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OBJECTIVES: We sought to identify immune biomarkers associated with severe Coronavirus disease 2019 (COVID-19) in patients admitted to a large urban hospital during the early phase of the SARS-CoV-2 pandemic. DESIGN: The study population consisted of SARS-CoV-2 positive subjects admitted for COVID-19 (n = 58) or controls (n = 14) at the Los Angeles County University of Southern California Medical Center between April 2020 through December 2020. Immunologic markers including chemokine/cytokines (IL-6, IL-8, IL-10, IP-10, MCP-1, TNF-α) and serologic markers against SARS-CoV-2 antigens (including spike subunits S1 and S2, receptor binding domain, and nucleocapsid) were assessed in serum collected on the day of admission using bead-based multiplex immunoassay panels. RESULTS: We observed that body mass index (BMI) and SARS-CoV-2 antibodies were significantly elevated in patients with the highest COVID-19 disease severity. IP-10 was significantly elevated in COVID-19 patients and was associated with increased SARS-CoV-2 antibodies. Interactions among all available variables on COVID-19 disease severity were explored using a linear support vector machine model which supported the importance of BMI and SARS-CoV-2 antibodies. CONCLUSIONS: Our results confirm the known adverse association of BMI on COVID-19 severity and suggest that IP-10 and SARS-CoV-2 antibodies could be useful to identify patients most likely to experience the most severe forms of the disease.

Objective  The objective of this study was to examine the effect of cochlear dose on hearing preservation in stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) for vestibular schwannoma (VS). Design  This is a retrospective case-control study. Setting  This study was completed at the Ronald Reagan UCLA Medical Center, a university-affiliated tertiary care center. Participants  Patients who underwent SRS (marginal dose of 12 Gy) or fSRT (marginal dose of 50.4 Gy) procedures for VS were included in the study. Main Outcome Measures  The main outcome measure was hearing preservation. Audiometric data, when available, were used to determine the level of hearing according to the Gardner Robertson scale. Results  A total of 38 patients (14 SRS and 24 fSRT) were analyzed. SRS patients with decreased hearing received a significantly higher minimum cochlear dose (7.41 vs. 4.24 Gy, p  = 0.02) as compared with those with stable hearing. In fSRT patients, there were no significant differences in cochlear dose for patients with decreased hearing as compared with those with stable hearing. For SRS patients, who received a minimum cochlear dose above 6 Gy, there was a significant risk of decreased hearing preservation (odds ratio: 32, p  = 0.02). Conclusion  Higher minimum cochlear dose was predictive of decreased hearing preservation following SRS. Though the study is low powered, the radiation dose to the cochlea should be a parameter that is considered when planning SRS or fSRT therapies for patients with VS.

BackgroundLong non-coding RNAs (lncRNAs) play a variety of cellular roles, including regulation of transcription and translation, leading to alterations in gene expression. Some lncRNAs modulate the expression of chromosomally adjacent genes. Here, we assess the roles of the lncRNA CASC15 in regulation of a chromosomally nearby gene, SOX4, and its function in RUNX1/AML translocated leukemia.ResultsCASC15 is a conserved lncRNA that was upregulated in pediatric B-acute lymphoblastic leukemia (B-ALL) with t (12; 21) as well as pediatric acute myeloid leukemia (AML) with t (8; 21), both of which are associated with relatively better prognosis. Enforced expression of CASC15 led to a myeloid bias in development, and overall, decreased engraftment and colony formation. At the cellular level, CASC15 regulated cellular survival, proliferation, and the expression of its chromosomally adjacent gene, SOX4. Differentially regulated genes following CASC15 knockdown were enriched for predicted transcriptional targets of the Yin and Yang-1 (YY1) transcription factor. Interestingly, we found that CASC15 enhances YY1-mediated regulation of the SOX4 promoter.ConclusionsOur findings represent the first characterization of this CASC15 in RUNX1-translocated leukemia, and point towards a mechanistic basis for its action.

B-cell development in the bone marrow is followed by specification into functional subsets in the spleen, including marginal zone (MZ) B-cells. MZ B-cells are classically characterized by T-independent antigenic responses and require the elaboration of distinct gene expression programs for development. Given their role in gene regulation, it is not surprising that microRNAs are important factors in B-cell development. Recent work demonstrated that deficiency of the NFκB feedback regulator, miR-146a, led to a range of hematopoietic phenotypes, but B-cell phenotypes have not been extensively characterized. Here, we found that miR-146a-deficient mice demonstrate a reduction in MZ B-cells, likely from a developmental block. Utilizing high-throughput sequencing and comparative analysis of developmental stage-specific transcriptomes, we determined that MZ cell differentiation was impaired due to decreases in Notch2 signaling. Our studies reveal miR-146a-dependent B-cell phenotypes and highlight the complex role of miR-146a in the hematopoietic system.

Abstract B cell development in bone marrow is followed by specification into spleen subsets, including marginal zone (MZ) cells. MZ require elaboration of distinct gene expression programs for development. Given their role in gene regulation, its not surprising that microRNAs (miRNAs) influence cell development. Recent work demonstrated that deficiency of NF-κB feedback regulator, Mir146 (miR-146a), led to a range of hematopoietic phenotypes, but B cells have not been extensively characterized. Here, we found miR-146a deficient mice demonstrate a reduction in MZ B cells, likely from a T cell independent developmental block. Utilizing comparative analysis of developmental stage-specific transcriptomes, we show MZ cell differentiation was impaired due to decreases in Notch2 signaling. Further, we discovered that the cell-fate regulatory protein, Numb, is a direct target of miR-146a, and its derepression in miR-146a deficient B cells underlies the decreases in Notch2. Our studies reveal miR-146a-dependent B cell phenotypes regulated by the Numb-Notch2 pathway. Disclosures No relevant conflicts of interest to declare.

Surgeons need to visualize the facial nerve reliably in relation to the vestibular schwannoma (VS) in surgical planning. Diffusion tensor imaging (DTI) tractography has enabled unprecedented in vivo preoperative visualization. We collected data to measure the accuracy of DTI for an accurate location of the nerve in preoperative VS resection planning. A PubMed search for relevant studies was conducted. Inclusion criteria were gross total resection of VS, preoperative DTI identification of the facial nerve, and intraoperative cranial nerve localization by the surgeon. Exclusion criteria were tumors other than VS and unsuccessful preoperative location of the cranial nerve. Accuracy rate was calculated by comparing the intraoperative and preoperative locations detailed by DTI. The query identified 38 cases of VS that fit our inclusion criteria. Overall, 89% had surgical findings that agreed with the DTI location of the facial nerve. Of these cases, 32 patients had a postoperative House-Brackmann grade I or II. Our findings suggest that DTI is a reliable method for facial nerve imaging. Implementation of this technique may help decrease facial nerve injury during surgery. Limitations and further studies are needed to better understand what factors correlate with successful location of the facial nerve and DTI in patients with VS.

In the process of pollination, a pollen tube grows from a pollen grain that has fallen on the stigma of a flower. This tube grows towards the ovary of the flower where it will deliver male reproductive material. Knowledge of the dynamics of pollen tube growth will provide a basis for understanding more complex cells that exhibit similar growth behavior. Current pollen tube growth models are a collection of differential equations that represent the level of understanding that biologists have concerning apical growth. Due to their complex nature, these models are not used to verify observed behavior in living cells as seen under a microscope. We present a model that can be used to describe the behavior of growing pollen tube cells in actual experiments. We propose biologically relevant functions based on knowledge of the growth process to explain the dynamics of model parameters. Our model uses an affine transformation to propagate the tip of the cell and statistical parameter estimation to measure necessary parameters during growth. Using experimental videos of pollen tube growth, we show that our model can adapt to various growth scenarios while extracting growth parameters from the videos.

Objective Chordomas are locally aggressive, highly recurrent tumors requiring adjuvant radiotherapy following resection for successful management. We retrospectively reviewed patients treated for intracranial chordomas with adjuvant stereotactic radiosurgery (SRS) and stereotactic radiation therapy (SRT). Methods A total of 57 patients underwent 83 treatments at the UCLA Medical Center between February 1990 and August 2011. Mean follow-up was 57.8 months. Mean tumor diameter was 3.36 cm. Overall, 8 and 34 patients received adjuvant SRS and SRT, and the mean maximal dose of radiation therapy was 1783.3 cGy and 6339 cGy, respectively. Results Overall rate of recurrence was 51.8%, and 1- and 5-year progression-free survival (PFS) was 88.2% and 35.2%, respectively. Gross total resection was achieved in 30.9% of patients. Adjuvant radiotherapy improved outcomes following subtotal resection (5-year PFS 62.5% versus 20.1%; p = 0.036). SRS and SRT produced comparable rates of tumor control (p = 0.28). Higher dose SRT (> 6,000 cGy) (p = 0.013) and younger age (< 45 years) (p = 0.03) was associated with improved rates of tumor control. Conclusion Adjuvant radiotherapy is critical following subtotal resection of intracranial chordomas. Adjuvant SRT and SRS were safe and improved PFS following subtotal resection. Higher total doses of SRT and younger patient age were associated with improved rates of tumor control.

The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. This study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.

B-cell development in the bone marrow is followed by specification into functional subsets in the spleen, including marginal zone (MZ) B-cells. MZ B-cells are classically characterized by T-independent antigenic responses and require the elaboration of distinct gene expression programs for development. Given their role in gene regulation, it is not surprising that microRNAs are important factors in B-cell development. Recent work demonstrated that deficiency of the NFκB feedback regulator, miR-146a, led to a range of hematopoietic phenotypes, but B-cell phenotypes have not been extensively characterized. Here, we found that miR-146a-deficient mice demonstrate a reduction in MZ B-cells, likely from a developmental block. Utilizing high-throughput sequencing and comparative analysis of developmental stage-specific transcriptomes, we determined that MZ cell differentiation was impaired due to decreases in Notch2 signaling. Our studies reveal miR-146a-dependent B-cell phenotypes and highlight the complex role of miR-146a in the hematopoietic system.

The objective of this study was to evaluate the characteristic symptoms of and treatments for lateral semicircular canal dehiscence (LSCD) and posterior semicircular canal dehiscence (PSCD) and its proposed mechanism. A dehiscence acquired in any of the semicircular canals may evoke various auditory symptoms (autophony and inner ear conductive hearing loss) or vestibular symptoms (vertigo, the Tullio phenomenon, and Hennebert sign) by creating a "third mobile window" in the bone that enables aberrant communication between the inner ear and nearby structures. A PubMed search was performed using the keywords lateral, posterior, and semicircular canal dehiscence to identify all relevant cases. Our data suggest that PSCD, although clinically rare, is most likely associated with a high-riding jugular bulb and fibrous dysplasia. Patients may experience auditory manifestations that range from mild conductive to extensive sensorineural hearing loss. LSCD is usually associated with chronic otitis media with cholesteatoma.

Introduction Papillary meningiomas (PMs) are characterized by their aggressive nature and high rate of recurrence. Due to their rarity, studies examining the relationship between treatment and clinical outcomes for this disease are limited. Gross total resection (GTR) with or without radiotherapy (RT) is considered the standard treatment; however, when GTR is not feasible, subtotal resection (STR) followed by RT may be an effective alternative. In this study, we analyzed the clinical outcomes in patients who either underwent GTR alone, GTR followed by RT, STR alone, or STR followed by RT. Methods A systematic analysis was performed to identify PM patients with sufficient follow-up and outcome data, as measured by recurrence. Patient data lacking extent of resection, follow-up, or recurrence information were excluded. Results A total of 29 patients with PM were treated with resections (23 GTRs and 6 STRs).The mean age and mean follow-up of patients in this study were 32.3 years and 42.1 months, respectively. Of these patients, 58.6% experienced recurrence. Overall, 47.8% of patients who underwent GTR experienced recurrence. These patients also demonstrated improved survival compared with STR. Among patients whose tumors were only partially excised, a recurrence rate of 83% was observed. Conclusion Our results confirm that GTR results in fewer recurrences compared with STR, supporting GTR as the treatment of choice for PM. Furthermore, GTR in conjunction with RT resulted in improved survival compared with GTR alone. When GTR was not feasible, STR with RT was associated with improved survival compared with STR alone. Future studies with more outcome data are needed to elucidate the optimal treatment for this rare disease.

Brain metastasis represents one of the most common causes of intracranial tumors in adults, and the incidence of brain metastasis continues to rise due to the increasing survival of cancer patients. Yet, the development of cystic brain metastasis remains a relatively rare occurrence. In this review, we describe the characteristics of cystic brain metastasis and evaluate the combined use of stereotactic aspiration and radiosurgery in treating large cystic brain metastasis. The results of several studies show that stereotactic radiosurgery produces comparable local tumor control and survival rates as other surgery protocols. When the size of the tumor interferes with radiosurgery, stereotactic aspiration of the metastasis should be considered to reduce the target volume as well as decreasing the chance of radiation induced necrosis and providing symptomatic relief from mass effect. The combined use of stereotactic aspiration and radiosurgery has strong implications in improving patient outcomes.