bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic changes in cell wall composition of mature sunflower leaves under distinct water regimes affect photosynthesis
Authors: Roig-Oliver Margalida , Bresta Panagiota , Nikolopoulos Dimosthenis , Bota Josefina , Flexas Jaume
Published: August 2021

In previous work, we identified that exposure to limited water availability induced changes in cell wall composition of mature Helianthus annuus L. leaves that affected mesophyll conductance to CO2 diffusion (gm). However, it is unclear on which timescale these changes in cell wall composition occurred. Here, we subjected H. annuus to control (i.e. water availability), different levels of short-term water deficit stress (ST), long-term water deficit stress (LT), and long-term water deficit stress followed by gradual recoveries addressed at different timescales (LT-Rec) to evaluate the dynamics of modifications in the main composition of cell wall (cellulose, hemicelluloses, pectins and lignins) affecting photosynthesis. During gradual ST treatments, pectins enhancement was associated with gm decline. However, during LT-Rec, pectins content decreased significantly after only 5 h, while hemicelluloses and lignins amounts changed after 24 h, all being uncoupled from gm. Surprisingly, lignins increased by around 200% compared with control and were related to stomatal conductance to gas diffusion (gs) during LT-Rec. Although we suspect that the accuracy of the protocols to determine cell wall composition should be re-evaluated, we demonstrate for the first time that a highly dynamic cell wall composition turnover differently affects photosynthesis in plants subjected to distinct water regimes.
Characterization of SARS2 Nsp15 nuclease activity reveals it's mad about U
Authors: Frazier Meredith N , Dillard Lucas B , Krahn Juno M , Perera Lalith , Williams Jason G , Wilson Isha M , Stewart Zachary D , Pillon Monica C , Deterding Leesa J , Borgnia Mario J , Stanley Robin E
Published: August 2021

Nsp15 is a uridine specific endoribonuclease that coronaviruses employ to cleave viral RNA and evade host immune defense systems. Previous structures of Nsp15 from across Coronaviridae revealed that Nsp15 assembles into a homo-hexamer and has a conserved active site similar to RNase A. Beyond a preference for cleaving RNA 3′ of uridines, it is unknown if Nsp15 has any additional substrate preferences. Here, we used cryo-EM to capture structures of Nsp15 bound to RNA in pre- and post-cleavage states. The structures along with molecular dynamics and biochemical assays revealed critical residues involved in substrate specificity, nuclease activity, and oligomerization. Moreover, we determined how the sequence of the RNA substrate dictates cleavage and found that outside of polyU tracts, Nsp15 has a strong preference for purines 3′ of the cleaved uridine. This work advances our understanding of how Nsp15 recognizes and processes viral RNA, and will aid in the development of new anti-viral therapeutics.
BSCI-05. ABL2-HSF1-E2F signaling axis promotes lung adenocarcinoma brain metastasis
Authors: Pendergast Ann Marie , Hoj Jacob , Mayro Benjamin
Published: August 2021

Brain metastases are the most common intracranial tumors in adults and are associated with increased patient morbidity and mortality. Limited therapeutic options are currently available for the treatment of brain metastasis. We have identified an actionable signaling pathway utilized by metastatic tumor cells whereby the transcriptional regulator Heat Shock Factor 1 (HSF1) drives a transcriptional program, divergent from its canonical role as the master regulator of the heat shock response, leading to enhanced expression of a subset of E2F transcription factor family gene targets. We showed that HSF1 is required for survival and outgrowth by metastatic lung cancer cells in the brain parenchyma. Unexpectedly, we identified the ABL2 tyrosine kinase as an upstream regulator of HSF1 protein expression, and showed that the Src-homology 3 (SH3) domain of ABL2 directly interacts with HSF1 protein at a non-canonical, proline-independent SH3 interaction motif. Importantly, knockdown of ABL2 impairs expression of HSF1 protein and HSF1-E2F transcriptional gene targets. Notably, we found that pharmacologic inhibition of the ABL kinases using selective ABL allosteric inhibitors, but not ATP-competitive inhibitors, ablates the physical interaction between ABL2 and HSF1, leading to markedly decreased expression of HSF1, E2F1 and E2F8 proteins in brain-metastatic lung cancer cells, and depletion of HSF1-E2F transcriptional targets. These findings highlight potential differences affecting intra- and inter-molecular protein-protein interactions induced by allosteric versus ATP-competitive kinase inhibitors that have important therapeutic implications. Importantly, the targetable nature of the ABL2-HSF1-E2F signaling network identifies ABL allosteric inhibitors as a potentially effective therapy for the treatment of metastatic lung cancers characterized by high expression of HSF1.
BSCI-09. Multiomic single cell analysis reveals emerging principles of tumor immune microenvironment inherent to NSCLC brain metastases
Authors: Wen Lei , Shan Changguo , Liu Da , Zhou Cheng , Cai Linbo
Published: August 2021

Brain is one of the most common sites for distant metastasis of lung cancer. Treatment naïve lung cancer patients diagnosed with brain metastasis are left with very limited options. Checkpoint inhibition is a powerful immunotherapy strategy but delivers benefit only to a small population of patients. Here we harnessed the power and resolution of single cell RNA sequencing and single cell TCR/BCR sequencing to investigate the tumor immune microenvironment (TIME) of NSCLC brain metastases. We enrolled treatment naïve lung cancer patients with brain metastasis. The enrolled subjects covered different histology types and driver gene mutation status. We revealed the emerging principles of innate and adaptive immune components inherent to NSCLC brain metastases. We also uncovered several significant intercellular communication patterns that potentiates cancer cell seeding and fosters cancer cell proliferation. Those results served as a starting point to design optimal immunotherapy strategies for advanced lung cancer patients with limited options.
TRLS-02. Trial in Progress: A Multicenter Phase 3 Study to Establish the Diagnostic Performance of 18F-Fluciclovine PET in Detecting Recurrent Brain Metastases after Radiation Therapy (REVELATE)
Authors: Teoh Eugene , Chaglassian Alain , Tainer Nancy
Published: August 2021

Background

Brain metastases occur in up to 40% of patients with cancer and are associated with poor prognosis and considerable levels of recurrence. Consequently, close follow-up with serial brain MRI is performed post-treatment to monitor for recurrent disease. Although conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) is the recommended follow-up modality, it has poor specificity with limited ability to differentiate between true disease recurrence and treatment-related changes such as radiation necrosis. Therefore, alternative imaging options are sought in order to help physicians confidently diagnose treatment-related changes and thus reliably stratify the risk of continuation of a therapeutic regimen, especially given the morbidity associated with current treatments. Amino acid PET imaging agent, 18F-fluciclovine, has increased uptake in brain tumors relative to normal tissue and may be useful for detecting recurrent brain metastases.

Methods

NCT04410133 is a prospective, open-label, single-arm, single-dose (185 MBq ±20%) study with a primary objective to confirm the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for detection of recurrent brain metastases where MRI is equivocal.

Approximately 150 subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled in this multicenter trial (~18 US sites) if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures such as biopsy/neurosurgical intervention or clinical follow-up. Subjects will undergo 18F-fluciclovine PET <28 days after the equivocal MRI and 2–21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Secondary objectives include evaluation of subject- and lesion-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity respectively) for recurrent brain metastases, inter-reader and intra-reader agreement, and safety evaluations. Enrolment began in October 2020 and the trial is open at the time of submission.
TRLS-04. A Nomogram for Predicting Survival in Patients with Brain Metastases
Authors: Wang Zhenning , He Zhenqiang , Jiang Xiaobing , Guo Chengcheng , Mou Yonggao
Published: August 2021

Background

Brain metastases are the most common intracranial tumors in adults, with a very poor prognosis, and poses distinct clinical challenges. This study aimed to develop a more accurate prognostic nomogram for predicting overall survival (OS) of patients with Brain Metastases.

Methods

We conducted a retrospective analysis of 1062 patients with brain metastases at the Sun Yat-sen University Cancer Center (SYSUCC, Guangzhou, China) between January 2010 and January 2018, Among them, 331 patients underwent surgery to remove brain metastases. Kaplan–Meier analysis was performed to screen for potential clinical variables that could be used to establish the nomogram for predicting overall survival.

Results

We found that age,gender, whether to remove intracranial lesions, radiotherapy, ECOG were independent prognostic factors for predicting the overall survival with brain metastases,and surgical resection for brain metastatic lesions could significantly improve OS,but only in certain groups of patients with brain metastases can benefit from intracranial lesion resection, such as no extracranial metastasis. And patients with brain metastases whose primary tumor is lung adenocarcinoma or breast cancer are more likely to benefit from surgery in terms of overall survival time.A nomogram for predicting 1- and 2-year overall survival rates was constructed, which exhibited good accuracy in predicting overall survival.

Conclusion

Through statistical analysis, we have found the factors related to the surgical benefit of patients with brain metastases, and established a prognostic nonogram,This nomogram may be used to guide individual treatments and in selecting an appropriate patient population for clinical trials.
TRLS-06. A Phase 1–2 clinical trial of EO1001 (APL-122), a novel irreversible pan-ErbB inhibitor with promising brain penetration
Authors: Frentzas Sophia , Richardson Gary , Bacha Jeffrey , Kanekal Sarath , Sankar Neil , Shen Wang , Redkar Sanjeev , Lai Chinglin , Yu Peony , Nisbet Ian , Skoff Kathy , Wheeler Helen , Pedersen Harry , Zhong Wang Zhen , Brown Dennis
Published: August 2021

CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive cross-talk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models.

We report on a first-in-human Phase 1–2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, with adequate bone marrow, renal and liver function are eligible.

Materials and methods Escalation: One subject per dose cohort is enrolled in an accelerated dose-escalation design until drug-related toxicity (≥G2) is observed in the first cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Cycle 1: Patients receive a single oral dose of EO1001 on day 1; single-dose pharmacokinetics are measured. Beginning on day 8, EO1001 is administered once daily for 21 days; multi-dose pharmacokinetics are measured. Cycles 2–6: EO1001 is administered once daily in continuous 28-day cycles for up to 20 weeks. Expansion: EO1001 is administered once daily to 20 patients at the MTD in continuous 28-day cycles for up to 6 cycles to determine a recommended Phase 2 dose (RP2D) for further study.

Toxicity is assessed based on NCI CTCAEv5 and tumor response is assessed by RECIST 1.1. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.
LMD-03. Single cell analysis reveals how therapy remodels the tumor microenvironment in melanoma CNS metastases and uncovers a novel predictor of improved survival
Authors: Smalley Inna , Chen Zhihua , Phadke Manali , Li Jiannong , Yu Xiaoqing , Wyatt Clayton , Evernden Brittany , Messina Jane , Sarnaik Amod , Sondak Vernon , Zhang Chaomei , Law Vincent , Tran Nam , Etame Arnold , Macaulay Robert , Eroglu Zaynep , Forsyth Peter , Rodriguez Paulo , Chen Ann , Smalley Keiran
Published: August 2021

We interrogated the microenvironment of 43 clinical samples from melanoma skin, brain (MBM) and leptomeningeal metastases (LMM) using single-cell RNA-seq analysis to determine how therapeutic intervention shaped the immune environment and affected patient survival. LMM is a poorly-characterized, devastating complication of late-stage disease, typically refractory to treatment and associated with dismal survival time. Analysis of serial specimens over the course of therapy demonstrated reductions in melanoma cells and macrophages, coupled with increased levels of T cells and dendritic cells in the CSF of a rare extraordinary responder, whereas typical poor survivors showed no improvement in T cell responses. In MBM patients, both targeted therapy and immunotherapy was associated with increased immune infiltrate. Treatment with targeted therapy was associated with an enrichment of CD8 T cells, while immunotherapy was associated with a more diverse lymphocyte landscape and higher numbers of antibody-producing cells. These findings were confirmed by multiplex-IF staining of patient specimens and using an immune-competent mouse model of MBM. Interestingly, a history of prior radiation therapy was associated with a diminished myeloid compartment. Although immune infiltrate was significantly lower in the brain compared to skin tumors, the phenotypic make-up of the lymphocyte compartment was quite similar, suggesting that the immune cells may have trafficked from the periphery to the brain post-therapy. Correlation analysis across the entire immune landscape identified the presence of a rare, novel population of dendritic cells (DC3s) to be correlated with increased overall survival, regardless of disease site/treatment. The presence of DC3s positively regulated the immune environment of both patient samples and preclinical melanoma models through modulation of activated T cells and MHC expression in the tumor. Overall, we present the first ever comprehensive single-cell atlas of the tumor microenvironment in melanoma CNS metastases in response to therapy.
LMD-11. Pure spinal cord invasion in recurrent classic Hodgkin’s Lymphoma - what is it?
Authors: Awori Violet , Cothern Jordan , Shaikh Nawal
Published: August 2021

We present the case of a 39-year-old male who initially presented in January 2017 with abdominal pain and weight loss. He was eventually diagnosed with stage IVB Classical Hodgkin’s Lymphoma. Brentuximab, Vinblastine, and Dacarbazine regimen was initiated with dose adjustments made due to cardiomyopathy and neuropathy. By cycle 5, good response was evident on systemic imaging. He was then lost to follow-up.

He represented in December 2020 with near paraplegia, preceded by months of tingling, numbness in both legs, gait imbalance and low back pain. MRI spine in January 2021 demonstrated multifocal abnormal cord signal changes with scattered areas of intramedullary cord enhancement as well as extensive enhancement of the cauda equina (Figures 1,2,3). CNS angiitis as a paraneoplastic phenomenon, mimics a similar clinical and radiographic appearance. Unfortunately none of the cord lesions were amenable to biopsy.

Full body PET CT showed florid disease concerning for recurrence. 2 lumbar punctures with limited CSF flow cytometry and cytology analyses were negative. Mediastinal lymph node biopsy revealed Classical Hodgkins Lymphoma. DHAP chemotherapy regimen was initiated, soon after. A 3rd time, high volume comprehensive CSF analysis performed later, was unremarkable. MRI spine, after 2 cycles demonstrated significant improvement(Figures 4,5,6)coinciding with systemic response and clinical improvement. This favored diagnosis of CNS Hodgkin lymphoma over secondary CNS angiitis.

CNS Hodgkin’s Lymphoma is a rare occurrence1, let alone, pure spinal intramedullary and leptomeningeal metastases. Intramedullary metastases arise from direct hematogenous spread or by, centripetal growth of tumor along spinal nerve roots with secondary invasion of spinal cord2. Systemic Hodgkin’s Lymphoma rarely affects the spine with a prevalence of 0.2% - 0.5%3,4. In an analysis of a large cohort of Hodgkin’s patients comprising 14,868 individuals, a prevalence of less than 0.02%, indicating it had been overestimated in the past5.
THER-01. Targeted therapy and intracranial metastatic disease: a population-based retrospective cohort study
Authors: Erickson Anders , Habbous Steven , Wright Frances , Lofters Aisha , Jerzak Katarzyna , Das Sunit
Published: August 2021

Background

Targeted therapies have been hypothesized to prolong survival in the management of patients with intracranial metastatic disease (IMD), but, paradoxically, to increase IMD incidence by improving systemic disease control and prolonging survival from the primary tumor. The real-world benefits of targeted therapy in management of patients with IMD are unclear, as clinical trials have excluded patients with IMD and lacked endpoints reporting intracranial outcomes.

Methods

This retrospective cohort study included all patients in Ontario, Canada, diagnosed with IMD from 2005 to 2018 with primary diagnoses of breast cancer, lung or bronchus cancer, or melanoma, and control patients matched by primary disease without IMD. Kaplan-Meier and multivariable Cox regression analyses were performed to compare overall survival (OS) between patient sub-cohorts divided by primary disease and stratified by targeted therapy receipt or IMD status.

Results

Post-IMD targeted therapy was associated with prolonged OS in patients with HER2-positive breast cancer (HR 0.41; 95% CI, 0.33–0.5), EGFR-positive lung cancer (HR 0.28; 95% CI, 0.23–0.34), and BRAF-positive melanoma (HR 0.2; 95% CI, 0.14–0.29), compared to those who did not receive post-IMD targeted therapy. Presence of IMD was associated with shorter OS in patients with metastatic HER2-positive breast cancer (HR 1.8; 95% CI, 1.56–2.08) and metastatic EGFR-positive lung cancer (HR 1.22; 95% CI, 1.08–1.39) but not metastatic BRAF-positive melanoma (HR 1.11; 95% CI, 0.77–1.61), compared to those without IMD.

Conclusions

Our findings show that real-world use of targeted therapies was associated with prolonged OS in patients with IMD in the setting of HER2-positive breast cancer, EGFR-positive lung cancer, and BRAF-positive melanoma. Inclusion of patients with IMD in clinical trials and use of endpoints that interrogate IMD will be critical to determine the role of targeted therapies in the management of patients with IMD.
OTHR-05. Diagnosis and Treatment of Solitary Pituitary Metastatic Cancer: A Case Series
Authors: Shan Changguo , Hong Weiping , Lai Mingyao , Wang Hui , Wen Lei , Cai Linbo
Published: August 2021

Objective

Metastatic pituitary carcinoma accounted for only 1% of pituitary lesions.

Methods

Patients with isolated pituitary metastatic carcinoma admitted to our hospital from 2014 to 2018 were retrospectively collected, clinical features and prognosis were analyzed.

Results

A total of 5 patients (4 males and 1 female) with a median age of 48 years (21 to 66 years) were included, all with single intracranial pituitary nodules as the initial clinical presentation. The related symptoms were visual impairment (5/5 cases), hypopituitarism (5/5 cases), visual field defect (5/5 cases), headache (4/5 cases), hypothyroidism (4/5 cases), diabetes insipidus (2/5 cases). All the 5 patients received surgical resection (total or partial resection) of tumors in the sellar region via nasal sphenoidal approach. Postoperative pathology confirmed that 4 cases were metastatic adenocarcinoma and 1 case was metastatic squamous carcinoma. Further imaging examinations, such as CT or whole-body PET/CT, confirmed that the primary lesions of all the 5 patients were from the lung. Gene testing indicated that 3 of the 4 adenocarcinoma patients were EGFR mutation positive and 1 of the 4 adenocarcinoma patients was ROS1 mutation positive. Patients received radiotherapy (5/5 cases), targeted therapy (4/5 cases), or chemotherapy (1/5 cases) after surgery. Survival follow-up to May 2019 showed that 4 patients had died, with a survival of 2, August, 28, and 30 months, respectively, and 1 patient was still alive with a survival of 4 months.

Conclusion

The first clinical manifestation of isolated pituitary metastatic carcinoma is nervous system related symptoms, which is easily misdiagnosed. The most of the primary lesions are from lung, especially lung adenocarcinoma with positive driver gene. Surgery, radiotherapy combined with targeted therapy or chemotherapy can provide survival benefits for patients with pituitary metastatic carcinoma.
RADI-06. Gamma knife surgery for brain stem metastases
Authors: Tan Choo Heng , Karlsson Bengt , Wang Shilin , Zhang John J Y , Ang Yvonne , Vellayappan Balamurugan , Teo Kejia , Nga Vincent D W , Lwin Sein , Yeo Tseng Tsai
Published: August 2021

Introduction

Gamma Knife Surgery (GKS) is widely used for treatment of brainstem metastases (BSMs) with or without whole bran radiation therapy (WBRT). We hypothesized that BSMs treated with GKS using lower doses and omitting WBRT result in acceptable tumor control rates and low complication rates.

Methods

A retrospective single center study was performed to investigate the outcome following GKS of BSMs. All 33 patients with follow-up information treated with GKS for 39 metastases located in the cerebral peduncle, midbrain, pons or medulla oblongata were included in the study. The median treatment dose, defined as the lowest dose to 95% of the tumor volume, was 18 Gy. The tumor control rate as well as the survival time were related to a number of patients, tumor and treatment parameters.

Results

The local tumor control rate was 100% at one year and 89% at five years, and the overall median survival was 17 months. A good performance status and a treatable extracranial disease were favorably related to survival time. Two complications were observed, one lethal hemorrhage at the day of the treatment and one transient complication three months following GKS, resulting in a 6% complication rate at five years. Four of the 10 patient with symptomatic BSM improved clinically after GKS, while six remained unchanged.

Conclusions

High local control and a low complication rates can be achieved using GKS for BSMs using lower doses as compared to brain metastases in other locations.
RADI-22. Toxicity and local control outcomes for brain metastases managed with resection and aggressive reirradiation after initial radiosurgery failure
Authors: Bhatia Rohini , Siu Catherine , Baker Brock , Redmond Kristin , Jackson Christopher , Bettegowda Chetan , Lim Michael , Kleinberg Lawrence
Published: August 2021

Objectives

To describe toxicity and tumor outcome after resection and aggressive re-irradiation (stereotactic radiosurgery(SRS) or brachytherapy) of brain metastasis that have pathologically confirmed recurrence after prior radiosurgery.

Methods

A retrospective chart review identified 40 lesions in 35 patients that were initially treated with SRS, then demonstrated evidence of recurrence with pathologic confirmation and underwent re-irradiation either with radiosurgery (n=28, 70%) or intracavitary brachytherapy with Cesium-131 seeds (n=12, 30%). Toxicity was measured by: steroids initiated or increased within 3 months, imaging evidence of treatment effect vs disease progression at any time point, further intervention for local recurrence or necrosis, and any grade 3/4 neurologic events. Local control (with failure defined by sustained progression on imaging or pathologic confirmation of tumor) was measured from time of retreatment.

Results

Median follow-up from time of re-irradiation was 11.8 months (range 1 – 89.7 months). Dose for repeat radiosurgery was 18–25 Gy in 1–5 fractions, and brachytherapy dose was 55–65 Gy at 5 mm depth. Twelve lesions subsequently had imaging evidence of radionecrosis vs. progression. Of these, eight underwent repeat resection with pathology demonstrating radiation necrosis in five patients (n=4 with SRS, n=1 with brachy) and tumor recurrence in 3 (n=2 with brachy, and n=1 with SRS). Toxicities included: Steroids, 14(35%); imaging progression/necrosis 12(30%); grade 3/4 event, 3(20%); and surgically confirmed radionecrosis 5(12.5%). Local control of retreated lesions at 6 months is 85.5%, and at 12 months is 79.3%, OS at 1 year is 52.5% and at 2 years 46.6%. Local control at one year for repeat stereotactic treatment was 82.9% and for Cs131 brachytherapy was 80.8%

Conclusions

Aggressive re-irradiation after resection for pathologic confirmation appears to be appropriately safe and effective for the majority of patients after local failure of initial radiosurgery.
SURG-06. Metastases in the pineal region: a systematic review of clinical features, treatment strategies and survival outcomes
Authors: Palmisciano Paolo , Haider Ali S , Ogasawara Christian , Nwagwu Chibueze D , Wahood Waseem , Sagoo Navraj S , El Ahmadieh Tarek Y
Published: August 2021

Background

Pineal region metastases are rare but often lead to severe neurological deficits. Surgical resection may play a therapeutic role.

Methods

We searched PubMed, EMBASE, Scopus, and Cochrane according to PRISMA guidelines. Studies reporting clinical outcomes data of patients with pineal region metastases were included. Clinical characteristics, management strategies, and survival data were reviewed.

Results

We included 30 studies comprising 46 patients. The median age at diagnosis was 58 years (range 27–82). Lung cancer (30.4%) and carcinomas of unknown origin (15.2%) were the most frequent primary tumors. In 50% of patients, symptomatic pineal metastases preceded primary tumor diagnosis. Headache (66.7%) and confusion (45.2%) were the most common presenting symptoms. Parinaud’s syndrome (47.6%) and hydrocephalus (87%) were commonly noted. Biopsy (67.4%) was preferred over surgical resection (32.6%). The most common CSF diversion protocols were endoscopic third ventriculostomy (45%) and ventriculoperitoneal shunting (27.5%). Eleven patients received adjuvant chemotherapy and 31 underwent radiotherapy. At post-treatment follow-up, symptomatic improvement (55.2%) and hydrocephalus reduction (80%) were described. Post-treatment performance status scores were statistically superior that pre-treatment scores for patients undergoing biopsy (P<0.001) and tumor resection (P=0.007) coupled with adjuvant chemo/radiotherapy. Mean follow-up was 8 months, and median overall survival was 3 months. Only two cases (4.8%) of pineal metastases recurrence were reported, and median progression-free survival was 3 months. In patients receiving adjuvant chemo/radiotherapy, no survival differences were reported between surgery and biopsy (P=0.912), nor between gross-total and subtotal resection (P=0.220). Overall survival was neither correlated with surgical approach (P=0.157), nor with CSF diversion protocol (P=0.822).

Conclusion

Pineal region metastases can severely impair clinical status. Biopsy or surgical resection may significantly improve symptoms and baseline performance status when combined with adjuvant chemo/radiotherapy and CSF diversion.
SURG-11. Surgery for control of brain metastases after prior checkpoint inhibitor immunotherapy: a single-center series
Authors: Morshed Ramin , Chung Jason , Sudhakar Vivek , Cummins Daniel , Young Jacob , Hervey-Jumper Shawn , Theodosopoulos Philip , Aghi Manish
Published: August 2021

Background

Despite the promising results for treating metastatic cancer with checkpoint inhibitor immunotherapies, there are limited data on surgical outcomes for brain metastases (BMs) that have progressed after prior checkpoint inhibitor treatment. The objective of this study was to identify factors associated with local progression, leptomeningeal disease, and survival for patients undergoing surgical resection of a BM in patients previously treated with checkpoint inhibitor immunotherapy.

Methods

A retrospective, single-center cohort study was conducted with inclusion of adult patients undergoing surgical resection of a BM in the setting of progression after prior checkpoint inhibitor treatment. Univariate and multivariate analyses were performed to identify factors associated with outcomes of interest.

Results

Over an 8-year period, 26 patients who underwent resection of 30 BMs met inclusion criteria. Median patient age at surgery was 63.9 years, and median clinical follow-up was 6.9 months (range 0.1 – 52.9). Extracranial disease was present at the time of surgery in 73.3% of cases. There were 6 postoperative complication events (20% of cases) by 30-days. By last follow-up, 65.4% of the cohort had died with a median censored survival of 7.6 months from surgery. Eight patients (30.8%) died within 3 months of surgery. On multivariate analysis, postoperative complications were associated with worse survival (HR 5.33, 95%CI 1.15–24.77, p=0.03). Four BMs had local progression (13.3%), and 60% of procedures were associated with distant progression within a median time of 3.6 months. Leptomeningeal disease developed in 32% of cases. On multivariate analysis, increased time from BM diagnosis to surgery was associated with a greater risk of leptomeningeal disease (OR 1.2, 95%CI 1.00–1.43, p=0.021).

Conclusion

Patients who require BM resection after prior checkpoint inhibitor treatment have an overall poor prognosis. Although local control rates are acceptable, these patients are at high risk for developing leptomeningeal disease postoperatively.
Macrolide Resistance, Clinical Features, and Cytokine Profiles in Taiwanese Children With Mycoplasma pneumoniae Infection
Authors: Wu Tsung-Hua , Wang Nancy M , Liu Fang-Ching , Pan Hui-Hsien , Huang Fang-Liang , Fang Yu-Ping , Chiang Ting-Wei , Yang Yu-Ying , Song Chiah-Sing , Wu Hsiang-Chin , Lee Chun-Yi
Published: August 2021

Background

The factors that predict the progression of Mycoplasma pneumoniae infection remain inconclusive. Therefore, we investigated macrolide resistance prevalence, M pneumoniae genotype, and clinical characteristics of childhood M pneumoniae respiratory tract infections in Taiwan.

Methods

A total of 295 children hospitalized with respiratory tract infections with positive serological M pneumoniae immunoglobulin M test results were enrolled in this 3-year prospective study. Oropharyngeal swabs were obtained for M pneumoniae cultures and polymerase chain reaction tests. All M pneumoniae specimens were further characterized by P1 typing, multilocus variable-number tandem-repeat analysis (MLVA), and macrolide resistance genotyping. The clinical characteristics and blood cytokine profiles were analyzed accordingly.

Results

Of 138 M pneumoniae specimens, type I P1 was the predominant (136 of 138, 98.6%). The MLVA type P (4-4-5-7-2) was the leading strain (42 of 138, 30.4%), followed by type J, U, A, and X. The overall macrolide-resistant rate was 38.4% (53 of 138); the resistance rate increased dramatically yearly: 10.6% in 2017, 47.5% in 2018, and 62.5% in 2019 (P < .001). All macrolide-resistant M pneumoniae (MRMP) harbored the A2063G mutation and were MLVA type 4-5-7-2 (49 of 53, 92.5%), especially type U and X. No significant differences in clinical symptoms, duration of hospital stay, and radiographic findings were identified among patients between MRMP and macrolide-sensitive M pneumoniae (MSMP) groups. Patients with MRMP infection had more febrile days before and during hospitalization and higher interleukin (IL)-13 and IL-33 levels than patients with MSMP infection (P < .05).

Conclusions

Macrolide-resistant M pneumoniae surged in Taiwan throughout the study period, but macrolide resistance was not a determinant factor of clinical severity.
Growth of Coronal Garnet in Anhydrous High-Fe Ultrabasic Rocks: The Interplay Between Metamorphic Reaction Progress, Local Strain Heterogeneity and Grain Boundary Diffusion
Authors: Bhattacharya Abhijit , Dey Joyjit , Kushwaha Aman , Sequeira Nicole
Published: August 2021

Coronal garnets at pyroxene-plagioclase interfaces are traditionally used to estimate P-T conditions and reconstruct P-T paths. However, the mechanism by which the coronal garnet grows is poorly constrained. We address the issue based on the analyses of textures, mineral compositions, and crystallographic orientations of coronal garnets and associated minerals. In the Bolangir anorthosite massif (Eastern India), coronal garnets are common at the interfaces of plagioclase phenocrysts and Fe-rich pyroxenes within ferrodiorites, and at ferrodiorite-anorthosite interfaces. The plagioclase phenocrysts comprise weakly recrystallized and chemically homogenous An-rich cores (Pl1) that are partly and/or completely replaced by mantles of smaller, chemically zoned, dynamically recrystallized An-poorer plagioclase (Pl2) grains. Chemically similar beads and coalescent grains of garnet occur inward within the recrystallized Pl2 mosaic lacking ferromagnesian minerals/Fe-Ti oxides. Aggregates of elongate garnet grains oriented orthogonal to ferrodiorite-anorthosite interfaces also form continuous corona layers. The coronal garnets formed at peak P-T conditions (900°C, ≤7 kb) due to the NC(FM)AS continuous reaction Pl1 + Opx + Cpx → Pl2 + Grt, and progressed from rim inwards into the phenocrysts. Well-faceted garnet corona associated with Pl2 exhibits a random crystal preferred orientation (CPO). However, low-angle subgrain boundaries, cellular microstructure, internal lattice distortion, and orientation dispersion with rational crystallographic rotation axis in the coronal garnets indicate locally developed growth-induced stress fields affecting the garnets.

The growth of coronal garnets hosted within Pl2 well inside the plagioclase necessitates the transport of Fe, Mg from the melanocratic matrix along distances comparable to the radii (∼350 µm) of the phenocrysts. We argue that grain boundary diffusion along networks of grain boundaries of Pl2 provided pathways for Fe, Mg transport to the zones where coronal garnets formed via reactions that consumed Pl1 and produced Pl2. The formation of garnet induced heterogeneous strain development within the plagioclase phenocrysts, intense at the plagioclase margin and neighboring coronal garnets. The lack of CPO in the garnets attests to the absence of far-field stress; but dislocations and lattice distortion indicate that local stresses developed to accommodate garnet growth within plagioclase. In other words, garnet grew by a feedback mechanism that linked chemical potential gradient with the elastic contribution induced by the time-space varying local stresses generated by the growing garnet grains within the confines of the plagioclase phenocrysts.
A small molecule antagonizes jasmonic acid perception and auxin responses in vascular and nonvascular plants
Authors: Chini Andrea , Monte Isabel , Fernández-Barbero Gemma , Boter Marta , Hicks Glenn , Raikhel Natasha , Solano Roberto
Published: August 2021

The phytohormone jasmonoyl-L-isoleucine (JA-Ile) regulates many stress responses and developmental processes in plants. A co-receptor complex formed by the F-box protein Coronatine Insensitive 1 (COI1) and a Jasmonate (JA) ZIM-domain (JAZ) repressor perceives the hormone. JA-Ile antagonists are invaluable tools for exploring the role of JA-Ile in specific tissues and developmental stages, and for identifying regulatory processes of the signaling pathway. Using two complementary chemical screens, we identified three compounds that exhibit a robust inhibitory effect on both the hormone-mediated COI–JAZ interaction and degradation of JAZ1 and JAZ9 in vivo. One molecule, J4, also restrains specific JA-induced physiological responses in different angiosperm plants, including JA-mediated gene expression, growth inhibition, chlorophyll degradation, and anthocyanin accumulation. Interaction experiments with purified proteins indicate that J4 directly interferes with the formation of the Arabidopsis (Arabidopsis thaliana) COI1–JAZ complex otherwise induced by JA. The antagonistic effect of J4 on COI1–JAZ also occurs in the liverwort Marchantia polymorpha, suggesting the mode of action is conserved in land plants. Besides JA signaling, J4 works as an antagonist of the closely related auxin signaling pathway, preventing Transport Inhibitor Response1/Aux–indole-3-acetic acid interaction and auxin responses in planta, including hormone-mediated degradation of an auxin repressor, gene expression, and gravitropic response. However, J4 does not affect other hormonal pathways. Altogether, our results show that this dual antagonist competes with JA-Ile and auxin, preventing the formation of phylogenetically related receptor complexes. J4 may be a useful tool to dissect both the JA-Ile and auxin pathways in particular tissues and developmental stages since it reversibly inhibits these pathways.

One-sentence summary: A chemical screen identified a molecule that antagonizes jasmonate perception by directly interfering with receptor complex formation in phylogenetically distant vascular and nonvascular plants.
Sulfur deficiency-induced genes affect seed protein accumulation and composition under sulfate deprivation
Authors: Aarabi Fayezeh , Rakpenthai Apidet , Barahimipour Rouhollah , Gorka Michal , Alseekh Saleh , Zhang Youjun , Salem Mohamed A , Brückner Franziska , Omranian Nooshin , Watanabe Mutsumi , Nikoloski Zoran , Giavalisco Patrick , Tohge Takayuki , Graf Alexander , Fernie Alisdair R , Hoefgen Rainer
Published: August 2021

Sulfur deficiency-induced proteins SDI1 and SDI2 play a fundamental role in sulfur homeostasis under sulfate-deprived conditions (−S) by downregulating glucosinolates. Here, we identified that besides glucosinolate regulation under –S, SDI1 downregulates another sulfur pool, the S-rich 2S seed storage proteins in Arabidopsis (Arabidopsis thaliana) seeds. We identified that MYB28 directly regulates 2S seed storage proteins by binding to the At2S4 promoter. We also showed that SDI1 downregulates 2S seed storage proteins by forming a ternary protein complex with MYB28 and MYC2, another transcription factor involved in the regulation of seed storage proteins. These findings have significant implications for the understanding of plant responses to sulfur deficiency.
Meristem transitions and plant architecture—learning from domestication for crop breeding
Authors: Gaarslev Natalia , Swinnen Gwen , Soyk Sebastian
Published: August 2021

Genetic networks that regulate meristem transitions were recurrent targets of selection during crop domestication and allow fine-tuning of plant architecture for improved crop productivity.
iRegNet: an

i

ntegrative

Reg

ulatory

Net

work analysis tool for Arabidopsis thaliana
Authors: Shim Sangrea , Park Chung-Mo , Seo Pil Joon
Published: August 2021

Gene expression is delicately controlled via multilayered genetic and/or epigenetic regulatory mechanisms. Rapid development of the high-throughput sequencing (HTS) technology and its derivative methods including chromatin immunoprecipitation sequencing (ChIP-seq) and DNA affinity purification sequencing (DAP-seq) have generated a large volume of data on DNA–protein interactions (DPIs) and histone modifications on a genome-wide scale. However, the ability to comprehensively retrieve empirically validated upstream regulatory networks of genes of interest (GOIs) and genomic regions of interest (ROIs) remains limited. Here, we present integrative Regulatory Network (iRegNet), a web application that analyzes the upstream regulatory network for user-queried GOIs or ROIs in the Arabidopsis (Arabidopsis thaliana) genome. iRegNet covers the largest empirically proven DNA-binding profiles of Arabidopsis transcription factors (TFs) and non-TF proteins, and histone modifications obtained from all currently available Arabidopsis ChIP-seq and DAP-seq data. iRegNet not only catalogs upstream regulomes and epigenetic chromatin states for single-query gene/genomic region but also suggests significantly overrepresented upstream genetic regulators and epigenetic chromatin states of user-submitted multiple query genes/genomic regions. Furthermore, gene-to-gene coexpression index and protein–protein interaction information were also integrated into iRegNet for a more reliable identification of upstream regulators and realistic regulatory networks. Thus, iRegNet will help discover upstream regulators as well as molecular regulatory networks of GOI(s) and/or ROI(s), and is freely available at http://chromatindynamics.snu.ac.kr:8082/iRegNet_main.
The Creepy White Guy and the Helpless Asian: How Sexual Racism Persists in a Gay Interracial Friendship Group
Authors: Phan Howard Khoa
Published: August 2021

How is sexual racism maintained in an organization that claims to resist it? This article applies the concept of sexual racism to an organizational case study of a friendship group of gay Asian and white men that aims to uplift Asian men’s erotic capital, but which actually upholds white desirability. Through ethnographic observations and interviews, the author first compares Asian and white men’s unequal positions on the gay sexual hierarchy before joining the group. The author unpacks four dimensions of organizational experience in which sexual racism is reproduced and white desirability is maintained: (1) a group monitoring practice that reproduces interracial stereotypes; (2) the normalized Asian-white pairing norm and the necessity of whiteness in romantic formation; (3) Asians vs. whites’ personal experiences of change in sexual capital that stabilize white desirability while Asians’ desirability increase with a cost; and (4) the reproduction of anti-Blackness in group-level constraints against non-white, non-Asian members. These findings contribute to sociological understandings of the racialization of sexuality and the sexualization of race by showing how an alternative space of desire for minority groups can still manifest sexual racism on individual and organizational levels.
9Pandemics and Popular Culture
Authors: Danesi Marcel
Published: August 2021

The three books reviewed here deal with the interrelation between pandemics, society, and culture. The common subtext within them is that pandemics have always had a shattering effect on the social status quo. Published at the threshold of the Covid-19 pandemic in 2020, they bear concrete implications for assessing how American popular culture is being impacted by the outbreak, and how it might evolve. The review is divided into five sections: 1. Introduction; 2. Plagues and Culture; 3. Covid-19 and Misinformation Culture; 4. Pandemics and Society; 5. Conclusion. In the span of two decades, the world has been subjected to several pandemics, including SARS in 2003, bird flu in 2005, swine flu in 2009, MERS in 2012, Ebola in 2014, and currently Covid-19 in 2020–21. Because of this, several cultural phenomena have crystallized that are the direct consequence of what can be called a pandemic era, ranging from a broad interest in the plague literature and cinema of the past to the burgeoning of books for the general public on pandemics and how their outcomes (medical and social) are shaped by the politics and discourses of misinformation. A recurring theme in the books under review is that coping with pandemics, and especially ‘pandemic fatigue’, involves an engagement with literature and the arts—both of which have themselves been shaped by pandemics of the past. The books are thus significant in shedding speculative light on how pandemics might alter (or not) our socio-cultural habitus.
A Slight Increase in Reverberation Time in the Classroom Affects Performance and Behavioral Listening Effort
Authors: Prodi Nicola , Visentin Chiara
Published: August 2021

Objectives:

The purpose of this study was to investigate the effect of a small change in reverberation time (from 0.57 to 0.69 s) in a classroom on children’s performance and listening effort. Aiming for ecological listening conditions, the change in reverberation time was combined with the presence or absence of classroom noise. In three academic tasks, the study examined whether the effect of reverberation was modulated by the presence of noise and depended on the children’s age.

Design:

A total of 302 children (aged 11–13 years, grades 6–8) with normal hearing participated in the study. Three typical tasks of daily classroom activities (speech perception, sentence comprehension, and mental calculation) were administered to groups of children in two listening conditions (quiet and classroom noise). The experiment was conducted inside real classrooms, where reverberation time was controlled. The outcomes considered were task accuracy and response times (RTs), the latter taken as a behavioral proxy for listening effort. Participants were also assessed on reading comprehension and math fluency. To investigate the impact of noise and/or reverberation, these two scores were entered in the statistical model to control for individual child’s general academic abilities.

Results:

While the longer reverberation time did not significantly affect accuracy or RTs under the quiet condition, it had several effects when in combination with classroom noise, depending on the task measured. A significant drop in accuracy with a longer reverberation time emerged for the speech perception task, but only for the grade 6 children. The effect on accuracy of a longer reverberation time was nonsignificant for sentence comprehension (always at ceiling), and depended on the children’s age in the mental calculation task. RTs were longer for moderate than for short reverberation times in the speech perception and sentence comprehension tasks, while there was no significant effect of the different reverberation times on RTs in the mental calculation task.

Conclusions:

The results indicate small, but statistically significant, effects of a small change in reverberation time on listening effort as well as accuracy for children aged 11 to 13 performing typical tasks of daily classroom activities. Thus, the results extend previous findings in adults to children as well. The findings also contribute to a better understanding of the practical implications and importance of optimal ranges of reverberation time in classrooms. A comparison with previous studies underscored the importance of early reflections as well as reverberation times in classrooms.