bluuebunny/crossref_metadata_2025 huggingface dataset:
Green Assay of Tolmetin Sodium Using Solid Contact Potentiometric Sensor Doped with Ionophore and Supported with Docking Study: Application to Human Plasma and Pharmaceutical Formulations
Authors: Mahrous Manal F. , Mabrouk Mokhtar M. , Habib Ahmed , Draz Mohammed E.
Published: March 2023

Tolmetin sodium (TOL) is a non-steroidal anti-inflammatory drug used to treat arthritis. Potentiometric ion selective electrodes (ISEs) bypass sample pre-treatment, high-tech apparatus, and toxic chemicals. The current study aimed to develop and validate a potentiometric analyser for the direct assay of TOL in pharmaceutical dosage form and human plasma. We designed an experimental approach to determine the factors that affect the performance of the developed sensor. A solid contact glassy carbon electrode was utilized as a support for the developed sensor. The interaction of TOL with several ionophore was studied using molecular docking. The optimized sensor was fabricated using dioctyl phthalate as plasticizer, tetra dodecyl ammonium bromide as anion exchanger, and β cyclodextrin as ionophore.The sensor achieved −58.78 Nernstian response within 1.00 × 10−2–2.00 × 10−6 mol l−1 linear range, 1.56 × 10−6 mol l−1 LOD, and fast response within 7 s. The greenness of the proposed method was assessed using the Analytical Eco-scale and the “Green Analytical Procedure Index” (GAPI) metric tools and compared with the reported methods and gained high scores. The proposed method has several advantages in encouraging quality control and clinical labs to routinely use the developed sensor in the assay of TOL in pharmaceutical dosage forms and human plasma.
Molecular Characterization and Mineralizing Potential of Phosphorus Solubilizing Bacteria Colonizing Common Bean (Phaseolus vulgaris L.) Rhizosphere in Western Kenya
Authors: Kiprotich Kelvin , Muoma John , Omayio Dennis O. , Ndombi Tavasi S. , Wekesa Clabe
Published: March 2023

Phosphorus solubilizing bacteria (PSB) are a category of microbes that transform insoluble phosphates in soil into soluble forms that crops can utilize. Phosphorus in natural soils is abundant but poorly soluble. Hence, introducing PSB is a safer way of improving its solubility. The aim of this study was to genetically characterize and determine the mineralization capability of selected PSB colonizing rhizospheres of common beans in Western Kenya. Seven potential phosphorus solubilizing bacteria (PSB) were isolated from various subregions of Western Kenya. 16S ribosomal RNA gene sequencing and National Center for Biotechnology Information (NCBI), Basic Local Alignment Search Tool (BLAST) identified the isolates. The phosphate solubilization potential of the isolates was evaluated under agar and broth medium of National Botanical Research Institute’s phosphate (NBRIP) supplemented with tricalcium calcium phosphate (TCP). Identified isolates were as follows: KK3 as Enterobacter mori, B5 (KB5) as Pseudomonas kribbensis, KV1 as Enterobacter asburiae, KB3 as Enterobacter mori, KK1 as Enterobacter cloacae, KBU as Enterobacter tabaci, and KB2 as Enterobacter bugandensis. The strains B5 and KV1 were the most effective phosphorus solubilizers with 4.16 and 3.64 indices, respectively. The microbes converted total soluble phosphate concentration in broth medium which was 1395 and 1471 P μg/mL, respectively. The least performing isolate was KBU with a 2.34 solubility index. Significant (

p

 ≤ 0.05) differences in plant biomass for Rose coco and Mwitemania bean varieties were observed under inoculation with isolates B5 and KV1. PSB isolates found in common bean rhizospheres exhibited molecular variations and isolates B5 and KV1 are the potential in solving the insufficiency of phosphorus for sustainable crop production.
A Parameter‐Uniform Numerical Scheme for Solving Singularly Perturbed Parabolic Reaction‐Diffusion Problems with Delay in the Spatial Variable
Authors: Ejere Ababi Hailu , Duressa Gemechis File , Woldaregay Mesfin Mekuria , Dinka Tekle Gemechu
Published: March 2023

The objective of this research work is to develop and analyse a numerical scheme for solving singularly perturbed parabolic reaction‐diffusion problems with large spatial delay. The presence of the small positive parameter on the term with the highest order of derivative exhibits two strong boundary layers in the solution of the problem, and the large delay term gives rise to a strong interior layer. The layers’ behavior makes it difficult to solve the problem analytically. To treat such a problem, we developed a numerical scheme using the Crank–Nicolson method in the time direction and the central difference method in the spatial direction via nonstandard finite difference methods on uniform meshes. Stability and convergence analyses for the obtained scheme have been established, which show that the developed numerical scheme is uniformly convergent. To confirm the theoretical analysis, model numerical examples are considered and demonstrated.
Efficient Breast Cancer Diagnosis from Complex Mammographic Images Using Deep Convolutional Neural Network
Authors: Rahman Hameedur , Naik Bukht Tanvir Fatima , Ahmad Rozilawati , Almadhor Ahmad , Javed Abdul Rehman
Published: March 2023

Medical image analysis places a significant focus on breast cancer, which poses a significant threat to women’s health and contributes to many fatalities. An early and precise diagnosis of breast cancer through digital mammograms can significantly improve the accuracy of disease detection. Computer‐aided diagnosis (CAD) systems must analyze the medical imagery and perform detection, segmentation, and classification processes to assist radiologists with accurately detecting breast lesions. However, early‐stage mammography cancer detection is certainly difficult. The deep convolutional neural network has demonstrated exceptional results and is considered a highly effective tool in the field. This study proposes a computational framework for diagnosing breast cancer using a ResNet‐50 convolutional neural network to classify mammogram images. To train and classify the INbreast dataset into benign or malignant categories, the framework utilizes transfer learning from the pretrained ResNet‐50 CNN on ImageNet. The results revealed that the proposed framework achieved an outstanding classification accuracy of 93%, surpassing other models trained on the same dataset. This novel approach facilitates early diagnosis and classification of malignant and benign breast cancer, potentially saving lives and resources. These outcomes highlight that deep convolutional neural network algorithms can be trained to achieve highly accurate results in various mammograms, along with the capacity to enhance medical tools by reducing the error rate in screening mammograms.
2-Deoxy-D-Glucose: A Novel Pharmacological Agent for Killing Hypoxic Tumor Cells, Oxygen Dependence-Lowering in Covid-19, and Other Pharmacological Activities
Authors: Singh Raman , Gupta Vidushi , Kumar Antresh , Singh Kuldeep
Published: March 2023

The nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) has shown promising pharmacological activities, including inhibition of cancerous cell growth and N-glycosylation. It has been used as a glycolysis inhibitor and as a potential energy restriction mimetic agent, inhibiting pathogen-associated molecular patterns. Radioisotope derivatives of 2-DG have applications as tracers. Recently, 2-DG has been used as an anti-COVID-19 drug to lower the need for supplemental oxygen. In the present review, various pharmaceutical properties of 2-DG are discussed.
A Bispecific METxMET Antibody–Drug Conjugate with Cleavable Linker Is Processed in Recycling and Late Endosomes
Authors: Perez Bay Andres E. , Faulkner Devon , DaSilva John O. , Young Tara M. , Yang Katie , Giurleo Jason T. , Ma Dangshe , Delfino Frank J. , Olson William C. , Thurston Gavin , Daly Christopher , Andreev Julian
Published: March 2023

Most antibody–drug conjugates (ADC) approved for the treatment of cancer contain protease-cleavable linkers. ADCs that traffic to lysosomes traverse highly acidic late endosomes, while ADCs that recycle to the plasma membrane traffic through mildly acidic sorting and recycling endosomes. Although endosomes have been proposed to process cleavable ADCs, the precise identity of the relevant compartments and their relative contributions to ADC processing remain undefined. Here we show that a METxMET biparatopic antibody internalizes into sorting endosomes, rapidly traffics to recycling endosomes, and slowly reaches late endosomes. In agreement with the current model of ADC trafficking, late endosomes are the primary processing site of MET, EGFR, and prolactin receptor ADCs. Interestingly, recycling endosomes contribute up to 35% processing of the MET and EGFR ADCs in different cancer cells, mediated by cathepsin-L, which localizes to this compartment. Taken together, our findings provide insight into the relationship between transendosomal trafficking and ADC processing and suggest that receptors that traffic through recycling endosomes might be suitable targets for cleavable ADCs.
Abstract ED13-3: Cardiovascular toxicity and breast cancer: Detection and prevention strategies
Authors: Thavendiranathan Dinesh
Published: March 2023

The presentation will discuss the potential cardiovascular toxicities (e.g., heart failure, coronary artery disease, arrhythmias) that are seen in women with breast cancer with a particular focus on those receiving cancer therapy. It will discuss the associated drugs, timing, the severity, and treatment options. The presentation will also include strategies that could be considered for risk stratification of patients prior to initiation of cancer therapy, methods to identify early cardiovascular injury, and primary prevention options. Recent guidelines including the ESC cardio-oncology guidelines and the prior ASCO guidelines will be highlighted. Practical approaches to assessment and management of cardiovascular toxicities will also be discussed. The presentation will wrap up providing potential future directions in the field.

Citation Format: Dinesh Thavendiranathan. Cardiovascular toxicity and breast cancer: Detection and prevention strategies [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 ED13-3.
Abstract F2-3: Immunosuppressive macrophages and PARP inhibitor resistance
Authors: Guerriero Jennifer
Published: March 2023

Despite objective responses to poly(ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high-dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in breast cancer susceptibility (BRCA)-associated TNBC. Macrophages are an innate immune cell that play a critical role in host defense and maintaining tissue homeostasis, however their infiltration into tumors has been associated with disease progression and resistance to therapy. Tumor associated macrophages (TAMs) represent a significant proportion of solid tumors, including breast cancer. TAMs play a major role in tumorigenesis as they can enhance tumor cell growth, angiogenesis and metastasis. In addition, TAMs can inhibit anti-tumor responses of T cells. Our recent work has shown that removal or conversion of TAMs to an anti-tumor phenotype enhances chemo- and immuno-therapy establishing TAMs as targets for anti-cancer therapy. Through multi-omics profiling, we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming, driven by the sterol regulatory element-binding protein 1 (SREBF1, SREBP1) pathway. Combining PARP inhibitor therapy with colony-stimulating factor 1 receptor (CSF1R)-blocking antibodies significantly enhanced innate and adaptive antitumor immunity and extended survival in mice with BRCA-deficient tumors in vivo, and this was mediated by CD8+ T cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate that combined PARP inhibition and macrophage-targeting therapy induces a durable reprogramming of the tumor microenvironment (TME), thus constituting a promising therapeutic strategy for TNBC. Therefore, targeting TAMs offers great potential to enhance both chemo- and immuno-therapy. Deep analysis of TAMs in solid tumors has revealed the complexity of TAMs and revealed major gaps in our knowledge of the functional and phenotypic characterization of TAM subsets associated with cancer, before and after treatment. Here we will discuss the complexity of TAMs in solid tumors including characterizing TAM subsets, location, and crosstalk with neighboring cells, as well as novel TAM-modulating strategies and combinations that are likely to enhance current therapies and overcome chemo- and immuno-therapy resistance.

Citation Format: Jennifer Guerriero. Immunosuppressive macrophages and PARP inhibitor resistance [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 F2-3.
Abstract F4-1: CDK4/6 inhibitor resistance: Biological mechanisms and novel approaches
Authors: Hanker Ariella
Published: March 2023

CDK4/6 inhibitors (CDK4/6i) in combination with antiestrogens have revolutionized the treatment of ER+ metastatic breast cancer (MBC), significantly prolonging survival. However, this combination is not curative in MBC, and resistance to CDK4/6i represents a major challenge. A diverse array of mechanisms of CDK4/6i resistance have been described, including deregulation of the G1/S cell cycle checkpoint (i.e. Rb, Cyclin E/CDK2, CDK6, INK4s), activation of growth factor signaling pathways (receptor tyrosine kinases, Ras/MAPK pathway, PI3K/AKT pathway), and contributions from the tumor microenvironment. A detailed understanding of these mechanisms is critical for overcoming CDK4/6i resistance. In this presentation, I will discuss recent advances in defining novel biomarkers that are causally associated with CDK4/6i resistance, therapeutic vulnerabilities linked to distinct mechanisms of resistance, and potential strategies to improve clinical responses to CDK4/6i in ER+ MBC.

Citation Format: Ariella Hanker. CDK4/6 inhibitor resistance: Biological mechanisms and novel approaches [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 F4-1.
Abstract MS2-3: Implications for clinical care
Authors: Thomas Alexandra
Published: March 2023

Late recurrence, commonly considered to be distant recurrence five or more years after initial diagnosis remains a formidable challenge in breast oncology. Current management focuses on slowing the growth of macroscopic recurrent disease which is generally considered incurable. Emerging tools to identify minimal residual disease or tumor dormancy hold great promise to transform the treatment landscape in this space. This mini-symposium discussion will review the scope of the clinical challenge, highlighting the numbers at risk and the timeframe for recurrence risk. Current and emerging tools to assess the risk in individual patients beyond 5 years from diagnosis will be discussed. Evidence and guidelines on the use of clinically available anatomic-based and genomic assay-based late risk assessment tools including Clinical Treatment Score post-5 years (CTS5) and the Breast Cancer Index (BCI) will be highlighted. Current data on the role of circulating biomarkers including ctDNA, to identify at risk patients will be discussed as will open questions on how this might impact treatment approach. Finally, possible therapeutic approaches following the identification minimal residual or dormant disease will be reviewed, as will trial design options in this rapidly evolving space in breast oncology.

Citation Format: Alexandra Thomas. Implications for clinical care [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 MS2-3.
Abstract P2-14-20: Comparison of robot-assisted nipple sparing mastectomy with conventional nipple sparing mastectomy: a single-center experience
Authors: You Ji Young , Lee Haemin , Lee Eun-Shin , Jung Seung Pil
Published: March 2023

Purpose: Robot-assisted nipple-sparing mastectomy (RANSM) improves cosmetic outcomes compared to conventional nipple-sparing mastectomy (CNSM) since RANSM is performed with minimal incisions. However, there are few studies on the feasibility and surgical outcome of RANSM. The aim of this study was to compare the surgical outcomes of RANSM and CNSM in breast cancer patients. Method: A retrospective observational study was conducted at our institution between January 2021 and December 2021. A total of 54 patients diagnosed with breast malignancy that underwent either a robotic-assisted or conventional nipple-sparing mastectomy were included. The demographics of the patient’s sex, age, body mass index (BMI), breast weight, and preoperative diagnosis were investigated. The surgical method, operation time (including docking time and console time in the case of robotic surgery), postoperative complications, length of hospital stay, pain score, and adjuvant therapy were analyzed. Result: A total of 57 breasts in 54 female patients were included in the study: 36 invasive ductal carcinoma patients, 11 ductal carcinoma cases, 6 invasive lobular carcinoma, 2 mucinous carcinoma, one solid papillary carcinoma and one lobular carcinoma in situ. A median age of 49(27-66), mean BMI of 22 (18.89-26.28), and mean breast weight was 246 g (120-305g). The mean operation time was 122 minutes (robotic 140 vs. conventional 118), and the average docking time was five minutes and console time 60 minutes in the robot-assisted surgery. There was only one postoperative complication in the robot group and ten cases in the conventional group. The mean hospital stay was 12.6 days (RANSM 10.75 vs. CNSM 12.92), and the average pain score was 3.53 (RANSM 3.50 vs. CNSM 3.54). None needed adjuvant therapy in the robot group. In the conventional surgical group, four patients underwent adjuvant radiotherapy and sixteen patients underwent chemotherapy including six neoadjuvant cases. Conclusion: Our results showed that RANSM had advantages of shorter hospitalization and lower pain scores although it had slightly longer operation time and could not applicable in relatively large breasts. In the near future, RANSM may be considered as the surgery of choice over CNSM in breast cancer patients.

Citation Format: Ji Young You, Haemin Lee, Eun-Shin Lee, Seung Pil Jung. Comparison of robot-assisted nipple sparing mastectomy with conventional nipple sparing mastectomy: a single-center experience. [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 P2-14-20.
Abstract P3-05-23: Pathological complete response rate and disease-free survival after neoadjuvant chemotherapy in patients with HER2-low and HER2-0 breast cancers
Authors: de Nonneville Alexandre , HOUVENAEGHEL Gilles , Cohen Monique , SABIANI Laura , BANNIER Marie , VIRET Frederic , Gonçalves Anthony , BERTUCCI François
Published: March 2023

ABSTRACT Background: Half of HER2-negative breast cancers (BC) show HER2-low expression. The strong efficacy of recent anti-HER2 antibody-drug conjugates (ADC) in HER2-low tumors has risen the interest of HER2-low as a proper BC subtype. Chemosensitivity and prognosis of this subtype are not clear when compared to HER2-0 tumors. We investigated the pathological complete response (pCR) and disease-free survival (DFS) rates in BC patients receiving neoadjuvant chemotherapy for HER2-low or HER2-0 tumors. Methods: Data were collected from the Institut Paoli-Calmettes European Comprehensive Cancer Center database. HER2-low tumors were defined by HER2 IHC score of 1+ or 2+ with negative FISH, and HER2-0 by IHC score of 0+. Clinicopathological characteristics, pCR (defined as [ypT0/ypTis] and [pN0sn or ypN0]) and DFS rates were compared between the two cohorts. Results: From Jan/2005 to Jun/2021, 1,111 patients receiving neoadjuvant chemotherapy were evaluable. The incidence of HER2-low was 41%, including 63% of hormone receptor (HR)-positive and 37% of HR-negative tumors (p< 0.001). In the whole population, the pCR rate was lower in HER2-low (23%) versus HER2-0 (30%) tumors (p=0.013), but this association was lost in multivariate analysis. In HR-positive patients, HER2-low negatively impacted pCR rates when compared to HER2-0 (10% vs. 16%, p=0.046), but not in HR-negatives (46% vs. 42%), and this result was maintained in multivariate analysis (OR 0.60 [95CI 0.36-1.00]; p=0.049, and OR 1.15 [95CI 0.77-1.71]; p=0.490, respectively. No correlation existed between DFS and HER2-status. Conclusion: HER2-low is associated with HR positivity. HER2 status did not impact pCR in HR-negative patients, whereas HER2-low was associated with lower pCR rate in HR-positive patients, supporting the development of anti-HER2 ADC in this setting.

Citation Format: Alexandre de Nonneville, Gilles HOUVENAEGHEL, Monique Cohen, Laura SABIANI, Marie BANNIER, Frederic VIRET, Anthony Gonçalves, François BERTUCCI. Pathological complete response rate and disease-free survival after neoadjuvant chemotherapy in patients with HER2-low and HER2-0 breast cancers [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 P3-05-23.
Abstract P3-08-04: Discovery of cancer genes and pathways operative in PI3K-activated mammary cancer reveals clinically relevant genotype-phenotype correlations
Authors: Kurata Morito , Pope Emiily , Shu Jingmin , Yuan Wenlin , Hudson Wendy , Sokolowski Mark , Bagherzadeh Setareh , Modrusan Zora , Stawiski Eric , Durinck Steffen , Seshigiri Sekar , Sarver Aaron , Temiz Nuri , Largaespada David
Published: March 2023

Human breast cancer (BRCA) shows tremendous genomic, gene expression, clinical, and phenotypic heterogeneity. Known driver gene alterations can only explain a portion of this heterogeneity, some of which likely arise from variation in the target cell for transformation, in addition to incompletely understood gene copy number and epigenetic alterations. These factors are difficult to identify with certainty using human patient samples due to widely varying germline genetic backgrounds, thousands of gene copy and epigenetic changes per sample, and, unknown target cell transformation. Activating mutations in the p110α catalytic subunit of PI3K are one of the most common genetic alterations in human BRCA. Here, we report results from two Sleeping Beauty (SB) transposon-accelerated mouse models of Pik3ca-mutant mammary cancer showing how genotype-phenotype correlations can be drawn providing strong candidates for mediating tumor phenotypes, including estrogen-receptor (ER)-dependent gene expression, high cell cycle activity, and immune cell exclusion. We used SB transposon mutagenesis in mice on a Pik3caH1047R activated mutant background to model mammary cancer development in two different mammary epithelial compartments. Both the target cell for mutagenesis and the specific transposon-induced mutations correlated with specific tumor phenotypes, including whether the tumors were ER positive or negative. RNA sequencing of tumors revealed novel genotype-phenotype correlations implicating specific transposon-altered gene drivers of high cell cycle activity, ER-dependent gene expression, and white blood cell exclusion from the tumor. Many transposon-implicated genes are altered at the gene copy number or epigenetic/methylation level in human BRCA, and several were functionally validated. These models provide a source of genetically heterogenous mouse mammary tumors with a uniform initiating mutation, Pik3caH1047R, useful for identifying cooperating pathways and drivers of specific tumor phenotypes.

Citation Format: Morito Kurata, Emiily Pope, Jingmin Shu, Wenlin Yuan, Wendy Hudson, Mark Sokolowski, Setareh Bagherzadeh, Zora Modrusan, Eric Stawiski, Steffen Durinck, Sekar Seshigiri, Aaron Sarver, Nuri Temiz, David Largaespada. Discovery of cancer genes and pathways operative in PI3K-activated mammary cancer reveals clinically relevant genotype-phenotype correlations. [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 P3-08-04.
Abstract P3-11-11: Impaired Succinate Metabolism Supports Endocrine Therapy Resistance in ER Positive Breast Cancers
Authors: Yadav Anil , de Oliveira Karla Andrade , Jin Lu , Clarke Robert , Sengupta Surojeet
Published: March 2023

Estrogen receptor positive (ER+) breast cancer is the most common subtype among all breast cancers and is responsible for most breast cancer related deaths. Endocrine therapies, such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI), often given in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, are initially effective but the majority of advanced ER+ breast cancers eventually become refractory to endocrine therapies. Therefore, understanding the underlying molecular mechanisms that enable or promote resistance to endocrine therapies may lead to novel therapeutic targets. Cancer cells consume greater quantities of glucose to meet their energy and anabolic demands to support cell growth and proliferation. In this study, we used breast cancer cell models that are endocrine therapy sensitive and resistant and investigated the metabolites by growing the cells in the presence of the stable glucose isotope, UC13-Glucose. We measured the C13-labelled metabolites of glycolysis and the TCA cycle. Glucose consumption was higher in endocrine therapy resistant MCF7/LCC9 (LCC9) cells compared with parental MCF7 (MCF7) and estrogen independent, endocrine therapy sensitive MCF7/LCC1 (LCC1) cells. Notably, in LCC9 cells the m+4 and m+6 isotopomer of C-13 labelled citrate was absent with a concurrent high succinate:fumarate ratio. Furthermore, in LCC9 cells, most of the fumarate was unlabeled suggesting that fumarate was not generated from glucose. These results suggest that the TCA cycle is impaired in LCC9 cells and the conversion of succinate to fumarate is dysregulated. Succinate dehydrogenase (SDH) enzyme is responsible for reversible catalytic conversion of succinate to fumarate. SDH is a multimeric protein comprised of four different subunits and SDH assembly factor 2 (SDHAF2), which is a tumor suppressor gene. Comparable SDH enzyme activity was observed in LCC9 and LCC1 cells. Intriguingly, when SDH activity was inhibited using dimethylmalonate, the LCC9 cells were re-sensitized to both Fulvestrant and 4-hydroxytamoxifen. Succinate accumulation was accompanied with HIF 1-alpha stabilization and SDH inhibition led to lower levels of HIF1-alpha. This indicated that SDH may function in the conversion of fumarate to succinate in LCC9 cells. Our study further investigates the source of fumarate in LCC9 cells. Overall, this study suggests that targeting succinate metabolism may help to restore sensitivity to Fulvestrant and tamoxifen in endocrine therapy resistance in ER+ breast cancer cells.

Citation Format: Anil Yadav, Karla Andrade de Oliveira, Lu Jin, Robert Clarke, Surojeet Sengupta. Impaired Succinate Metabolism Supports Endocrine Therapy Resistance in ER Positive Breast Cancers [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 P3-11-11.
Abstract P4-01-07: FS-1502, an anti-HER2 ADC, in Patients with HER2-Expressing Advanced Solid Tumors: A Phase 1a Dose-Escalation Study
Authors: Li Qiao , Wang Xian , Cheng Ying , Liu Yunjiang , Chang Jianhua , Wang Zhuo , Wu Chunjiao , Wang Mingxia , Hui Ai-Min , Wu Zhuli , Jin Yongli , Huang Xin , Zhong Liping , Diao Lei , Zhao Han , Xu Binghe
Published: March 2023

Background: FS-1502 is a HER2-targeting antibody drug-conjugate with a cleavable β-glucuronide linker and an antimitotic agent (monomethyl auristatin F) which showed promising antitumor activity in preclinical studies. We are evaluating the safety and tolerability of FS-1502 in patients with HER2-expressing advanced solid tumors (NCT03944499). Methods: Patients with HER2-expresssing advanced solid tumors who had failed prior standard of care therapies were enrolled in a single-arm, open-label, dose-escalation phase Ia study in China. FS-1502 was given IV once in 21-day or 28-day cycles. The primary endpoint was incidence of dose-limiting toxicity (DLT). Adverse events (AEs), objective response rate (ORR) and duration of response (DoR) were also assessed. Data cutoff was December 30, 2021. Results: A total of 67 patients, 64 with breast cancer and 3 with other solid tumors, with median 3 prior therapies (range 1-10), were enrolled in 5 sites and treated with FS-1502 at doses of 0.1-3.5 mg/kg. Two DLTs, as defined by the protocol, were observed, with one G2 decrease in creatinine clearance at 3.0 mg/kg and one G3 thrombocytopenia with hemorrhage at 3.5 mg/kg. No Grade 4/5 events were observed. Grade 3 TRAEs were observed in 24 (35.8%) patients with the most common AEs of hypokalemia (14.9%) and decreased platelet count (9.0%). ORRs were observed at doses at or above 1.0 mg/kg with an ORR of 66.7% (4/6) at the recommended phase 2 dose (RP2D) of 2.3 mg/kg. Median duration of response (DoR) across all dose levels was 9.2 months (95%CI 5.6-NR). ORR for HER2-low patients was 42.9% (3/7). Plasma concentration and exposure (AUC) based on total ADC and total antibody increased dose proportionally at ≥1.0 mg/kg, with a T1/2 of 2.4-4.9 days. The incidence and magnitude of immunogenicity were low. While no MTD was determined, the 2.3mg/kg dose once in a 21-day cycle was selected as the RP2D based on safety, antitumor activity and PK data. Conclusions: FS-1502 was well-tolerated and demonstrated encouraging antitumor activity in both HER2-high and -low patients. Phase Ib and phase II clinical trials with FS-1502 are currently ongoing in various solid tumor indications including breast, gastric, and colorectal cancer.

Citation Format: Qiao Li, Xian Wang, Ying Cheng, Yunjiang Liu, Jianhua Chang, Zhuo Wang, Chunjiao Wu, Mingxia Wang, Ai-Min Hui, Zhuli Wu, Yongli Jin, Xin Huang, Liping Zhong, Lei Diao, Han Zhao, Binghe Xu. FS-1502, an anti-HER2 ADC, in Patients with HER2-Expressing Advanced Solid Tumors: A Phase 1a Dose-Escalation 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 P4-01-07.
Abstract P4-08-09: Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2-deficiency
Authors: Guantay María L. , Garro Cintia A. , Siri Sebastian , Pansa María , Ghidelli-Disse Sonja , Paviolo Natalia , Racca Ana , Nicotra Viviana , Radu Caius , Bocco José L. , Felice Rosana , Gloger Israel , Muelbaier Marcel , Drewes Gerard , Madauss Kevin , García Manuela , Gottifredi Vanesa , Soria Gastón
Published: March 2023

BRCA2 is a well-established cancer driver in several human malignancies. While the remarkable success of PARP inhibitors proved the clinical potential of targeting BRCA deficiencies, the emergence of resistance mechanisms underscores the importance of seeking novel Synthetic Lethal (SL) targets for future drug development efforts. In this work, we performed a BRCA2-centric SL screen with a collection of plant-derived compounds from South America. We identified the steroidal alkaloid Solanocapsine as a selective SL inducer, and we were able to substantially increase its potency by deriving multiple analogs. The use of two complementary chemoproteomic approaches led to the identification of the nucleotide salvage pathway enzyme deoxycytidine kinase (dCK) as Solanocapsine’s target responsible for its BRCA2-liked SL induction. Additional confirmatory evidence was obtained by using a highly specific dCK inhibitor (DI-87), which induces SL in multiple BRCA2-deficient and KO contexts. Interestingly, dCK-induced SL is mechanistically different from the one induced by PARP inhibitors. dCK inhibition generates substantially lower levels of DNA damage, and cytotoxic phenotypes are associated exclusively with mitosis, thus suggesting that the fine-tuning of nucleotide supply in mitosis is critical for the survival of BRCA2-deficient cells. Moreover, by using a xenograft model of contralateral tumors, we show that dCK impairment suffices to trigger SL in-vivo. Taken together, our findings unveil dCK as a promising new target for BRCA2-deficient cancers, which provides future therapeutic alternatives to PARP inhibitors.

Citation Format: María L. Guantay, Cintia A. Garro, Sebastian Siri, María Pansa, Sonja Ghidelli-Disse, Natalia Paviolo, Ana Racca, Viviana Nicotra, Caius Radu, José L. Bocco, Rosana Felice, Israel Gloger, Marcel Muelbaier, Gerard Drewes, Kevin Madauss, Manuela García, Vanesa Gottifredi, Gastón Soria. Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2-deficiency [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 P4-08-09.
Abstract P6-01-03: Tumor-infiltrating lymphocytes (TILs) and 21-gene recurrence score in 1,883 patients with ER+/HER2- breast cancer
Authors: Ahn Sung Gwe , Jang Ji Soo , Kook Yoonwon , Baek Seung Ho , Lee Sae Byul , Bae Soong June , Jeong Joon
Published: March 2023

Background: In ER+/HER2- breast cancer, several lines of evidence suggest that tumors with high level of tumor-infiltrating lymphocytes (TILs) have a greater chance of obtaining a pathological complete response (pCR) after neoadjuvant chemotherapy. In addition, high 21-gene recurrence score (RS) is associated with an increasing rate of pCR in luminal tumors. We investigated the relationship between TIL and RS in 1,883 patients with early ER+HER2- breast cancer.

Method: In 1,883 ER+ breast cancer patients with 21-gene assay, TIL level was evaluated. Correlation between continuous TIL and RS was investigated. Logistic-regression analysis was performed to identify risk factors for high RS (26). The cut-off for high TIL was 50%. Recurrence-free survival (RFS) was investigated.

Results: A weak positive correlation between TIL level and RS was observed (correlation coefficient=0.283, p< 0.001) in all patients. Average TIL level of the high RS tumors was significantly higher. Two parameters were positively correlated in both two groups classified by age 50 years (correlation coefficient=0.281 in the age 50; correlation coefficient=0.288 in the age>50). Either continuous TILs or binary high TIL level was demonstrated to be an independent factor for high RS. When all patients were divided into 4 groups using TIL and RS (low-RS/low-TIL, low-RS/high-TIL, high-RS/low-TIL, and high-RS/high-TIL), the RFS was worst in the low-TIL/high-RS group (p< 0.001).

Conclusions: Our findings show that TIL level is correlated with RS in ER+ breast cancer regardless of age and suggest that high TIL level can be regarded as a risk factor for high RS. Multigene assay could be integrated in designing clinical trials evaluating immune-check point blockades in luminal breast cancer.

Recurrence-free survival according to RS and TIL

Table 1. 5-years RFS according to TIL and RS

Citation Format: Sung Gwe Ahn, Ji Soo Jang, Yoonwon Kook, Seung Ho Baek, Sae Byul Lee, Soong June Bae, Joon Jeong. Tumor-infiltrating lymphocytes (TILs) and 21-gene recurrence score in 1,883 patients with ER+/HER2- 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 P6-01-03.
Abstract P6-05-21: Quality of Life and Perspectives of Older Adults with Early & Locally Advanced Breast Cancers Undergoing Pre-operative Therapy
Authors: Ma Jun , Zhang Zewen , Tan Jasmine Yun Ting , Ong Whee Sze , Kamis Sulastri , Tan Benita Kiat Tee , Tan Veronique Kiak Mien , Kanesvaran Ravindran , Tan Tira Jing Ying
Published: March 2023

Background: Breast cancer (BC) is the commonest diagnosed cancer in Singaporean women. Increasingly, non-metastatic BC are treated aggressively with neoadjuvant therapy (NAT). Early identification and addressing supportive care needs of NAT treated patients is important for effective cancer care whilst maintaining optimal physical, psychological and social function. This project aims to explore the longitudinal trends of quality of life (QOL) of BC patients enrolled in a NAT program. Methods: This was a prospective cohort study of females aged 21 diagnosed with non-metastatic BC, referred to the NAT program at the SingHealth network of acute hospitals. The Functional Assessment of Cancer Therapy-Breast (FACT-B) was used as a health related QOL measure prior to NAT, within 2 months post definitive breast surgery and at 1-year post diagnosis. In older adults (OA) ≥65 years, the Attitude scale, Now vs Later as well as Health Outcome tool were also performed at baseline. Here we report pre-NAT baseline FACT-B and questionnaire results of OA patients recruited into the NAT program between Jun 2020 and Jun 2021. Results: Pre-NAT median FACT-B scores was 117 (IQR 102-126) for the entire cohort (n=119) and 116 (IQR 104-126) for OA (n=22). OA had significantly lower median Social Wellbeing score at baseline compared to patients < 65 years (p=0.01), while Physical, Emotional, and Functional Wellbeing were not significantly different. More than 50% of OA favoured QOL over quantity of life on the Attitude Scale. 68% of patients would rather have QOL now than 1 year later with half expecting their QOL to reduce by 50% in this time period. When the time scale was extended to 5 years, 64% would rather have QOL 5-years from now instead of QOL now with close to 80% expecting their QOL to be lower in 5 years than presently. Of the 4 outcomes, maintaining independence scored the highest, followed by keeping alive, then reducing/eliminating pain and other symptoms. Conclusion: Our study suggests that OA with BC report similar QOL to younger patients at baseline prior to NAT. Majority of OA patients favoured QOL over quantity of life, and viewed the ability to maintain independence as more important than survival prolongation representing their unique attitude towards cancer treatment and outcomes.

Citation Format: Jun Ma, Zewen Zhang, Jasmine Yun Ting Tan, Whee Sze Ong, Sulastri Kamis, Benita Kiat Tee Tan, Veronique Kiak Mien Tan, Ravindran Kanesvaran, Tira Jing Ying Tan. Quality of Life and Perspectives of Older Adults with Early & Locally Advanced Breast Cancers Undergoing Pre-operative Therapy [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 P6-05-21.
Shugoshin Regulates Cohesin, Kinetochore-Microtubule Attachments, and Chromosomal Instability
Authors: Sun Qiqi , Liu Feng , Mo Xiaolong , Yao Bo , Liu Guanghai , Chen Shanshan , Ren Yanping
Published: March 2023

Correct regulation of cohesin at chromosome arms and centromeres and accurate kinetochore-microtubule connections are significant for proper chromosome segregation. At anaphase of meiosis I, cohesin at chromosome arms is cleaved by separase, leading to the separation of homologous chromosomes. However, at anaphase of meiosis II, cohesin at centromeres is cleaved by separase, leading to the separation of sister chromatids. Shugoshin-2 (SGO2) is a member of the shugoshin/MEI-S332 protein family in mammalian cells, a crucial protein that protects centromeric cohesin from cleavage by separase and corrects wrong kinetochore-microtubule connections before anaphase of meiosis I. Shugoshin-1 (SGO1) plays a similar role in mitosis. Moreover, shugoshin can inhibit the occurrence of chromosomal instability (CIN), and its abnormal expression in several tumors, such as triple-negative breast cancer, hepatocellular carcinoma, lung cancer, colon cancer, glioma, and acute myeloid leukemia, can be used as biomarker for disease progression and potential therapeutic targets for cancers. Thus, this review discusses the specific mechanisms of shugoshin which regulates cohesin, kinetochore-microtubule connections, and CIN.
Life Course Education, Health, and Ageing Well: A Short Inter-Academic Report
Authors: Frangos Emilia , Barriguete-Mélendez Armando , Debré Patrice , Gutiérrez Robledo Luis Miguel , Parodi André-Laurent , Michel Jean-Pierre
Published: March 2023

After the first wave of the COVID-19 pandemic, during which the severity of the disease in certain countries was attributed to a lack of basic education of the inhabitants, the authors of this paper initiated a literature review of educational trajectories, health, and ageing well. The findings strongly demonstrate that alongside genetics, the affective and educational family environment, as well as the general environment, greatly interact starting from the very first days of life. Thus, epigenetics plays a major role in the determination of health and disease [DOHAD] in the first 1,000 days of life as well as in the characterization of gender. Other factors such as socio-economic level, parental education, schooling in urban or rural areas, also play a major role in the differential acquisition of health literacy. This determines adherence (or lack thereof) to healthy lifestyles, risky behaviours, substance abuse, but also compliance with hygiene rules, and adherence to vaccines and treatments. The combination of all these elements and lifestyle choices facilitates the emergence of metabolic disorders (obesity, diabetes), which promote cardiovascular and kidney damage, and neurodegenerative diseases, explaining that the less well educated have shorter survival and spend more years of life in disability. After having demonstrated the impact of the educational level on health and longevity, the members of this inter-academic group propose specific educational actions at three levels: (1) teachers and health professionals, (2) parents, (3) the public, emphasizing that these crucial actions can only be carried out with the unfailing support of state and academic authorities.
Development of Bangle Rhizome and Purple Sweet Potato Flour Biscuit and Its in vivo Antioxidant Activity in High-Fat Diet-Induced Rats
Authors:   Faculty of Pharmacy, Universitas Ahmad Dahlan, Sulistyani Nanik , Mahfudh Nurkhasanah ,   Faculty of Pharmacy, Universitas Ahmad Dahlan, Umar Rofidah ,   Faculty of Pharmacy, Universitas Ahmad Dahlan, Mantali Muhammad ,   Faculty of Health Sciences, Universitas Muhammadiyah Manado
Published: March 2023

Bangle rhizome and purple sweet potato could be used as functional food to overcome health problems such as hyperlipidemia. The anti-hyperlipidemic, nutritional properties of the above-said root vegetables could be formulated into a more community-preferred food in the form of biscuits. For this reason, this study aims to formulate biscuits from the mixed flour of bangle rhizome and purple sweet potato. Next, the prepared product's antioxidant activity and lipid-lowering properties are tested in vivo in high-fat diet-induced Wistar rats. In this study, bangle rhizome and purple sweet potato were turned into flour and formulated into three types of biscuits comprising different ratios of bangle rhizome and purple sweet potato flour (5:39 % w/w (F1), 3:41 % w/w (F2), and 2:42 % w/w (F3)). The study found that the baked products showed good organoleptic and physical properties, yielding golden- to brown-colored biscuits with a distinctive aroma and vaguely bitter after-taste, with F3 showing the highest hardness (8.94 0.18). The proximate analysis test showed that the biscuits achieved three of the six SNI 01-2973-2011 quality requirements. The best formula (F3) exhibited acceptable in vivo antioxidant catalase (5.12 0.16 U/mL) and glutathione peroxidase activity (64.44 2.11 U/mg) in high-fat diet Wistar rats tested for 28 days. The F3 formula was deemed the best, yielding biscuits with low moisture content and good crispiness. The formulated biscuits increased catalase's antioxidant activity (285.47%) and glutathione peroxidase (265.08%) more than the negative control. Hence, the study demonstrated that bangle rhizome and purple sweet potato-containing biscuits were potentially useful functional foods for improving antioxidant activity in high-fat diet-induced Wistar rats.
Assessing the Stability of Peppermint Oil Encapsulated in Hydrogel Beads
Authors:   Department of Biotechnology, International Islamic Universiti Malaysia, Bandar Indera Mahkota, 25200, Kuantan, Pahang Malaysia, Wong Nurjeha
Published: March 2023

Essential oil mainly contains volatile constituents making it vulnerable upon exposure to the external environment. The encapsulation method is known to protect the bioac-tive components of the essential oil from damage, in which alginate was used as the hydrogel in this study. This work investigates the physicochemical stability of the pep-permint oil encapsulated within alginate beads (1.5% and 2.0%) during its five weeks of storage. Peppermint oil (PO) was added at four different weight ratios to alginate, which were 1:3, 1:2, 1:1, and 2:1. The encapsulation technique involves mixing algi-nate and oil using a homogeniser. Constituents profiling was done weekly using UV-Vis spectrophotometer and Gas chromatography-mass spectroscopy (GC-MS). Inves-tigation revealed that 1.5% (w/w) alginate in a weight ratio of 1:1 has the highest en-capsulation efficiency, which was 42.00%, while for 2.0% (w/w) alginate, the weight ratio of 1:2 gave a maximum encapsulation efficiency of 33.38%. Assessment of the beads' diameter with time showed little physical changes throughout storage time. The constituents profile of the oil indicates a decline in the chemical constituents between a pure sample and the encapsulated peppermint oil. This might be associated with the heat generated during mixing or exposure to the light during the preparation stage. Even so, the analysis of the encapsulated oil each week suggested no striking changes, indicating the stability of the peppermint oil encapsulated in the alginate beads.