bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P6-01-41: Influence of HER2 expression status in the distribution of recurrence score from the OncotypeDx assay among women with early-stage estrogen-receptor-positive/HER2-negative breast cancer
Authors: Shah Anish , Budhathoki Pravash , Gaire Suman , Joshi Utsav , Yadav Siddhartha
Published: March 2023

BACKGROUND: The OncotypeDX assay analyzes the expression of 21 genes, including HER2 and Grb7, to assess the predictive effect of chemotherapy in breast cancer recurrence among women with early-stage estrogen-receptor (ER) positive/HER2-negative breast cancer. In this study, we evaluate the distribution of recurrence score from the OncotypeDX assay based on the HER2 expression status by immunohistochemistry (IHC). METHODOLOGY: Utilizing the National Cancer Database, we identified adult women with a diagnosis of stage I – III ER+/HER2- invasive ductal carcinoma of the breast between the years 2010 and 2018. Recurrence scores were classified into low (< 11), intermediate (11-26), and high risk (>26); and the distribution of these recurrence scores cross-tabulated with different IHC scores of HER2 expression (0, 1+, and 2+) by IHC. Women with an IHC score of 2+ had to be negative for HER2 gene amplification by FISH. Multivariate logistic regression model adjusting for age, race, origin, progesterone receptor status, grade, and cancer stage was used to assess the odds of receiving a high OncotypeDx Score (≥26). RESULT: Among 198,931 women with ER+/HER2 negative breast cancer, 59,632 (30.0%) had HER2 IHC score of 0, 102,170 (51.4%) had IHC score of 1+, and 37,129 (18.6%) women were with IHC score of 2+. The median age at diagnosis of breast cancer among all three categories of HER2 expression was 59 years. The median recurrence score for women with IHC scores of 0,1+, and 2+ was 15, 15, and 16 respectively (p < 0.001). A higher proportion of women with HER2 IHC score of 2+ had a high recurrence score compared to women with an IHC score of 0 (15.2% vs. 13%, p < 0.001). In multivariate analysis, compared to women with HER2 IHC score of 0, women with HER2 IHC score of 2+/FISH negative were observed to have higher Odds (OR: 1.16; 95% CI: 1.11 – 1.20, p < 0.001) of receiving high recurrence score. There was no significant difference in the odds of receiving a high recurrence score between women with IHC 0+ and 1+(OR: 0.99; 95% CI: 0.96 – 1.03, p 0.82). CONCLUSION: Women with a HER2 IHC score of 2+ were observed to have a higher odds of receiving high-risk recurrence scores as compared to women with IHC score of 0. This needs to be further correlated with the response to chemotherapy and the risk of recurrence.

Citation Format: Anish Shah, Pravash Budhathoki, Suman Gaire, Utsav Joshi, Siddhartha Yadav. Influence of HER2 expression status in the distribution of recurrence score from the OncotypeDx assay among women with early-stage estrogen-receptor-positive/HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-41.
Abstract P6-03-02: Social determinants, food deserts, and their combined contribution to breast cancer mortality
Authors: McCormack Kara
Published: March 2023

Recent studies have found that both food deserts (FD) and lower socio-economic status (SES) are individually associated with increased breast cancer mortality in the US. However, further work is needed to investigate their combined contribution to breast cancer mortality. Furthermore, valid inference for area-level disease mapping requires careful consideration of spatial clustering. In our study, we utilize data from the USDA Food Access Research Atlas and the American Community Survey. Breast cancer mortality data come from the National Center of Health Statistics 2014 report. We consider a latent class mixture model to determine deprivation categories which incorporate six SES proportion variables (no car, poverty, no HS graduation, crowded housing, unemployment, crowded housing), two FD (Low income and > 1 mile from supermarket and receiving snap benefits and > 1 mile from supermarket) variables. Our latent class model has three levels: Low, Moderate, and High, making up 36.6%, 45.6%, and 17.8% of US counties, respectively. We then incorporated these levels as a fixed effect in a Bayesian hierarchical spatial negative binomial model using R-INLA. In this model, we account for both spatially structured and unstructured effects. Counties classified as “High” on our deprivation categories were associated with a 50% increase in breast cancer mortality rates (95% CrI: [1.12, 2.02]). Also, the county proportion of women >65 was significantly associated with 1.42 times higher breast cancer mortality (95% CrI [1.37, 1.42]). Policies that allow for access in the face of deprivation may contribute to lower overall breast cancer mortality.

Citation Format: Kara McCormack. Social determinants, food deserts, and their combined contribution to breast cancer mortality [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-03-02.
Abstract P6-04-07: Primary Diagnosis of Breast Biopsies supported by AI versus Microscope: Multi-Site Clinical Reader Study
Authors: Salomon Anne , Nudelman Alona , Cyrta Joanna , Maklakovski Marina , Shach Anat Albrecht , Sebag Geraldine , Mallel Giuseppe , Krasnitsky Ira , Feinberg Tali , Vecsler Manuela , Sandbank Judith
Published: March 2023

Objective This study aimed to clinically validate the use of an AI-based solution by pathologists for the primary diagnosis of breast core needle biopsies as compared with the gold standard practice (review on the microscope). Methods A two-arm prospective reader study comparing the performance of pathologists using an AI-based solution with pathologists using a microscope was performed at two sites (different staining and digital scanners). Both arms were compared to ground truth (GT) established by the consensus of two breast pathologists. Rates of major discrepancies between each arm and GT, as determined by an adjudicating pathologist, were compared. Results Eight pathologists participated in the study and reported on 385 cases (442 HES and 330 H&E slides), each case being reported twice, once in each study arm. Pathologists first reviewed only H&E/HES slides, if requested and available, they were provided with IHCs, while the AI results were on H&E/HES only. The major discrepancy rates of the microscope arm and of the AI arm against GT were 4.42% and 3.12%, respectively, demonstrating a 29.4% reduction in major discrepancies. Pathologists with AI demonstrated very high accuracy for the detection of invasive carcinoma with sensitivity and specificity of 100% for both, as well as for DCIS/ADH with sensitivity of 92.4% and specificity of 97.8%. Conclusions This multi-site reader study reports diagnostic accuracy improvements by pathologists performing diagnosis and reporting with the support of a first read AI solution for breast biopsies. The AI solution performed accurately and generalized well for different staining platforms and different scanners. Thus, AI solutions could be used as significant aiding tools for pathologists in clinical decision-making in routine pathology practice, enhancing the quality and reproducibility of diagnosis.

Citation Format: Anne Salomon, Alona Nudelman, Joanna Cyrta, Marina Maklakovski, Anat Albrecht Shach, Geraldine Sebag, Giuseppe Mallel, Ira Krasnitsky, Tali Feinberg, Manuela Vecsler, Judith Sandbank. Primary Diagnosis of Breast Biopsies supported by AI versus Microscope: Multi-Site Clinical Reader Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-04-07.
Abstract P6-08-14: Breast Cancer Treatment Choices and Results in Hispanic Women Without Funding for Radiation
Authors: Leon-Camarena Maria De Los , Reddy Neha , Ellison Kimberly , Goodgame Boone
Published: March 2023

Background: Although the survival rates for breast cancer have improved, there is still a disparity gap between Hispanic women and non-Hispanic women. Hispanic women in the US are vulnerable to cancer inequalities due to a plethora of barriers including disproportionate poverty, lack of health insurance, and citizenship status. A Surveillance, Epidemiology, and End Results analysis found that Hispanic women had lower rates of both early-stage breast cancer and receipts of radiation therapy (RT) after breast-conserving surgery than White women. For patients without private or government health insurance, charity and county indigent programs have variable levels of coverage, and some patients cannot access radiation services. The aim of this study is to identify disparities in breast cancer treatment for patients referred to the Travis County indigent cancer treatment program. Methods: We analyzed new referrals to the Ascension Seton Breast Clinic from April 2020 to January 2022. Demographics, disease stage, funding and treatments were extracted from medical records. We compared funding status at the time of referral vs time of surgery. We also analyzed the type of surgery elected and if RT was indicated and received. Results: We found that out of 242 referrals, 116 were diagnosed with a new malignancy. Of the 116, a total of 76 underwent breast surgery and RT was considered in 64 of these patients. 61% received RT. Of the remaining 25 patients, 16 patients elected simple mastectomies and 9 did not have funding to cover radiation (income was not low enough to qualify for RT benefit under the health district). Of the 9 women who did not have funding about 78% identified as Hispanic or Latino. 4 opted for simple mastectomies thus no longer needing RT, 3 received modified radical mastectomies without RT, 1 accessed charity funding for RT and 1 had lumpectomy without radiation and had recurrence of her breast cancer. Overall, the rate of breast conserving surgery was 43%. Discussion: The safety net system for patients in the US without access to private or government funding for healthcare is inherently limited. Costs of radiation treatment for cancer can be prohibitive for charity and indigent programs, but patients are forced to choose between mastectomy or risk a higher rate of recurrence. This data will be used to advocate for health district funding for this patient population.

Citation Format: Maria De Los Leon-Camarena, Neha Reddy, Kimberly Ellison, Boone Goodgame. Breast Cancer Treatment Choices and Results in Hispanic Women Without Funding for Radiation [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-08-14.
Abstract P6-12-01: ALCAM (Activated Leukocyte Cell Adhesion Molecule) is associated with HGF/MET signalling pathway in different subtypes of breast cancer
Authors: Yang Yiming , Sanders Andrew J. , Jiang Wen G.
Published: March 2023

Introduction. ALCAM (Activated Leukocyte Cell Adhesion Molecule), also known as CD166, is a cell adhesion molecule which belongs to the immunoglobulin superfamily and is widely expressed in various human tissues. It has been demonstrated that ALCAM plays an important role in the progression of malignant diseases and tumour metastasis in multiple cancer types including breast cancer. However, the molecular mechanism of ALCAM and cancer progression is currently unclear. The present study performed protein array analyses using ALCAM genetically manipulated cell models to select potential protein partners of ALCAM. The study focused on MET (Hepatocyte Growth Factor (HGF) Receptor), a prominent ALCAM interacting protein kinase and a protooncogene contributing to cancer progression and spread. Method. Human breast cancer cell lines MCF-7 and MDA-MB-231 were selected to create ALCAM knockdown cell models. A range of other breast cancer cell line with differing hormone receptor status were also used. Protein samples of transfected cells were used to perform Kinexus protein kinase microarray analysis. The protein interaction between ALCAM and other prospective protein kinases including MET was verified by the method of immunoprecipitation. Additionally, the ALCAM knockdown model was also assessed for the impact of ALCAM and HGF/MET on the biological functions by Electric Cell-substrate Impedance Sensing (ECIS). Results. MCF-7 and MDA MB-231 cells both were strongly expressed ALCAM. Cells models with ALCAM knocking down were successfully created by way of anti-ALCAM shRNA. We have shown on the protein kinase microarray analysis that the hepatocyte growth factor (HGF) receptor, MET was one of the kinases significantly affected following ALCAM knocking down. It was also found that the alteration of protein interaction between the MET protein kinase and ALCAM protein showed an opposite pattern between ER positive and ER negative ALCAM knocking down cells. This protein interaction was observed by immunoprecipitation in MDA-MB-361 and MDA-MB-231 cell lines, but not in MCF-7 cells. The biological analyses using the ECIS technologies showed that MET kinase inhibitors and exogenous recombinant HGF affected the ALCAM-mediated cell adhesion in different breast cancer subtypes. Conclusion. ALCAM is associated with HGF/MET signalling and the interaction between ALCAM and MET is different amongst subtypes of breast cancer which have different hormone receptor status.

Citation Format: Yiming Yang, Andrew J. Sanders, Wen G. Jiang. ALCAM (Activated Leukocyte Cell Adhesion Molecule) is associated with HGF/MET signalling pathway in different subtypes of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-12-01.
Abstract P6-14-05: Regulation of cellular identity and spatial organization during collective breast cancer invasion
Authors: Doak Andrea E. , Cheung Kevin J.
Published: March 2023

An early step in breast cancer progression is invasion of tumor cells into surrounding tissues. In many breast cancers, particularly ductal carcinomas, this invasion is accomplished by tumor cells migrating as a cohesive group. This often involves cells that take on heterogeneous roles as either leader or follower cells. While studies in common mouse and human breast cancer models have established that leader cells express high levels of keratin-14 (K14) and other basal epithelial markers, the molecular mechanisms regulating K14+ leader cell identity remain obscure. Here we performed time-sampled single cell RNA-sequencing in 3D type I collagen-embedded tumor organoids isolated from the MMTV-PyMT luminal B model of breast cancer. 11 distinct cellular transcriptional states were identified and correlated with K14 expression and invasive strand formation. Having identified the leader cell state we next asked what transcription factors were enriched, reasoning that transcription factors could be master regulators of leader cell fate. 30 different shRNAs targeting 10 genes were systematically evaluated for their effects on collective invasion. From this screen, suppression of Hes1, the downstream target of Notch signaling, yielded a marked switch from collective to single cell invasion. Disseminating single tumor cells maintained high expression of K14 in Hes1 knockdown organoids which was phenocopied by gamma-secretase inhibition in a human TNBC PDX model. Because K14+ tumor cells highly express the Notch ligand Jag1, these results support a model in which Notch signaling, specifically through activation of Hes1, dictates leader cell identity and spatial organization during collective invasion. Studies are ongoing investigating the impact of Hes1 dynamics on leader cell adhesion, hybrid EMT state, and preference for single versus collective metastasis. Because Notch suppression induces leader cell dissemination, we propose that Notch targeted therapy should be combined with therapies eradicating leader cells.

Citation Format: Andrea E. Doak, Kevin J. Cheung. Regulation of cellular identity and spatial organization during collective breast cancer invasion. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-05.
Abstract P6-14-10: Jagged-1 promotes breast cancer metastasis through the lymphatic system
Authors: Gordon Benjamin , Swaminathan Bhairavi , Naiche LA , Kitajewski Jan
Published: March 2023

While early detection of breast cancer (BC) has improved prognoses, there is an urgent need to improve outcomes for patients with distant metastatic disease. Higher expression of the Notch ligand JAG1 in primary BC tumors is strongly associated with lymph node metastasis and patient mortality, but causality is unclear. We show that JAG1 expression is higher in patients’ metastatic BC cells colonizing lymph nodes than in primary tumors, suggesting that tumor cells with high JAG1 are preferentially able to metastasize to lymph nodes. JAG1 expression is higher in a derivative of BC line MDA-MB-231 selected for tropism to lymph nodes (MDA231-LN) than in the parental line or derivatives with other tropisms. To determine the mechanism(s) of JAG1-mediated metastasis, we generated clonal JAG1 knockout cell lines from MDA231-LN cells with corresponding JAG1 rescue lines. We investigated the role of JAG1 in spontaneous metastasis under clinically relevant conditions by orthotopically implanting JAG1 knockout and expressing cells, resecting the primary tumor, and following long-term metastatic spread in a mouse model. Quantification of tumor cells in blood showed that survival, metastatic burden, and JAG1 expression did not correlate with the number of circulating tumor cells. Conversely, JAG1 expression drove an increase in lymph node and body-wide metastatic burden and a trend toward decreased survival. In this model metastatic cells were abundant throughout lymph vessels, suggesting lymphatics are the primarily route of dissemination. Preliminary transcriptional analysis suggests that JAG1 alters interactions with lymphatic endothelial cells (LEC), potentially via VEGF signaling, leading us to examine downstream events in co-cultures of LEC with lymphatically invasive BC lines. Deciphering tumor-lymphatic endothelial signaling events may open new avenues to target BC metastasis.

Citation Format: Benjamin Gordon, Bhairavi Swaminathan, LA Naiche, Jan Kitajewski. Jagged-1 promotes breast cancer metastasis through the lymphatic system [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-10.
Abstract PD2-07: Tumor CD73 regulates zoledronate induced TIL accumulation into triple negative breast cancer
Authors: Petruk Nataliia , Siddiqui Arafat , Tadayon Sina , Jukkola Arja , Määttä Jorma , Mattila Pieta , Sandholm Jouko , Selander Katri S.
Published: March 2023

Background: CD73 is a membrane-bound protein that by extracellular adenosine production, regulates immune cell function. Low CD73 expression is associated with better prognosis among triple-negative breast cancer (TNBC) patients. Adjuvant bisphosphonates (BPs, such as zoledronate) improve survival among post-menopausal breast cancer patients, but the mechanism for this is unknown. Since BPs also affect immune cells, we studied 1) whether zoledronate-treatment has an effect on tumor infiltrating lymphocytes (TILs) and 2) whether tumor CD73 expression affects these responses in TNBC tumors. Methods: 4T1 mouse mammary cells, stably expressing non-targeting shRNA (sh-NT, control cells) or sh-CD73 were inoculated into the mammary fat pads of Balb/c mice. The mice were treated with i.p. vehicle or zoledronate (ZOL) each 4th day for total of six times. Additionally, to deplete B-cells, the mice were treated with an anti-CD20 or control IgG antibody. Tumor sizes were assessed with a caliper, TILs were studied with immunostainings. Blood lymphocytes were analyzed with Flow cytometry. Results: Sh-CD73 cells formed significantly smaller tumors, than sh-NT cells. ZOL significantly inhibited the growth of both sh-CD73 and sh-NT tumors, but at sacrifice, this effect of ZOL was more significant against sh-CD73 tumors. ZOL increased the % of CD19+/CD21+ and CD19+/23+ in blood of both mice groups, and this effect was inhibited by anti-CD20 antibody. Although neither treatment alone had an effect, the % of CD3+/CD8+ cells in blood were increased in both mice groups by the combination of ZOL and anti-CD20-antibody. ZOL induced accumulation of B220+, CD4+ and CD8+ TILs into both tumor groups. These TIL effects were reduced with anti-CD20 antibody treatment. Anti-CD20 antibody alone inhibited significantly sh-CD73 tumor growth. Anti-CD20 antibody did not interfere with ZOL inhibition of tumor growth in either group. Conclusions: ZOL has inflammatory effects on blood lymphocytes and TILs, which may be affected by tumor expression of immune system regulating proteins, such as CD73. B cell depletion may further prevent tumor growth, in the context of CD73 inhibition. Further studies are needed to investigate whether B-cell inhibition affects ZOL-induced tumor growth inhibition.

Citation Format: Nataliia Petruk, Arafat Siddiqui, Sina Tadayon, Arja Jukkola, Jorma Määttä, Pieta Mattila, Jouko Sandholm, Katri S. Selander. Tumor CD73 regulates zoledronate induced TIL accumulation into triple negative breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD2-07.
Abstract PD5-07: PD5-07 Hepatic Leukemia Factor (HLF), a potential therapeutic target in triple negative breast cancer
Authors: BOUAKKA Ibrahim , TRAN-DIEN Alicia , SIREROL Marine , Silvin Aymeric , Andre Fabrice , ROCCA Anna
Published: March 2023

The importance of the antitumor immune response in triple negative breast cancer (TNBC) is well established. We showed previously that the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after neoadjuvant chemotherapy is associated with a better prognosis. By analyzing 99 pretreatment samples we discovered that the expression of the transcription factor Hepatic Leukemia Factor (HLF) in tumor cells is associated with lower infiltration of immune cells, leading to bad prognosis. Thereby, the aim of our project is to investigate the cellular and molecular mechanism regulated by HLF to better understand the tumor immune microenvironment, so we can develop better treatment options for patients with TNBC. Analysis of publicly available datasets of TNBC (METABRIC and TCGA) showed that tumors with low levels of HLF correlate with the upregulation of genes involved in biological processes associated with the regulation of immune response and in particular with neutrophils activation. Analysis of HLF expression patterns in these patients indicate that tumors presenting a mesenchymal profile exhibited higher HLF levels than the other TNBC subtypes. To elucidate the mechanism of this phenomenon regulated by HLF and his implication in anti-tumoral immune response, we developed several human TNBC cell lines knock-out or knock-down for our target gene using CRISPR/Cas9 editing technology. Comparison of the transcriptomes showed that the silencing of HLF in some mesenchymal TNBC cell lines lead to the upregulation of components involved in the attraction and activation of neutrophils, including CXCL8 (Neutrophil-activating peptide 1), a major cytokine directly responsible for the attraction of neutrophils in the tumor site. In vitro migration experiments supported these observations since purified blood circulating neutrophils have defective migration capacity that depends on the presence or absence of HLF. Finally, the co-culture of neutrophils with tumor cells silenced for HLF showed us, using a large panel of antibodies by spectral flow cytometry, an activated state of mature neutrophils. In conclusion, our study suggest that HLF plays a fundamental role in the regulation of genes involved in the control of tumoral immune microenvironment through the attraction and the activation of mature neutrophils. These findings have the potential for important implications since they suggest that HLF can be a potential target in treating TNBC.

Citation Format: Ibrahim BOUAKKA, Alicia TRAN-DIEN, Marine SIREROL, Aymeric Silvin, Fabrice Andre, Anna ROCCA. PD5-07 Hepatic Leukemia Factor (HLF), a potential therapeutic target in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD5-07.
Abstract PD5-10: PD5-10 Dual therapeutic targeting of CDK8/19 and mTOR in triple negative breast cancer
Authors: Ding Xiaokai , Ji Hao , Sharko Amanda C. , Loskutov Juergen , Mack Zachary , Myers Jadyn , Chen Mengqian , Pugacheva Elena , Roninson Igor , Broude Eugenia
Published: March 2023

Triple negative breast cancer (TNBC) is the most aggressive subtype of all breast cancers. However, unlike other breast cancer subtypes, current treatments for TNBC are restricted and this scarcity of viable options is the key contributor to the poorer prognosis. Despite early response, almost all the targeted drugs tested in TNBC eventually fail due to the development of resistance. Patients’ data have shown that the expression level of Mediator kinases CDK8 and CDK19 are elevated in TNBC, and that higher expression of CDK8/19 is correlated with more advanced diseases and worse prognosis. Selective CDK8/19 inhibitor SNX631, when used as a single agent, inhibited the growth of several TNBC cell lines in vitro, cell-derived xenografts (CDXs) as well as patient derived xenografts (PDXs) in vivo, suggesting the potential of targeting CDK8/19 in treating TNBC. We also analyzed the effect of CDK8/19 inhibition on the outcome of treatment with mTORC1 inhibitor everolimus (RAD001), an approved drug for several cancers with mutations of PTEN or PI3KCA. SNX631 exhibited a synergistic effect in combination with everolimus on suppressing TNBC cell growth in vitro. In vivo treatment with everolimus alone achieved a strong tumor growth inhibition in TNBC xenograft models but all the tumors eventually resumed growth, indicated the development of resistance. Significantly, the addition of a CDK8/19 inhibitor prevented the emergence of in vivo everolimus resistance both in CDX and PDX tumors upon treatment for up to 150 days, suggesting a potential for extending remission or even achieving cures in TNBC. Transcriptomic analysis demonstrated that this effect was due to the prevention of transcriptional reprogramming associated with everolimus resistance in tumor cells.

Citation Format: Xiaokai Ding, Hao Ji, Amanda C. Sharko, Juergen Loskutov, Zachary Mack, Jadyn Myers, Mengqian Chen, Elena Pugacheva, Igor Roninson, Eugenia Broude. PD5-10 Dual therapeutic targeting of CDK8/19 and mTOR in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD5-10.
Predictors of Early Neurological Improvement and Its Relationship to Thrombolysis Treatment and Long-Term Outcome in the WAKE-UP Study
Authors: Heinze Marlene , Cheng Bastian , Cho Tae-Hee , Ebinger Martin , Endres Matthias , Fiebach Jochen B. , Fiehler Jens , Puig Josep , Lemmens Robin , Thijs Vincent , Muir Keith W. , Nighoghossian Norbert , Königsberg Alina , Jensen Märit , Barow Ewgenia , Lettow Iris , Pedraza Salvador , Simonsen Claus Z. , Gerloff Christian , Thomalla Götz
Published: March 2023

Introduction: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. Methods: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0–1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. Results: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954–1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932–0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989–0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9–96%) of the treatment effect. Conclusion: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.
Bacterial Community Structure, Diversity, and Fertility of Soil with and without Press Mud in Two Sites in Panay, Philippines
Authors:   Division of Biological Sciences, College of Arts and Sciences, University of the Philippines Visayas, Miag-ao, 5203, Iloilo, Philippin, Billonid Joswa , Padilla Philip ,   Division of Biological Sciences, College of Arts and Sciences, University of the Philippines Visayas, Miag-ao, 5203, Iloilo, Philippin, Muege May ,   Institute of Fish Processing Technology,College of Fisheries and Ocean Sciences, University of the Philippines Visayas, Miag-ao, 5203, Iloilo, Philippines, Sumaryo Marliyn ,   Division of Biological Sciences, College of Arts and Sciences, University of the Philippines Visayas, Miag-ao, 5203, Iloilo, Philippin, Geduspan Jane ,   Division of Biological Sciences, College of Arts and Sciences, University of the Philippines Visayas, Miag-ao, 5203, Iloilo, Philippin
Published: March 2023

Sugarcane farmers commonly use press mud as organic fertilizer to improve the properties of soil and increase crop production. This study compared the effects of press mud on bacterial community structure, bacterial diversity, and physicochemical parameters of sugar mill soil in two sites, the URC Passi Sugar Central and Passi Sugar Central, Inc. both in Panay, Philippines. DNA and soil analyses were conducted to characterize the soil samples with and without press mud from both sites. The results showed that all nutrient contents increased in both areas after press mud application, except in URC Passi Sugar Central, where no increase in phosphorus and sulfur was observed. Bacterial diversity did not significantly increase six months after press mud application. Community pattern results showed that if soil samples within sites were compared, soil with press mud was significantly higher compared to the soil without press mud in terms of OTU richness (Capiz sugar central: 46.00±1.00, 40.00±1.50, respectively; URC Passi Sugar Central: 48.00±0.50, 45.00±0.00, respectively) and carrying capacity (Capiz sugar central: 169±7.36, 125±9.48, respectively; URC Passi Sugar Central: 181±3.80, 162±0.00, respectively) (p<0.05). The same trend was observed in soil samples between sites that were compared. Soil without press mud from URC Passi Sugar Central had a significantly higher compared with soil without press mud of Capiz Sugar Central in terms of OTU richness (45.00±0.00, 40.00±1.50, respectively) and carrying capacity (162±0.00, 125±9.48, respectively) (p<0.05). However, no significant difference was observed in soil with press mud between the two sites in OTU richness, carrying capacity, Shannon, and Evenness analyses (p>0.05). The phylogenetic tree analysis showed that Massilia sp. is closely related to Burkholderia arboris, and Lysobacter sp. is closely related to both Massilia sp.and B. arboris. Generally, press mud application helps increase the available nutrients, diversity, and community patterns in soil, making it good organic fertilizer.
Trends in Seagrass Research and Conservation in Malaysian Waters
Authors:   Department of Animal Science and Fishery, Faculty of Agricultural and Forestry Sciences, Universiti Putra Malaysia Bintulu Sarawak Campus, Sarawak, 97008, Malaysia, Asif Abdullah , Kamal Abu ,   Faculty of Fisheries and Food Science, Universiti Malaysia Terengganu, Terengganu, 21030, Malaysia, Idris Mohd ,   Faculty of Fisheries and Food Science, Universiti Malaysia Terengganu, Terengganu, 21030, Malaysia, Bhuiyan Mohd ,   Department of Physical Chemistry, Faculty of Marine and Environmental Sciences, University of Cádiz, Cádiz, 11510, Spain, Rahman AFM ,   Faculty of Fisheries and Food Science, Universiti Malaysia Terengganu, Terengganu, 21030, Malaysia
Published: March 2023

The seagrass ecosystems found in the marine and coastal areas, with substantial eco-nomic and ecological services and span all over the globe excluding the Antarctic region. The Coral Triangle and Southeast Asia are recognized as a worldwide hotspot of seagrass species and habitats, encompassing 10-21 species of seagrass in every na-tion, although the study, understanding, and quantity of publications on seagrass eco-systems are rather limited in the region, including Malaysia. Malaysia contains 18 seagrass species from three families, which occupy 16.8 km2of coastal area, where the study and discovery of seagrass species and meadows began in 1904 with the re-port of Beccari. All of the published papers reviewed reported on Malaysian seagrass-related research, which was divided into nine topic groups: biology and distribution, carbon sequestration, fauna, remote sensing, impact and pollution genetic study, res-toration, microbiological investigation, and others. The extensive study of the seagrass ecosystem began in 1993, and we have identified 183 published papers from Scopus, 141 publications from Web of Science, and 42 from Google Scholar. However, the average trend of the number of publications from 1993 to 1999 was 0.71 ± 0.36, while from 2000 to 2022 was 7.70 ± 1.16 followed by the average trend of the yearly number of publications was 6.78 ± 1.08. The highest number of publications was found on faunal categories (43.17%), followed by biology and distribution (21.85%). The num-ber of articles that were published on Malaysian seagrass meadows each year has been discovered to be rising, which indicates that the trends in seagrass study and publish-ing were progressively garnering the attention of researchers, academics, and the gov-ernment. However, to better understand the sustainable ecology and ecosystem ser-vices provided by seagrass habitats, an emphasis on certain research niches, such as the genetic study of flora and fauna in seagrass meadows, microbial ecology, and res-toration as well as conservation of seagrass species might be helpful.
Antimicrobial Activity of Bacterial Strains Isolated from Macrotermes belli-cosus Termite Mound
Authors:   Faculty of Earth and Life Sciences, Université Nazi BONI, Sawadogo Benewinde' , Hien Sandrine ,   Laboratory of Microbiology and Microbial Biotechnology, CRSBAN, University Joseph KI-ZERBO, 03 BP 7131 Ouagadougou, Burkina Faso, Pale Dagoro ,   Laboratory of Microbiology and Microbial Biotechnology, CRSBAN, University Joseph KI-ZERBO, 03 BP 7131 Ouagadougou, Burkina Faso, Maiga Ynoussa ,   Laboratory of Microbiology and Microbial Biotechnology, CRSBAN, University Joseph KI-ZERBO, 03 BP 7131 Ouagadougou, Burkina Faso, Nikiema Mahamadi ,   University of Fada N’Gourma, 01 BP 54 Fada N’Gourma, Burkina Faso, Mogmenga Illiassou ,   University Center of Banfora, University Nazi BONI, 01 BP 1091 Bobo-Dioulasso, Burkina Faso, Dabire Yerobessor ,   Laboratory of Microbiology and Microbial Biotechnology, CRSBAN, University Joseph KI-ZERBO, 03 BP 7131 Ouagadougou, Burkina Faso, Ouattara Cheik ,   Laboratory of Microbiology and Microbial Biotechnology, CRSBAN, University Joseph KI-ZERBO, 03 BP 7131 Ouagadougou, Burkina Faso, Ouattara Aboubakar ,   Laboratory of Microbiology and Microbial Biotechnology, CRSBAN, University Joseph KI-ZERBO, 03 BP 7131 Ouagadougou, Burkina Faso
Published: March 2023

Natural environments like termite mounds can be a reservoir for novel microbial strains and antimicrobial metabolite producers. Hence, this study aimed to investigate the antimicrobial activities of bacterial strains isolated from Macrotermes bellicosus (M. bellicosus) termite mound materials. These materials were sampled from active termite mounds in the Somgandé botanic reserve in Ouagadougou, Burkina Faso. The study collected sixty-three bacterial isolates and assessed their antimicrobial activity against several pathogenic bacteria (Bacillus subtilis, Escherichia coli, Micrococcus luteus, Pseudomonas aeruginosa and Staphylococcus aureus) and two pathogenic fungi (Aspergillus niger and Candida albicans). The dual culture and paper disc diffusion assays revealed that 10 isolates (5 bacteria and 5 actinobacteria) inhibited the growth of at least one pathogenic microorganism. In comparison, four isolates inhibited both Gram-positive and Gram-negative bacteria. Overall, isolates MBm2, MBm8 (bacteria), and MBm26 (actinobacterium) displayed better antibacterial- and antifungal activity against all tested pathogenic microorganisms. It is germane to indicate here that several typical bacteria and actinobacteria isolated from the M. bellicosus termite mound materials were good producers of antibacterial and antifungal agents. Thus, future studies could further characterize these isolates and optimize their growth for producing antimicrobial compounds. The bioactive compounds should also be identified for further biotechnological applications.
Stroke Prevention and Treatment in People With Type 2 Diabetes: Is There a Role for GLP-1 (Glucagon-Like Peptide-1) Analogues?
Authors: Williams David M. , Atkinson Michael , Evans Marc
Published: March 2023

Stroke is a leading cause of disability and death, and people with type 2 diabetes (T2D) have a greater risk of stroke and death or disability from stroke. The underlying pathophysiology associating stroke and T2D is complicated by the association of risk factors for stroke frequently seen in people with T2D. Treatments to reduce the excess risk of new-onset stroke or to improve outcomes in people with T2D following stroke would be of major clinical interest. In practice, the focus of care in people with T2D remains treating risk factors for stroke, such as lifestyle and pharmacological interventions for hypertension, dyslipidemia, obesity, and glycemic control. More recently, cardiovascular outcome trials primarily designed to assess the cardiovascular safety of GLP-1RAs (glucagon-like peptide-1 receptor analogues) have consistently observed a reduced stroke risk in people with T2D. This is supported by several meta-analyses of cardiovascular outcome trials observing clinically important risk reductions in stroke. Moreover, phase II trials have described reductions in poststroke hyperglycemia in people with acute ischemic stroke suggestive of improved outcomes following admission to hospital with acute stroke. In this review, we discuss the increased risk of stroke in people with T2D and outline the key associated mechanisms responsible. We discuss the evidence from cardiovascular outcome trials exploring GLP-1RA use and highlight areas of potential interest for future work in this rapidly developing area of clinical research.
Justified emendation for a species-group name of longhorned beetle (Coleoptera, Cerambycidae, Psyrassa)
Authors: GARCÍA KIMBERLY , TOLEDO-HERNÁNDEZ VÍCTOR H.
Published: March 2023

N/A
Sensitivity of Intrinsic Error Growth to Large-Scale Uncertainty Structure in a Record-Breaking Summertime Rainfall Event
Authors: Zhang Yunji
Published: March 2023

It is recognized that the atmosphere’s predictability is intrinsically limited by unobservably small uncertainties that are beyond our capability to eliminate. However, there have been discussions in recent years on whether forecast error grows upscale (small-scale error grows faster and transfers to progressively larger scales) or up-amplitude (grows at all scales at the same time) when unobservably small-amplitude initial uncertainties are imposed at the large scales and limit the intrinsic predictability. This study uses large-scale small-amplitude initial uncertainties of two different structures—one idealized, univariate, and isotropic, the other realistic, multivariate, and flow dependent—to examine the error growth characteristics in the intrinsic predictability regime associated with a record-breaking rainfall event that happened on 19–20 July 2021 in China. Results indicate upscale error growth characteristics regardless of the structure of the initial uncertainties: the errors at smaller scales grow fastest first; as the forecasts continue, the wavelengths of the fastest error growth gradually shift toward larger scales with reduced error growth rates. Therefore, error growth from smaller to larger scales was more important than the growth directly at the large scales of the initial errors. These upscale error growth characteristics also depend on the perturbed and examined quantities: if the examined quantity is perturbed, then its errors grow upscale; if there is no initial uncertainty in the examined quantity, then its errors grow at all scales at the same time, although its smaller-scale errors still grow faster for the first several hours, suggesting the existence of the upscale error growth.

Significance Statement

This study compared the error growth characteristics associated with the atmosphere’s intrinsic predictability under two different structures of unobservably small-amplitude, large-scale initial uncertainties: one idealized, univariate, and isotropic, the other realistic, multivariate, and flow dependent. The characteristics of the errors growing upscale rather than up-amplitude regardless of the initial uncertainties’ structure are apparent. The large-scale errors do not grow if their initial amplitudes are much bigger than the small-scale errors. This study also examined how the error growth characteristics will change when the quantity that is used to describe the error growth is inconsistent with the quantity that contains uncertainty, suggesting the importance of including multivariate, covariant uncertainties of state variables in atmospheric predictability studies.
Barotropic and Nonlinear Decay of the Wintertime Baroclinic Wave Packets over the North Pacific: Energetics Analysis
Authors: Zhuge Anran , Tan Benkui , Bueh Cholaw , Xie Zuowei
Published: March 2023

Based on daily data from the Japanese 55-year Reanalysis (JRA-55) covering the winters (NDJFM) from 1958 to 2018, this study examines the growth and decay mechanisms of the baroclinic wave packet (BWP) inferred from regression analysis over the North Pacific. Day-to-day kinetic energy (KE) and available potential energy (APE) budget analysis suggest that BWP is driven mainly by baroclinic energy conversion (CPB), barotropic energy conversion (CKB), and the nonlinear term (CKE). CPB acts as a predominant APE source for BWP. Part of CPB acts to overcome the APE loss caused by transient eddy flux and most of it acts as a dominant KE source to drive BWP throughout its lifespan. CKB acts as a KE source before day −1, and as a major KE sink to damp BWP afterward, in which the north–south gradient of the climatological meridional flow plays a key role. Similarly, CKE acts as a KE source before day 0 and as a major KE sink afterward. The damping effect of CKE comes mainly from the scale interaction through the advection of high-frequency meridional momentum by the low-frequency zonal flow. It turns out that the vertical geopotential flux divergence also plays an active role in the dynamical coupling of different vertical BWP parts. There is persistent geopotential flux transfer from the middle-tropospheric layer into the lower- and upper-tropospheric layers, which serves as a major KE source to drive the BWP anomalies for the two layers and a major KE sink for the middle-tropospheric layer where the baroclinic energy conversion is the strongest.

Significance Statement

Previous studies indicate that baroclinic waves tend to organize into wave packets and are driven by the baroclinic instability. This study finds that the baroclinic waves decay mainly through the barotropic energy conversion and nonlinear processes. The results also indicate that the vertical geopotential flux divergence plays an active role in the dynamical coupling of the BWP anomalies in different layers of the troposphere. It is therefore very important to improve the representations of the climatological-mean flow, wave–mean flow interaction, and wave–wave interaction between high- and low-frequency waves in the midlatitudes, as well as the process of vertical transfer of the geopotential flux in numerical models for a better prediction of weather and climate variability in the extratropic regions.
The Perceived Impacts of COVID-19 on Users’ Acceptance of Virtual Reality Hardware: A Digital Divide Perspective
Authors: Huang Kuo-Ting , Ball Christopher , Francis Jess
Published: March 2023

The COVID-19 pandemic has directly or indirectly impacted everyone around the globe. However, the pandemic and its long-term consequences have not been distributed evenly within societies. These disparities have in many cases intensified existing social and economic inequalities such as the uptake of novel digital technologies. This study investigates the influence of the pandemic on the acceptance of virtual reality (VR) hardware within the framework of the technology acceptance model (TAM) and the digital divide/inequality scholarship. A survey was designed to examine the perceived impact of COVID-19 on the potential adoption of VR hardware. Specifically, this study included variables related to perceived ease of using VR hardware (ease of use), perceived usefulness of VR hardware (usefulness), intention to use VR hardware (use intention), and intention to purchase VR hardware (purchase intention). The predictors included two digital divide variables (material access and VR experience) and two other variables (COVID-19 and demographic variables). A total of 298 participants were recruited from Amazon Mechanical Turk. The results suggest that the perceived impacts of COVID-19 positively predicted participants’ perceived usefulness of VR hardware as well as their intention to use and purchase VR hardware.