bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Nanoparticle-Based Celecoxib and Plumbagin for the Synergistic Treatment of Melanoma
Authors: Gowda Raghavendra , Kardos Gregory , Sharma Arati , Singh Sanjay , Robertson Gavin P.
Published: April 2023

Abstract
Using multiple drugs to kill cancer cells can decrease drug resistance development. However, this approach is frequently limited by the bioavailability and toxicity of the combined agents and delivery at ratios to specific locations that synergistically kill cancer cells. Loading the individual agents into a nanoparticle that releases the drugs at synergizing ratios at a single location is one approach to resolve this concern. Celecoxib and plumbagin are two drugs that were identified from a screen to synergistically kill melanoma cells compared with normal cells. Combined use of these agents by traditional approaches was not possible due to poor bioavailability and toxicologic concerns. This study details the development of a nanoliposomal-based agent containing celecoxib and plumbagin, called CelePlum-777, which is stable and releases these drugs at an optimal ratio for maximal synergistic killing efficacy. CelePlum-777 was more effective at killing melanoma than normal cells and inhibited xenograft melanoma tumor growth by up to 72% without apparent toxicity. Mechanistically, the drug combination in CelePlum-777 led to enhanced inhibition of melanoma cell proliferation mediated by decreasing levels of key cyclins important for cancer cell proliferation and survival, which was not observed with the individual agents. Thus, a novel nanoparticle-based drug has been developed containing celecoxib and plumbagin that lacks toxicity and delivers the agents at a synergistically killing drug ratio to kill cancer cells. Mol Cancer Ther; 16(3); 440–52. ©2016 AACR.
Data from Radiation Responses of 2D and 3D Glioblastoma Cells: A Novel, 3D-specific Radioprotective Role of VEGF/Akt Signaling through Functional Activation of NHEJ
Authors: Gomez-Roman Natividad , Chong Ming Y , Chahal Sandeep K. , Caragher Seamus P. , Jackson Mark R. , Stevenson Katrina H. , Dongre Sidhartha A. , Chalmers Anthony J.
Published: April 2023

Abstract
Glioblastoma is resistant to conventional treatments and has dismal prognosis. Despite promising in vitro data, molecular targeted agents have failed to improve outcomes in patients, indicating that conventional two-dimensional (2D) in vitro models of GBM do not recapitulate the clinical scenario. Responses of primary glioblastoma stem-like cells (GSC) to radiation in combination with EGFR, VEGF, and Akt inhibition were investigated in conventional 2D cultures and a three-dimensional (3D) in vitro model of GBM that recapitulates key GBM clinical features. VEGF deprivation had no effect on radiation responses of 2D GSCs, but enhanced radiosensitivity of GSC cultures in 3D. The opposite effects were observed for EGFR inhibition. Detailed analysis of VEGF and EGF signaling demonstrated a radioprotective role of Akt that correlates with VEGF in 3D and with EGFR in 2D. In all cases, positive correlations were observed between increased radiosensitivity, markers of unrepaired DNA damage and persistent phospho-DNA-PK nuclear foci. Conversely, increased numbers of Rad51 foci were observed in radioresistant populations, indicating a novel role for VEGF/Akt signaling in influencing radiosensitivity by regulating the balance between nonhomologous end-joining and homologous recombination–mediated DNA repair. Differential activation of tyrosine kinase receptors in 2D and 3D models of GBM explains the well documented discrepancy between preclinical and clinical effects of EGFR inhibitors. Data obtained from our 3D model identify novel determinants and mechanisms of DNA repair and radiosensitivity in GBM, and confirm Akt as a promising therapeutic target in this cancer of unmet need.
Data from A Chemosensitivity Study of Colorectal Cancer Using Xenografts of Patient-Derived Tumor-Initiating Cells
Authors: Maekawa Hisatsugu , Miyoshi Hiroyuki , Yamaura Tadayoshi , Itatani Yoshiro , Kawada Kenji , Sakai Yoshiharu , Taketo M. Mark
Published: April 2023

Abstract
Current genomic and gene expression analyses provide versatile tools to improve cancer chemotherapy. However, it is still difficult to predict whether each patient responds to a particular regimen or not. To predict chemosensitivity in each patient with colorectal cancer, we developed an evaluation method using the primary tumor-initiating cells (TIC, aka cancer stem cells) xenografted in nude mice subcutaneously (patient-derived spheroid xenografts; PDSX). Simultaneously, we also prepared the conventional patient-derived xenografts (PDX) from the same patients' tumors and compared the dosing results with those of PDSXs. We further compared the chemosensitivities of PDSXs with those of 7 patients who had been given regimens such as FOLFOX and FOLFIRI to treat their metastatic lesions. As per the results, the PDSX method provided much more precise and predictable tumor growth with less variance than conventional PDX, although both retained the epithelial characteristics of the primary tumors. Likewise, drug-dosing tests showed essentially the same results in PDXs and PDSXs, with stronger statistical power in PDSXs. Notably, the cancer chemosensitivity in each patient was precisely reflected in that of the PDSX mice along the clinical course until the resistance emerged at the terminal stage. This “paraclinical” xenograft trials using PDSXs may help selection of chemotherapy regimens efficacious for each patient, and, more importantly, avoiding inefficient ones by which the patient can lose precious time and QOL. Furthermore, the PDSX method may be employed for evaluations of off-label uses of cancer chemotherapeutics and compassionate uses of yet-unapproved new drugs in personalized therapies. Mol Cancer Ther; 17(10); 2187–96. ©2018 AACR.
Data from Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype
Authors: Cvrljevic Anna N. , Butt Umar , Huhtinen Kaisa , Grönroos Tove J. , Böckelman Camilla , Lassus Heini , Butzow Ralf , Haglund Caj , Kaipio Katja , Arsiola Tiina , Laajala Teemu D. , Connolly Denise C. , Ristimäki Ari , Carpen Olli , Pouwels Jeroen , Westermarck Jukka
Published: April 2023

Abstract
Identification of ovarian cancer patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high-grade ovarian cancer tumors at diagnosis express CIP2A oncoprotein at low levels. Furthermore, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient ovarian cancer cells, we identified reactive oxygen species inducer APR-246, tested previously in ovarian cancer clinical trials. Consistent with CIP2A-deficient ovarian cancer subtype in humans, CIP2A is dispensable for development of MISIIR-Tag–driven mouse ovarian cancer tumors. Nevertheless, CIP2A-null ovarian cancer tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the ovarian cancer cells to APR-246 by inhibition of NF-κB activity. Accordingly, combination of APR-246 and NF-κB inhibitor compounds strongly synergized in killing of CIP2A-positive ovarian cancer cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient ovarian cancer tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.
Abstract 1071: Tipifarnib synergizes with TKIs in clear cell renal cell carcinoma models
Authors: Gatchalian Jovylyn , Kessler Linda , Chan Stacia , Burrows Francis , Malik Shivani
Published: April 2023

Clear cell renal cell carcinoma (ccRCC) is a highly vascularized tumor type, primarily due to loss of the Von Hippel-Lindau (VHL) gene, which is observed in ~88% of ccRCC cases. Deletion of VHL stabilizes hypoxia-inducible factor alpha protein (HIFα) to drive the hypoxic transcriptional response, including induction of VEGF and PDGF2 that mediate tumor angiogenesis. Anti-angiogenic tyrosine kinase inhibitors (TKIs) such as sunitinib and axitinib have demonstrated therapeutic benefit in patients with ccRCC by exploiting the critical dependency of ccRCC tumors on the vasculature for oxygen, nutrients, and growth factors. However, resistance to TKIs is commonly observed, leading to clinical relapse. Here, we report that the combination of the farnesyltransferase inhibitor (FTI), tipifarnib, and any of several anti-angiogenic TKIs results in deeper and more durable responses in the VHL-mutant 786-O CDX model and an RCC PDX model, compared to TKI alone. While the anti-angiogenic TKIs or tipifarnib alone merely slowed or occasionally arrested tumor growth, the TKI-tipifarnib combination induced marked tumor regressions in all treated animals. To investigate the mechanism of action, VHL-mutant RCC cell lines were subjected to hypoxia (1% O2) in vitro to mimic the hypoxic conditions induced by TKIs in vivo and were treated with tipifarnib to evaluate tipifarnib’s impact on signaling pathways in hypoxia-exposed cells. In the Caki2 cell line, hypoxia initially reduced mTOR signaling, but it rebounded strongly after 24 hours in hypoxia, suggesting that mTOR pathway reactivation is a potential mechanism of resistance to TKIs. Addition of tipifarnib blocked hypoxia-induced mTOR reactivation. Mechanistically, tipifarnib potently inhibits the farnesylation, and hence the activity, of an obligate farnesylated protein RHEB, a positive regulator of mTOR, suggesting that the synergy may arise through RHEB inhibition in this model. The mechanistic data in cell lines suggest that tipifarnib’s ability to inhibit mTOR reactivation observed in ccRCC cell lines under hypoxic stress contributes to the enhanced treatment durability observed in vivo. Because FTIs are pleiotropic drugs, there are likely additional cell intrinsic mechanisms that may influence synergy with TKIs. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of TKI-tipifarnib effects and strengthen the therapeutic rationale for combining TKIs with tipifarnib in the treatment of patients with ccRCC.

Citation Format: Jovylyn Gatchalian, Linda Kessler, Stacia Chan, Francis Burrows, Shivani Malik. Tipifarnib synergizes with TKIs in clear cell renal cell carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1071.
Abstract 2268: Single cell RNA sequencing defines dynamic immune cell subsets in serial colon and peripheral blood samples in a patient with checkpoint inhibitor-induced colitis
Authors: Mann Jacqueline E. , Lucca Liliana , Austin Matthew , Merkin Ross D. , Aizenbud Lilach , Herold Kevan , Robert Marie , Kluger Harriet M.
Published: April 2023

Background: Immune checkpoint inhibition is an increasingly popular strategy for the management of numerous malignancies. Unfortunately, severe inflammatory toxicities affect up to 60% of patients, often leading to treatment discontinuation in settings where few alternative therapies are available to control disease. Checkpoint inhibitor induced colitis is a common toxicity for which the underlying mechanisms are poorly defined.

Methods: To better understand the changing colon-specific and peripheral immune environments over the course of disease progression and treatment, we collected blood and colon tissue from a Merkel Cell carcinoma patient who developed colitis after treatment with pembrolizumab. We performed 10X Genomics single cell RNA sequencing on samples collected before, during and after checkpoint inhibition and various interventions to mitigate toxicity.

Results: We identified both shared and colon-exclusive clonal expansion of T cells defined by distinct transcriptional programs, including cytotoxicity, memory, and proliferation markers, at various stages of the disease process. These clones decreased dramatically in the colon after infliximab and vedolizumab therapies.

Conclusions: We identified several distinct T cell subsets as potential drivers of colitis in the colon. T cell clones that potentially recognize colonic tissue with a high degree of specificity can be harnessed for therapeutic intervention. Our findings emphasize the need for a more detailed understanding of the immune environment in the colon and suggest the potential for peripheral blood as a readout for immune activity during CPI treatment.

Citation Format: Jacqueline E. Mann, Liliana Lucca, Matthew Austin, Ross D. Merkin, Lilach Aizenbud, Kevan Herold, Marie Robert, Harriet M. Kluger. Single cell RNA sequencing defines dynamic immune cell subsets in serial colon and peripheral blood samples in a patient with checkpoint inhibitor-induced colitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2268.
Abstract 259: Fully automated targeted sequencing sample prep on open platform liquid handlers
Authors: Wahba Ashraf , Bao Yun , Wang Heng , Watson Kinnari , Zhao Grace Q. , Lin Shengrong
Published: April 2023

To accommodate the growing demands of sample throughput, reliability, and reduced hands-on time of targeted sequencing, automation is critical. The implementation of sample preparation automation is limited by several factors — complicated protocols and long incubation times. As an industry first, Avida’s Point-n-Seq™ hybridization-based targeted sequencing kit solution features 1 hr hybridization time and PCR free capture which enables full automation on a broad range of open platform liquid handlers, from the economical Opentrons (OT-2) to the high throughput Hamilton (Microlab Star).

We report a walk-away targeted sequencing sample-prep solution based on the highly efficient chemistry of our Point-n-Seq technology. This strategy supports PCR-free capture for variant detection. A sequencing-ready captured library is prepared in 6 hours, with just 25 minutes of hands-on time. More importantly, a PCR-free protocol increases sequence uniformity, decreases amplicon bias as well as GC-bias, and eliminates the need for purification and quantification before capture. We have demonstrated the feasibility of automated workflows using 40 ng of genomic DNA with panel sizes ranging from 20 Kb to 2 Mb. Using a comprehensive oncology panel containing 500 genes to analyze Horizon oncology cfDNA (30 ng) or FFPE gDNA (40 ng) reference standards, we demonstrated reliable detection of SNV and structural variations with allele frequency matching the expected values. The Point-n-Seq technology enables fully automated targeted sequencing sample prep on open platform liquid handlers, enhancing accuracy and reliability while reducing hands-on time. The one hour hybridization time makes hybridization more economical on the liquid handler when compared to off-instrument for overnight/longer hybridization. This automated solution greatly accelerates the development of fast, simple, and accurate genomic profiling assays. Furthermore, Point-n-Seq targeted methylation sequencing and targeted RNA assays can also be easily adapted to the same automation platforms for research and clinical applications.

Citation Format: Ashraf Wahba, Yun Bao, Heng Wang, Kinnari Watson, Grace Q. Zhao, Shengrong Lin. Fully automated targeted sequencing sample prep on open platform liquid handlers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 259.
Abstract 2622: Targeting Rac/Cdc42 GTPases to overcome HER2-targeted therapy resistance
Authors: Reyes Miciely Cristal Aponte , Vega Luis E. Velazquez , Dharmawardhane Suranganie
Published: April 2023

Breast cancer is the most common cancer in women. Breast cancer is categorized by the overexpression (or lack thereof) of estrogen receptors (ER+/-), progesterone receptors (PR+/-) or human epidermal growth factor 2 receptors (HER2+/-). Specifically, HER2+ breast cancer is one of the most aggressive subtypes, comprising ~20% of all cases. Overexpression of the HER2 receptor leads to active downstream signaling that results in cell proliferation and metastasis. Clinically, this problem has been tackled by targeting the HER2 receptor with antibodies (e.g., Trastuzumab, Pertuzumab) and (or) tyrosine kinase inhibitors (TKIs; e.g., Lapatinib). However, patients may present with intrinsic or acquired resistance to these therapies. Molecular mechanisms of resistance to HER2 targeted therapy include activating mutations, alterations in downstream effectors, and compensation from other growth factor receptors. The active signaling sequelae from such mechanisms converge on the activation of guanine nucleotide exchange factors (GEFs) that regulate the GTPases Rac and Cdc42. These GTPases are critical for cell migration/invasion and have been correlated with poor prognosis in breast cancer patients. Therefore, targeting the activation of Rac/Cdc42 is a rational strategy to overcome HER2-targeted therapy resistance. Previously, we characterized the dual Rac/Cdc42 inhibitor MBQ-167 with IC50s of 103nM and 78nM for Rac and Cdc42, respectively. Our objective is to test MBQ-167 as an alternative to overcome HER2-targeted therapy resistance. To test the hypothesis that MBQ-167 will overcome HER2 therapy resistance, metastatic trastuzumab resistant HER2 overexpressing cells were treated with vehicle or individual or combined Trastuzumab and MBQ-167. Rac activity was determined by pulldown assays for active (GTP-bound) Rac, and viability was tested by MTT assays. Additionally, we measured apoptosis via caspase 3/7 activity and western blotted for the active signaling sequelae downstream of Rac. MBQ-167 reduced Rac activity and downstream signaling, as well as cell viability with a GI50 of 78nM after 72 hours, while caspase activity was increased after 24 hours of treatment. The results presented herein show the utility of the Rac/Cdc42 inhibitor MBQ-167 in overcoming HER2-targeted therapy resistance.

Citation Format: Miciely Cristal Aponte Reyes, Luis E. Velazquez Vega, Suranganie Dharmawardhane. Targeting Rac/Cdc42 GTPases to overcome HER2-targeted therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2622.
Abstract 3188: Patient-derived TAC01-HER2 TAC T cells produced in Cocoon® Platform is highly functional in models of solid tumors
Authors: Wang Ling , Xu Stacey X. , Benatar Tania , Randhawa Ritu R. , Ip Philbert , Lal Prabha , Nitya-Nootan Thanyashanthi , Ravensbergen Laura , MacGregor Heather , Prosser Suzy , Sengupta Sadhak , Helsen Christopher W. , Bader Andreas G.
Published: April 2023

Background:

The T cell antigen coupler (TAC) is a novel, proprietary chimeric receptor that facilitates the re-direction of T cells to tumor cells and activates T cells by co-opting the endogenous T cell receptor complex with the goal to elicit a safe and durable anti-tumor response. TAC01-HER2, a first-in-class TAC T product targeting HER2 (ERBB2), has entered a Phase I/II clinical trial in patients with HER2-positive solid tumors. Here, we characterized the TAC T cell phenotypes and anti-tumor activity of TAC01-HER2 manufactured using leukocytes from Phase I/II patients in nonclinical in vitro and in vivo assays.

Materials and Methods:

TAC T cell proliferation, activation, and phenotype of patient-derived TAC01-HER2 were assessed by flow cytometric analysis. In vitro anti-tumor cytotoxicity was assessed via a real-time microscopy-based co-culture assay, and in vivo anti-tumor activity of TAC01-HER2 was assessed in mice engrafted with established solid HER2-expressing human tumors.

Results:

Complex phenotype analysis showed that patient-derived TAC01-HER2 products consisted of a high percentage of memory T cells similar to products generated from healthy donors. Patient-derived products had significant proportions of CD4 and CD8 T cells, with CD4 being the predominant population in several of these. In a 5-day in vitro potency assay, patient-derived products showed effective tumor cell killing at low E:T rations (1:1 to 1:20) which was comparable to product generated from healthy donors. Similarly, intravenous administration of patient-derived TAC01-HER2 in mice carrying HER2-positive tumors xenografts led to a complete and sustained tumor clearance.

Conclusion:

The in vitro and in vivo data confirm the potency of patient-derived TAC01-HER2 against HER2-expressing solid tumor models. This work combined with other biomarkers may help correlate nonclinical potency with clinical outcomes.

Citation Format: Ling Wang, Stacey X. Xu, Tania Benatar, Ritu R. Randhawa, Philbert Ip, Prabha Lal, Thanyashanthi Nitya-Nootan, Laura Ravensbergen, Heather MacGregor, Suzy Prosser, Sadhak Sengupta, Christopher W. Helsen, Andreas G. Bader. Patient-derived TAC01-HER2 TAC T cells produced in Cocoon® Platform is highly functional in models of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3188.
Abstract 3532: Activator protein-1 (AP-1) signaling inhibits the growth of Ewing sarcoma cells in response to DNA replication stress
Authors: Gordon David , Croushore Emma , Koppenhafer Stacia , Goss Kelli , Geary Elizabeth
Published: April 2023

Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis of deoxyribonucleoside triphosphates (dNTPs) and is required for DNA replication and the repair of DNA damage. Multiple types of cancer, including Ewing sarcoma tumors, are sensitive to RNR inhibitors or a reduction in the levels of either the RRM1 or RRM2 subunits of RNR. However, the polypharmacology and off-target effects of RNR inhibitors has complicated the identification of the precise mechanisms that regulate sensitivity and resistance to this class of drugs. Consequently, we used a conditional knockout (CRISPR/Cas9) and rescue approach to target RRM1 in Ewing sarcoma cells and identified that loss of RRM1 results in upregulation of the expression of multiple members of the activator protein-1 (AP-1) transcription factor complex, including c-Jun and c-Fos. This upregulation of AP-1 is mediated, in part, by SLFN11, which is expressed at high levels in Ewing sarcoma tumor and other pediatric sarcomas. Notably, the inducible expression of c-Jun and c-Fos in Ewing sarcoma cells impairs cell growth, downregulates the expression of the stem cell factor Sox2, and upregulates markers of cellular differentiation. In addition, small-molecule inhibitors of RNR, including gemcitabine and hydroxyurea, and HDAC inhibitors, which reduce the level of the RRM1 protein, also activate this AP-1 signaling pathway in Ewing sarcoma cells. Overall, these results provide novel insight into the critical pathways activated by loss of RNR activity and the mechanisms of action of inhibitors of RNR.

Citation Format: David Gordon, Emma Croushore, Stacia Koppenhafer, Kelli Goss, Elizabeth Geary. Activator protein-1 (AP-1) signaling inhibits the growth of Ewing sarcoma cells in response to DNA replication stress. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3532.
Abstract 378: Ferritin regulates oxaliplatin sensitivity and immunosuppression in pancreatic ductal adenocarcinoma
Authors: Chiu Ching-Feng
Published: April 2023

Oxaliplatin, a third-generation of platinum analog, has been used for the treatment of colorectal, gastric, and advanced pancreatic ductal adenocarcinoma (PDAC); however, its relatively high toxicity reduced its efficacy in clinical use. Recently, we found that organic cation transporter 2 (OCT2) expression is positively correlated to Oxaliplatin sensitivity in PDAC cells and better survival outcomes in PDAC patients with chemotherapy, suggesting that OCT2 level is important not only in predicting sensitivity to oxaliplatin but also in guiding dose adjustments to minimize toxicity. Here, we observed the significance of serum Ferritin as a prognostic marker for pancreatic cancer, and further identified Ferritin heavy chain (FTH1) down-regulated OCT2 level and reduced Oxaliplatin sensitivity of advanced PDAC cells in vitro and in vivo. Our study reveals the negative correlation between FTH1 and OCT2 levels in PDAC database analysis and reducing FTH1 expression with Deferasirox (DFX), which is an agent that has been widely used for patients with iron overload, reversed OCT2 expression and Oxaliplatin sensitization in metastatic PDAC cells. Additionally, we identified that exosomal Ferritin/FTH1 from PDAC cells may enhance M1-type to M2-type macrophage polarization to build up immunosuppression in the tumor microenvironment.

Citation Format: Ching-Feng Chiu. Ferritin regulates oxaliplatin sensitivity and immunosuppression in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 378.
Abstract 3830: The anticancer activity of a water-soluble extract from the leaves of the indigenous Southern African plant Tulbaghia violacea against a triple negative breast cancer cell line
Authors: Hull Rodney , Dlamini Zodwa , Penny Clement , Alaouna Mohammed
Published: April 2023

Triple negative breast cancer (TNBC) is difficult to treat and leads to a low five-year survival rate.In South Africa, a sizable percentage of the population still relies on traditional plant-based medicine. One of these plants, Tulbaghia violacea), has traditionally been used to treat cancer. In order to establish the usefulness of both methanol and water-soluble extracts from the leaves of this plant, extracts were used to treat a TNBC cell. Cytotoxicity assays were carried out to establish the IC50 values against the TNBC cell line. These concentrations were used to carry out assays to study the ability of these extracts to inhibit cell migration, invasion, as well as the effect of these extracts on the cell cycle and their ability to induce apoptosis in these cells. Finally, the antioxidant activity of these cells was assayed. The IC50 values for the water and methanol soluble extracts was determined to be 400 and 820 µg/mL respectively. Due to the high IC50 value and inconsistent performance of the methanol soluble extract, further studies focussed on the water-soluble extract. Treatment of the TNBC cells with the water-soluble extract led to an increase in apoptosis, with the extract causing approximately 82% of the TNBC cells to undergo apoptosis compared to only 32% of the normal breast cells. This extract also significantly decreased the ability of the TNBC cells to migrate or penetrate abasement membrane in scratch and invasion assays. These results demonstrate that the water-soluble extract from T. violacea leaves contains compounds that are able to preferentially induce apoptosis in TNBC cells while also inhibiting the ability of these cells to metastasize. The exact molecular make up of this extract will need to be determined on order to develop the extract as a potential therapy for TNBC.

Citation Format: Rodney Hull, Zodwa Dlamini, Clement Penny, Mohammed Alaouna. The anticancer activity of a water-soluble extract from the leaves of the indigenous Southern African plant Tulbaghia violacea against a triple negative breast cancer cell line. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3830.
Abstract 6057: Association of liver cancer and chronic liver disease with urinary glyphosate and its metabolites in Thailand
Authors: Patel Daxesh P. , Pupacdi Benjarath , Rabibhadana Siritida , Toulabi Leila , Haznadar Majda , Dalal Bhavik , Khan Mohammed , Stone Joshua , Bhudhisawasdi Vajarabhongsa , Lertprasertsuke Nirush , Chotirosniramit Anon , Pairojkul Chawalit , Auewarakul Chirayu U. , Sricharunrat Thaniya , Phornphutkul Kannika , Sangrajrang Suleeporn , Budhu Anuradha , Mahidol Chulabhorn , Wang Xin W. , Gonzalez Frank J. , Ruchirawat Mathuros , Loffredo Christopher A. , Harris Curtis C. ,   TIGER-LC Consortium
Published: April 2023

Background: Glyphosate, the primary weed-killing ingredient in Roundup®, is the most widely used herbicide worldwide. The World Health Organization’s International Agency for Research on Cancer (IARC) Monographs Program classified glyphosate is a probable human carcinogen (Group 2A), capable of causing human cancer under some circumstances.

Methods: We analyzed urine specimens from 848 sequential patients with liver cancer and matched non-cancer controls from five different regional hospitals in Thailand. Gas chromatography electrospray ionization mass spectrometry (GC-ESI/MS) technique was used to measure glyphosate and its metabolites aminomethylphosphonic acid (AMPA) and phosphoric acid (PPA) to study their levels in hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA), and chronic liver disease (CLD) in comparison to matched population controls.

Findings: Significantly higher levels of glyphosate were found in CLD patients compared to cancer cases and population controls, while significantly elevated levels of both AMPA and PPA were observed in HCC and CLD patients. Glyphosate and its metabolites were also detected at low to moderately high levels in convenience samples of food products and drinking water.

Interpretation: These results raise concern about the potential role of glyphosate in chronic human liver disease and cancer.

Citation Format: Daxesh P. Patel, Benjarath Pupacdi, Siritida Rabibhadana, Leila Toulabi, Majda Haznadar, Bhavik Dalal, Mohammed Khan, Joshua Stone, Vajarabhongsa Bhudhisawasdi, Nirush Lertprasertsuke, Anon Chotirosniramit, Chawalit Pairojkul, Chirayu U. Auewarakul, Thaniya Sricharunrat, Kannika Phornphutkul, Suleeporn Sangrajrang, Anuradha Budhu, Chulabhorn Mahidol, Xin W. Wang, Frank J. Gonzalez, Mathuros Ruchirawat, Christopher A. Loffredo, Curtis C. Harris, TIGER-LC Consortium . Association of liver cancer and chronic liver disease with urinary glyphosate and its metabolites in Thailand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6057.
Abstract 6158: BGB-24714, a novel oral IAP antagonist, displayed significant anti-tumor activities in preclinical models as a monotherapy and in combination with paclitaxel
Authors: Li Jie , Hu Nan , Zhang Yilu , Yang Xiaolong , Deng Minjuan , Gong Wenfeng , Yin Longbo , Liu Yong , Gao Yajuan , Wei Wei , Wang Xing , Liang Xinyi , Ma Yanwen , Sang Xuxing , Liu Chang , Wang Jingyuan , Lu Qianqian , Song Fengtao , Yuan Xi , Wang Yibing , Li Jing , Jin Wei , Liu Xuesong , Song Xiaomin
Published: April 2023

Background: Evasion of apoptosis is identified as one of the essential hallmarks of cancer and upregulation of inhibitor of apoptosis proteins (IAPs) is one of the mechanisms by which tumor cells evade apoptosis. An oral SMAC mimetic and antagonist of cellular IAP1 (cIAP1) and X-linked IAP (XIAP), BGB-24714, is currently investigated in a phase 1a/1b oncology trial in patients with advanced or metastatic solid tumors (NCT05381909). Here, we evaluated the anti-tumor activity of BGB-24714 as a single agent or in combination with paclitaxel in preclinical models.

Results: BGB-24714 effectively inhibited cIAP1 by inducing its degradation in MDA-MB-231 cells, with an EC50 of 2.5 nM. BGB-24714 also potently antagonized the inhibitory interaction of XIAP with caspase-9 and induced caspase-9 autoactivation in MDA-MB-231 cells, with an EC50 of 23 nM. In a total of 25 breast cancer cell lines treated with TNFα, BGB-24714 potently inhibited the in vitro proliferation of 5 breast cancer cells with EC50 < 100 nM. In pharmacodynamics studies, single dose administration of BGB-24714 significantly induced degradation of cIAP1 and antagonism of the XIAP: Smac interaction in the MDA-MB-231 xenograft model in a dose dependent manner. Using the same model, BGB-24714 exhibited dose-dependent anti-tumor activities as a single agent. The tumor growth inhibition rates were 30%, 52% and 73% in low to high dosage treatment groups. Furthermore, BGB-24714 at medium dosage level demonstrated synergized anti-tumor activity in HCC1806 xenograft model when used in combination with paclitaxel. In intermittent dosing study, BGB-24714 with the intermittent dosing schedule demonstrated significant but slightly less effective anti-tumor activity than the continuous dosing schedule. In summary, BGB-24714, as a novel oral IAP antagonist, showing significant anti-tumor activities in preclinical models, which is promising and warrants the testing of the compound in human.

Citation Format: Jie Li, Nan Hu, Yilu Zhang, Xiaolong Yang, Minjuan Deng, Wenfeng Gong, Longbo Yin, Yong Liu, Yajuan Gao, Wei Wei, Xing Wang, Xinyi Liang, Yanwen Ma, Xuxing Sang, Chang Liu, Jingyuan Wang, Qianqian Lu, Fengtao Song, Xi Yuan, Yibing Wang, Jing Li, Wei Jin, Xuesong Liu, Xiaomin Song. BGB-24714, a novel oral IAP antagonist, displayed significant anti-tumor activities in preclinical models as a monotherapy and in combination with paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6158.
Abstract 666: Targeting the CD47/SIRPα “Do not eat me” phagocytic pathway in macrophages to improve anti-CD47 immune therapy
Authors: Gajendran Nithya , Hernandez Maria Gracia , Yende Ashutosh , Alahmadi Zubaydah , Li Xintang , Munoz Zuleima , Suresh Manasa , Quiceno David , Tan Karen , Shibata Maho , Noonepalle Satish , Villagra Alejandro
Published: April 2023

The cluster of differentiation 47(CD47) is a ubiquitously expressed innate immune checkpoint transmembrane protein but is often overexpressed in cancer cells. CD47 interacts with signal regulatory protein alpha (SIRPα) on macrophages leading to tyrosine phosphatase activation and preventing myosin accumulation at the phagocytic synapse. SIRPa activation triggers the “Do not eat me” signal, negatively regulating phagocytosis in macrophages. Blockade of CD47-SIRPα is a novel immunotherapeutic approach to enhance innate antitumor responses in cancer patients, and clinical data from melanoma patients also showed promising outcomes when CD47 blockade combined with other therapeutic approaches, such as anti-PD-L1. Publications from our lab have provided compelling evidence that histone deacetylase 6 (HDAC6) inhibitors with PD1 blockade delayed tumor progression, enhanced survival, and modulated macrophage phenotype both in vitro and in vivo. The present study aimed to explore the role of HDAC 6 in the CD47/SIRPα axis in phagocytosis and innate antitumor immunity. HDAC inhibition in primary mouse bone marrow-derived macrophages and human THP1 cells enhanced the pro-inflammatory M1 macrophages while downregulating the anti-inflammatory M2 phenotype. In the subsequent studies, we found that HDAC6 inhibition diminished the expression of SIRPα and enhanced the expression of other pro-phagocytic signals, such as Lrp1, CD36, and Mfge8 in macrophages. HDAC6 inhibition also downregulated the CD47 expression in mouse and human melanoma cells. Furthermore, modulation of CD47/SIRPα by HDAC6 inhibitors leads to an increase in phagocytosis in NextA-treated macrophages, further enhanced in CD47-blocking antibodies. We also demonstrated that the combination of systemic administration of the HDAC6 inhibitor Nexturastat A and intertumoral delivery of anti-CD47 reduced SM1 melanoma growth in vivo by increasing immune cell infiltration in the tumor microenvironment. Collectively our results suggest that HDAC6 inhibitors synergize with CD47 blockade to reduce tumor growth and enhance innate antitumor immunity.

Citation Format: Nithya Gajendran, Maria Gracia Hernandez, Ashutosh Yende, Zubaydah Alahmadi, Xintang Li, Zuleima Munoz, Manasa Suresh, David Quiceno, Karen Tan, Maho Shibata, Satish Noonepalle, Alejandro Villagra. Targeting the CD47/SIRPα “Do not eat me” phagocytic pathway in macrophages to improve anti-CD47 immune therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 666.
Supplementary Figure 6 from Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology
Authors: Camaj Peter , Jäckel Carsten , Krebs Stefan , DeToni Enrico N. , Blum Helmut , Jauch Karl-Walter , Nelson Peter J. , Bruns Christiane J.
Published: April 2023

PDF file - 45K, S6. Cross-talk between important Sx9-target pathways.
Supplementary Figure 4 from Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology
Authors: Camaj Peter , Jäckel Carsten , Krebs Stefan , DeToni Enrico N. , Blum Helmut , Jauch Karl-Walter , Nelson Peter J. , Bruns Christiane J.
Published: April 2023

PDF file - 50K, S4. Sox9 does not influence stability of HIF1alpha.
Supplementary Figure 2 from FBXW7 Mediates Chemotherapeutic Sensitivity and Prognosis in NSCLCs
Authors: Yokobori Takehiko , Yokoyama Yozo , Mogi Akira , Endoh Hideki , Altan Bolag , Kosaka Takayuki , Yamaki Ei , Yajima Toshiki , Tomizawa Kenji , Azuma Yoko , Onozato Ryoichi , Miyazaki Tatsuya , Tanaka Shigebumi , Kuwano Hiroyuki
Published: April 2023

PDF - 98KB, Supplementary Figure 2. FBXW7 expression in cell lines treated with MS-275.
Supplementary Figure 4 from Inhibition of mTOR Pathway Sensitizes Acute Myeloid Leukemia Cells to Aurora Inhibitors by Suppression of Glycolytic Metabolism
Authors: Liu Ling-Ling , Long Zi-Jie , Wang Le-Xun , Zheng Fei-Meng , Fang Zhi-Gang , Yan Min , Xu Dong-Fan , Chen Jia-Jie , Wang Shao-Wu , Lin Dong-Jun , Liu Quentin
Published: April 2023

PDF file - 1470K, Aurora kinases inhibitors had synergistic effect with mTOR inhibitors on the glycolytic metabolism of U937 cells.
Supplementary Figure 1 from Inhibition of mTOR Pathway Sensitizes Acute Myeloid Leukemia Cells to Aurora Inhibitors by Suppression of Glycolytic Metabolism
Authors: Liu Ling-Ling , Long Zi-Jie , Wang Le-Xun , Zheng Fei-Meng , Fang Zhi-Gang , Yan Min , Xu Dong-Fan , Chen Jia-Jie , Wang Shao-Wu , Lin Dong-Jun , Liu Quentin
Published: April 2023

PDF file - 927K, The effect of Aurora kinases inhibitors on HL-60 and KG1a cell lines.
Supplementary Figure Legends from Genomic Analysis of Head and Neck Squamous Cell Carcinoma Cell Lines and Human Tumors: A Rational Approach to Preclinical Model Selection
Authors: Li Hua , Wawrose John S. , Gooding William E. , Garraway Levi A. , Lui Vivian Wai Yan , Peyser Noah D. , Grandis Jennifer R.
Published: April 2023

PDF file - 94K
Supplementary Figure 1 from Genomic Analysis of Head and Neck Squamous Cell Carcinoma Cell Lines and Human Tumors: A Rational Approach to Preclinical Model Selection
Authors: Li Hua , Wawrose John S. , Gooding William E. , Garraway Levi A. , Lui Vivian Wai Yan , Peyser Noah D. , Grandis Jennifer R.
Published: April 2023

PDF file - 75K, Mutation frequencies by source (cell line or tumor) and disease site (larynx, oral cavity, pharynx).
Supplementary Table 1 from Activation of the Wnt Pathway through AR79, a GSK3β Inhibitor, Promotes Prostate Cancer Growth in Soft Tissue and Bone
Authors: Jiang Yuan , Dai Jinlu , Zhang Honglai , Sottnik Joe L. , Keller Jill M. , Escott Katherine J. , Sanganee Hitesh J. , Yao Zhi , McCauley Laurie K. , Keller Evan T.
Published: April 2023

PDF file - 56K, DNA profiling of LNCaP, C4-2B and DU145
Supplementary Figure 4 from Activation of the Wnt Pathway through AR79, a GSK3β Inhibitor, Promotes Prostate Cancer Growth in Soft Tissue and Bone
Authors: Jiang Yuan , Dai Jinlu , Zhang Honglai , Sottnik Joe L. , Keller Jill M. , Escott Katherine J. , Sanganee Hitesh J. , Yao Zhi , McCauley Laurie K. , Keller Evan T.
Published: April 2023

PDF file - 200K, Figure S4. AR79 increases the cell number of Du145luc cells in the presence or absence of ST-2 co-culture.
Supplementary Table 3 from DNA Damage-Inducible Gene, Reprimo Functions as a Tumor Suppressor and Is Suppressed by Promoter Methylation in Gastric Cancer
Authors: Ooki Akira , Yamashita Keishi , Yamaguchi Kensei , Mondal Anupom , Nishimiya Hiroshi , Watanabe Masahiko
Published: April 2023

XLS file - 52K, Supplementary Table 3. Univariate and multivariate prognostic analyses in 68 patients with advanced gastric cancer.
Supplementary Movie 1 from Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis
Authors: Ahn Joseph , Truesdell Peter , Meens Jalna , Kadish Carli , Yang Xiaolong , Boag Alexander H. , Craig Andrew W.B.
Published: April 2023

MP4 file - 307K
Supplementary Materials and Methods, Supplementary Figures 1-6, and Supplementary Tables 1-3 from ARF Regulates the Stability of p16 Protein Via REGγ-Dependent Proteasome Degradation
Authors: Kobayashi Takashi , Wang Jingqiang , Al-Ahmadie Hikmat , Abate-Shen Cory
Published: April 2023

PDF 656K, Supplementary Materials and Methods. Supplementary Figure S1: ARF does not affect expression levels of p16 mRNA in human cancer cell lines. Supplementary Figure S2: p16 does not affect ARF protein expression levels in human cancer cell lines. Supplementary Figure S3: Characterization of Arf-positive and Arf-null MEFs. Supplementary Figure S4: Arf regulates the stability of p16 protein via REGgamma-dependent proteasome degradation in MEFs. Supplementary Figure S5: REGgamma is degraded by an Arf-dependent manner. Supplementary Figure S6: ARF regulates the stability of p16 protein via REGgamma- dependent proteasome degradation in human cancer cells. Supplementary Table S1: Description of tissue microarrays used in this study. Supplementary Table S2: Sequences of oligos and siRNA used in this study. Supplementary Table S3: Antibodies used in this study.
Supplementary Figures 1 - 6 from miR-155–Deficient Bone Marrow Promotes Tumor Metastasis
Authors: Yu Fang , Jia Xuemei , Du Fen , Wang Junfeng , Wang Yuzhen , Ai Walden , Fan Daping
Published: April 2023

PDF file - 252K, S1. miR-155 expression in spleen of WT and miR-155-/- chimeric mice. S2. Effects on bone marrow miR-155 deficiency on bone marrow cell mobilization in tumor-bearing mice. S3. The effects of bone marrow miR-155 deficiency on the leukocyte subpopulations in spleen of tumor-bearing mice. S4. The effects on bone marrow miR-155 deficiency on the expression of tumor-derived factors. S5. A, Expression level of miR-155 in LLC and B16-F10 cells. Quantitative real-time PCR was performed to measure the expression of miR-155 in the lung tissue of WT mice, and cultured LLC and B16-F10 cells. Data are presented as the mean plus-minus SEM of three replicates. **, p<0.001 by Student's t test. B. Quantitative real-time PCR analysis of miR-155 levels in WT macrophages incubated with serum-free medium (SFM), LLC cell conditioned medium (LLC-CM) and B16-F10 cell conditioned medium (B16-CM) for 24 h. Data are presented as the mean plus-minus SEM of three replicates. S6. miR-155 deficiency MΦ promoted migration of B16-F10 cells.
Supplementary Figure 2 from Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis
Authors: Ahn Joseph , Truesdell Peter , Meens Jalna , Kadish Carli , Yang Xiaolong , Boag Alexander H. , Craig Andrew W.B.
Published: April 2023

PDF file - 80K, Vav2 domains and regulation via tyrosine phosphorylation.
Supplementary Table 2 from Interleukin-6 and Oncostatin-M Synergize with the PI3K/AKT Pathway to Promote Aggressive Prostate Malignancy in Mouse and Human Tissues
Authors: Smith Daniel A. , Kiba Atsushi , Zong Yang , Witte Owen N.
Published: April 2023

XLSX file - 12K, Quantification of phenotypes observed in human samples across four histological sections from independent biological replicates.
Supplementary Figure 4 from Interleukin-6 and Oncostatin-M Synergize with the PI3K/AKT Pathway to Promote Aggressive Prostate Malignancy in Mouse and Human Tissues
Authors: Smith Daniel A. , Kiba Atsushi , Zong Yang , Witte Owen N.
Published: April 2023

PDF file - 3076K, Human regenerations with IL6 and OSM alone exhibit dramatic inhibition of epithelial regeneration.
Supplementary Figure 2 from Interleukin-6 and Oncostatin-M Synergize with the PI3K/AKT Pathway to Promote Aggressive Prostate Malignancy in Mouse and Human Tissues
Authors: Smith Daniel A. , Kiba Atsushi , Zong Yang , Witte Owen N.
Published: April 2023

PDF file - 1490K, Autocrine expression of OSM with activation of AKT promotes invasive epithelial growth from benign lesions.
Supplementary Figure 6 from Crizotinib-Resistant NPM-ALK Mutants Confer Differential Sensitivity to Unrelated Alk Inhibitors
Authors: Ceccon Monica , Mologni Luca , Bisson William , Scapozza Leonardo , Gambacorti-Passerini Carlo
Published: April 2023

PDF file - 9018K, Chromatograms show the presence of the correct point mutations in our site-directed mutagenized Ba/F3 NPM-ALK cell lines.
Supplementary Figure 5 from NF-YA Underlies EZH2 Upregulation and Is Essential for Proliferation of Human Epithelial Ovarian Cancer Cells
Authors: Garipov Azat , Li Hua , Bitler Benjamin G. , Thapa Roshan J. , Balachandran Siddharth , Zhang Rugang
Published: April 2023

PDF file - 51K, Knockdown of NF-YA downregulates EZH2 in lung cancer and breast cancer cell lines.
Supplementary Figure 4 from Crizotinib-Resistant NPM-ALK Mutants Confer Differential Sensitivity to Unrelated Alk Inhibitors
Authors: Ceccon Monica , Mologni Luca , Bisson William , Scapozza Leonardo , Gambacorti-Passerini Carlo
Published: April 2023

PDF file - 177K, ALK phosphorylation status for K299 and K299CR06 at low Crizotinib doses.
Supplementary Figure 5 from Systems Analysis of the NCI-60 Cancer Cell Lines by Alignment of Protein Pathway Activation Modules with “-OMIC” Data Fields and Therapeutic Response Signatures
Authors: Federici Giulia , Gao Xi , Slawek Janusz , Arodz Tomasz , Shitaye Amanuel , Wulfkuhle Julia D. , De Maria Ruggero , Liotta Lance A. , Petricoin Emanuel F.
Published: April 2023

PDF file - 55K, Scatterplots of RPPA measurements for total and phosphorylated forms of ERK1/2 (A), AKT (B) and ERBB3. Normalized relative intensity values for the total protein are plotted along the x-axis and values for the phosphorylated protein along the y-axis. Regression lines and r2 goodness of fit values are also shown.
Supplementary Figure 5 from Nullifying the CDKN2AB Locus Promotes Mutant K-ras Lung Tumorigenesis
Authors: Schuster Katja , Venkateswaran Niranjan , Rabellino Andrea , Girard Luc , Peña-Llopis Samuel , Scaglioni Pier Paolo
Published: April 2023

PDF file - 2931K, Evaluation of primary mouse cell lines.
Supplementary Fig. 7 from Transcription Factor Interactions Mediate EGF-Dependent COX-2 Expression
Authors: Xu Kaiming , Shu Hui-Kuo G.
Published: April 2023

Supplementary Fig. 7 - PDF file 84K,The Sp1-FOXM1 complex is regulated by p38-MAPK but not ERK1/2
Supplementary Methods from Loss of a Negative Feedback Loop Involving Pea3 and Cyclin D2 Is Required for Pea3-Induced Migration in Transformed Mammary Epithelial Cells
Authors: Ladam Franck , Damour Isabelle , Dumont Patrick , Kherrouche Zoulika , de Launoit Yvan , Tulasne David , Chotteau-Lelievre Anne
Published: April 2023

PDF file - 93K