Publications by authors named "Eric Wang"

399 Publications

Automated intracellular pharmacological electrophysiology for ligand-gated ionotropic receptor and pharmacology screening.

Mol Pharmacol 2021 May 6. Epub 2021 May 6.

George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, United States

Communication between neuronal cells, central to brain function, is performed by several classes of ligand-gated ionotropic receptors. The gold standard technique for measuring rapid receptor response to agonist is manual patch-clamp electrophysiology, capable of the highest temporal resolution of any current electrophysiology technique. We report an automated high-precision patch-clamp system which substantially improves the throughput of these time-consuming pharmacological experiments. The patcherBot enables recording from cells expressing receptors of interest and manipulation of them to enable millisecond solution exchange to activate ligand-gated ionotropic receptors. The solution-handling control allows for autonomous pharmacological concentration-response experimentation on adherent cells, lifted cells, or excised outside-out patches. The system can perform typical ligand-gated ionotropic receptor experimentation protocols autonomously, possessing a high success rate in completing experiments, and up to a 10-fold reduction in research effort over the duration of the experiment. Using it, we could rapidly replicate previous datasets, reducing the time it took to produce an 8-point concentration response curve of the effect of propofol on GABAR deactivation from likely weeks of recording to ~13 hours of recording. On average, the rate of data collection of the patcherBot was a data point every 2.1 minutes that the operator spent interacting with the patcherBot The patcherBot provides the ability to conduct complex and comprehensive experimentation that yields datasets not normally within reach of conventional systems that rely on constant human control. This technical advance can contribute to accelerating the examination of the complex function of ion channels and the pharmacological agents that act on them. This work presents an automated intracellular pharmacological electrophysiology robot, patcherBot, that substantially improves throughput and reduces human time requirement in pharmacological patch-clamp experiments. The robotic system includes millisecond fluid exchange handling and can perform highly efficient ligand-gated ionotropic receptor experiments. The patcherBot is built using a conventional patch-clamp rig, and the technical advances shown in this work greatly accelerate the ability to conduct high-fidelity pharmacological electrophysiology.
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http://dx.doi.org/10.1124/molpharm.120.000195DOI Listing
May 2021

Inhibition of CDK4/6 promotes CD8 T-cell memory formation.

Cancer Discov 2021 May 3. Epub 2021 May 3.

Dana-Farber Cancer Institute

CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8 T cells during early stages of activation. Mice receiving tumor-specific CD8 T cells treated with CDK4/6 inhibitors displayed increased T cell persistence and immunologic memory. CDK4/6 inhibition upregulated Mxd4, a negative regulator of Myc, in both mouse and human CD8 T cells. Silencing of Mxd4 or Myc in mouse CD8 T cells demonstrated the importance of this axis for memory formation. We used single cell transcriptional profiling and TCR clonotype tracking to evaluate recently activated human CD8 T cells in breast cancer patients before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8 memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in cancer patients may augment long-term protective immunity.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1540DOI Listing
May 2021

Staged Repositioning in Endoscopic Endonasal Odontoidectomy Maximizes Decompression while Allowing Preservation of the C1 Anterior Arch: A Technical Note.

World Neurosurg 2021 Apr 30. Epub 2021 Apr 30.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213; Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213. Electronic address:

Background: Preservation of the anterior arch of C1 in endoscopic endonasal odontoidectomy has been proposed as an alternative to complete C1 arch resections, potentially affording less destabilization of the craniocervical junction. Nonetheless, this approach may limit the decompression achieved. In this case, intra-operative repositioning allowed maximal decompression while preserving the anterior arch of C1.

Case Description: A 79-year-old woman presented with suboccipital pain caused by an expansile and compressive mass centered on the dens. Notably, the mass occluded both vertebral arteries resulting in small cerebellar strokes. An endoscopic endonasal approach for diagnosis and decompression was performed followed by posterior fixation. Given the significant compression, the patient was initially positioned in slight cervical extension. After rhinopharyngeal flap harvest, the top half of the anterior arch of C1 was resected, maintaining its structural integrity. The odontoidectomy was completed flush to the superior border of the reduced C1 arch. After an intra-operative CT scan, performed in a neutral position, the patient was then repositioned with cervical flexion. This maneuver presented the residual odontoid above the C1 arch, but given the partial removal of the dens, it did not result in any change in neuromonitoring. Further odontoid resection was then completed and follow-up CT scan revealed maximal dens removal, which extended below the C1 anterior arch in neutral position.

Conclusion: In cases of odontoid/atlantoaxial pathology causing significant neural compression, staged intra-operative repositioning can safely maximize the odontoidectomy, while affording preservation of the structural integrity of the anterior arch of C1.
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http://dx.doi.org/10.1016/j.wneu.2021.04.105DOI Listing
April 2021

SSTR2 Expression in Olfactory Neuroblastoma: Clinical and Therapeutic Implications.

Head Neck Pathol 2021 Apr 30. Epub 2021 Apr 30.

Department of Pathology and Laboratory Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Somatostatin receptor 2 (SSTR2) expression has previously been documented in olfactory neuroblastoma (ONB). Here, we fully characterize SSTR2 expression in ONB and correlate staining results with clinicopathologic parameters including Hyams grade. We also assess SSTR2 immunohistochemistry expression in various histologic mimics of ONB to assess its diagnostic functionality. 78 ONBs (51 primary biopsies/excisions and 27 recurrences/metastases) from 58 patients were stained for SSTR2. H-scores based on intensity (0-3 +) and percentage of tumor cells staining were assigned to all cases. 51 histologic mimics were stained and scored in an identical fashion. 77/78 (99%) ONB cases demonstrated SSTR2 staining (mean H-score: 189, range: 0-290). There were no significant differences in staining between primary tumors and recurrences/metastases (mean H-score: 185 vs 198). Primary low-grade ONB had somewhat stronger staining than high-grade tumors (mean H-score: 200 vs 174). SSTR2 expression had no prognostic value when considering disease-free or disease-specific survival. SSTR2 staining is significantly higher in ONB than its histologic mimics (mean H-score: 189 vs 12.9, p < 0.001) suggesting a potential use of the marker in diagnosis of ONB. In conclusion, SSTR2 is consistently expressed in ONB suggesting a role for somatostatin-analog based imaging and therapy in this disease. More generally, SSTR2 may be another marker of neuroendocrine differentiation in ONB.
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http://dx.doi.org/10.1007/s12105-021-01329-1DOI Listing
April 2021

Balanced Cellular and Humoral Immune Responses Targeting Multiple Antigens in Adults Receiving a Quadrivalent Inactivated Influenza Vaccine.

Vaccines (Basel) 2021 Apr 23;9(5). Epub 2021 Apr 23.

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.

The role of T cell immunity has been acknowledged in recent vaccine development and evaluation. We tested the humoral and cellular immune responses to Flucelvax, a quadrivalent inactivated seasonal influenza vaccine containing two influenza A (H1N1 Singapore/GP1908/2015 IVR-180 and H3N2 North Carolina/04/2016) and two influenza B (Iowa/06/2017 and Singapore/INFTT-16-0610/2016) virus strains, using peripheral blood mononuclear cells stimulated by pools of peptides overlapping all the individual influenza viral protein components. Baseline reactivity was detected against all four strains both at the level of CD4 and CD8 responses and targeting different proteins. CD4 T cell reactivity was mostly directed to HA/NA proteins in influenza B strains, and NP/M1/M2/NS1/NEP proteins in the case of the Influenza A strains. CD8 responses to both influenza A and B viruses preferentially targeted the more conserved core viral proteins. Following vaccination, both CD4 and CD8 responses against the various influenza antigens were increased in day 15 to day 91 post vaccination period, and maintained a Th1 polarized profile. Importantly, no vaccine interference was detected, with the increased responses balanced across all four included viral strains for both CD4 and CD8 T cells, and targeting HA and multiple additional viral antigens.
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http://dx.doi.org/10.3390/vaccines9050426DOI Listing
April 2021

An Investigation of Human Errors in Medication Adverse Event Improvement Priority Using a Hybrid Approach.

Healthcare (Basel) 2021 Apr 9;9(4). Epub 2021 Apr 9.

Nursing Department, Hsinchu Mackay Memorial Hospital, Hsinchu 30071, Taiwan.

The aim of this study was to analyze and provide an in-depth improvement priority for medication adverse events. Thus, the Human Factor Analysis and Classification System with subfactors was used in this study to analyze the adverse events. Subsequently, the improvement priority for the subfactors was determined using the hybrid approach in terms of the Analytical Hierarchy Process and the fuzzy Technique for Order of Preference by Similarity to Ideal Solution. In Of the 157 medical adverse events selected from the Taiwan Patient-safety Reporting system, 25 cases were identified as medication adverse events. The Human Factor Analysis and Classification System and root cause analysis were used to analyze the error factors and subfactors that existed in the medication adverse events. Following the analysis, the Analytical Hierarchy Process and the fuzzy Technique for Order of Preference by Similarity to Ideal Solution were used to determine the improvement priority for subfactors. The results showed that the decision errors, crew resource management, inadequate supervision, and organizational climate contained more types of subfactors than other error factors in each category. In the current study, 16 improvement priorities were identified. According to the results, the improvement priorities can assist medical staff, researchers, and decisionmakers in improving medication process deficiencies efficiently.
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http://dx.doi.org/10.3390/healthcare9040442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069284PMC
April 2021

Quantifying the Psychosocial Benefits of Masculinizing Mastectomy in Trans Male Patients with Patient-Reported Outcomes: The University of California, San Francisco, Gender Quality of Life Survey.

Plast Reconstr Surg 2021 May;147(5):731e-740e

From the Division of Plastic and Reconstructive Surgery, Department of Surgery, University of California, San Francisco; and Yale University School of Medicine.

Background: Gender-affirming surgery is a medically necessary treatment to alleviate gender dysphoria for transgender patients. Although previous studies suggest improved psychosocial outcomes after gender-affirming surgery, there are no transgender-specific instruments available to assess its effects on patient quality of life.

Methods: Using qualitative methods, the authors developed the first quality-of-life survey, the University of California, San Francisco, Gender Quality of Life (UCSF Gender QoL) survey, for trans male patients undergoing gender-affirming mastectomy. The UCSF Gender QoL survey was then administered prospectively to 51 trans male patients undergoing inframammary mastectomy with free nipple grafting at the University of California, San Francisco. The brief version of the World Health Organization Quality of Life survey was also given as a measure of external validity. The Cronbach alpha was value calculated to measure internal validity.

Results: Thirty-six patients completed surveys 6 weeks after surgery, and 22 patients completed surveys 1 year after surgery, for response rates of 71 percent and 43 percent, respectively. The UCSF Gender QoL survey detected a significant improvement in quality of life 6 weeks and 1 year after chest surgery. The effect sizes were large, and the Cronbach alpha exhibited excellent internal validity.

Conclusions: This study establishes the UCSF Gender QoL survey as one of the first patient-reported outcomes tools for evaluating quality of life in trans male patients after gender-affirming chest reconstruction. Although the study is limited by a small cohort at a single center, establishing the validity of the UCSF Gender QoL survey provides an invaluable tool for future research into various aspects of gender-affirming chest surgery.
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http://dx.doi.org/10.1097/PRS.0000000000007883DOI Listing
May 2021

Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition.

Nat Genet 2021 May 12;53(5):707-718. Epub 2021 Apr 12.

Human Oncology and Pathogenesis Program, Memorial Sloan KetterAbsolute numbers of live mature hematopoietic cellsing Cancer Center, New York, NY, USA.

Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.
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http://dx.doi.org/10.1038/s41588-021-00828-9DOI Listing
May 2021

Applications of Biocompatible Scaffold Materials in Stem Cell-Based Cartilage Tissue Engineering.

Front Bioeng Biotechnol 2021 25;9:603444. Epub 2021 Mar 25.

Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, United States.

Cartilage, especially articular cartilage, is a unique connective tissue consisting of chondrocytes and cartilage matrix that covers the surface of joints. It plays a critical role in maintaining joint durability and mobility by providing nearly frictionless articulation for mechanical load transmission between joints. Damage to the articular cartilage frequently results from sport-related injuries, systemic diseases, degeneration, trauma, or tumors. Failure to treat impaired cartilage may lead to osteoarthritis, affecting more than 25% of the adult population globally. Articular cartilage has a very low intrinsic self-repair capacity due to the limited proliferative ability of adult chondrocytes, lack of vascularization and innervation, slow matrix turnover, and low supply of progenitor cells. Furthermore, articular chondrocytes are encapsulated in low-nutrient, low-oxygen environment. While cartilage restoration techniques such as osteochondral transplantation, autologous chondrocyte implantation (ACI), and microfracture have been used to repair certain cartilage defects, the clinical outcomes are often mixed and undesirable. Cartilage tissue engineering (CTE) may hold promise to facilitate cartilage repair. Ideally, the prerequisites for successful CTE should include the use of effective chondrogenic factors, an ample supply of chondrogenic progenitors, and the employment of cell-friendly, biocompatible scaffold materials. Significant progress has been made on the above three fronts in past decade, which has been further facilitated by the advent of 3D bio-printing. In this review, we briefly discuss potential sources of chondrogenic progenitors. We then primarily focus on currently available chondrocyte-friendly scaffold materials, along with 3D bioprinting techniques, for their potential roles in effective CTE. It is hoped that this review will serve as a primer to bring cartilage biologists, synthetic chemists, biomechanical engineers, and 3D-bioprinting technologists together to expedite CTE process for eventual clinical applications.
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http://dx.doi.org/10.3389/fbioe.2021.603444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026885PMC
March 2021

Differential T cell reactivity to endemic coronaviruses and SARS-CoV-2 in community and health care workers.

J Infect Dis 2021 Apr 2. Epub 2021 Apr 2.

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA.

Herein we measured CD4 + T cell responses against common cold corona (CCC) viruses and SARS-CoV-2 in high-risk health care workers (HCW) and community controls. We observed higher levels of CCC reactive T cells in SARS-CoV-2 seronegative HCW compared to community donors, consistent with potential higher occupational exposure of HCW to CCC. We further show that SARS-CoV-2 T cell reactivity of seronegative HCW was higher than community controls and correlation between CCC and SARS-CoV-2 responses is consistent with cross-reactivity and not associated with recent in vivo activation. Surprisingly, CCC T cell reactivity was decreased in SARS-CoV-2 infected HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses, either directly or indirectly. This result was unexpected, but consistently detected in independent cohorts derived from Miami and San Diego.
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http://dx.doi.org/10.1093/infdis/jiab176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083569PMC
April 2021

Multi-Center Evaluation of Survival and Toxicities following Radioembolization: analysis of the RESiN Registry.

J Vasc Interv Radiol 2021 Apr 1. Epub 2021 Apr 1.

Interventional Radiology, Vanderbilt University Medical Center, Nashville, TN. Electronic address:

Purpose: To determine overall survival (OS), progression-free survival (PFS) and toxicity in a multicenter, real-world data collection using transarterial radioembolization (TARE) with resin microspheres.

Materials And Methods: 448 patents were treated at 36 centers between 2015-2019. Treatment history, baseline laboratory and imaging, and treatment goal were assessed. OS and PFS were stratified using Barcelona Clinic Liver Cancer (BCLC) and Child Pugh (CP) stratification. Kaplan-Meier analyses compared OS and PFS with 95% confidence intervals. Transplants were tracked. Toxicities were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5. Cox Proportional Hazard of baseline demographics assessed factors affecting survival.

Results: Prior chemoembolization and systemic therapy were used in 107 (26%) and 68 (16%) of patients. Sixty-six patients (19%) were BCLC A and 202, 51, and 26 were BCLC B/C/D. Median OS for BCLC A patients was not reached at 30 months. Median OS for BCLC B/C/D patients was 19.5, 13.6, and 11.5 months (p=0.0006). Median PFS for BCLC A/B/C/D patients was 19.8, 10.0, 6.3, and 5.9 months (p=0.003). Twenty patients underwent transplant representing 14/43 (33%) undergoing bridge and 6/28 (21%) downstaging therapy. Common Grade 3 toxicities were encephalopathy (11/448, 2.5%), hyperbilirubinemia (10/448, 2.2%) and ascites (9/448, 2.0%). Factors predicting longer survival included CP A (X=4.2, p=0.04) and BCLC A (X=5.2, p=0.02).

Conclusion: In a frequently pretreated patient cohort with disease burden in 81% beyond Milan criteria, TARE with resin microspheres provided OS comparable to other studies in this multicenter review.
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http://dx.doi.org/10.1016/j.jvir.2021.03.535DOI Listing
April 2021

Aerosol and Droplet Risk of Common Otolaryngology Clinic Procedures.

Ann Otol Rhinol Laryngol 2021 Mar 18:34894211000502. Epub 2021 Mar 18.

Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Objectives: Define aerosol and droplet risks associated with routine otolaryngology clinic procedures during the COVID-19 era.

Methods: Clinical procedures were simulated in cadaveric heads whose oral and nasal cavities were coated with fluorescent tracer (vitamin B2) and breathing was manually simulated through retrograde intubation. A cascade impactor placed adjacent to the nares collected generated particles with aerodynamic diameters ≤14.1 µm. The 3D printed models and syringes were used to simulate middle and external ear suctioning as well as open suctioning, respectively. Provider's personal protective equipment (PPE) and procedural field contamination were also recorded for all trials using vitamin B2 fluorescent tracer.

Results: The positive controls of nebulized vitamin B2 produced aerosol particles ≤3.30 µm and endonasal drilling of a 3D model generated particles ≤14.1 µm. As compared with positive controls, aerosols and small droplets with aerodynamic diameter ≤14.1 µm were not detected during rigid nasal endoscopy, flexible fiberoptic laryngoscopy, and rigid nasal suction of cadavers with simulated breathing. There was minimal to no field contamination in all 3 scenarios. Middle and external ear suctioning and open container suctioning did not result in any detectable droplet contamination. The clinic suction unit contained all fluorescent material without surrounding environmental contamination.

Conclusion: While patients' coughing and sneezing may create a baseline risk for providers, this study demonstrates that nasal endoscopy, flexible laryngoscopy, and suctioning inherently do not pose an additional risk in terms of aerosol and small droplet generation. An overarching generalization cannot be made about endoscopy or suctioning being an aerosol generating procedure.

Level Of Evidence: 3.
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http://dx.doi.org/10.1177/00034894211000502DOI Listing
March 2021

Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits.

Nat Neurosci 2021 04 15;24(4):504-515. Epub 2021 Mar 15.

Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.

The basal ganglia regulate a wide range of behaviors, including motor control and cognitive functions, and are profoundly affected in Parkinson's disease (PD). However, the functional organization of different basal ganglia nuclei has not been fully elucidated at the circuit level. In this study, we investigated the functional roles of distinct parvalbumin-expressing neuronal populations in the external globus pallidus (GPe-PV) and their contributions to different PD-related behaviors. We demonstrate that substantia nigra pars reticulata (SNr)-projecting GPe-PV neurons and parafascicular thalamus (PF)-projecting GPe-PV neurons are associated with locomotion and reversal learning, respectively. In a mouse model of PD, we found that selective manipulation of the SNr-projecting GPe-PV neurons alleviated locomotor deficit, whereas manipulation of the PF-projecting GPe-PV neurons rescued the impaired reversal learning. Our findings establish the behavioral importance of two distinct GPe-PV neuronal populations and, thereby, provide a new framework for understanding the circuit basis of different behavioral deficits in the Parkinsonian state.
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http://dx.doi.org/10.1038/s41593-021-00810-yDOI Listing
April 2021

B cells modulate mouse allergen-specific T cells in nonallergic laboratory animal-care workers.

JCI Insight 2021 Feb 22;6(4). Epub 2021 Feb 22.

La Jolla Institute for Immunology, La Jolla, California, USA.

Understanding the mechanisms of allergen-specific immune modulation in nonallergic individuals is key to recapitulate immune tolerance and to develop novel allergy treatments. Herein, we characterized mouse-specific T cell responses in nonallergic laboratory animal-care workers before and after reexposure to mice. PBMCs were collected and stimulated with developed peptide pools identified from high-molecular-weight fractions of mouse allergen extracts. Sizable CD4 T cell responses were noted and were temporarily decreased in most subjects upon reexposure, with the magnitude of decrease positively correlated with time of reexposure but not the duration of the break. Interestingly, the suppression was specific to mouse allergens without affecting responses of bystander antigens. Further, PBMC fractioning studies illustrated that the modulation is unlikely from T cells, while B cell depletion and exchange reversed the suppression of responses, suggesting that B cells may be the key modulators. Increased levels of regulatory cytokines (IL-10 and TGF-β1) in the cell culture supernatant and plasma mouse-specific IgG4 were also observed after reexposure, consistent with B cell-mediated modulation mechanisms. Overall, these results suggest that nonallergic status is achieved by an active, time-related, allergen-specific, B cell-dependent regulatory process upon reexposure, the mechanisms of which should be detailed by further molecular studies.
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http://dx.doi.org/10.1172/jci.insight.145199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934936PMC
February 2021

The rhinopharyngeal flap for reconstruction of lower clival and craniovertebral junction defects.

J Neurosurg 2021 Feb 12:1-9. Epub 2021 Feb 12.

Departments of1Neurosurgery and.

Objective: The endoscopic endonasal approach (EEA) to the lower clivus and craniovertebral junction (CVJ) has been traditionally performed via resection of the nasopharyngeal soft tissues. Alternatively, an inferiorly based rhinopharyngeal (RP) flap (RPF) can be dissected to help reconstruct the postoperative defect and separate it from the oropharynx. To date, there is no evidence regarding the viability and potential clinical impact of the RPF. The aim of this study was to assess RPF viability and its impact on clinical outcome.

Methods: A retrospective cohort of 60 patients who underwent EEA to the lower clivus and CVJ was studied. The RPF was used in 30 patients (RPF group), and the nasopharyngeal soft tissues were resected in 30 patients (control group).

Results: Chordoma was the most common surgical indication in both groups (47% in the RPF group vs 63% in the control group, p = 0.313), followed by odontoid pannus (20% in the RPF group vs 10%, p = 0.313). The two groups did not significantly differ in terms of extent of tumor (p = 0.271), intraoperative CSF leak (p = 0.438), and skull base reconstruction techniques other than the RPF (nasoseptal flap, p = 0.301; fascia lata, p = 0.791; inlay graft, p = 0.793; and prophylactic lumbar drain, p = 0.781). Postoperative soft-tissue enhancement covering the lower clivus and CVJ observed on MRI was significantly higher in the RPF group (100% vs 26%, p < 0.001). The RPF group had a significantly lower rate of nasoseptal flap necrosis (3% vs 20%, p = 0.044) and surgical site infection (3% vs 27%, p = 0.026) while having similar rates of postoperative CSF leakage (17% in the RPF group vs 20%, p = 0.739) and meningitis (7% in the RPF group vs 17%, p = 0.424). Oropharyngeal bacterial flora dominated the infections in the control group but not those in the RPF group, suggesting that the RPF acted as a barrier between the nasopharynx and oropharynx.

Conclusions: The RPF provides viable vascularized tissue coverage to the lower clivus and CVJ. Its use was associated with decreased rates of nasoseptal flap necrosis and local infection, likely due to separation from the oropharynx.
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http://dx.doi.org/10.3171/2020.8.JNS202193DOI Listing
February 2021

A functional genomics screen identifying blood cell development genes in Drosophila by undergraduates participating in a course-based research experience.

G3 (Bethesda) 2021 Jan;11(1)

Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Undergraduate students participating in the UCLA Undergraduate Research Consortium for Functional Genomics (URCFG) have conducted a two-phased screen using RNA interference (RNAi) in combination with fluorescent reporter proteins to identify genes important for hematopoiesis in Drosophila. This screen disrupted the function of approximately 3500 genes and identified 137 candidate genes for which loss of function leads to observable changes in the hematopoietic development. Targeting RNAi to maturing, progenitor, and regulatory cell types identified key subsets that either limit or promote blood cell maturation. Bioinformatic analysis reveals gene enrichment in several previously uncharacterized areas, including RNA processing and export and vesicular trafficking. Lastly, the participation of students in this course-based undergraduate research experience (CURE) correlated with increased learning gains across several areas, as well as increased STEM retention, indicating that authentic, student-driven research in the form of a CURE represents an impactful and enriching pedagogical approach.
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http://dx.doi.org/10.1093/g3journal/jkaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022729PMC
January 2021

The Breast Response to Estrogenic Stimulation in Transwomen Classification: Evaluation of Breast Response to Estrogenic Stimulation in Transwomen.

Ann Plast Surg 2021 Feb 3. Epub 2021 Feb 3.

From the Division of Plastic and Reconstructive Surgery, Department of Surgery, University of California, San Francisco, CA.

Background: Hormone therapy with exogenous estrogen and/or spironolactone is commonly used in transfemales to induce breast development. However, inherent differences in adult male and female anatomy create persistent deformities and inadequate gender congruency despite glandular breast development. This includes nipple characteristics, position of inframammary fold, and the distribution of breast tissue. Accordingly, the Tanner stages do not accurately reflect these persistent deformities because they relate to breast development in transwomen. Herein, we describe a classification system for breast development in transwomen treated with hormone therapy.

Methods: Ninety-nine transfemale patients who underwent breast augmentation from 2014 to 2018 were retrospectively reviewed and categorized using a novel scheme, the Breast Response to Estrogenic Stimulation in Transwomen (BREST) scale. Preoperative demographics, anatomic measurements, surgical technique, and postoperative results were also compared among BREST types.

Results: Most patients were rated as BREST type II (25%) or type IV (37%). The BREST scale exhibited moderate interrater reliability (κ = 0.58) between 3 plastic surgeons. Objective breast measurements such as sternal notch-to-nipple distance and nipple-to-inframammary fold distance correlated with the BREST scale. Multivariate logistical regression identified the nipple-to-inframammary fold distance and different between the bust and chest circumference as the strongest predictors of BREST type (odds ratio, 2.57 and 1.96, respectively). Body mass index was not a predictor of BREST type after controlling for confound variables on multivariate analysis.

Conclusions: The BREST scale uniquely captures the differences in breast phenotypes in transgender women according to hormone therapy response. Although some subjectivity exists with moderate interrater reliability, the BREST scale correlates with objective breast measurements. The BREST scale provides a transwoman-specific metric allowing for a common language in assessment of transgender breast development and optimal communication among providers, different specialties, and insurance companies.
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http://dx.doi.org/10.1097/SAP.0000000000002729DOI Listing
February 2021

Mucosal Grafting Reduces Recurrence After Endonasal Surgery of Petrous Apex Cholesterol Granulomas.

Laryngoscope 2021 Feb 9. Epub 2021 Feb 9.

Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Objectives/hypothesis: The endoscopic endonasal approach (EEA) is increasingly utilized for management of petrous apex cholesterol granuloma (PACG). Surgical goals include drainage and marsupialization of the cyst. Various techniques have been described to try to reduce the rates of recurrence. We studied the effect of mucosal grafting on recurrence.

Study Design: Retrospective Cohort study.

Methods: Patients who underwent EEA for PACG at two tertiary care centers between 1999 and 2018 were identified and divided into two cohorts: Mucosal versus no mucosal reconstruction. Surgical approach, reconstructive method, and recurrence were recorded. Primary endpoint was symptomatic or radiographic recurrence.

Results: Thirty-four patients were identified undergoing 37 surgeries. Four patients developed recurrences of which three elected to undergo revision. Some form of mucosa was used to line the drainage tract in 20 cases. A free mucosal graft was used in 8, and a small customized nasal septal flap (miniflap) in 12. All four recurrences occurred in cases where no mucosa was used, demonstrating decreased recurrences with mucosal reconstruction (P < .05). There was no difference found between free mucosal grafts and miniflaps.

Conclusions: Utilization of mucosa to partially line a circumferentially de-epithelialized drainage pathway after EEA for PACG reduce recurrence rates.

Level Of Evidence: 3 Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29432DOI Listing
February 2021

Reply: A preclinical model to tackle chronic rhinosinusitis.

Int Forum Allergy Rhinol 2021 Apr 27;11(4):828-829. Epub 2021 Jan 27.

Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.

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http://dx.doi.org/10.1002/alr.22769DOI Listing
April 2021

Transcriptome alterations in myotonic dystrophy frontal cortex.

Cell Rep 2021 Jan;34(3):108634

Department of Molecular Genetics & Microbiology, Center for NeuroGenetics, Genetics Institute, University of Florida, Gainesville, FL, USA. Electronic address:

Myotonic dystrophy (DM) is caused by expanded CTG/CCTG repeats, causing symptoms in skeletal muscle, heart, and central nervous system (CNS). CNS issues are debilitating and include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Here, we generate RNA-seq transcriptomes from DM and unaffected frontal cortex and identify 130 high-confidence splicing changes, most occurring only in cortex, not skeletal muscle or heart. Mis-spliced exons occur in neurotransmitter receptors, ion channels, and synaptic scaffolds, and GRIP1 mis-splicing modulates kinesin association. Optical mapping of expanded CTG repeats reveals extreme mosaicism, with some alleles showing >1,000 CTGs. Mis-splicing severity correlates with CTG repeat length across individuals. Upregulated genes tend to be microglial and endothelial, suggesting neuroinflammation, and downregulated genes tend to be neuronal. Many gene expression changes strongly correlate with mis-splicing, suggesting candidate biomarkers of disease. These findings provide a framework for mechanistic and therapeutic studies of the DM CNS.
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http://dx.doi.org/10.1016/j.celrep.2020.108634DOI Listing
January 2021

Differential T cell reactivity to seasonal coronaviruses and SARS-CoV-2 in community and health care workers.

medRxiv 2021 Jan 15. Epub 2021 Jan 15.

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.

Herein we measured CD4 T cell responses against common cold corona (CCC) viruses and SARS-CoV-2 in high-risk health care workers (HCW) and community controls. We observed higher levels of CCC reactive T cells in SARS-CoV-2 seronegative HCW compared to community donors, consistent with potential higher occupational exposure of HCW to CCC. We further show that SARS-CoV-2 reactivity of seronegative HCW was higher than community controls and correlation between CCC and SARS-CoV-2 responses is consistent with cross-reactivity and not associated with recent in vivo activation. Surprisingly, CCC reactivity was decreased in SARS-CoV-2 infected HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses, either directly or indirectly. This result was unexpected, but consistently detected in independent cohorts derived from Miami and San Diego.
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http://dx.doi.org/10.1101/2021.01.12.21249683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814840PMC
January 2021

Surface antigen-guided CRISPR screens identify regulators of myeloid leukemia differentiation.

Cell Stem Cell 2021 Apr 14;28(4):718-731.e6. Epub 2021 Jan 14.

Department of Pathology and Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address:

Lack of cellular differentiation is a hallmark of many human cancers, including acute myeloid leukemia (AML). Strategies to overcome such a differentiation blockade are an approach for treating AML. To identify targets for differentiation-based therapies, we applied an integrated cell surface-based CRISPR platform to assess genes involved in maintaining the undifferentiated state of leukemia cells. Here we identify the RNA-binding protein ZFP36L2 as a critical regulator of AML maintenance and differentiation. Mechanistically, ZFP36L2 interacts with the 3' untranslated region of key myeloid maturation genes, including the ZFP36 paralogs, to promote their mRNA degradation and suppress terminal myeloid cell differentiation. Genetic inhibition of ZFP36L2 restores the mRNA stability of these targeted transcripts and ultimately triggers myeloid differentiation in leukemia cells. Epigenome profiling of several individuals with primary AML revealed enhancer modules near ZFP36L2 that associated with distinct AML cell states, establishing a coordinated epigenetic and post-transcriptional mechanism that shapes leukemic differentiation.
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http://dx.doi.org/10.1016/j.stem.2020.12.005DOI Listing
April 2021

Stem Cell-Friendly Scaffold Biomaterials: Applications for Bone Tissue Engineering and Regenerative Medicine.

Front Bioeng Biotechnol 2020 14;8:598607. Epub 2020 Dec 14.

Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, United States.

Bone is a dynamic organ with high regenerative potential and provides essential biological functions in the body, such as providing body mobility and protection of internal organs, regulating hematopoietic cell homeostasis, and serving as important mineral reservoir. Bone defects, which can be caused by trauma, cancer and bone disorders, pose formidable public health burdens. Even though autologous bone grafts, allografts, or xenografts have been used clinically, repairing large bone defects remains as a significant clinical challenge. Bone tissue engineering (BTE) emerged as a promising solution to overcome the limitations of autografts and allografts. Ideal bone tissue engineering is to induce bone regeneration through the synergistic integration of biomaterial scaffolds, bone progenitor cells, and bone-forming factors. Successful stem cell-based BTE requires a combination of abundant mesenchymal progenitors with osteogenic potential, suitable biofactors to drive osteogenic differentiation, and cell-friendly scaffold biomaterials. Thus, the crux of BTE lies within the use of cell-friendly biomaterials as scaffolds to overcome extensive bone defects. In this review, we focus on the biocompatibility and cell-friendly features of commonly used scaffold materials, including inorganic compound-based ceramics, natural polymers, synthetic polymers, decellularized extracellular matrix, and in many cases, composite scaffolds using the above existing biomaterials. It is conceivable that combinations of bioactive materials, progenitor cells, growth factors, functionalization techniques, and biomimetic scaffold designs, along with 3D bioprinting technology, will unleash a new era of complex BTE scaffolds tailored to patient-specific applications.
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http://dx.doi.org/10.3389/fbioe.2020.598607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767872PMC
December 2020

Seizure Risk following Open and Expanded Endoscopic Endonasal Approaches for Intradural Skull Base Tumors.

J Neurol Surg B Skull Base 2020 Dec 27;81(6):673-679. Epub 2019 Aug 27.

Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.

 The incidence of seizures following a craniotomy for tumor removal varies between 15 and 20%. There has been increased use of endoscopic endonasal approaches (EEAs) for a variety of intracranial lesions due to its more direct approach to these pathologies. However, the incidence of postoperative seizures in this population is not well described.  This is a single-center, retrospective review of consecutive patients undergoing EEA or open craniotomy for resection of a cranial base tumor between July 2007 and June 2014. Patients were included if they underwent an EEA for an intradural skull base lesion. Positive cases were defined by electroencephalograms and clinical findings. Patients who underwent a craniotomy to remove extra-axial skull base tumors were analyzed in the same fashion.  Of the 577 patients treated with an EEA for intradural tumors, 4 experienced a postoperative seizure (incidence 0.7%, 95% confidence interval [CI]: 0.002-0.02). Over the same period, 481 patients underwent a craniotomy for a skull base lesion of which 27 (5.3%, 95% CI: 0.03-0.08) experienced a seizure after surgery. The odds ratio for EEA was 0.13 (95% CI: 0.05-0.35). Both populations were different in terms of age, gender, tumor histology, and location.  This study is the largest series looking at seizure incidence after EEA for intracranial lesions. Seizures are a rare occurrence following uncomplicated endonasal approaches. This must be tempered by selection bias, as there are inherent differences in which patients are treated with either approach that influence the likelihood of seizures.
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http://dx.doi.org/10.1055/s-0039-1694968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755514PMC
December 2020

Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice.

Hum Mol Genet 2021 Feb;29(24):3900-3918

Center for NeuroGenetics, Colllege of Medicine, University of Florida, Gainesville, FL 32610, USA.

C9orf72 ALS/FTD patients show remarkable clinical heterogeneity, but the complex biology of the repeat expansion mutation has limited our understanding of the disease. BAC transgenic mice were used to better understand the molecular mechanisms and repeat length effects of C9orf72 ALS/FTD. Genetic analyses of these mice demonstrate that the BAC transgene and not integration site effects cause ALS/FTD phenotypes. Transcriptomic changes in cell proliferation, inflammation and neuronal pathways are found late in disease and alternative splicing changes provide early molecular markers that worsen with disease progression. Isogenic sublines of mice with 800, 500 or 50 G4C2 repeats generated from the single-copy C9-500 line show longer repeats result in earlier onset, increased disease penetrance and increased levels of RNA foci and dipeptide RAN protein aggregates. These data demonstrate G4C2 repeat length is an important driver of disease and identify alternative splicing changes as early biomarkers of C9orf72 ALS/FTD.
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http://dx.doi.org/10.1093/hmg/ddaa279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906756PMC
February 2021

Facial Feminization Surgery: Key CT Findings for Preoperative Planning and Postoperative Evaluation.

AJR Am J Roentgenol 2020 Dec 30. Epub 2020 Dec 30.

University of California San Francisco Department of Radiology and Biomedical Imaging, 505 Parnassus Ave, San Francisco, CA 94143, Phone: 415-353-2573.

Facial feminization surgery (FFS) is an increasingly performed component of gender affirmation surgery for transgender women. Preoperative facial CT is performed to plan the adjustment of the patient's masculine characteristics to feminine, and to plan operative navigation around specific readily identifiable anatomic structures. In the upper face, surgery is performed to reduce the prominence of the brow and increase the nasofrontal angle; the radiology report should indicate the frontal sinus and supraorbital foramen anatomy. In the midface, rhinoplasty is performed to increase the nasofrontal and nasolabial angles; the radiology report should indicate presence of a dorsal hump and septal deviation or spurring. In the lower face, prominence of the chin and squareness of the jaw are adjusted via genioplasty and mandible contouring, respectively; the radiology report should describe the location and potential anatomic variations of the inferior alveolar nerve and mental foramina, as well as presence of dental abnormalities that directly inform the surgical approach. CT may also be performed if there is clinical suspicion for postoperative complications such as hardware fraction or osteotomy through the supraorbital or mental foramen. Familiarity with these findings will facilitate improved communication between radiologists and surgeons, thereby contributing to the care of transgender women.
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http://dx.doi.org/10.2214/AJR.20.25228DOI Listing
December 2020

Facial Feminization Surgery: Key CT Findings for Preoperative Planning and Postoperative Evaluation.

AJR Am J Roentgenol 2020 Dec 30. Epub 2020 Dec 30.

University of California San Francisco Department of Radiology and Biomedical Imaging, 505 Parnassus Ave, San Francisco, CA 94143, Phone: 415-353-2573.

Facial feminization surgery (FFS) is an increasingly performed component of gender affirmation surgery for transgender women. Preoperative facial CT is performed to plan the adjustment of the patient's masculine characteristics to feminine, and to plan operative navigation around specific readily identifiable anatomic structures. In the upper face, surgery is performed to reduce the prominence of the brow and increase the nasofrontal angle; the radiology report should indicate the frontal sinus and supraorbital foramen anatomy. In the midface, rhinoplasty is performed to increase the nasofrontal and nasolabial angles; the radiology report should indicate presence of a dorsal hump and septal deviation or spurring. In the lower face, prominence of the chin and squareness of the jaw are adjusted via genioplasty and mandible contouring, respectively; the radiology report should describe the location and potential anatomic variations of the inferior alveolar nerve and mental foramina, as well as presence of dental abnormalities that directly inform the surgical approach. CT may also be performed if there is clinical suspicion for postoperative complications such as hardware fraction or osteotomy through the supraorbital or mental foramen. Familiarity with these findings will facilitate improved communication between radiologists and surgeons, thereby contributing to the care of transgender women.
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http://dx.doi.org/10.2214/AJR.20.25528DOI Listing
December 2020

Acute Digital Necrosis in a Patient With Raynaud's Phenomenon and COVID-19 Infection.

Am Surg 2020 Dec 19:3134820979788. Epub 2020 Dec 19.

Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, 3989Baylor College of Medicine, Houston, TX, USA.

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http://dx.doi.org/10.1177/0003134820979788DOI Listing
December 2020

Diverse Functional Autoantibodies in Patients with COVID-19.

medRxiv 2020 Dec 12. Epub 2020 Dec 12.

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses . While pathological innate immune activation is well documented in severe disease , the impact of autoantibodies on disease progression is less defined. Here, we used a high-throughput autoantibody discovery technique called Rapid Extracellular Antigen Profiling (REAP) to screen a cohort of 194 SARS-CoV-2 infected COVID-19 patients and healthcare workers for autoantibodies against 2,770 extracellular and secreted proteins (the "exoproteome"). We found that COVID-19 patients exhibit dramatic increases in autoantibody reactivities compared to uninfected controls, with a high prevalence of autoantibodies against immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins. We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition, and found that murine surrogates of these autoantibodies exacerbate disease severity in a mouse model of SARS-CoV-2 infection. Analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics and disease severity. In summary, these findings implicate a pathological role for exoproteome-directed autoantibodies in COVID-19 with diverse impacts on immune functionality and associations with clinical outcomes.
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http://dx.doi.org/10.1101/2020.12.10.20247205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743105PMC
December 2020

RNA structure probing to characterize RNA-protein interactions on a low abundance pre-mRNA in living cells.

RNA 2020 Dec 11. Epub 2020 Dec 11.

University at Albany

In vivo RNA structure analysis has become a powerful tool in molecular biology, largely due to the coupling of an increasingly diverse set of chemical approaches with high-throughput sequencing. This has resulted in a transition from single target to transcriptome-wide approaches. However, these methods require sequencing depths that preclude studying low abundance targets, which are not sufficiently captured in transcriptome-wide approaches. Here we present a ligation-free method to enrich for low abundance RNA sequences, which improves the diversity of molecules analyzed and results in improved analysis. In addition, this method is compatible with any choice of chemical adduct or read-out approach. We utilized this approach to study an autoregulated event in the pre-mRNA of the splicing factor, muscleblind-like splicing regulator 1 (MBNL1).
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http://dx.doi.org/10.1261/rna.077263.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901844PMC
December 2020