bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolation and Identification of Phosphate Solubilising Bacteria from Potato Rhizosphere on Andisol
Authors: Marpaung A E , Susilowati D N
Published: August 2021

Andisol soil is a very strong soil that binds phosphate nutrients, because most of it is bound by allophane clay minerals which can retain P up to 97.8%. Therefore, P in the soil available for plants is very little found, while the total P in the soil is high. Where the P nutrient is one of the essential nutrients that plants need to grow and produce well. The availability of P in Andisols soil can be done by giving phosphate solubilising microbes to providing P nutrients to plants. The using of phosphate solubilising bacteria as the inoculants simultaneously increased the uptake of P by plants and increase production. Therefore, a study aimed to isolate, identify phosphate solubilising bacteria to the species level and to test the phosphate dissolution rate of potato plant rhizosphere on andisol soil in Tongkoh-Karo Regency. Isolation can be done by the spread plate method on solid pikovskaya media, the phosphate dissolving activity was tested qualitatively by looking at the appearance of clear zones around the colony, measuring the phosphate dissolution index and identifying the isolates using PCR 16S rRNA. Four phosphate solubilising bacterial isolates were successfully obtained from the potato plant rhizosphere from andisol soil in Tongkoh-Karo regency. Where each islote are BPFT 1: Bacillus cereus, BPFT 2 : Bacillus pseudomycoides, BPFT 3 : Bacillus cereus and BPFT 4 : Bacillus amyloliquefaciens. BPFT 4 (Bacillus amyloliquefaciens) has the highest phosphate dissolubility index, which is 6,00.
Fitness of Paraquat Resistant and Susceptible Biotypes Population of Goosegrass (Eleusine indica (L.) Gaetrn.)
Authors: Napitupulu B S , Purba E , Mukhlis
Published: August 2021

A biotype of Paraquat resistant goosegrass (Eleusine indica (L.) Gaertn.) has envolved in an oil palm plantation in North Sumatera after been treated with Paraquat herbicide in a long period of time. This study aims to investigate the fitness of Paraquat resistant biotype when growing with susceptible biotype in the absence of herbicide. Seeds of Paraquat resistant biotype of Eleusine indica were collected from an oil palm plantation in Deli Serdang and had been proven to have resistant of Paraquat herbicide whereas the susceptible population from a field near campus of Universitas Sumatera Utara which never been exposed to Paraquat herbicide. Both biotypes were planted with proportions of 100 R: 0 S, 75 R: 25 S, 50 R: 50 S, 25 R: 75 S, and 0 R: 100 S with four replications. The result showed that Paraquat resistant biotypes had stronger fitness that the susceptible biotypes.
Comparative analysis of molecular fingerprints in prediction of drug combination effects
Authors: Zagidullin B , Wang Z , Guan Y , Pitkänen E , Tang J
Published: August 2021

Application of machine and deep learning methods in drug discovery and cancer research has gained a considerable amount of attention in the past years. As the field grows, it becomes crucial to systematically evaluate the performance of novel computational solutions in relation to established techniques. To this end, we compare rule-based and data-driven molecular representations in prediction of drug combination sensitivity and drug synergy scores using standardized results of 14 high-throughput screening studies, comprising 64 200 unique combinations of 4153 molecules tested in 112 cancer cell lines. We evaluate the clustering performance of molecular representations and quantify their similarity by adapting the Centered Kernel Alignment metric. Our work demonstrates that to identify an optimal molecular representation type, it is necessary to supplement quantitative benchmark results with qualitative considerations, such as model interpretability and robustness, which may vary between and throughout preclinical drug development projects.
Leveraging the attention mechanism to improve the identification of DNA N6-methyladenine sites
Authors: Zhang Ying , Liu Yan , Xu Jian , Wang Xiaoyu , Peng Xinxin , Song Jiangning , Yu Dong-Jun
Published: August 2021

DNA N6-methyladenine is an important type of DNA modification that plays important roles in multiple biological processes. Despite the recent progress in developing DNA 6mA site prediction methods, several challenges remain to be addressed. For example, although the hand-crafted features are interpretable, they contain redundant information that may bias the model training and have a negative impact on the trained model. Furthermore, although deep learning (DL)-based models can perform feature extraction and classification automatically, they lack the interpretability of the crucial features learned by those models. As such, considerable research efforts have been focused on achieving the trade-off between the interpretability and straightforwardness of DL neural networks. In this study, we develop two new DL-based models for improving the prediction of N6-methyladenine sites, termed LA6mA and AL6mA, which use bidirectional long short-term memory to respectively capture the long-range information and self-attention mechanism to extract the key position information from DNA sequences. The performance of the two proposed methods is benchmarked and evaluated on the two model organisms Arabidopsis thaliana and Drosophila melanogaster. On the two benchmark datasets, LA6mA achieves an area under the receiver operating characteristic curve (AUROC) value of 0.962 and 0.966, whereas AL6mA achieves an AUROC value of 0.945 and 0.941, respectively. Moreover, an in-depth analysis of the attention matrix is conducted to interpret the important information, which is hidden in the sequence and relevant for 6mA site prediction. The two novel pipelines developed for DNA 6mA site prediction in this work will facilitate a better understanding of the underlying principle of DL-based DNA methylation site prediction and its future applications.
Integrating Educational Technology to Address Disparities in Education: Implications for School Social Work
Authors: Rogers Kelli
Published: August 2021

Educational disparity has been a long-standing social and political concern, and is a grand challenge for social work because of its implications for equal opportunity and social justice. As stewards of social justice in public K–12 educational settings, school social workers help students gain access to and effectively use resources and support necessary to maximize their potential in the educational process as well as identify areas of need that are not being addressed by the local education agency and community, and working to create services that address those needs. Several studies have applied educational technology interventions to address academic achievement equity issues and found improved performance on state test scores. Thus, 12 evaluation studies of educational technology in primary and secondary schools in the United States conducted after 2001 were synthesized, examining the impact of educational technology applications on student academic achievement. Although much of the research conducted emphasizes a positive correlation between these variables, not all approaches of using educational technology resulted in equally good performance, and not all students learning with educational technology learned better than those learning without educational technology under all conditions. This critique identifies both strengths and weaknesses of existing literature; suggests research priorities; and outlines specific implications for educators, policymakers, and school social workers.
GATA6 Deficiency Leads to Epithelial Barrier Dysfunction and Enhances Susceptibility to Gut Inflammation
Authors: Laudisi Federica , Stolfi Carmine , Bevivino Gerolamo , Maresca Claudia , Franzè Eleonora , Troncone Edoardo , Lolli Elisabetta , Marafini Irene , Pietrucci Daniele , Teofani Adelaide , Di Grazia Antonio , Di Fusco Davide , Colantoni Alfredo , Ortenzi Angela , Desideri Alessandro , Monteleone Ivan , Monteleone Giovanni
Published: August 2021

Background and Aims

Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases [IBD], but the mechanisms that lead to such a defect are not fully understood. This study was aimed at characterising the factors involved in the defective barrier function in IBD.

Methods

Transcriptome analysis was performed on colon samples taken from healthy controls [CTR] and IBD patients. Expression of GATA-binding factor 6 [GATA6], a transcription factor involved in intestinal epithelial cell differentiation, was evaluated in colon samples taken from CTR and IBD patients by real-time polymerase chain reaction [PCR] and immunohistochemistry. Intestinal sections of wild-type and Gata6del mice, which exhibit a conditional Gata6 deletion in intestinal epithelial cells and which are either left untreated or receive subcutaneous indomethacin or rectal trinitrobenzene sulphonic acid, were stained with haematoxylin and eosin. In parallel, some Gata6del mice received antibiotics to deplete intestinal flora. Mucosal inflammatory cell infiltration and cytokine production were evaluated by flow cytometry and real-time PCR, respectively, and tight junction proteins were examined by immunofluorescence. Intestinal barrier integrity was assessed by fluorescein isothiocyanate [FITC]-dextran assay.

Results

Multiple genes involved in cell commitment/proliferation and wound healing were differentially expressed in IBD compared with CTR. Among these, GATA6 was significantly decreased in the IBD epithelium compared with CTR. In mice, conditional deletion of GATA6 in the intestinal epithelium induced primarily epithelial damage, diminished zonula occludens-1 expression, and enhanced intestinal permeability, ultimately resulting in bacteria-driven local immune response and enhanced susceptibility to gut inflammation.

Conclusions

Reduced expression of GATA6 promotes intestinal barrier dysfunction, thus amplifying intestinal inflammatory pathology.
Nesting Ecology and Colony Survival of Two Invasive Polistes Wasps (Hymenoptera: Vespidae) in New Zealand
Authors: McGruddy Rose , Howse Matthew W F , Haywood John , Toft Richard J , Lester Philip J
Published: August 2021

We examined the abundance, nesting ecology, and colony survival of two invasive species of paper wasp, Polistes dominula Christ (Hymenoptera: Vespidae) and Polistes chinensis Pérez (Hymenoptera: Vespidae), within their invaded range in New Zealand. The more recent invader, P. dominula, exhibited a strong habitat preference, reaching the highest abundances within suburban areas with an average of 87.4 wasps per 1,000 m2. Coastal habitats were also found to be suitable environments for P. dominula, although wasp abundance in these areas was comparatively lower than suburban sites at 26.5 wasps per 1,000 m2. Although P. chinensis were observed to build more nests in coastal habitats, this was not reflected in the abundance of adult wasps in these areas. Nests of P. dominula were larger and more productive, likely a result of the multiple founding and earlier emergence of workers compared to P. chinensis. Both species exhibited significant differences in nest survival, with P. dominula observed to have a higher colony survival rate, particularly in suburban habitats where this species utilized man-made substrates as nesting sites. Neither species nested within forest sites and translocated nests of P. dominula failed to thrive within forest habitats. Findings of this research suggest that P. dominula will not pose a threat to species inhabiting forested areas. Instead, biodiversity managers should focus their efforts on suburban and coastal environments as native species in these areas will require the greatest protection.
Unhoming Pedagogies: Collaborative Wandering and Wondering with Literature
Authors: Pollard Natalie , Ashfield Deborah , Jelley Jasmin
Published: August 2021

This collaborative article reflects on a set of shared practices that were inspired by a Year 3 undergraduate Literary Studies module, which took place in 2018. In co-teaching and learning on this module, the authors found their disciplinary and pedagogic norms unsettled and set adrift (unhomed). This article traces how their processes of working together – in and beyond the University classroom – stimulated a critique of the rational individualist principles which had unconsciously steered their learning and teaching practices until this point. The article includes case studies from the experiences of three students who took the module, and a narrative frame that speaks from the perspective of a collaborative ‘we’ (which includes students and ‘teacher’). The article tests out writing practices which reorient the customary Humanist terms in which educational research is conducted, and which disrupt the objective voice in which pedagogical reflection is often narrated. From this vertiginous perspective, the article also considers the authors’ particular entanglements with the cultural politics of the contemporary UK Higher Education Institution (HEI), and the role of unhomed Humanities teaching as part of the 21C University.
A highly polymorphic caprine keratin-associated protein gene identified and its effect on cashmere traits
Authors: Li Shaobin , Xi Qiming , Zhao Fangfang , Wang Jiqing , He Zhaohua , Hu Jiang , Liu Xiu , Luo Yuzhu
Published: August 2021

Five keratin-associated protein 6 genes (KRTAP6) have been identified in sheep and variation in some KRTAP6 has been associated with wool fiber diameter-related traits, but none of these homologues have been identified in goats. In this study, we reported the identification of the sheep KRTAP6-5 homologue on goat chromosome 1 and polymerase chain reaction (PCR)-single strand conformation polymorphism analysis in 300 Longdong cashmere goats revealed the existence of 12 variant sequences. Both coding region and 3′UTR of the putative caprine KRTAP6-5 displayed a biggest sequence similarity to ovine KRTAP6-5 gene. This suggested that the gene represents caprine KRTAP6-5 sequences, and these sequences composed 23 genotypes, which was the most polymorphism gene in KRTAPs that have been studied. Among these sequences, 15 nucleotide substitutions and a 24-bp insertion/detection were identified. Variation in goat KRTAP6-5 was associated with variation in mean-fiber diameter, suggesting that KRTAP6-5 is worthy of further study in the context of variation in cashmere traits.
Breast Fibromatosis: Radiologic–Pathologic Correlation
Authors: Winkler Nicole , Peterson Michael , Factor Rachel
Published: August 2021

Fibromatosis of the breast is a rare, benign locally infiltrative tumor without metastatic potential. Patients typically present with a painless, palpable, firm breast mass, which may be mobile or fixed to the pectoralis muscle. While some cases are related to familial mutations in the adenomatous polyposis coli (APC) gene, the majority are sporadic due to somatic mutations or prior injury to the breast tissue. On mammography, fibromatosis is typically seen as an irregular, dense, spiculated mass. US demonstrates a hypoechoic, irregular mass with indistinct margins. Fibromatosis is indistinguishable from breast cancer on imaging, and core biopsy is required for definitive diagnosis. Wide local excision is the historical standard for treatment; however, recurrence rates are high, and other emerging therapies are being explored. This article reviews the clinical features, imaging and histopathologic findings, along with brief overview of management.
Managing Fall Armyworm in Africa: Can Bt Maize Sustainably Improve Control?
Authors: Van den Berg Johnnie , Prasanna Boddupalli M , Midega Charles A O , Ronald Pamela C , Carrière Yves , Tabashnik Bruce E
Published: August 2021

The recent invasion of Africa by fall armyworm, Spodoptera frugiperda, a lepidopteran pest of maize and other crops, has heightened concerns about food security for millions of smallholder farmers. Maize genetically engineered to produce insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) is a potentially useful tool for controlling fall armyworm and other lepidopteran pests of maize in Africa. In the Americas, however, fall armyworm rapidly evolved practical resistance to maize producing one Bt toxin (Cry1Ab or Cry1Fa). Also, aside from South Africa, Bt maize has not been approved for cultivation in Africa, where stakeholders in each nation will make decisions about its deployment. In the context of Africa, we address maize production and use; fall armyworm distribution, host range, and impact; fall armyworm control tactics other than Bt maize; and strategies to make Bt maize more sustainable and accessible to smallholders. We recommend mandated refuges of non-Bt maize or other non-Bt host plants of at least 50% of total maize hectares for single-toxin Bt maize and 20% for Bt maize producing two or more distinct toxins that are each highly effective against fall armyworm. The smallholder practices of planting more than one maize cultivar and intercropping maize with other fall armyworm host plants could facilitate compliance. We also propose creating and providing smallholder farmers access to Bt maize that produces four distinct Bt toxins encoded by linked genes in a single transgene cassette. Using this novel Bt maize as one component of integrated pest management could sustainably improve control of lepidopteran pests including fall armyworm.
Mass Production of Neoseiulus cucumeris (Acari: Phytoseiidae): An Assessment of 50 Generations Reared on Almond Pollen
Authors: Yazdanpanah Shima , Fathipour Yaghoub , Riahi Elham , Zalucki Myron P
Published: August 2021

Neoseiulus cucumeris (Oudemans) (Acari: Phytoseiidae), an economically important biocontrol agent, was reared on almond pollen for 50 generations. We evaluated the effect of rearing predators on this pollen by comparing biological parameters at different generations (G1–G50). The shortest and longest development time occurred in G5 and G10, respectively. Females at the fifth and 50th generations laid eggs earlier than those of other generations. Females at G50 laid eggs over a longer period and produced more eggs than females of other generations, although females in the earlier generations had a higher gross reproductive rate and net reproductive rate than later generations. The intrinsic rate of increase, as well as the finite rate of increase of N. cucumeris in the fifth and 50th generations was significantly greater than those in other generations, while the first generation had the lowest values of these parameters. The dorsal shield length of both females and males and the width of females were found to be unaffected by their constant feeding on almond pollen. However, the number of rearing generations significantly affected the width of males. Long-term rearing of N. cucumeris for at least 50 generation on almond pollen did not substantially affect the predator's quality and this food source could be used for the mass production of this predator. Almond pollen should be assessed in rearing other phytoseiid mites that are important in biocontrol strategies.
Risk Assessment of Ozone Fumigation Under Vacuum to Control Potential Infestation of Coffee Berry Borer and Coffee Leaf Rust in Green Coffee Beans Imported Into Hawaii
Authors: Portilla M , Follett P A , Armstrong J W , Leesch J G , Tebbets J S , Smilanick J , McHugh T H , Olsen C W , Whitehand L , Cavaletto C , Bittenbender H C S , Bustillo A E , Peña J E
Published: August 2021

Studies were conducted with ozone gas fumigation under vacuum as a methyl bromide alternative against life stages of coffee berry borer (CBB) Hypothenemus hampei (Ferrari) (Coleoptera: Curculionidae: Scolytinae), and the urediniospores of coffee leaf rust (CLR), Hemileia vastatrix Berkeley & Broome (Basidiomycota: Pucciniales) in green coffee, Coffea spp. L. Fumigation with 10,000 ppm O3 gas under −25.4 mm Hg vacuum1 at 13.0 ± 3.0°C for 6.0 h killed all CBB larvae, pupae, and adults, but did not kill all CBB eggs (~15% survival). Mortality of CLR urediniospores was 100% within the first hour of the 6-h fumigation. Ozone fumigation had no adverse effects on coffee quality. Results indicated that CBB adult hitchhikers may be the only target life stage of quarantine concern, and additional studies focused on this stage. CBB adult survival and reproduction decreased significantly at moisture contents ≤20%, and F1 generation survival did not occur in green coffee at moisture contents ≤15%. As the international standard for green coffee moisture content is 9–12%, adult CBB should not survive or reproduce in exported dry green coffee. Standard industry processing of harvested coffee cherries to the green coffee stage using either mechanical- or sun-drying eliminated CBB infestations from the field. A systems approach is recommended for exporting green coffee to control CBB and CLR that includes eliminating CBB life stages with standard processing methods, reducing moisture content to 9–12% to prevent egg deposition, survival or reproduction, and O3 fumigation to ensure quarantine security against potential CBB adult hitchhikers.
Novel Methods for Detecting Human Cholesterol Crystals from Sampled Blood
Authors: Iwa Nobuzo , Yutani Chikao , Komatsu Sei , Takahashi Satoru , Takewa Mitsuhiko , Ohara Tomoki , Kodama Kazuhisa
Published: August 2021

Objective

Nonobstructive general angiography (NOGA) is a novel modality to detect and sample spontaneous ruptured aortic plaques (SRAPs). We aimed to establish novel methods to detect cholesterol crystals (CCs) in sampled SRAPs.

Methods

Blood specimens containing SRAPs were obtained from patients using NOGA. Blood was instantly frozen on a glass slide and subsequently thawed for quantitative analysis and spread onto a filter paper that was rinsed using distilled water. Qualitative analysis was performed for the rinsed water using polarized light microscopy, and the filter paper was embedded in paraffin for histologic analysis.

Results

The CCs were clearly observed after hemolysis using the instant freeze-thaw method. The filter paper rinse method indicated free CCs of varying shapes under polarized light microscopy without erythrocytes. On the filter paper, sampled SRAPs showed Lamé-like small particles. Histopathology revealed various atheromatous components.

Conclusion

A set of novel methods for detecting CCs from sampled blood was established.
BSCI-03. Adaptation of colorectal cancer cells to the brain microenvironment: The role of IRS2
Authors: Greenberg Inbal , Klein Anat , Grossman Rachel , Sokol Ethan , Yeini Eilam , Ofek Paula , Satchi-Fainaro Ronit , Liang Bertrand , Reuveni Hadas , Rubinek Tami , Wolf Ido
Published: August 2021

Colorectal cancer (CRC) reflects the fourth most frequent etiology of brain metastasis (BM). Yet, molecular mechanisms supporting it are unknown. We aimed to explore drivers enabling adaptation of CRC cells to the brain and decipher mechanisms facilitating the process.

We analyzed the FoundationOne database, which contains genomic alterations data of cancer-related genes in over 16,000 human CRC primary and metastasis samples. Increased prevalence of IRS2 gene amplification was observed in 13% of BM, compared to only 3% of primary tumors or other metastatic sites. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is involved in more aggressive behavior of different cancer types. In agreement with the genomic data, immunohistochemistry of human clinical samples showed increased expression of IRS2 protein in BM. We constructed an in-vitro system mimicking the brain microenvironment using cultured human astrocytes or their conditioned media. Under these conditions, IRS2-overexpressed CRC cells survived better and formed larger 3D spheres. IRS2-silenced CRC cells showed a mirror image. Moreover, in an intracranial CRC BM mouse model, IRS2-overexpressed cells generated larger brain lesions, while silencing IRS2 dramatically decreased tumor outgrowth and extended survival. Interestingly, transcriptomic analysis revealed enrichment of oxidative phosphorylation (OXPHOS) and Wnt/β-catenin pathways by IRS2. Indeed, IRS2-expressing cells showed increased mitochondrial activity and glycolysis-independent viability. Furthermore, IRS2-expressing cells had increased β-catenin transcriptional activity. Interestingly, β-catenin or IRS2 inhibition (using NT219) in IRS2-expressing cells decreased their viability, β-catenin transcriptional activity, and OXPHOS gene expression, suggesting involvement of IRS2 in modulating OXPHOS through β-catenin. β-catenin is known to confer 5-FU resistance; consequently, we showed that combination of 5-FU and NT219 worked in synergy, inhibited the formation of BM, and extended animal survival.

These data reveal the unique genomic profile of CRC BM and suggest IRS2 inhibition as a novel target for treatment of these patients.
BSCI-06. Phage display biopanning identifies Amot regulating cell motility in brain metastasis-initiating cells
Authors: She Chunhua , Potez Marine , Kim JongMyung , Liu James
Published: August 2021

Objective

Metastatic brain tumors (MBTs) are the most common type of malignant brain tumors. Due to the deviation of MBTs from the parental tumors, the effective therapies for primary tumors often are not working in brain metastases. Even more new intracranial lesions were developed though the primary lesion was controlled. The occurrence of brain metastasis-initiating cells (BMICs) suggested the possibility of its spread intracranially. Here we aimed to explore the biological behavior in cell motility of BMICs and understand the potential mechanisms.

Methods

In vitro and in vivo phage display biopanning strategies were used to isolate dodecapeptides that specifically target BMICs by selecting against primary lung cancer cells and normal brain cells. In silico analysis was used to derive specific protein targets in BMICs. Potential targets were narrowed down through analysis in patient databases and verified for their presence in BMIC through RT-PCR. Cell migration and adhesion in BMICs were analyzed using Transwell, scratch, and adhesion assays. Protein expression and cell morphology were detected by immunofluorescence. Immune blot was performed to detect the epithelial-mesenchymal related molecules and explore protein-protein interactions.

Results

In silico analysis of BMICs specific peptides revealed Angiomotin (Amot) as a potential target in BMICs. Amot was found to be overexpressed in BMICs compared to primary lung cancer cells. Kaplan-Meier analysis demonstrated Amot was negatively correlated with overall survival among lung adenocarcinoma patients. Knockdown of AMOT in BMICs decreased the capability of cell migration and adhesion, through the downregulation of E-Cadherin. Amot was found to maintain the E-Cadherin in BMICs through reducing ubiquitination of E-Cadherin. Furthermore, the knockdown of E-Cadherin decreased cell migration and adhesion due to the decrease in cdc42 activity.

Conclusions

Amot plays a role in promoting migration and adhesion in BMICs through preservation of E-Cadherin.
BSCI-16. Olfactory receptor 5B21 drives breast cancer metastasis
Authors: Li Mao , Schweiger Markus , Nakano Ichiro , Ryan Daniel , Carvalho Litia , Tannous Bakhos
Published: August 2021

Olfactory receptors (ORs), responsible for the sense of smell, play an essential role in physiological processes (even outside the nasal epithelium) and cancer. In breast cancer, however, the expression and role of ORs remain understudied. We examined the significance of ORs transcript abundance in breast cancer metastasis to different tissues including the brain, bone, and lung. While we found 20 OR genes to be differentially expressed in different metastasis versus primary tumor, OR5B21 displayed high relation with all metastases. Knockdown of OR5B21 significantly decreased the invasion and migration of breast cancer cells in culture as well as metastasis to different organs including the brain, in vivo. On the other hand, overexpression of OR5B21 in the primary cells had the opposite effect. Mechanistically, OR5B21 was associated with epithelial to mesenchymal transition through STAT3/NFkB/CEBPβ signaling pathway. We propose OR5B21 (and potentially other ORs) as a novel oncogene contributing to breast cancer metastasis, and as a potential target for therapy.
BSCI-17. Targeting SIRPα as a therapeutic strategy for the treatment of breast cancer brain metastasis
Authors: Stirling Elizabeth R , Bronson Steven M , Crowe William N , Wilson Adam , Kooshki Mitra , Zhao Dawen , Triozzi Pierre L , Lesser Glenn J , Soto-Pantoja David R
Published: August 2021

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by the lack of druggable targets and an incidence of brain metastasis from the primary site of approximately 35%. There is no standard treatment for managing brain metastasis associated with TNBC; therefore, new strategies are urgently needed to overcome disease mortality. The CD47/SIRPα signaling pathway is implicated in tumor progression due to bypassing innate and adaptive immune surveillance. Most strategies targeting this pathway focus on targeting the receptor CD47; however, targeting SIRPα as a potential strategy to mitigate tumor burden remains understudied. Analysis of gene expression database shows that SIRPα expression is significantly elevated in invasive breast cancer when compared to primary. Furthermore, single-cell data indicates that SIRPα is expressed in basal epithelial cells in TNBC tumors aside from the myeloid compartment. Our immune staining against SIRPα in patient biopsies shows a five-fold increase in SIRPα expression in metastatic brain tumors compared to the primary lesions. Therefore, targeting SIRPα may be a new immunotherapeutic strategy to treat breast cancer brain metastases. Anti-SIRPα treatment of mice bearing brain metastatic 4T1br3 orthotopic tumors showed reduced tumor volume and tumor weight by over 50% compared to isotype control-treated mice. Furthermore, in a model of intracardial brain metastasis, treatment with SIRPα antibody was associated with a 60% increase in survival compared to isotype control-treated mice. RNA sequencing of tumors indicated that SIRPα blockade is associated with a reduction in genes linked to mitochondrial respiratory chain and increases in negative regulation of the cell cycle. Furthermore, in vitro SIRPα targeting enhanced the cell-mediated cytotoxicity of microglia against 4T1Br3 breast cancer cells. This suggests that SIRPα blockade may influence both tumor and innate immune cells to limit brain metastatic breast cancer growth and enhance survival.
BSCI-18. Identifying novel drivers of lung-to-brain metastasis through in vivo functional genomics
Authors: Aghaei Nikoo , Lam Fred C , Kasper Ekkehard , Venugopal Chitra , Singh Sheila
Published: August 2021

Introduction

Brain metastases, the most common tumors of the central nervous system, occur in approximately 20% of primary adult cancers. In particular, 40% of patients with non-small cell lung cancer develop brain metastasis. As systemic therapies for the treatment of non-small cell lung cancer become increasingly effective at controlling primary disease, patients are ironically succumbing to their brain metastases. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). We hypothesize that an in vivo functional genomic screen can identify novel genes that drive LBM.

Methods

To do this, we developed a patient-derived xenograft (PDX) mouse model of LBM using patient lung cancer cell lines. This PDX model of LBM enables the use of fluorescent and bioluminescent in vivo imaging to track the progression of lung tumor and brain metastases.

Results

We have performed an in vivo genome-wide CRISPR activation screening to identify novel drivers of LBM. We will derive candidate genes through mouse brain and lung tissue sequencing after mice reach endpoint.

Expected Area of findings

This platform will lead to potential therapeutic targets to prevent the formation of LBM and prolong the survival of patients with non-small cell lung cancer.

Limitations

There may be limitations in getting candidate hits that overlap in all mice in our first replicate. This can be remedied by conducting the in vivo screen in at least three biological replicates.

Conclusion

To the best of our knowledge, this is the first genome-wide in vivo CRISPR activation screen searching for drivers of LBM using a PDX animal model. This study can provide a framework to gain a deeper understanding of the regulators of BM formation which will hopefully lead to targeted drug discovery.
TRLS-05. A multicenter observational study of Cs-131 seeds embedded in a collagen carrier tile for newly diagnosed and recurrent operable intracranial neoplasms –Trial in progress
Authors: Dunbar Erin , McCracken D Jay , Nowlan Adam , Chen Clark , Dusenbery Kathryn , Ferreira Clara , Kotecha Rupesh , McDermott Michael , Jaikumar Sivakumar , Shen Colette , Monyak David , Trusheim John , Wanebo John , Day Samuel , Lee Stuart , Wardak Zabi , Patel Toral , Choi Mehee , Misell Lisa , Brachman David
Published: August 2021

Background

For patients with operable intracranial neoplasms, there are opportunities to augment local control beyond traditional methods, such as external beam radiation therapy (EBRT),. Brachytherapy, the implantation of radioactive sources into the resection cavity, can be useful in this setting by providing immediate initiation of radiation and limiting the exposure of surrounding normal tissue to radiation. Traditional intracranial brachytherapy methods have been limited by uneven dose distributions, complicated workflows, extended procedural times, the cost of dedicated equipment, and frequent adverse events. To address these issues, a permanently implanted device with Cs-131 radiation seeds embedded in a bioresorbable collagen carrier tile (GammaTile, GT Medical Technologies, Tempe, AZ USA) was developed. Described as surgically targeted radiation therapy (STaRT), it is FDA-cleared for use in newly-diagnosed malignant intracranial neoplasms and recurrent intracranial tumors, including brain metastases, and has demonstrated excellent safety and local control in early commercial use. The primary objectives of this multicenter, prospective, observational (phase IV) registry study [NCT04427384] are to evaluate “real-world” clinical outcomes and patient-reported outcomes that measure the safety and efficacy of STaRT using the device.

Methods

Subjects (N=600) at up to 50 enrolling sites undergoing resection of brain tumors of any pathology with intra-operative GammaTile placement are eligible for enrollment. We project 40% of enrollees to have brain metastasis. Tumor pathology, overall survival, radiation- and surgery-related adverse events, quality of life, serial MRIs, and timing of surgical bed recurrence and/or distant recurrence will be collected. The powered primary endpoint for recurrent brain metastases, surgical bed-progression free survival, will compare STaRT to standard-of-care benchmarks. This study will be the first observational study of resection plus GammaTile. Results will be used to benchmark clinical outcomes in the real-world setting, allow for comparisons to existing treatments, and facilitate the design of future clinical trials.
LMD-01. Quantifying intrathecal drug delivery utilizing programmable ventriculoperitoneal shunts
Authors: McThenia Sheila , Pandit-Taskar Neeta , Grkovski Milan , Donzelli Maria , Diagana Safiatu , Greenfield Jeffrey , Souweidane Mark , Kramer Kim
Published: August 2021

Background

Programmable ventriculoperitoneal shunts (pVP shunts) are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of thecal space drug concentrations with minimization in the peritoneum. Drug delivery quantification using several types of pVP shunts has not been reported.

Methods

We performed a retrospective analysis on patients with CNS tumors and pVP shunts at Memorial Sloan Kettering Cancer Center from 2003–2020, noting shunt model. CSF flow through the pVP shunt was evaluated using In-111-DTPA scintigraphy at approximately 4 and 24 hours after injection. pVP shunts were calibrated pre-injection to minimize peritoneal flow and re-calibrated to baseline setting 4–5 hours following injection. Scintigraphy studies quantified ventricular-thecal and peritoneal drug activity at these 2 time points.

Results

Twenty-one CSF flow studies were administered to 15 patients, ages 1–27 years. Diagnoses included medulloblastoma (N=10), metastatic neuroblastoma (N=3), pineoblastoma (N=1), and choroid plexus carcinoma (N=1). Models of pVP shunts included Aesculap Miethke proGAV (N=3), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 5), and Sophysa Polaris (N= 1). All 21 studies (100%) demonstrated ventriculo-thecal drug activity. 29% (6 of 21) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 21) of the studies had minimal peritoneal uptake (<12%), and 24% (5 of 21) demonstrated moderate peritoneal uptake (12–37%). Models of pVP shunts measuring minimal to no peritoneal uptake included: Aesculap Miethke proGAV (N=2), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 3), and Sophysa Polaris (N= 1).

Conclusions

pVP shunts successfully deliver drugs to the ventriculo-thecal space with 80% of studies having minimal (<12%) peritoneal drug activity. Though efficacy varies by shunt model, low numbers preclude conclusions regarding model superiority. CSF flow scintigraphy studies reliably assess drug distribution.
LMD-10. The role of immune checkpoint inhibitors in leptomeningeal disease: a systematic review
Authors: Palmisciano Paolo , Haider Ali S , Nwagwu Chibueze D , Wahood Waseem , Sagoo Navraj S , Yu Kenny , Ene Chibawane I , O’Brien Barbara J , Cohen-Gadol Aaron A , El Ahmadieh Tarek Y
Published: August 2021

Background

Leptomeningeal disease (LMD) is a devastating complication of advanced malignancy with a poor prognosis and limited therapeutic options. Whether immune checkpoint inhibitors (ICIs) alter disease course is unknown.

Methods

We searched PubMed, EMBASE, Scopus, Cochrane, and clinicaltrials.gov according to PRISMA guidelines to analyze the therapeutic role and toxicity profiles of ICIs in the management of LMD. Studies reporting clinical outcome data of patients with LMD treated with ICIs were included. A comprehensive review of clinical characteristics and survival analysis was conducted.

Results

We included 14 studies encompassing 61 patients. The median age at LMD diagnosis was 57 years (female=63.9%). Lung cancer (44.3%), breast cancer (27.9%), and melanoma (23.0%) were the most frequent primary tumors. Parenchymal brain metastases occurred in 37 patients, mostly treated with radiotherapy (83.3%). LMD most frequently presented with headache (42.1%) and was diagnosed by MRI findings (leptomeningeal T1-contrast enhancement: 96.7%) and/or positive cerebrospinal fluid cytology (86.5%). Patients received ICIs for a median duration of 7 months (range, 0.5–58.0): pembrolizumab (49.2%), nivolumab (32.8%), and/or ipilimumab (18.0%). The most common concurrent LMD treatments were radiotherapy (54.7%) and steroids (35.7%). Radiological responses at 6-months were complete (33.3%) and partial response (12.5%), stable disease (33.3%), and progression (20.8%). 22 patients developed ICI-related adverse events, mostly mild (100%) and uncommonly severe (15.6%). Median progression-free survival was 5.1 months, median overall survival was 6.3 months, and 12-month survival was 32.1%. Survival was correlated with ICIs (P=0.042), but not with primary tumors (P=0.144). Patients concurrently receiving steroids showed worse survival (P=0.040), with a median overall survival of 1.9 months.

Conclusion

ICI therapy shows promise and appears to be well-tolerated in patients with LMD. Concurrent use of steroids is associated with worse survival. The role of ICIs in the multimodal management of LMD and their combination with steroids requires further analysis.
LMD-17. Neoplastic meningitis in lung cancer: retrospective review of clinical features, diagnosis and outcome in adult patients
Authors: Yorio Florencia , Blaquier Juan Bautista , Calabrese Bernadette , Cerrato Sebastián , Diez Blanca , Muggeri Alejandro
Published: August 2021

Background

Neoplastic Meningitis (NM) is a lethal complication of cancer. Its incidence is rising and in 10% of the cases NM is the first manifestation of the disease. Diagnosis relies on the clinical manifestations, neuroimages, and finding of malignant cells in cerebrospinal fluid (CSF). Diagnosis is often challenging due to the low sensitivity of the different diagnostic modalities. The aim of this study is to identify the clinical features, diagnosis, treatment and outcome of lung cancer patients with NM.

Methods

Clinical records from patients with diagnosis of lung cancer and NM between 2011–2021 were retrospectively reviewed at a tertiary neurological center in Buenos Aires, Argentina.

Results

Twenty-seven patients were included. Median age was 58 years (IQR 52–64). 17 (65%) were female. Twenty-four patients had non-small cell lung cancer (91% adenocarcinoma), two had neuroendocrine lung cancer and one small cell lung cancer. In 19 (70%), meningeal involvement was a result of progressive disease from previously diagnosed cancer. In 12 (44%) patients meningeal disease developed posterior to parenchymal brain metastases surgical approach, 5 (41%) with posterior fossa craniotomy. Headache was the most frequent symptom (53%). CSF analysis was abnormal in 13 (48%) patients, with positive cytology in 10 (37%). Meningeal enhancement was detected with magnetic resonance imaging of brain or spine in 24 (92%) patients. Twenty-one (77%) patients received oncological treatment, 14 (51%) with chemotherapy (8 systemic, 3 intrathecal and 3 intrathecal plus systemic). Thirteen (48%) patients underwent treatment with either immunotherapy or target-therapy. 11 patients underwent whole brain radiotherapy. Median overall survival was 7 months (CI 95%: 3.5–10.4).

Conclusion

Headache was the most frequent symptom. Ninety-two percent of patients had meningeal pathological enhancement in high-quality MRI with gadolinium contrast of brain and spine. Despite median survival was poor (7 months), small subsets of these patients (22%) survived more than 2 years.
LMD-19. Anatomic and Surgical Factors Predict Development of Leptomeningeal Disease in Patients with Metastatic Melanoma
Authors: Lowe Stephen , Wang Christopher P , Brisco Amanda , Ahmed Kamran , Vogelbaum Michael A , Liu James K C
Published: August 2021

Background

Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, portending a poor prognosis with an estimated median survival of 4–6 weeks if left untreated. Several reports have suggested surgical resection, particularly piecemeal resection, as a potential causative factor. Herein, we explore if surgical and anatomical factors are correlated with development of LMD in patients with melanoma brain metastases.

Methods

Patients treated at our institution between 1999–2019 for primary melanoma with brain metastasis were compiled into a database based on ICD9/10 coding. 1,079 patients with melanoma brain metastases and appropriate imaging were identified, and 834 patients with a minimum of 3 months’ follow up were included. Patients were dichotomized by development of LMD or lack thereof. General demographic information, surgical and anatomic data, and ventricular access during surgery were investigated as possible correlative factors for the development of LMD.

Results

On univariate analysis, female gender (p=0.033), presence of dural metastasis (p=0.018), presence of periventricular lesions (p<.001), presence of intraventricular lesions (p<.001), and ventricular access during surgery (p<.001) were significantly associated with LMD. Patients undergoing surgery, or those undergoing surgery without ventricular access, were not at higher risk of LMD. Administration of immunotherapy, either as first-line or salvage therapy, did not impact rates of LMD. On multivariate analysis, female gender (p=.033), presence of periventricular lesions (p<.001), presence of intraventricular lesions (p<.002), and presence of dural metastasis (p=0.032) were significantly associated with development of LMD. In patients who had surgery, iatrogenic ventricular access (p<.001) was significantly correlated with LMD.

Conclusions

In a retrospective cohort of patients with melanoma metastatic to the brain, those patients with pre-existing lesions in contact with the CSF space are more likely to develop LMD than those who do not. In addition, iatrogenic access to the CSF space during surgery is highly correlated with LMD development.
LMD-21. Headache Improvement Predicts Survival after CSF diversion in Leptomeningeal Disease
Authors: Robin Adam , Haider Sameah , Distefano Natalie , Reiner Anne , Tabar Viviane , Pawloski Jacob
Published: August 2021

Background

Leptomeningeal carcinomatosis (LMD) is a seeding of the leptomeninges by malignant cells. Clinical, treatment and patient-related factors have been described in patients with LMD. Current data are limited by small sample size, particularly in patients undergoing ventriculoperitoneal shunting (VPS) as part of the treatment regimen.

Objective

This study presents the largest cohort of LMD patients in the literature undergoing cerebrospinal fluid (CSF) diversion and seeks to identify prognostic factors related to survival.

Methods

A retrospective review of patients diagnosed with LMD between 2010 and 2016 at a quaternary referral center was performed. Cox proportional hazards modeling was utilized to identify variables associated with improved overall survival from LMD diagnosis. Overall survival was depicted using Kaplan-Meier methodology. Competing risk methodology was used to identify variables associated with VPS, considering death as a competing event.

Results

Of the 314 patients identified, 112 underwent VPS placement. The median overall survival from LMD diagnosis was 3.9 months (95% CI: 3.2–4.4). The presence of headaches, increased opening pressure, and gait difficulty increased the likelihood of VPS placement (all p<0.05). VPS, older age, lower Karnofsky Performance Status (KPS), higher opening pressure and CSF nucleated cell count (NCC) increased the risk of death (all p<0.05). Patients reporting headache improvement after VPS had better survival (p<0.05).

Conclusions

Headache, increased opening pressure and gait instability were associated with higher rate of VPS placement and may portend more aggressive disease. Headache improvement following VPS is a favorable prognostic sign, suggesting survival advantage for patients with hydrocephalus undergoing VPS. Age, KPS, VPS, opening pressure, CSF NCC, concomitant visceral metastases and histology-specific molecular profile impact survival.