bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-contact heart rate variability monitoring using Doppler radars located beneath bed mattress: a case report
Authors: Otake Yusuke , Kobayashi Tsuyoshi , Hakozaki Yukiya , Matsui Takemi
Published: August 2021

Background

Heart rate variability (HRV) has been investigated previously in autonomic nervous system-related clinical settings. In these settings, HRV is determined by the time-series heartbeat peak-to-peak intervals using electrocardiography (ECG). To reduce patient discomfort, we designed a Doppler radar-based autonomic nervous activity monitoring system (ANMS) that allows cardiopulmonary monitoring without using ECG electrodes or spirometry monitoring.

Case summary

Using our non-contact ANMS, we observed a bedridden 80-year-old female patient with terminal phase sepsis developed the daytime Cheyne-Stokes respiration (CSR) associated with the attenuation of the low frequency (LF) and high frequency (HF) of HRV components 20 days prior to her death. The patient developed a marked linear decrease in the LF and the HF of HRV components for over 3 days in a row. Furthermore, after the decrease both the LF and the HF showed low and linear values. Around the intersection of the two lines, the decreasing LF and HF lines and the constant LF and HF lines, the ANMS automatically detected the daytime CSR pathogenesis. The attenuation rate of HF (1340 ms2/day) was higher than that of LF (956 ms2/day). Heart rate increased by ∼10 b.p.m. during these 3 days.

Discussion

We detected CSR-associated LF and HF attenuation in a patient with terminal phase sepsis using our ANMS. The proposed system without lead appears promising for future applications in clinical settings, such as remote cardiac monitoring of patients with heart failure at home or in long-term acute care facilities.
Case report of subacute presentation of tricuspid valve thrombus complicated by widespread bilateral pulmonary emboli: a multifactorial aetiology
Authors: Myslivecek Libor , Gue Ying , Vasiliadis Ioannis
Published: August 2021

Background 

Right heart thrombus (RHTh) complicated by pulmonary embolism (PE) usually presents as a medical emergency with significant haemodynamic instability. However, less is known about subacute presentations.

Case summary 

We present a 74-year-old haemodynamically stable gentleman with a 3-week history of mild pleuritic chest pain and exertional dyspnoea preceded by lower respiratory tract infection. Early trans-thoracic echocardiogram (TTE) revealed a 3 cm elongated tricuspid valve thrombus with right ventricular dysfunction, new-onset atrial fibrillation, and new-onset severe left ventricular impairment. Subsequent computed tomography pulmonary angiogram showed widespread bilateral pulmonary emboli with retrograde opacification of the hepatic veins. The RHTh successfully resolved with warfarin therapy with no further complications, and the patient was discharged on Day 8 of hospitalization.

Discussion 

An early TTE is crucial in detecting the RHTh in patients suspected of PE and can significantly change the management compared with uncomplicated PE. The index of suspicion for PE and RHTh should remain high even in subacute cases.
To the manor born: a new microlevel wage database for eighteenth-century Denmark
Authors: Jensen Peter Sandholt , Radu Cristina Victoria , Sharp Paul
Published: August 2021

We document and make available to the scholarly community a uniquely detailed database of 20,680 observations of wages for men, women, and children and 30,000 observations of prices from eighteenth-century rural Denmark. These microlevel data were originally collected by the Danish Price History Project but have not previously been released. To illustrate the usefulness of such data, we discuss possible applications.
Age-Friendly for Whom? An Aperture to the Lived Experiences of Older San Franciscans
Authors: Yeh Jarmin
Published: August 2021

Background and Objectives

Spatial practices and changing urban environments affecting identity, experiences, and everyday life were examined among a diverse sample of older adults as they negotiated and navigated an age-friendly city.

Research Design and Methods

Ethnographic interviews, observations, and visual methods were used to understand spatial practices and lived experiences of 4 older adults, who chronicled their lives using disposable cameras.

Results

Informant identities emerged in their everyday practices, reflecting varied positionalities that fundamentally shaped their notions of “age-friendly.” Informants sought to sustain or improve their lives while attempting to negotiate socioenvironmental forms and forces that often threatened their identity and increased their precarity.

Discussion and Implications

Contrast exists between “invariant” macro/meso issues all older adults face as they age and “multivariant” ways in which age is accomplished based on place, biography, and intersectionality. Age-friendly environments may simultaneously maintain the status quo and exacerbate inequalities. Gerontology must take seriously how stratified life chances can undermine seemingly universal potential benefits of age-friendly environments.
Reflection on modern methods: visualizing the effects of collinearity in distributed lag models
Authors: Basagaña Xavier , Barrera-Gómez Jose
Published: August 2021

Collinearity can be a problem in regression models. When examining the effects of an exposure at different time points, constrained distributed lag models can alleviate some of the problems caused by collinearity. Still, some consequences of collinearity may remain and they are often unexplored. We aimed to illustrate the effects of collinearity in the context of distributed lag models, and to provide a tool to assess whether the results of a study could be influenced by collinearity. We used simulations under different scenarios of hypothesized effects of an exposure to visualize the resulting curves of lagged effects. We analysed three real datasets: a cohort study looking for windows of vulnerability to air pollution, a time series study examining the linear association of air pollution with hospital admissions, and a time series study examining the non-linear association between temperature and mortality. We showed that collinearity could be the explanation for some unexpected results, e.g. for statistically significant associations in the opposite direction from that expected, or for wrongly suggesting that some periods are more important than others. We implemented the collin R package to explore the potential consequences of collinearity in the context of distributed lag models. Our visual tool can be a useful way to assess if the results of an analysis may be influenced by collinearity.
Identifying critical failure information of thermal damaged sandstone through acoustic emission signal
Authors: Zhang Weiqiang , Shi Zhoujian , Wang Zuoquan , Zhang Shaoteng
Published: August 2021

The changes in the acoustic emission signals of sandstone after treatment at different high temperatures are examined in this study. The results show that there is a critical point on the cumulative energy curve of the acoustic emission signals (almost between 60 and 90% of the ratio of the loading time and the total loading time), which can be used to identify the failure of sandstone that has been damaged by exposure to a temperature of 900°C. As the temperature increases, the position of the critical point gradually changes, which indicates that high temperatures increase the plasticity of rock, and this gradually reduces the brittleness. The changes in b-value of acoustic emission shows that the transition behavior of rock from brittleness to plasticity is more obvious at temperatures higher than 600°C, and the large-scale micro cracking takes place at that temperature range, which is the main reason for the weakening and brittleness and the strengthening of plasticity of the sandstone.
Genomic Assessment of Global Population Structure in a Highly Migratory and Habitat Versatile Apex Predator, the Tiger Shark (Galeocerdo cuvier)
Authors: Bernard Andrea M , Finnegan Kimberly A , Pavinski Bitar Paulina , Stanhope Michael J , Shivji Mahmood S
Published: August 2021

Understanding the population dynamics of highly mobile, widely distributed, oceanic sharks, many of which are overexploited, is necessary to aid their conservation management. We investigated the global population genomics of tiger sharks (Galeocerdo cuvier), a circumglobally distributed, apex predator displaying remarkable behavioral versatility in its diet, habitat use (near coastal, coral reef, pelagic), and individual movement patterns (spatially resident to long-distance migrations). We genotyped 242 tiger sharks from 10 globally distributed locations at more than 2000 single nucleotide polymorphisms. Although this species often conducts massive distance migrations, the data show strong genetic differentiation at both neutral (FST = 0.125–0.144) and candidate outlier loci (FST = 0.570–0.761) between western Atlantic and Indo-Pacific sharks, suggesting the potential for adaptation to the environments specific to these oceanic regions. Within these regions, there was mixed support for population differentiation between northern and southern hemispheres in the western Atlantic, and none for structure within the Indian Ocean. Notably, the results demonstrate a low level of population differentiation of tiger sharks from the remote Hawaiian archipelago compared with sharks from the Indian Ocean (FST = 0.003–0.005, P < 0.01). Given concerns about biodiversity loss and marine ecosystem impacts caused by overfishing of oceanic sharks in the midst of rapid environmental change, our results suggest it imperative that international fishery management prioritize conservation of the evolutionary potential of the highly genetically differentiated Atlantic and Indo-Pacific populations of this unique apex predator. Furthermore, we suggest targeted management attention to tiger sharks in the Hawaiian archipelago based on a precautionary biodiversity conservation perspective.
Biosynthesis and biological function of secondary metabolites of the rice blast fungus Pyricularia oryzae
Authors: Motoyama Takayuki , Yun Choong-Soo , Osada Hiroyuki
Published: August 2021

Filamentous fungi have many secondary metabolism genes and produce a wide variety of secondary metabolites with complex and unique structures. However, the role of most secondary metabolites remains unclear. Moreover, most fungal secondary metabolism genes are silent or poorly expressed under laboratory conditions and are difficult to utilize. Pyricularia oryzae, the causal pathogen of rice blast disease, is a well-characterized plant pathogenic fungus. P. oryzae also has a large number of secondary metabolism genes and appears to be a suitable organism for analyzing secondary metabolites. However, in case of this fungus, biosynthetic genes for only four groups of secondary metabolites have been well characterized. Among two of the four groups of secondary metabolites, biosynthetic genes were identified by activating secondary metabolism. These secondary metabolites include melanin, a polyketide compound required for rice infection; tenuazonic acid, a well-known mycotoxin produced by various plant pathogenic fungi and biosynthesized by a unique nonribosomal peptide synthetase–polyketide synthase hybrid enzyme; nectriapyrones, antibacterial polyketide compounds produced mainly by symbiotic fungi, including plant pathogens and endophytes, and pyriculols, phytotoxic polyketide compounds. This review mainly focuses on the biosynthesis and biological functions of the four groups of P. oryzae secondary metabolites.
Root infection by the nematode Meloidogyne incognita modulates leaf antiherbivore defenses and plant resistance to Spodoptera exigua
Authors: Mbaluto Crispus M , Vergara Fredd , van Dam Nicole M , Martínez-Medina Ainhoa
Published: August 2021

Studies on plant-mediated interactions between root parasitic nematodes and aboveground herbivores are rapidly increasing. However, outcomes for the interacting organisms vary, and the mechanisms involved remain ambiguous. We hypothesized that the impact of root infection by the root-knot nematode Meloidogyne incognita on the performance of the aboveground caterpillar Spodoptera exigua is modulated by the nematode’s infection cycle. We challenged root-knot nematode-infected tomato plants with caterpillars when the nematode’s infection cycle was at the invasion, galling, and reproduction stages. We found that M. incognita root infection enhanced S. exigua performance during the galling stage, while it did not affect the caterpillar’s performance at the invasion and reproduction stages. Molecular and chemical analyses performed at the different stages of the nematode infection cycle revealed that M. incognita root infection systemically affected the jasmonic acid-, salicylic acid-, and abscisic acid-related responses, as well as the changes in the leaf metabolome triggered during S. exigua feeding. The M. incognita-induced leaf responses varied over the nematode’s root infection cycle. These findings suggest that specific leaf responses triggered systemically by the nematode at its different life-cycle stages underlie the differential impact of M. incognita on plant resistance against the caterpillar S. exigua.
Inference of the optical depth to reionization from low multipole temperature and polarization Planck data
Authors: de Belsunce Roger , Gratton Steven , Coulton William , Efstathiou George
Published: August 2021

This paper explores methods for constructing low multipole temperature and polarization likelihoods from maps of the cosmic microwave background anisotropies that have complex noise properties and partial sky coverage. We use Planck 2018 High Frequency Instrument (HFI) and updated SRoll2 temperature and polarization maps to test our methods. We present three likelihood approximations based on quadratic cross spectrum estimators: (i) a variant of the simulation-based likelihood (SimBaL) techniques used in the Planck legacy papers to produce a low multipole EE likelihood; (ii) a semi-analytical likelihood approximation (momento) based on the principle of maximum entropy; (iii) a density-estimation ‘likelihood-free’ scheme (delfi). Approaches (ii) and (iii) can be generalized to produce low multipole joint temperature-polarization (TTTEEE) likelihoods. We present extensive tests of these methods on simulations with realistic correlated noise. We then analyse the Planck data and confirm the robustness of our method and likelihoods on multiple inter- and intra-frequency detector set combinations of SRoll2 maps. The three likelihood techniques give consistent results and support a low value of the optical depth to reoinization, τ, from the HFI. Our best estimate of τ comes from combining the low multipole SRoll2momento (TTTEEE) likelihood with the CamSpec high multipole likelihood and is $\tau = 0.0627^{+0.0050}_{-0.0058}$. This is consistent with the SRoll2 team’s determination of τ, though slightly higher by ∼0.5σ, mainly because of our joint treatment of temperature and polarization.
The survival of globular clusters in a cuspy Fornax
Authors: Shao Shi , Cautun Marius , Frenk Carlos S , Reina-Campos Marta , Deason Alis J , Crain Robert A , Kruijssen J M Diederik , Pfeffer Joel
Published: August 2021

It has long been argued that the globular clusters (GCs) in the Fornax dwarf galaxy indicate that its dark matter halo is likely to have a shallow density profile with a core of size ∼1 kpc. We revisit this argument by investigating analogues of Fornax formed in MOdelling Star cluster population Assembly In Cosmological Simulations within eagle (E-MOSAICS), a cosmological hydrodynamical simulation that follows the formation and evolution of GCs in the Evolution and Assembly of GaLaxies and their Environments (EAGLE) galaxy formation model. In eagle, Fornax-mass haloes are cuspy and well described by the Navarro–Frenk–White profile. We post-process the E-MOSAICS to account for GC orbital decay by dynamical friction, which is not included in the original model. Dynamical friction causes 33 per cent of GCs with masses $M_{\rm GC}\ge 4\times 10^4{~\rm M_\odot }$ to sink to the centre of their host with the majority being tidally disrupted before forming a nuclear star cluster. Fornax has a total of five GCs, an exceptionally large number compared to other galaxies of similar stellar mass. In the simulations, we find that only 3 per cent of the Fornax analogues have five or more GCs, while 30 per cent have only one and 35 per cent have none. We find that GC systems in satellites are more centrally concentrated than in field dwarfs, and that those formed in situ (45 per cent) are more concentrated than those that were accreted. The present-day radial distribution of GCs in E-MOSAICS Fornax analogues is indistinguishable from that in Fornax, demonstrating that the presence of five GCs in the central kiloparsec of Fornax is consistent with a cuspy dark matter halo.
Cooperative DNA binding mediated by KicGAS/ORF52 oligomerization allows inhibition of DNA-induced phase separation and activation of cGAS
Authors: Bhowmik Debipreeta , Du Mingjian , Tian Yuan , Ma Siming , Wu Jianjun , Chen Zhijian , Yin Qian , Zhu Fanxiu
Published: August 2021

Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor that detects aberrant cytosolic DNA arising from pathogen invasions or genotoxic stresses. Upon binding to DNA, cGAS is activated and catalyzes the synthesis of cyclic GMP-AMP (cGAMP), which induces potent antimicrobial and antitumor responses. Kaposi sarcoma-associated herpesvirus (KSHV) is a human DNA tumor virus that causes Kaposi sarcoma and several other malignancies. We previously reported that KSHV inhibitor of cGAS (KicGAS) encoded by ORF52, inhibits cGAS enzymatic activity, but the underlying mechanisms remained unclear. To define the inhibitory mechanisms, here we performed in-depth biochemical and functional characterizations of KicGAS, and mapped its functional domains. We found KicGAS self-oligomerizes and binds to double stranded DNA cooperatively. This self-oligomerization is essential for its DNA binding and cGAS inhibition. Interestingly, KicGAS forms liquid droplets upon binding to DNA, which requires collective multivalent interactions with DNA mediated by both structured and disordered domains coordinated through the self-oligomerization of KicGAS. We also observed that KicGAS inhibits the DNA-induced phase separation and activation of cGAS. Our findings reveal a novel mechanism by which DNA viruses target the host protein phase separation for suppression of the host sensing of viral nucleic acids.
BSCI-02. METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy
Authors: Zhu Lucía , Blanco-Aparicio Carmen , Bertero Luca , Soffietti Riccardo , Weiss Tobias , Muñoz Javier , Sepúlveda Juan Manuel , Weller Michael , Pastor Joaquín , Valiente Manuel
Published: August 2021

The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. We report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. By applying this approach to brain metastasis, we identified heat shock protein 90 (HSP90) as a promising therapeutic target for CNS dissemination. DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis of brain metastases treated with the chaperone inhibitor revealed non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. Finally, we have exploited METPlatform as “avatars” to show that brain tumor PDOCs predict response of the corresponding patient to standard of care, thus proving the potential of METPlatform for improving personalized care in cancer. In conclusion, our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.
BSCI-08. In vivo two-photon characterization of tumor-associated macrophages and microglia (TAM/M) and CX3CR1 during different steps of brain metastasis formation from lung cancer
Authors: Zhang Wenlong , Karschnia Philipp , von Mücke-Heim Iven-Alex , Mulazzani Matthias , Zhou Xiolan , Xu Tao , Blobner Jens , Teske Nico , Langer Sigrid , Thon Niklas , Ishikawa-Ankerhold Hellen , Straube Andreas , Tonn Joerg-Christian , von Baumgarten Louisa
Published: August 2021

Background

Brain metastases represent a common complication of lung cancer and dramatically limit prognosis in affected patients. The influence of tumor-associated macrophages and microglia (TAM/M) and their receptor CX3CR1 on different steps of brain metastasis formation from lung cancer is poorly characterized, but might be of therapeutic relevance.

Methods

We established an orthotopic cerebral metastasis model using CX3CR1-proficient (CX3CR1GFP/wt) and -deficient (CX3CR1GFP/GFP) mice with green-fluorescent TAM/M. A cranial window was prepared, and intracarotid injection of red-fluorescent Lewis Lung Carcinoma-cells (tdtLLC) was performed two weeks later. Formation of brain metastases was followed by repetitive two-photon laser scanning microscopy.

Results

After intracarotid injection, intravascular tumor cells extravasated into the cerebral parenchyma and eventually formed micrometastases (≤50 cells) and mature macrometastases (>50 cells). We observed phagocytosis of extravasated tumor cells by TAM/M during early steps of metastatic growth. Notably, these anti-tumor effects of TAM/M diminished during later steps of metastasis formation and were accompanied by TAM/M accumulation and activation. CX3CR1-deficiency resulted in a lower number of extravasated tumor cells, and only a small number of TAM/M were visualized during early steps of metastasis formation (extravasation, formation of micrometastases) in such mice. In contrast, progression of extravasated tumor cells into micrometastases was more frequently found in CX3CR1-deficient mice. Overall, these mechanisms resulted in a comparable number of mature macrometastases between CX3CR1-deficient and -proficient mice.

Conclusion

Our findings indicate that unspecific inhibition of CX3CR1 might not be a suitable therapeutic approach to prevent cerebral dissemination of lung cancer cells. Given the close interaction between TAM/M and tumour cells during metastasis formation, other therapeutic approaches targeting TAM/M function warrant evaluation. Such concepts might be evaluated in vivo using the herein established orthotopic mouse model.
BSCI-10. Invasive growth of brain metastases is driven by cancer cell-pSTAT3+ reactive astrocyte crosstalk
Authors: Dankner Matthew , Maritan Sarah , Zhuang Rebecca , Caron Maxime , Priego Neibla , Valiente Manuel , Petrecca Kevin , Siegel Peter
Published: August 2021

Background

Brain metastases (BrM) with a highly invasive (HI) histological growth pattern are associated with poor prognosis compared to minimally invasive (MI) masses. Compared to MI lesions, HI BrM form greater contacts with cells in the peritumoral brain, particularly reactive astrocytes (RAs). RAs expressing phosphorylated STAT3 (pSTAT3+RAs) have been shown to promote BrM colonization. Here, we investigate the role of pSTAT3+RAs in promoting invasive growth of HI BrM.

Methods

We performed immunohistochemistry to identify pSTAT3+RAs in HI and MI human and patient-derived xenograft BrM. We assessed how pharmacological STAT3 inhibition or RA-specific STAT3 genetic ablation affected HI and MI BrM growth in vivo. scRNA-seq data generated from HI BrM astrocytes were integrated with published RA secretome data to identify STAT3 targets expressed by RAs that may drive invasion. Cancer cell invasion was modeled in vitro using a brain slice-tumor co-culture assay.

Results

HI BrM display increased pSTAT3-positivity within RAs when compared to MI lesions. Pharmacological STAT3 inhibition with Legasil (Silibinin) or genetic ablation decreased in vivo growth of HI, but not MI, BrM. Brain slice cultures treated with STAT3-activating cytokines induced cancer cell invasion, a response that was ablated following STAT3 inhibition. Chi3L1 was identified as a STAT3 target expressed by RAs. Cancer cells treated with recombinant Chi3L1 showed greater invasion into brain slice cultures compared to untreated cells.

Conclusions

pSTAT3+RAs are over-represented in HI BrM, rendering HI BrM preferentially sensitive to STAT3 inhibition. pSTAT3+RAs functionally contribute to BrM invasion within the brain, in part through Chi3L1-mediated activity. This work identifies STAT3 and Chi3L1 as clinically relevant therapeutic targets in management of HI BrM.
BSCI-12. Inhibition of melanoma brain metastasis by targeting miR-146a
Authors: Wang Jiwei , Rigg Emma , Lunavat Taral R , Zhou Wenjing , Feng Zichao , Hoang Tuyen , Bjerkvig Rolf , Thorsen Frits
Published: August 2021

Background

Melanoma has the highest propensity of any cancer to metastasize to the brain, with late-stage patients developing brain metastasis (MBM) in 40% of cases. Survival of patients with MBM is around 8 months with current therapies, illustrating the need for new treatments. MBM development is likely caused by molecular interactions between tumor cells and the brain, constituting the brain metastatic niche. miRNAs delivered by exosomes released by the primary tumor cells may play a role in niche establishment, yet the mechanisms are poorly understood.

Here, the aim was to identify miRNAs released by exosomes from melanomas, which may be important in niche establishment and MBM progression.

Materials and Methods

miRNAs from exosomes collected from human astrocytes, melanocytes, and MBM cell lines were profiled to determine differential expression. Functional in vitro validation was performed by cell growth and migration assays, cytokine arrays, qPCR and Western blots. Functional in vivo studies were performed after miR knockdown in MBM cell lines. An in silico docking study was performed to determine drugs that potentially inhibit transcription of miR-146a to impede MBM development.

Results

miR-146a was the most upregulated miRNA in exosomes from MBM cells and was highly expressed in human and animal MBM samples. miR-146a mimics activated human astrocytes, shown by increased proliferation and migration, elevated expression of GFAP in vitro and in mouse brain tumor samples, and increased cytokine production. In animal studies, knockdown of miR-146a in MBM cells injected intracardially into mice reduced BM burden and increased animal survival. Based on the docking studies, deserpidine was found to be an effective inhibitor of MBM growth in vitro and in vivo.

Conclusions

MiR-146a may play an important role in MBM development, and deserpidine is a promising candidate for clinical use.
BSCI-14. tGLI1 is an actionable therapeutic target in breast cancer brain metastases
Authors: Doheny Daniel , Manore Sara , Wong Grace , Zhu Dongqin , Sirkisoon Sherona , Rimkus Tadas , Anguelov Marlyn , Aguayo Noah , Regua Angelina , Cox Anderson O’Brian , Furdui Cristina , Thomas Alexandra , Masters Adrianna Henson , Strowd Roy , Lo Hui-Wen
Published: August 2021

Breast cancer is the second leading cause of brain metastases in women; patients with breast cancer brain metastasis (BCBM) survive a median of 14.1 months following diagnosis. Cancer stem cells are thought to be one of the driving forces behind distant metastasis, treatment resistance, and late-stage recurrence. Despite advances made in understanding breast cancer stem cells (BCSC), it remains challenging to effectively target BCSC underscoring the need to identify and inhibit novel mediators of BCSC for treating BCBM patients. The hedgehog-smoothened pathway is an important mediator of breast cancer stem cells (BCSC); however, FDA-approved therapies targeting smoothened have demonstrated limited clinical efficacy in breast cancer. Truncated glioma-associated oncogene homolog 1 (tGLI1) was discovered in our laboratory as an alternative GLI1 splice variant that functions as a tumor-specific gain-of-function transcription factor and terminal effector of the hedgehog pathway. Our laboratory recently reported that tGLI1 promotes preferential metastasis to the brain in breast cancer by activating BCSC and astrocytes in the tumor microenvironment (Oncogene 39:64–78, 2020). tGLI1 knockdown abrogated BCBM, providing the rationale to therapeutically target tGLI1. This study aimed to determine if tGLI1 can be therapeutically targeted. Cell-based chemical screens followed by validations demonstrated that ketoconazole, an FDA-approved azole antifungal, and novel derivatives specifically inhibit tGLI1 leading to suppression of BCSC in vitro and BCBM in vivo. Mechanistic studies suggest that KCZ-dependent cell kill is, in part, mediated through downregulation of tGLI1 target genes OCT4, Nanog, and VEGFA. Based on these data, we opened a window-of-opportunity study in patients with BCBM to determine if ketoconazole penetrates the blood-brain barrier (BBB) and alters tGLI1 signaling in humans (NCT03796273). Preliminary sample analysis demonstrates ketoconazole crosses the blood-tumor barrier and that tGLI1 expression correlates with tGLI1 signaling in resected samples. Collectively, these data establish tGLI1 as an actionable target for BCBM.
BSCI-19. Therapeutic intervention of lung-, breast-, and melanoma-brain metastasis
Authors: Kieliszek Agata , Bassey-Archibong Blessing , Venugopal Chitra , Singh Sheila
Published: August 2021

Background

The incidence of brain metastases (BM) is tenfold higher than that of primary brain tumours. BM predominantly originate from primary lung, breast, and melanoma tumours with a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need to identify novel therapies against BM.

Methods

Using a large in-house biobank of patient-derived BM cell lines, the Singh Lab has generated murine orthotopic patient-derived xenograft models of BM and captured a “premetastatic” population of BM cells that have just seeded the brains of mice before forming clinically detectable tumours: a cell population that is impossible to detect in human patients but represents a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable tumours.

Results

RNA sequencing of pre-metastatic BM cells from all three primary tumour models with subsequent Connectivity Map analysis identified a lead compound that exhibits selective anti-BM activity in vitro. Preliminary in vivo work has shown that this lead compound reduces the tumor burden of treated mice compared to vehicle control while providing a significant survival advantage. Ongoing mechanistic investigations aim to delineate the protein target of this compound in the context of the observed selective anti-BM phenotype.

Conclusion

Therapeutic targeting of premetastatic BM cells could prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.
LMD-06. A NSCLC patient with leptomeningeal metastasis harboring rare EGFR mutations G719S and L861Q benefited from doubling dosage of osimertinib: a case report
Authors: Wang Hui , Shan Changguo , Hong Weiping , Wen Lei , Lai Mingyao , Cai Linbo
Published: August 2021

Leptomeningeal metastasis (LM) is a rare but lethal complication of advanced non-small cell lung cancer (NSCLC) that has a devastating impact on patient survival and quality of life. Osimertinib, an irreversible tyrosine kinase inhibitor, is approved as a therapy for advanced NSCLC with epidermal growth factor receptor (EGFR) mutation. However, the efficacy and optimal dosage of osimertinib in the treatment of NSCLC patients with LM who harbor uncommon EGFR mutations have yet to be fully investigated. Herein, we report a case of an advanced NSCLC patient with LM carrying EGFR G719S and L861Q, who was successfully treated by osimertinib at 160 mg. The patient initially presented with clear cell renal carcinoma and renal metastatic adenocarcinoma, and underwent right nephrectomy. At 2 months after nephrectomy, He developed a disturbance of consciousness and was subsequently diagnosed with NSCLC with LM by meningeal biopsy pathology and cerebrospinal fluid (CSF) cytology. Next-generation sequencing detected the rare EGFR mutations G719S and L861R in the meningeal biopsy tissues. The patient was then administered osimertinib at 80 mg quaque die (QD); after 1 month of treatment, his symptoms were alleviated. However, two months later, he experienced epileptic episode. Subsequently, the osimertinib dosage was doubled to 160 mg QD. After 1 month of treatment, the patient achieved central nervous system (CNS) response, and at the time of this manuscript’s submission, he had maintained stable disease (SD) for more than 1 year. To our knowledge, this study provides the first clinical evidence that the administration of osimertinib at 160 mg once daily can achieve an encouraging, durable response in an NSCLC patients with LM carrying EGFR G719S and L861Q. Aslo, it is recommended to consider performing leptomeningeal biopsy for precision treatment in NSCLC paiernts with leptomeningeal metastasis.
LMD-08. Precision medicine for Leptomeningeal Carcinomatosis: a case report
Authors: Sinicrope Kaylyn , Sturgeon Emily , Coombs Lennea , Ghiassi Mahan , Sun David , Rocca Renato La , Spalding Aaron
Published: August 2021

Leptomeningeal disease (LMD) is an aggressive late-stage event in cancer. It is rare in gynecological malignancies. We present a case of a patient diagnosed with cervical adenocarcinoma grade III, stage Ib1 who developed LMD treated with immunotherapy based on modern molecular medicine.

The patient is 61-year-old female diagnosed with locally advanced cervical adenocarcinoma in November of 2017 and was rendered without evidence of disease after combined chemotherapy and pelvic irradiation. One year after initial treatment, she was found to have a solitary right cerebellar lesion on MRI for which she underwent gross total resection followed by stereotactic radiosurgery to the resection cavity. The pathology of the lesion was consistent with metastatic carcinoma of cervical primary. Next generation sequencing was performed on the brain metastasis tissue and was notable for a high tumor mutational burden (tTMB-high). One year after surgery she developed left arm weakness, and vertical diplopia. She underwent MRI of the brain and spine that demonstrated new nodular enhancement within the folia of the vermis and multi-level leptomeningeal enhancement in the cervical spine, consistent with LMD. She was treated for LMD with radiation to the whole brain and cervical spine. Radiation was followed with single-agent Pembrolizumab due to the reported response in cancer patients with tTMB-high status to immunotherapy. She is currently 6 months from her initial LMD diagnosis and is clinically stable with radiographic improvement.

This case presents an extremely rare complication of cervical cancer. It also highlights a unique treatment option for patients with LMD found to have tTMB-high status. Immunotherapy is of particular interest in cases of cervical adenocarcinoma as this cancer commonly has moderately-high TMB. Several studies have investigated the response of leptomeningeal disease to immunotherapy with variable results, though none have evaluated the response of tumors with tTMB-high.
LMD-15. Beyond cytologY - A single institution experience using CNSideTM for diagnosing and monitoring treatment response in Non-Small Cell Lung Cancer patients with Leptomeningeal Carcinomatosis (LMC)
Authors: Akerley Wallace , Puri Sonam , Chalmers Anna , Blouw Barbara , Boorgula Smitha , Schultz Robbie , Fisher Deanna , Dugan Michael , Mayer Julie
Published: August 2021

Introduction

Leptomeningeal Carcinomatosis (LMC) occurs in 3–9% of Non-Small Cell Lung Cancer (NSCLC) patients. Diagnosis of LMC includes clinical evaluation, imaging, and cytology. These have modest sensitivity and are inadequate for monitoring treatment response. Biocept’s CNSideTM is a proprietary assay utilizing a 10-antibody capture cocktail with microfluidic chamber that quantitatively detects tumor cells in the cerebrospinal fluid (CSF). Switch BlockerTM is a proprietary single gene assay that detects actionable mutations in the CSF. We describe a retrospective single institution experience using these assays in NSCLC patients with confirmed LMC or suspected LMC, treated between 2017 and 2021.

Methods

For fresh samples, CNSide and cytology were used to detect tumor cells, NGS and Switch Blocker was used to detect actionable mutations. Frozen samples were analyzed by NGS and/or Switch Blocker assays.

Results

CSF was collected from 30 samples (16 unique patients), of which frozen (8 unique patients) and fresh samples (8 unique patients; 5 with and 3 without LMC). CNSide detected tumor cells in 100% samples (10/10) vs cytology in 40% samples (4/10). Of those without LMC, neither CNSide nor cytology identified tumor cells. In patients with serial samples, CNSide tracked the clinical course. Analysis of frozen CSF by NGS identified mutations including EGFR in six (6), ALK in three (3) and BRAF in one (1) patient, which correlated with the primary tumor. The median survival from diagnosis of LMC for those with frozen samples was 71.6 weeks.

Conclusion

We demonstrate that 1) survival of patients with LMC can be prolonged, especially when an actionable target is identified, 2) CNSide has greater sensitivity in detecting LMC than cytology, and 3) quantitative monitoring of CSF tumor cells can be used to guide initial and subsequent therapies. Larger clinical trials are needed to better establish the utility of CNSide in managing LMC.
LMD-20. Immune Suppressive Macrophages and Signal Transducer and Activator of Transcription 3 (STAT3) Expression are common in Melanoma Leptomeningeal Disease
Authors: Najem Hinda , Marisetty Anantha , Horbinski Craig , Burks Jared , Heimberger Amy B
Published: August 2021

Leptomeningeal disease (LMD) in melanoma patients is associated with significant neurological impairments and has a dismal outcome with a median survival of 1.8 months. Despite the therapeutic benefit of targeted therapies and immunotherapies for most kinds of Stage IV melanoma, patients with LMD do not typically benefit. A deeper understanding of the tumor microenvironment (TME) of LMD may provide more appropriate therapeutic selection. A retrospective analysis of subjects who underwent surgical resection with LMD (n=8) were profiled with seven color multiplex to evaluate the expression of the global immune suppressive hub - the signal transducer and activator of transcription 3 (STAT3) and for the presence of CD3 T cells, CD68+ monocytes, CD163 immune suppressive macrophages, CD11c+ antigen presenting cells (APCs) in association with the melanoma tumor marker S100B and DAPI for cellular nuclear identification. High-resolution cellular imaging and quantification was conducted using the Akoya Vectra Polaris. CD163+ macrophage is the most frequent immune cell population in the LMD TME. Occasional CD3+ T cells and CD11c+ APC are also identified, although the latter has concurrent expression of CD163. STAT3 nuclear localization is heterogeneously expressed in the various immune cell populations. Occasional immune cluster interactions can be seen in the tumor stroma and the tumor edge. In conclusion, the TME of LMD is largely devoid of CD3+ T cells, but is enriched for immune suppression and innate immunity.
LMD-22. Clinicopathological spectrum of leptomeningeal metastases: A 3 year retrospective study
Authors: Pahwa Saloni , Sharma Anila , Kamboj Meenakshi , Mehta Anurag
Published: August 2021

Objectives

Cytological examination of cerebrospinal fluid is a widely used cost effective, simple procedure and a reliable routine diagnostic test. CSF cytology helps in detection of inflammatory diseases of the CNS, diagnosis of subarachnoid haemorrhage and the identification of malignant cells in metastatic or rarely primary CNS malignancies.Leptomeningeal metastases (LM) is estimated to occur in 5% of all patients with cancer. It has a higher propensity to occur in solid tumours compared to haematological malignancies.In view of poor prognosis, early diagnosis may aid in appropriate tumour staging and aggressive therapeutic intervention.

Methods

All the samples of CSF received in the Department of Laboratory for cytological examination and reported as ‘positive for malignant cells’ during the year January 2018 to December 2020were included in the study. All the cases were routinely evaluated on Neubauer’s chamber, direct smear and a cytospin preparation stained using MGG stain. The clinical records and any further ancillary testing performed were retrospectively analysed.

Results

87cases with LM were identified over 3 year duration. Mean age of presentation was 43 years. Metastatic solid malignancies (56%) had a higher incidence of leptomeningeal metastases compared to haematolymphoid malignancies (40%) and CNS medulloblastomas(2%). Most common solid tumour with involvement of CSF was adenocarcinoma lung (51%) followed by breast carcinoma (37%). Of all the cases of adenocarcinoma lung with LM, EGFR mutant NSCLC were 40% while 8% showed ALK gene rearrangement. Amongst the haematological malignancies, acute leukaemia’s constituted 67% of cases while systemic NHLs were 34%. Most of the cases (97%) presented with neurological symptoms during the course of treatment while 3 cases (3%) showed LM at the time of first presentation.

Conclusions

With appropriate clinicoradiological correlation, CSF cytology remains the gold standard for identification of malignant cells in cases with already known primary tumour (leptomeningeal dissemination of the disease). In this study, clinical features of both solid and haematolymphoid malignancies were evaluated. The group of solid malignancies included adenocarcinomas lung, breast, gastrointestinal tract and renal cell carcinoma. With the availability of EGFR TKIs and ALK inhibitors, overall survival of the patients may be prolonged with therapeutic interventions despite limited CSF and CNS penetration of these drugs.
OTHR-02. Engineered “of the shelf” allogeneic cellular therapies for metastatic brain tumors
Authors: Shah Khalid , Kitamura Yohei , Du Wanlu , Kanaya Nobu
Published: August 2021

Brain metastatic patients have multiple metastatic lesions or diagnostically challenging asymptomatic lesions, making surgery an inadequate therapeutic option. Given the challenges related to systemic delivery of a majority of therapeutic agents across the BBB, engineered cell based therapies offer an excellent platform to target metastatic tumors in the brain. We have established the use tumor cell surface receptor targeted allogeneic “off the shelf” gene engineered cellular therapies and developed two different approaches to treat brain metastases. In one approach, we have armed allogenic stem cells (SC) with oncolytic herpes virus (oHSV) variants and tested them in different mouse models of brain metastatic (BM) tumor derived from brain seeking metastatic melanoma tumor cells from patients. We show that intracarotid artery administration of SC-oHSV effectively tracks metastatic tumor lesions and significantly prolongs the survival of brain tumor bearing mice. We also show that a combination of SC-oHSV and PD-L1 blockade increases IFNγ-producing CD8+ tumor-infiltrating T lymphocytes and results in a profound extension of the median survival in syngeneic brain metastatic melanoma mouse models. In another approach, we have explored the versatility of cell mediated bi-functional EGFR and DR4/5-targeted treatment in basal like breast cancer (BLBC) mouse models featuring different patterns of brain metastasis. Most BLBC lines demonstrated a high sensitivity to EGFR and DR4/5 bi-targeting therapeutic protein, EVDRL [anti-EGFR VHH (EV) fused to DR ligand (DRL)]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the EV domain facilitated in augmenting DR4/5-DRL binding and enhancing DRL-induced apoptosis. EVDRL releasing allogeneic SCs alleviated tumor-burden and significantly increased survival in mouse models of residual-tumor after macrometastasis resection, perivascular niche micrometastasis, and leptomeningeal metastasis. These findings provide a clinically applicable therapeutic platform to target disseminated metastatic lesions in the brain and define a new paradigm for treatment of brain metastases.
OTHR-04. Gynecological Malignancies With Metastasis To The Central Nervous System: A Case Series and Systematic Review of the Literature
Authors: Sajjad Azeem , Adesina Adeleso , Halkiadakis Penelope , Murphy Kelsey , Mulligan Kathleen , Labak Collin , Wijesekera Olindi , Hodges Tiffany
Published: August 2021

Introduction

Gynecologic malignancies are an increasingly common proportion of central nervous system metastatic disease. As genetic sequencing technology improves and becomes more accessible, mutations associated with CNS metastasis are easier to elucidate. The aims of this case series and systematic literature review are to describe the patient population with CNS metastatic disease from a gynecologic primary, and to investigate why the proportion of CNS metastasis from gynecologic malignancies is increasing. Ultimately, we hope to improve understanding of this subset of metastatic CNS malignancies and improve management strategies.

Methods

A literature review of articles describing patients from 1990–2020 who were diagnosed with CNS metastasis from a known gynecologic primary malignancy was performed. Demographics, cancer type, mutation characteristics, management for metastatic disease, progression free survival, number of CNS metastases, and location of metastatic disease were assessed. Inclusion criteria were age>18 years, diagnosis of primary ovarian, uterine, or cervical cancer with confirmed metastatic disease to the CNS, including brain parenchyma, leptomeninges, or intradural spinal cord or dural metastases. Exclusion criteria included pediatric population and bony metastases (e.g., bony spine metastases without evidence of meningeal/parenchymal invasion).

Results

Our review showed that patients with gynecological metastasis to the CNS generally have worse outcomes regarding overall survival, progression free survival, and quality of life than patients without CNS metastasis.

Discussion

Our results infer that the reported increase in incidence of CNS metastasis from gynecologic malignancies is a reflection of improvement of detection given advances in technology, improved patient follow up, and increased overall survival of patients with gynecologic malignancies. Further characterization of mutations from gynecologic malignancies associated with brain metastasis could result in development of more treatment options for patients in the future and help determine factors that contribute to developing metastasis to the CNS of various degrees, thus, potentially inform treatment strategies.