasis pattern, and may serve as a novel prognostic biomarker for BM.
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http://dx.doi.org/10.3390/cancers13030380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864205PMC
January 2021

Complete Characterization of Polyacyltrehaloses from H37Rv Biofilm Cultures by Multiple-Stage Linear Ion-Trap Mass Spectrometry Reveals a New Tetraacyltrehalose Family.

Biochemistry 2021 Feb 25;60(5):381-397. Epub 2021 Jan 25.

Mass Spectrometry Resource, Division of Endocrinology, Diabetes, Metabolism, and Lipid Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, United States.

Polyacylated trehaloses in play important roles in pathogenesis and structural roles in the cell envelope, promoting the intracellular survival of the bacterium, and are potential targets for drug development. Herein, we describe a linear ion-trap multiple-stage mass spectrometric approach (LIT MS) with high-resolution mass spectrometry to the structural characterization of a glycolipid family that includes a 2,3-diacyltrehalose, 2,3,6-triacyltrehalose, 2,3,6,2',4'-petaacyltrehalose, and a novel 2,3,6,2'-tetraacyltrehalose (TetraAT) subfamily isolated from biofilm cultures of H37Rv. The LIT MS spectra ( = 2, 3, or 4) provide structural information to unveil the location of the palmitoyl/stearoyl and one to four multiple methyl-branched fatty acyl substituents attached to the trehalose backbone, leading to the identification of hundreds of glycolipid species with many isomeric structures. We identified a new TetraAT subfamily whose structure has not been previously defined. We also developed a strategy for defining the structures of the multiple methyl-branched fatty acid substituents, leading to the identification of mycosanoic acid, mycolipenic acid, mycolipodienoic acid, mycolipanolic acid, and a new cyclopropyl-containing acid. The observation of the new TetraAT family, and the realization of the structural similarity between the various subfamilies, may have significant implications in the biosynthetic pathways of this glycolipid family.
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http://dx.doi.org/10.1021/acs.biochem.0c00956DOI Listing
February 2021

Genetic Knowledge and Communication Among Mexican Farmworkers and Non-farmworkers in North Carolina.

J Immigr Minor Health 2021 Jan 19. Epub 2021 Jan 19.

Department of Family and Community Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.

It is important to understand genetics within the context of health. This paper assesses (a) genetic knowledge among Mexican-born farmworker and non-farmworker adults; (b) their interpersonal and device sources of genetic knowledge; and (c) the association between their genetic knowledge and the sources of this genetic knowledge.Interviews were conducted with Mexican-born farmworkers (100) and non-farmworkers (100) in North Carolina. Participants answered 15 questions to assess genetic knowledge, and sources from which they had seen or heard about genes and genetics.Results show limited knowledge of genetics, with farmworkers and non-farmworkers providing a similar level of correct responses (6.6 versus 7.3), but with farmworkers providing more incorrect responses (4.0 versus 2.7). Important sources of genetic information for farmworkers were promotoras (47%), compared to teachers (49%) for non-farmworkers.This study demonstrates a need for increased dissemination of genetic information to Mexican-origin farmworkers and non-farmworkers.
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http://dx.doi.org/10.1007/s10903-020-01136-wDOI Listing
January 2021

Characteristics and overall survival in pediatric versus adult skull base chordoma: a population-based study.

Childs Nerv Syst 2021 Jan 18. Epub 2021 Jan 18.

Department of Neurosurgery, University of California, Irvine, CA, USA.

Purpose: Less than 5% of chordomas occur in pediatric patients. While many studies have explored the treatment and outcomes of skull base chordomas, few have focused on the differences between pediatric and adult populations. The aim of this study is to analyze the epidemiological variables and clinical outcomes between pediatric and adult skull base chordomas using a large-sample, population-based cancer database.

Methods: The National Cancer Database was queried between 2004 and 2015 for skull base chordomas. We stratified patients as pediatric (<18 years) and adults (≥18 years). We compared several clinical covariates between the two groups.

Results: Our cohort consisted of 658 patients, 61 pediatric (9.3%), and 597 adults (90.7%). Pediatric patients were more likely to have larger tumor size (41.4 ± 15.7 mm versus 34.1 ± 15.8 mm, p < 0.01) and universally treated at academic facilities. There was no significant difference in overall survival.

Conclusions: Pediatric skull base chordomas are rare tumors that are managed with aggressive surgical resection, followed by radiation. While there may be difference between tumor presentation, outcomes between pediatric and adult patients are similar.
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http://dx.doi.org/10.1007/s00381-021-05046-6DOI Listing
January 2021

A retrospective study of clinicopathologic and molecular features of inoperable early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy.

J Formos Med Assoc 2021 Jan 12. Epub 2021 Jan 12.

Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Background/purpose: Stereotactic ablative radiotherapy (SABR) is the treatment of choice for medically inoperable, early-stage non-small cell lung cancer (ES-NSCLC). The influence of oncogenic driver alterations and comorbidities are not well known. Here we present treatment outcomes based on clinicopathologic features and molecular profiles.

Methods: We retrospectively analyzed patients treated with SABR for inoperable ES-NSCLC. Molecular features of oncogenic driver alterations included EGFR, ALK, and ROS1. Comorbidities were assessed using the age-adjusted Charlson Comorbidity Index (ACCI). Survival was calculated using the Kaplan-Meier method. The Cox regression model was performed for univariate and multivariate analyses of prognostic factors. Competing risk analysis was used to evaluate the cumulative incidence of disease progression.

Results: From 2008 to 2020, 100 patients (median age: 82 years) were enrolled. The majority of patients were male (64%), ever-smokers (60%), and had adenocarcinoma (65%). With a median follow-up of 21.5 months, the median overall survival (OS) and real-world progression-free survival were 37.7 and 25.1 months, respectively. The competing-risk-adjusted 3-year cumulative incidences of local, regional, and disseminated failure were 8.2%, 14.5%, and 31.2%, respectively. An ACCI ≥7 was independently associated with inferior OS (hazard ratio [HR] 2.45, p = 0.03). Tumor size ≥4 cm (HR 4.16, p < 0.001) was the most important independent prognostic factor predicting real-world progression. EGFR mutation status had no impact on the outcomes.

Conclusion: SABR provides excellent local control in ES-NSCLC, although disseminated failures remains a major concern. ACCI is the best indicator for OS, while tumor sizes ≥4 cm predicts poor disease control.
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http://dx.doi.org/10.1016/j.jfma.2020.12.028DOI Listing
January 2021

An interbacterial DNA deaminase toxin directly mutagenizes surviving target populations.

Elife 2021 Jan 15;10. Epub 2021 Jan 15.

Department of Microbiology, University of Washington School of Medicine, Seattle, United States.

When bacterial cells come in contact, antagonism mediated by the delivery of toxins frequently ensues. The potential for such encounters to have long-term beneficial consequences in recipient cells has not been investigated. Here, we examined the effects of intoxication by DddA, a cytosine deaminase delivered via the type VI secretion system (T6SS) of . Despite its killing potential, we observed that several bacterial species resist DddA and instead accumulate mutations. These mutations can lead to the acquisition of antibiotic resistance, indicating that even in the absence of killing, interbacterial antagonism can have profound consequences on target populations. Investigation of additional toxins from the deaminase superfamily revealed that mutagenic activity is a common feature of these proteins, including a representative we show targets single-stranded DNA and displays a markedly divergent structure. Our findings suggest that a surprising consequence of antagonistic interactions between bacteria could be the promotion of adaptation via the action of directly mutagenic toxins.
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http://dx.doi.org/10.7554/eLife.62967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901873PMC
January 2021

The adverse events of haematopoietic stem cell transplantation are associated with gene polymorphism within human leukocyte antigen region.

Sci Rep 2021 Jan 14;11(1):1475. Epub 2021 Jan 14.

Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan City, 333, Taiwan.

Adverse reactions may still occur in some patients after receiving haematopoietic stem cell transplantation (HSCT), even when choosing a human leukocyte antigen (HLA)-matched donor. The adverse reactions of transplantation include disease relapse, graft-versus-host disease (GVHD), mortality and CMV infection. However, only the relapse was discussed in our previous study. Therefore, in this study, we investigated the correlation between the gene polymorphisms within the HLA region and the adverse reactions of post-HSCT in patients with acute leukaemia (n = 176), where 72 patients were diagnosed with acute lymphocytic leukaemia (ALL) and 104 were acute myeloid leukaemia (AML). The candidate single nucleotide polymorphisms were divided into three models: donor, recipient, and donor-recipient pairs and the data of ALL and AML were analysed individually. Based on the results, we found 16 SNPs associated with the survival rates, the risk of CMV infection, or the grade of GVHD in either donor, recipient, or donor-recipient matching models. In the ALL group, the rs209132 of TRIM27 in the donor group was related to CMV infection (p = 0.021), the rs213210 of RING1 in the recipient group was associated with serious GVHD (p = 0.003), and the rs2227956 of HSPA1L in the recipient group correlated with CMV infection (p = 0.001). In the AML group, the rs3130048 of BAG6 in the donor-recipient pairs group was associated with serious GVHD (p = 0.048). Moreover, these SNPs were further associated with the duration time of survival after transplantation. These results could be applied to select the best donor in HSCT.
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http://dx.doi.org/10.1038/s41598-020-79369-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809291PMC
January 2021

Osteoblasts derived from mouse mandible enhance tumor growth of prostate cancer more than osteoblasts derived from long bone.

J Bone Oncol 2021 Feb 30;26:100346. Epub 2020 Dec 30.

Department of Cancer Biology and Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.

Prostate cancer (PCa) metastasizes to bone, where the bone marrow microenvironment controls disease progression. However, the cellular interactions that result in active bone marrow metastases are poorly understood. A better understanding of these interactions is critical to success in the pursuit of effective treatments for this life ending disease. Anecdotally, we observe that after intracardiac injection of PCa cells, one of the greatest tools to investigate the mechanisms of bone-metastatic disease, animals frequently present with mandible metastasis before hind limb metastasis. Therefore, in this study, we investigated whether the bone cells derived from the mouse mandible influence PCa progression differently than those from the hind limb. Interestingly, we found that osteoblasts harvested from mouse mandibles grew faster, expressed more vascular endothelial growth factor (VEGF), increased vascularity and formed more bone, and stimulated faster growth of PCa cells when cultured together than osteoblasts harvested from mouse hind limbs. Additionally, these findings were confirmed when mouse mandible osteoblasts were co-implanted into mice with PCa cells. Importantly, the enhancement of PCa growth mediated by mandible osteoblasts was not shown to be due to their differentiation or proliferation activities, but may be partly due to increased vascularization and expression of VEGF.
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http://dx.doi.org/10.1016/j.jbo.2020.100346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779864PMC
February 2021

Lenvatinib Inhibits AKT/NF-κB Signaling and Induces Apoptosis Through Extrinsic/Intrinsic Pathways in Non-small Cell Lung Cancer.

Anticancer Res 2021 Jan;41(1):123-130

Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C.;

Background/aim: Non-small cell lung cancer (NSCLC) is a serious disease and the leading cause of death globally. Overexpression of protein kinase B/nuclear factor-kappa B (NF-κB) signaling transduction of NSCLC cells was recognized as a potential therapeutic target. Lenvatinib is a multiple kinase inhibitor against vascular endothelial growth factor receptor family. However, whether lenvatinib may affect AKT/NF-κB in NSCLC remains unknown.

Materials And Methods: MTT assay, NF-κB reporter gene assay, flow cytometry, tranwell migration/invasion analysis and western blotting were used to identify the alteration of cell viability, NF-κB activation, apoptosis effect, migration/invasion potential and AKT/NF-κB related protein expression, respectively, in CL-1-5-F4 cells after lenvatinib treatment.

Results: The cell viability and NF-κB activity were suppressed by lenvatinib. Extrinsic and intrinsic apoptosis were activated by lenvatinib. Additionally, the metastatic potential of CL-1-5-F4 cells was also suppressed by lenvatinib.

Conclusion: Altogether, lenvatinib induced extrinsic/intrinsic apoptosis and suppressed migration/invasion ability of NSCLC cells that was associated with AKT/NF-κB signaling inactivation.
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http://dx.doi.org/10.21873/anticanres.14757DOI Listing
January 2021

Brain cell-derived exosomes in plasma serve as neurodegeneration biomarkers in male cynomolgus monkeys self-administrating oxycodone.

EBioMedicine 2021 Jan 6;63:103192. Epub 2021 Jan 6.

Department of Cancer Biology, Wake Forest Baptist Medical Center, United States; Comprehensive Cancer Center, Wake Forest Baptist Health, United States; Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, United States; Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC, United States. Electronic address:

Background: The United States is currently facing an opioid crisis. Novel tools to better comprehend dynamic molecular changes in the brain associated with the opioid abuse are limited. Recent studies have suggested the usefulness of plasma exosomes in better understanding CNS disorders. However, no study has ever characterized exosomes (small extracellular vesicles of endocytic origin) secreted by brain cells to understand the potential neurodegenerative effects of long-term oxycodone self-administration (SA).

Methods: MRI of Cynomolgus monkeys (Macaca fascicularis) was performed to assess alterations in gray matter volumes with oxycodone SA. We isolated total exosomes (TE) from the plasma of these monkeys; from TE, we pulled-out neuron-derived exosomes (NDE), astrocytes-derived exosomes (ADE), and microglia-derived exosomes (MDE) using surface biomarkers L1CAM (L1 cell adhesion molecule), GLAST (Glutamate aspartate transporter) and TMEM119 (transmembrane protein119), respectively.

Findings: We observed a significantly lower gray matter volume of specific lobes of the brain (frontal and parietal lobes, and right putamen) in monkeys with ∼3 years of oxycodone SA compared to controls. Higher expression of neurodegenerative biomarkers (NFL and α-synuclein) correlates well with the change in brain lobe volumes in control and oxycodone SA monkeys. We also identified a strong effect of oxycodone SA on the loading of specific miRNAs and proteins associated with neuro-cognitive disorders. Finally, exosomes subpopulation from oxycodone SA group activated NF-κB activity in THP1- cells.

Interpretation: These results provide evidence for the utility of brain cells-derived exosomes from plasma in better understanding and predicting the pro-inflammatory and neurodegenerative consequence of oxycodone SA.

Funding: NIH.
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http://dx.doi.org/10.1016/j.ebiom.2020.103192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804975PMC
January 2021

Siglec-E retards atherosclerosis by inhibiting CD36-mediated foam cell formation.

J Biomed Sci 2021 Jan 5;28(1). Epub 2021 Jan 5.

Institute of Biomedical Sciences, Academia Sinica, No.128, Sec.II, Academy Road, Taipei, 115, Taiwan.

Background: The accumulation of lipid-laden macrophages, foam cells, within sub-endothelial intima is a key feature of early atherosclerosis. Siglec-E, a mouse orthologue of human Siglec-9, is a sialic acid binding lectin predominantly expressed on the surface of myeloid cells to transduce inhibitory signal via recruitment of SH2-domain containing protein tyrosine phosphatase SHP-1/2 upon binding to its sialoglycan ligands. Whether Siglec-E expression on macrophages impacts foam cell formation and atherosclerosis remains to be established.

Methods: ApoE-deficient (apoE) and apoE/Siglec-E-double deficient (apoE/Siglec-E) mice were placed on high fat diet for 3 months and their lipid profiles and severities of atherosclerosis were assessed. Modified low-density lipoprotein (LDL) uptake and foam cell formation in wild type (WT) and Siglec-E- peritoneal macrophages were examined in vitro. Potential Siglec-E-interacting proteins were identified by proximity labeling in conjunction with proteomic analysis and confirmed by coimmunoprecipitation experiment. Impacts of Siglec-E expression and cell surface sialic acid status on oxidized LDL uptake and signaling involved were examined by biochemical assays.

Results: Here we show that genetic deletion of Siglec-E accelerated atherosclerosis without affecting lipid profile in apoE mice. Siglec-E deficiency promotes foam cell formation by enhancing acetylated and oxidized LDL uptake without affecting cholesterol efflux in macrophages in vitro. By performing proximity labeling and proteomic analysis, we identified scavenger receptor CD36 as a cell surface protein interacting with Siglec-E. Further experiments performed in HEK293T cells transiently overexpressing Siglec-E and CD36 and peritoneal macrophages demonstrated that depletion of cell surface sialic acids by treatment with sialyltransferase inhibitor or sialidase did not affect interaction between Siglec-E and CD36 but retarded Siglec-E-mediated inhibition on oxidized LDL uptake. Subsequent experiments revealed that oxidized LDL induced transient Siglec-E tyrosine phosphorylation and recruitment of SHP-1 phosphatase in macrophages. VAV, a downstream effector implicated in CD36-mediated oxidized LDL uptake, was shown to interact with SHP-1 following oxidized LDL treatment. Moreover, oxidized LDL-induced VAV phosphorylation was substantially lower in WT macrophages comparing to Siglec-E counterparts.

Conclusions: These data support the protective role of Siglec-E in atherosclerosis. Mechanistically, Siglec-E interacts with CD36 to suppress downstream VAV signaling involved in modified LDL uptake.
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http://dx.doi.org/10.1186/s12929-020-00698-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784283PMC
January 2021

Temporal focusing multiphoton microscopy with optimized parallel multiline scanning for fast biotissue imaging.

J Biomed Opt 2021 Jan;26(1)

National Chiao Tung University, College of Photonics, Tainan, Taiwan.

Significance: Line scanning-based temporal focusing multiphoton microscopy (TFMPM) has superior axial excitation confinement (AEC) compared to conventional widefield TFMPM, but the frame rate is limited due to the limitation of the single line-to-line scanning mechanism. The development of the multiline scanning-based TFMPM requires only eight multiline patterns for full-field uniform multiphoton excitation and it still maintains superior AEC.

Aim: The optimized parallel multiline scanning TFMPM is developed, and the performance is verified with theoretical simulation. The system provides a sharp AEC equivalent to the line scanning-based TFMPM, but fewer scans are required.

Approach: A digital micromirror device is integrated in the TFMPM system and generates the multiline pattern for excitation. Based on the result of single-line pattern with sharp AEC, we can further model the multiline pattern to find the best structure that has the highest duty cycle together with the best AEC performance.

Results: The AEC is experimentally improved to 1.7  μm from the 3.5  μm of conventional TFMPM. The adopted multiline pattern is akin to a pulse-width-modulation pattern with a spatial period of four times the diffraction-limited line width. In other words, ideally only four π  /  2 spatial phase-shift scans are required to form a full two-dimensional image with superior AEC instead of image-size-dependent line-to-line scanning.

Conclusions: We have demonstrated the developed parallel multiline scanning-based TFMPM has the multiline pattern for sharp AEC and the least scans required for full-field uniform excitation. In the experimental results, the temporal focusing-based multiphoton images of disordered biotissue of mouse skin with improved axial resolution due to the near-theoretical limit AEC are shown to clearly reduce background scattering.
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http://dx.doi.org/10.1117/1.JBO.26.1.016501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778456PMC
January 2021

Executive functions in agenesis of the corpus callosum: Working memory and sustained attention in the BTBR inbred mouse strain.

Brain Behav 2021 Jan 10;11(1):e01933. Epub 2020 Dec 10.

U.S. Department of Veterans Affairs, Coatesville, PA, USA.

Introduction: Agenesis of the corpus callosum (AgCC) is characterized by the congenital partial or complete absence of the corpus callosum. Several strains of mice have been reported to carry AgCC, with the BTBR T Itpr3 /J (BTBR) inbred mouse strain consistently showing a complete absence of the corpus callosum, as well as a variable reduction in the size of the hippocampal commissure. While much research has focused on the social deficits of the BTBR strain, little research on its cognitive behavior has been conducted. The goal of our study was to compare two facets of executive functioning, spatial working memory, and sustained attention between the BTBR and C57BL/6J (B6) strains.

Methods: Spatial working memory was measured utilizing a delayed matching-to-position (DMTP) task and sustained attention was measured utilizing an operant task in which mice were trained to distinguish signal and nonsignal events.

Results: Both the BTBR and B6 mice demonstrated a predictable decline in performance on the DMTP task as the delay interval increased and predictable increase in performance on the sustained attention task as the duration of the signal event increased. Although no significant differences were found between strains on the performance of these tasks, there was a significant difference in learning the association between lever pressing and food reward. Histological investigation confirmed the complete absence of commissural fibers from the corpus callosum, but also the hippocampal commissure, counter to a previous study.

Conclusion: The results suggest spatial working memory and sustained attention are unaffected by the absence of these commissural fibers alone.
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http://dx.doi.org/10.1002/brb3.1933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821616PMC
January 2021

Anticancer Efficacy and Mechanism of Amentoflavone for Sensitizing Oral Squamous Cell Carcinoma to Cisplatin.

Anticancer Res 2020 Dec 7;40(12):6723-6732. Epub 2020 Dec 7.

Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C.

Background/aim: Nuclear factor kappa B (NF-κB) inactivation and apoptosis activation have been shown to enhance the anticancer effect of cisplatin in oral squamous cell carcinoma (OSCC). Amentoflavone may suppress NF-κB activity and trigger apoptosis in different types of cancer. The aim of this study was to investigate the anticancer effect and mechanism of amentoflavone in combination with cisplatin in OSCC.

Materials And Methods: We investigated the combination effect and mechanism of amentoflavone and cisplatin via cell viability analysis, flow cytometry-based apoptosis analyses, transwell migration/invasion assay, immunofluorescence staining and western blotting assay.

Results: Both amentoflavone and QNZ (NF-κB inhibitor) significantly increased cisplatin-induced cytotoxicity. Amentoflavone reduced cisplatin-triggered NF-κB activity and enhanced cisplatin-induced intrinsic caspase-dependent and independent apoptotic pathways. Moreover, amentoflavone augments cisplatin-suppressed invasion and migration ability of OSCC cells.

Conclusion: Inactivation of NF-κB and induction of apoptosis through intrinsic caspase-dependent and independent apoptotic pathways are associated with amentoflavone enhanced anti-OSCC efficacy of cisplatin.
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http://dx.doi.org/10.21873/anticanres.14695DOI Listing
December 2020

Electrospray ionization with higher-energy collision dissociation tandem mass spectrometry toward characterization of ceramides as [M + Li] ions: Mechanisms of fragmentation and structural identification.

Authors:
Fong-Fu Hsu

Anal Chim Acta 2021 Jan 5;1142:221-234. Epub 2020 Oct 5.

Mass Spectrometry Resource, Division of Endocrinology, Diabetes, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63130, USA. Electronic address:

Ceramide is a huge lipid family consisting of diversified structures in which various modifications are seen in the fatty acyl chain and the long chain base (LCB). In this contribution, a higher collision energy (HCD) linear ion-trap mass spectrometric method (LIT MS) was applied to study the mechanisms underlying the fragmentation processes of ceramide molecules in 12 subclasses, which were desorbed by ESI as the [M + Li] ions. Multiple sets of fragment ions reflecting the fatty acyl chain and LCB were observed in the HCD MS spectra for all the ceramide classes, resulting in unambiguous definition of the ceramide structures, including the chain length and the modification (α-hydroxy-, β-hydroxy-, ω-hydroxy-FA) of the fatty acyl moiety, and the types of LCB (sphingosine, phytosphigosine, 6-hydroxy-sphingosine). Thereby, this approach permits differentiation of isomeric structures and ceramide species in the biological specimen can be unveiled in detail. By application of sequential MS, the double bond position along the fatty acyl chain of the molecule can be located, and a complete structural characterization of ceramides can be achieved.
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http://dx.doi.org/10.1016/j.aca.2020.09.056DOI Listing
January 2021

3D optical/CT as a preclinical companion imaging platform for glioblastoma drug development.

Drug Deliv 2020 Dec;27(1):1686-1694

Columbia University PET Center, Department of Radiology, Columbia University Medical Center, New York, NY, USA.

Multimodality 3D Optical Imaging (OI)/CT has the potential to play a major role in drug development for glioblastomas (GBM), as it is an accessible preclinical method. To demonstrate the potential of 3D OI/CT to visualize orthotopic GBM implantation, we labeled GBM cells with Cy7 and imaged their location using 3D OI/CT. To confirm the accuracy of the spatial localization and demonstrate the ability to image locoregionally delivered therapies, we labeled mouse albumin with Cy7 (Cy7ALB) and delivered it via locoregional infusion 1 mm or 3 mm into the brain and demonstrated correlation of signal between the 3D OI/CT and post necropsy brain slices. In addition, we demonstrated the potential of systemically delivered Cy7ALB contrast to detect blood-brain barrier (BBB) permeability caused by orthotopic GBMs using 3D OI/CT. We also tested the potential of 3D OI/CT to assess focal BBB permeability induced by high intensity focused ultrasound (HIFU), a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. We demonstrated the ability of systemic Cy7ALB contrast together with 3D OI/CT to accurately assess real-time HIFU-induced BBB permeability, which correlated to post necropsy imaging of brains. Furthermore, we demonstrated that 3D OI/CT can also image the therapeutic distribution of a Cy7-labeled anti-PD-1 antibody, a prototype translational antibody therapy. We successfully imaged real-time antibody distribution after HIFU-induced BBB permeability, which correlated with post necropsy Cy7 signal and translational PET imaging after injection of [Zr] anti-PD-1 antibody. Thus, we demonstrated the broad potential of using 3D OI/CT as an accessible preclinical tool to develop anti-GBM therapies.
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http://dx.doi.org/10.1080/10717544.2020.1833381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717859PMC
December 2020

Female human primordial germ cells display X-chromosome dosage compensation despite the absence of X-inactivation.

Nat Cell Biol 2020 12 30;22(12):1436-1446. Epub 2020 Nov 30.

Molecular Cell and Developmental Biology Department, University of California Los Angeles, Los Angeles, CA, USA.

X-chromosome dosage compensation in female placental mammals is achieved by X-chromosome inactivation (XCI). Human pre-implantation embryos are an exception, in which dosage compensation occurs by X-chromosome dampening (XCD). Here, we examined whether XCD extends to human prenatal germ cells given their similarities to naive pluripotent cells. We found that female human primordial germ cells (hPGCs) display reduced X-linked gene expression before entering meiosis. Moreover, in hPGCs, both X chromosomes are active and express the long non-coding RNAs X active coating transcript (XACT) and X inactive specific transcript (XIST)-the master regulator of XCI-which are silenced after entry into meiosis. We find that XACT is a hPGC marker, describe XCD associated with XIST expression in hPGCs and suggest that XCD evolved in humans to regulate X-linked genes in pre-implantation embryos and PGCs. Furthermore, we found a unique mechanism of X-chromosome regulation in human primordial oocytes. Therefore, future studies of human germline development must consider the sexually dimorphic X-chromosome dosage compensation mechanisms in the prenatal germline.
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http://dx.doi.org/10.1038/s41556-020-00607-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717582PMC
December 2020

An Improved Method for Developing Injury Risk Curves Using the Brier Metric Score.

Ann Biomed Eng 2020 Nov 20. Epub 2020 Nov 20.

Biomedical Engineering, Wake Forest School of Medicine, 575 N. Patterson Avenue, Winston-Salem, NC, 27101, USA.

Many injury metrics are routinely proposed from measured or derived quantities from biomechanical experiments using post mortem human subjects (PMHS). The existing literature did not provide guidance on deciding between parameters collected in an experiment that would be best to use for the development of human injury probability curves (HIPC). The objective of this study was to use the Brier Metric Score (BMS) to identify the most appropriate metric from an experiment that predicts injury outcomes. The Brier Metric Score assesses how well a metric predicts the outcome for a censored data point (a lower BMS is better). Survival analysis was then conducted with the selected metric and the best distribution was selected using Akaike information criterion (AIC). Confidence intervals (CIs) and the normalized confidence interval width (NCIS) were calculated for the injury probability curve. The testing and validation of the methods described were performed using biomechanics data in the open literature. The methods for the HIPC development procedure detailed herein have been rigorously tested and used in the generation of WIAMan HIPCs and Injury Assessment Reference Curves (IARCs) for the WIAMan ATD, but can also be used in other ATD or PMHS injury risk curve development.
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http://dx.doi.org/10.1007/s10439-020-02686-8DOI Listing
November 2020

CEPT1-Mediated Phospholipogenesis Regulates Endothelial Cell Function and Ischemia-Induced Angiogenesis Through PPARα.

Diabetes 2021 Feb 19;70(2):549-561. Epub 2020 Nov 19.

Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO.

De novo phospholipogenesis, mediated by choline-ethanolamine phosphotransferase 1 (CEPT1), is essential for phospholipid activation of transcription factors such as peroxisome proliferator-activated receptor α (PPARα) in the liver. Fenofibrate, a PPARα agonist and lipid-lowering agent, decreases amputation incidence in patients with diabetes. Because we previously observed that CEPT1 is elevated in carotid plaque of patients with diabetes, we evaluated the role of CEPT1 in peripheral arteries and PPARα phosphorylation (Ser12). CEPT1 was found to be elevated in diseased lower-extremity arterial intima of individuals with peripheral arterial disease and diabetes. To evaluate the role of in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of via induced ---mediated recombination (/). / ECs demonstrated decreased proliferation, migration, and tubule formation, and / mice had reduced perfusion and angiogenesis in ischemic hind limbs. Peripheral ischemic recovery and PPARα signaling were further compromised by streptozotocin-induced diabetes and ameliorated by feeding fenofibrate. endoribonuclease-prepared siRNA decreased PPARα phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike / mice, / mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate. Therefore, we demonstrate that CEPT1 is essential for EC function and tissue recovery after ischemia and that fenofibrate rescues CEPT1-mediated activation of PPARα.
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http://dx.doi.org/10.2337/db20-0635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881870PMC
February 2021

Extensive Polyostotic Craniofacial Fibrous Dysplasia With Optic Nerve Impingement.

J Craniofac Surg 2020 Nov 17. Epub 2020 Nov 17.

Department of Plastic Surgery.

Fibrous dysplasia is a benign overgrowth of metaplastic fibrous material resulting in disorganized deposition of bony matrix. Surgical intervention is the primary treatment modality. Here the authors present the case of a 36-year-old male with extensive and severe fibrous dysplasia of the calvarium, orbit, sphenoid, and facial bones causing significant facial distortion and impingement of his optic nerve. Combined operative treatment with craniofacial plastic surgery and neurosurgery was performed. Repair consisted of extensive intra- and extracranial resection and contouring of involved bones followed by reconstruction of the superior orbital rims, forehead, orbital roof, and calvarium with custom polyetheretherketone (PEEK) implant. The authors discuss the advantages of using computer assisted design/modeling, intraoperative neuronavigation, and custom prosthetic cranioplasty for surgical treatment of extensive fibrous dysplasia; a review of the current surgical literature is provided.
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http://dx.doi.org/10.1097/SCS.0000000000007241DOI Listing
November 2020

Type and timing of systemic therapy use predict overall survival for patients with brain metastases treated with radiation therapy.

J Neurooncol 2021 Jan 18;151(2):231-240. Epub 2020 Nov 18.

University of British Columbia, Vancouver, BC, Canada.

Introduction: This study aimed to investigate whether systemic therapy (ST) use surrounding radiation therapy (RT) predicts overall survival (OS) after RT for patients with brain metastases (BMs).

Methods: Provincial RT and pharmacy databases were used to review all adult patients in British Columbia, Canada, who received a first course of RT for BMs between 2012 and 2016 (n = 3095). Multivariate analysis on a randomly selected subset was used to develop an OS nomogram.

Results: In comparison to the 2096 non-recipients of ST after RT, the median OS of the 999 recipients of ST after RT was 5.0 (95% Confidence interval (CI) 4.1-6.0) months longer (p < 0.0001). Some types of ST after RT were independently predictive of OS: targeted therapy (hazard ratio (HR) 0.42, CI 0.37-0.48), hormone therapy (HR 0.45, CI 0.36-0.55), cytotoxic chemotherapy (HR 0.71, CI 0.64-0.79), and immunotherapy (HR 0.64, CI 0.37-1.06). Patients who discontinued ST after RT had 0.9 (CI 0.3-1.4) months shorter median OS than patients who received no ST before or after RT (p < 0.0001). In the multivariate analysis of the 220-patient subset, established prognostic variables (extracranial disease, performance status, age, cancer diagnosis, and number of BMs), and the novel variables "ST before RT" and "Type of ST after RT" independently predicted OS. The nomogram predicted 6- and 12-month OS probability and median OS (bootstrap-corrected Harrell's Concordance Index = 0.70).

Conclusions: The type and timing of ST use surrounding RT predict OS for patients with BMs.
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http://dx.doi.org/10.1007/s11060-020-03657-8DOI Listing
January 2021

Treatment of Multi-Focal Epilepsy With Resective Surgery Plus Responsive Neurostimulation (RNS): One Institution's Experience.

Front Neurol 2020 29;11:545074. Epub 2020 Oct 29.

Department of Neurological Surgery, University of California, Irvine, Irvine, CA, United States.

Patients with medically refractory focal epilepsy can be difficult to treat surgically, especially if invasive monitoring reveals multiple ictal onset zones. Possible therapeutic options may include resection, neurostimulation, laser ablation, or a combination of these surgical modalities. To date, no study has examined outcomes associated with resection plus responsive neurostimulation (RNS, Neuropace, Inc., Mountain View, CA) implantation and we describe our initial experience in patients with multifocal epilepsy undergoing this combination therapy. A total of 43 responsive neurostimulation (RNS) devices were implanted at UCI from 2015 to 2019. We retrospectively reviewed charts of patients from the same time period who underwent both resection and RNS implantation. Patients were required to have independent or multifocal onset, undergo resection and RNS implantation, and have a minimum of six-months for follow-up to be included in the study. Demographics, location of ictal onset, location of surgery, complications, and seizure outcome were collected. Ten patients met inclusion criteria for the study, and seven underwent both procedures in the same setting. The average age was 36. All patients had multifocal ictal onset on video electroencephalogram or invasive EEG with four patients undergoing subdural grid placement and four patients undergoing bilateral sEEG prior to the definitive surgery. Five patients underwent resection plus ipsilateral RNS placement and the remainder underwent resection with contralateral RNS placement. Two minor complications were encountered in this group. At six months follow up, there was an average of 81% ± 9 reduction in seizures, while four patients experienced complete seizure freedom at 1 year. Patients with multifocal epilepsy can be treated with partial resection plus RNS. The complication rates are low with potential for worthwhile seizure reduction.
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http://dx.doi.org/10.3389/fneur.2020.545074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658333PMC
October 2020

Ergonomics of Endoscopic Skull Base Surgery: A Systematic Review.

World Neurosurg 2021 Feb 12;146:150-155. Epub 2020 Nov 12.

Department of Neurosurgery, University of California, Irvine, Orange, California, USA; Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine, Orange, California, USA. Electronic address:

Objective: There has been a significant expansion in endonasal endoscopic skull base surgery (EES) that has been used to address a wide range of intracranial and sinonasal pathologies. Although there exists a large amount of literature on approaches and patient outcomes, there is a paucity of data describing ergonomics in this field. Our goal was to evaluate and summarize the literature on ergonomics in EES.

Methods: We systematically reviewed all published, peer-reviewed, English language literature in the PubMed and Web of Science databases as screened by multiple reviewers describing ergonomics as related to EES.

Results: A total of 50 articles were found that described significant conclusions and descriptions on ergonomics in EES. We found and summarized the different technical aspects of ergonomics as pertaining to EES and provided evidence-based suggestions on operating room and surgeon setup.

Conclusions: There are several improvements in EES ergonomics that can decrease fatigue, improve efficiency, and overall surgeon well-being.
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http://dx.doi.org/10.1016/j.wneu.2020.11.026DOI Listing
February 2021