bluuebunny/crossref_metadata_2025 huggingface dataset:
Polar Metals: Principles and Prospects
Authors: Bhowal Sayantika , Spaldin Nicola A.
Published: April 2023

We review the class of materials known as polar metals, in which polarity and metallicity coexist in the same phase. While the notion of polar metals was first invoked more than 50 years ago, their practical realization has proved challenging since the itinerant carriers required for metallicity tend to screen any polarization. Huge progress has been made in the last decade, with many mechanisms for combining polarity and metallicity proposed and the first examples, LiOsO3 and WTe2, identified experimentally. The availability of polar metallic samples has opened a new paradigm in polar metal research, with implications in the fields of topology, ferroelectricity, magnetoelectricity, spintronics, and superconductivity. Here, we review the principles and techniques that have been developed to design and engineer polar metals and describe some of their interesting properties, with a focus on the most promising directions for future work.
Motor control complexity can be dynamically simplified during gait pattern exploration using motor control-based biofeedback
Authors: Spomer Alyssa M. , Yan Robin Z. , Schwartz Michael H. , Steele Katherine M.
Published: April 2023

We used a motor control-based biofeedback system and machine learning to characterize the extent to which nondisabled adults can modulate synergies during gait pattern exploration. Results revealed that a small library of synergies underlies an array of gait patterns but that recruitment from this library changes as a function of the imposed biomechanical constraints. Our findings enhance understanding of the neural control of gait and may inform biofeedback strategies to improve synergy recruitment after neurological injury.
Price Dynamics of a Delay Differential Cobweb Model
Authors: Anokye Martin , Barnes Benedict , Ohene Boateng Francis , Adom-Konadu Agnes , Amoah-Mensah John
Published: April 2023

The paper uses a new technique to find a unique solution to a delay differential cobweb model (formulated from a joint supply-demand function of price) with real model parameters via the Lambert W-function without considering any complex branches. The dynamics of the model are demonstrated with simulations and found to complement previous studies using literature values. However, the condition for instability

δ
/
β

>
1

in the previous studies was defied by our model due to the time delay associated with the supply function. The practical application and advantage of this model over the existing models are that the stability of this model is not limited to only the ratio of price elasticity of demand and supply but also the time-delay parameter (i.e., a missing link in the previous models). Our model, on the other hand, loses its stability when the time delay associated with the supply function is fixed at

τ
=
1.8

. Since most of the physical systems, including economical systems, are time-delay inherent and such stability conditionalities should not limit their performance, it is recommended that such systems be modelled using delay differential functions. The novelty of this research is that there has not been a definite general solution to the cobweb model with a time delay whose price dynamics mimic the behaviour of the existing cobweb models in the literature. An illustrative example in a delayed fractional-order differential equation also buttressed the importance of the time delay in the model, aside from the impact of the ratio of the price elasticity of supply and demand.
Low Computational Burden Adaptive Overcurrent Protection for Active Distribution Networks
Authors: Grisales-Soto B. , Pérez-Londoño S. , Mora-Flórez J.
Published: April 2023

Conventional distribution networks have evolved into active distribution networks due to the high penetration of distributed energy resources. These new networks have several protection issues; some are related to the high fault and load current variations due to the various operating conditions. This situation is faced by adaptive protection development, as proposed in this study, where variations among active distribution network operating conditions are considered to estimate the adaptive pickup current. This is used to estimate the overcurrent relay’s time dial setting, avoiding miscoordination. The proposed protection approach uses fast calculations and local measurements; consequently, a low computational burden is required to update the adaptive relay parameters for each operating condition without using communication infrastructure. The obtained results in the IEEE 34-nodes test feeder demonstrate the advantages of the proposed approach, accomplishing the coordinating time interval for phase and ground faults. These results show a high performance of primary and backup protection at different operating conditions of the proposed test system compared to the performance of the conventional protection approach. The proposed approach’s high performance, low computational burden, and communicationless characteristics make it suitable for immediate real-field implementation.
Study on Impact of Various Void Conditions on Shallow Rectangular Masonry-Concrete Power Tunnel and Surrounding Roads
Authors: Tian Gang , Jin Chunfeng , Zhang Haijun , Shi Hai , Du Yanqing , Qi Yanli , Bai Mingzhou
Published: April 2023

To solve the problem of a potential void near a shallow rectangular masonry-concrete power tunnel, the ground-penetrating radar (GPR) detection technology is used and multiple GPR detection lines are placed to detect concealed void. The GPR images of circular and square voids are obtained, which can help increase accuracy of void identification. The models that cover 9 circular voids and 9 square voids are created to investigate how various forms and positions of void will affect the internal forces of the power tunnel structure and surrounding roads. In terms of morphological characteristics, according to the research results, the impact of a circular void on tunnel and surrounding roads is slightly stronger than that of a square void. If the circular void and square void are at 135° and 115°, respectively, the maximum shear force of the tunnel structure occurs at the floor. If both circular and square voids are at 115°, the maximum axial force of tunnel structure occurs at the right side wall. If both circular and square voids are at 135°, the maximum bending moment of tunnel structure occurs at the floor. If both circular and square voids are at 155°, the ground settlement and pavement stress of surrounding roads are maximized. Generally, if a void occurs at the middle or lower part of the side wall or near the side of the floor in a shallow rectangular masonry-concrete power tunnel, its adverse impact is at its worst. Therefore, GPR detection of the voids at the lower and middle parts and the side of the floor in the power tunnel should be intensified, in order to eliminate the risk of a void near power tunnel.
Predicting of Ki-67 Expression Level Using Diffusion-Weighted and Synthetic Magnetic Resonance Imaging in Invasive Ductal Breast Cancer
Authors: Zhang Liying , Hao Jisen , Guo Jia , Zhao Xin , Yin Xing
Published: April 2023

Objectives. To investigate the association between quantitative parameters generated using synthetic magnetic resonance imaging (SyMRI) and diffusion-weighted imaging (DWI) and Ki-67 expression level in patients with invasive ductal breast cancer (IDC). Method. We retrospectively reviewed the records of patients with IDC who underwent SyMRI and DWI before treatment. Precontrast and postcontrast relaxation times (T1, longitudinal; T2, transverse), proton density (PD) parameters, and apparent diffusion coefficient (ADC) values were measured in breast lesions. Univariate and multivariate regression analyses were performed to screen for statistically significant variables to differentiate the high (≥30%) and low (<30%) Ki-67 expression groups. Their performance was evaluated by receiver operating characteristic (ROC) curve analysis. Results. We analyzed 97 patients. Multivariate regression analysis revealed that the high Ki-67 expression group (n = 57) had significantly higher parameters generated using SyMRI (pre-T1,

p
=
0.001

) and lower ADC values (

p
=
0.036

) compared with the low Ki-67 expression group (n = 40). Pre-T1 showed the best diagnostic performance for predicting the Ki-67 expression level in patients with invasive ductal breast cancer (areas under the ROC curve (AUC), 0.711; 95% confidence interval (CI), 0.609–0.813). Conclusions. Pre-T1 could be used to predict the pretreatment Ki-67 expression level in invasive ductal breast cancer.
Analytical Solution to a Third-Order Rational Difference Equation
Authors: Salas S. Alvaro H. , Cieza Altamirano Gilder , Sandoval Núñez Rafaél Artidoro
Published: April 2023

Inspired by some open conjectures in a rational dynamical system by G. Ladas and Palladino, in this paper, we consider the problem of solving a third-order difference equation. We comment the conjecture by Ladas. A third-order rational difference equation is solved analytically. The solution is compared with the solution to the linearized equation. We show that the solution to the linearized equation is not good, in general. The methods employed here may be used to solve other rational difference equations. The period of the solution is calculated. We illustrate the accuracy of the obtained solutions in concrete examples.
Figure S2 from TGFBI Production by Macrophages Contributes to an Immunosuppressive Microenvironment in Ovarian Cancer
Authors: Lecker Laura S.M. , Berlato Chiara , Maniati Eleni , Delaine-Smith Robin , Pearce Oliver M.T. , Heath Owen , Nichols Samuel J. , Trevisan Caterina , Novak Marian , McDermott Jacqueline , Brenton James D. , Cutillas Pedro R. , Rajeeve Vinothini , Hennino Ana , Drapkin Ronny , Loessner Daniela , Balkwill Frances R.
Published: April 2023

Effect of macrophages and FTSE and HGSOC cell lines co-culture on CD163 and CD206 expression
Figure S2 from Specific Activation of the CD271 Intracellular Domain in Combination with Chemotherapy or Targeted Therapy Inhibits Melanoma Progression
Authors: Saltari Annalisa , Dzung Andreas , Quadri Marika , Tiso Natascia , Facchinello Nicola , Hernández-Barranco Alberto , Garcia-Silva Susana , Nogués Laura , Stoffel Corinne Isabelle , Cheng Phil F. , Turko Patrick , Eichhoff Ossia M. , Truzzi Francesca , Marconi Alessandra , Pincelli Carlo , Peinado Héctor , Dummer Reinhard , Levesque Mitchell P.
Published: April 2023

AÎ²(25-35) + chemotherapy reduces viability and induces cell death of melanoma cells
Data from HBx-Induced HSPA8 Stimulates HBV Replication and Suppresses Ferroptosis to Support Liver Cancer Progression
Authors: Wang Yufei , Zhao Man , Zhao Lina , Geng Yu , Li Guanghao , Chen Lin , Yu Jingxuan , Yuan Hongfeng , Zhang Huihui , Yun Haolin , Yuan Ying , Wang Guowen , Feng Jinyan , Xu Liang , Wang Shuai , Hou Chunyu , Yang Guang , Zhang Ningning , Lu Wei , Zhang Xiaodong
Published: April 2023

Abstract
Hepatitis B virus (HBV) infection is a major driver of hepatocarcinogenesis. Ferroptosis is a type of iron-mediated cell death that can suppress liver transformation. Previous studies have linked HBV to ferroptosis in liver fibrosis and acute liver failure. However, whether ferroptosis is involved in HBV-mediated liver cancer is poorly understood. Here, we identified heat shock protein family A member 8 (HSPA8) as a crucial host factor that modulates HBV replication and ferroptosis in liver cancer. Hepatitis B X protein (HBx) upregulated HSPA8 by coactivating the transcription factor heat shock factor 1 (HSF1) in cells. HSPA8 enhanced HBV replication by recruiting hepatitis B core protein (HBc) to the HBV covalently closed circular DNA (cccDNA) minichromosome, forming a positive feedback loop. Moreover, HSPA8 suppressed ferroptosis in liver cancer cells by upregulating the expression of SLC7A11/GPX4 and decreasing erastin-mediated reactive oxygen species and Fe2+ accumulation in cells in vitro and in vivo. Inhibition of HSPA8 reduced the growth of HBV-positive liver tumors and increased sensitivity to erastin. In conclusion, HBx-elevated HSPA8 regulates both HBV replication and ferroptosis in liver cancer. Targeting HSPA8 could be a promising strategy for controlling HBV and hepatocarcinogenesis.
Significance:
HBV-induced upregulation of HSPA8 promotes hepatocarcinogenesis by suppressing ferroptosis and stimulating HBV replication, identifying HSPA8 as a potential therapeutic target in liver cancer.
Data from Mutated HRAS Activates YAP1–AXL Signaling to Drive Metastasis of Head and Neck Cancer
Authors: Jagadeeshan Sankar , Prasad Manu , Badarni Mai , Ben-Lulu Talal , Liju Vijayasteltar Belsamma , Mathukkada Sooraj , Saunders Claire , Shnerb Avital Beeri , Zorea Jonathan , Yegodayev Ksenia M. , Wainer Monica , Vtorov Liza , Allon Irit , Cohen Ofir , Gausdal Gro , Friedmann-Morvinski Dinorah , Cheong Sok Ching , Ho Alan L. , Rosenberg Ari J. , Kessler Linda , Burrows Francis , Kong Dexin , Grandis Jennifer R. , Gutkind J. Silvio , Elkabets Moshe
Published: April 2023

Abstract
The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.
Significance:
Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1–AXL axis and to stimulate lymphovascular angiogenesis.
Data from A PLCB1–PI3K–AKT Signaling Axis Activates EMT to Promote Cholangiocarcinoma Progression
Authors: Liang Shuhang , Guo Hongrui , Ma Kun , Li Xianying , Wu Dehai , Wang Yiqi , Wang Wei , Zhang Shugeng , Cui Yifeng , Liu Yufeng , Sun Linmao , Zhang Bo , Xin Mengyang , Zhang Ning , Zhou Huanran , Liu Yao , Wang Jiabei , Liu Lianxin
Published: April 2023

Abstract
As a member of the phospholipase family, phospholipase C beta 1 (PLCB1) is involved in phospholipid hydrolysis and is frequently upregulated in human cancer. However, little is known about the role of PLCB1 in cholangiocarcinoma (CCA). In this study, we uncover a role for PLCB1 in CCA progression and identify the underlying mechanisms. Both human CCA tissues and CCA cell lines expressed high levels of PLCB1. PLCB1 promoted tumor development and growth in various CCA mouse models, including transposon-based tumorigenesis models. PLCB1 activated PI3K/AKT signaling to induce CCA cells to undergo epithelial-to-mesenchymal transition (EMT). Mechanistically, PABPC1 interacted with PLCB1 and PI3K to amplify PLCB1-mediated EMT via PI3K/AKT/GSK3β/Snail signaling. Ectopic PLCB1 induced resistance to treatment with gemcitabine combined with cisplatin, which could be reversed by the AKT inhibitor MK2206. PLCB1 expression was regulated by miR-26b-5p through direct interaction with PLCB1 3′UTR. Collectively, these data identify a PLCB1–PI3K–AKT signaling axis vital for CCA development and EMT, suggesting that AKT can be used as a therapeutic target to overcome chemotherapy resistance in CCA patients with high PLCB1 expression.
Significance:
PLCB1 functions as an oncogenic driver in cholangiocarcinoma development that confers an actionable therapeutic vulnerability to AKT inhibition.
Data from Specific Activation of the CD271 Intracellular Domain in Combination with Chemotherapy or Targeted Therapy Inhibits Melanoma Progression
Authors: Saltari Annalisa , Dzung Andreas , Quadri Marika , Tiso Natascia , Facchinello Nicola , Hernández-Barranco Alberto , Garcia-Silva Susana , Nogués Laura , Stoffel Corinne Isabelle , Cheng Phil F. , Turko Patrick , Eichhoff Ossia M. , Truzzi Francesca , Marconi Alessandra , Pincelli Carlo , Peinado Héctor , Dummer Reinhard , Levesque Mitchell P.
Published: April 2023

Abstract
CD271 (NGFR) is a neurotrophin receptor that belongs to the tumor necrosis receptor (TNFR) family. Upon ligand binding, CD271 can mediate either survival or cell death. Although the role of CD271 as a marker of tumor-initiating cells is still a matter of debate, its role in melanoma progression has been well documented. Moreover, CD271 has been shown to be upregulated after exposure to both chemotherapy and targeted therapy. In this study, we demonstrate that activation of CD271 by a short β-amyloid–derived peptide (Aβ(25–35)) in combination with either chemotherapy or MAPK inhibitors induces apoptosis in 2D and 3D cultures of eight melanoma cell lines. This combinatorial treatment significantly reduced metastasis in a zebrafish xenograft model and led to significantly decreased tumor volume in mice. Administration of Aβ(25–35) in ex vivo tumors from immunotherapy- and targeted therapy–resistant patients significantly reduced proliferation of melanoma cells, showing that activation of CD271 can overcome drug resistance. Aβ(25–35) was specific to CD271-expressing cells and induced CD271 cleavage and phosphorylation of JNK (pJNK). The direct protein–protein interaction of pJNK with CD271 led to PARP1 cleavage, p53 and caspase activation, and pJNK-dependent cell death. Aβ(25–35) also mediated mitochondrial reactive oxygen species (mROS) accumulation, which induced CD271 overexpression. Finally, CD271 upregulation inhibited mROS production, revealing the presence of a negative feedback loop in mROS regulation. These results indicate that targeting CD271 can activate cell death pathways to inhibit melanoma progression and potentially overcome resistance to targeted therapy.
Significance:
The discovery of a means to specifically activate the CD271 death domain reveals unknown pathways mediated by the receptor and highlights new treatment possibilities for melanoma.
Supplementary Figure 2 from Inactivation of Mirk/Dyrk1b Kinase Targets Quiescent Pancreatic Cancer Cells
Authors: Ewton Daina Z. , Hu Jing , Vilenchik Maria , Deng Xiaobing , Luk Kin-chun , Polonskaia Ann , Hoffman Ann F. , Zipf Karen , Boylan John F. , Friedman Eileen A.
Published: April 2023

PDF file - 1.2MB
Supplementary Figure S4 from TLR4 Is a Novel Determinant of the Response to Paclitaxel in Breast Cancer
Authors: Rajput Sandeep , Volk-Draper Lisa D. , Ran Sophia
Published: April 2023

Supplementary Figure S4 - PDF file 314K, TLR4 knockdown increases G2/M cell cycle arrest in breast cancer cells
Supplementary Table 1 from Maytansine and Cellular Metabolites of Antibody-Maytansinoid Conjugates Strongly Suppress Microtubule Dynamics by Binding to Microtubules
Authors: Lopus Manu , Oroudjev Emin , Wilson Leslie , Wilhelm Sharon , Widdison Wayne , Chari Ravi , Jordan Mary Ann
Published: April 2023

Supplementary Table 1 from Maytansine and Cellular Metabolites of Antibody-Maytansinoid Conjugates Strongly Suppress Microtubule Dynamics by Binding to Microtubules
Supplementary Materials and Methods, Figures 1 - 2, Table 1 from Effect of Small-Molecule Modification on Single-Cell Pharmacokinetics of PARP Inhibitors
Authors: Thurber Greg M. , Reiner Thomas , Yang Katherine S. , Kohler Rainer H. , Weissleder Ralph
Published: April 2023

PDF file - 401KB, Supplemental file containing a mathematical model description, Figure S1 showing the modeling approach, Table S1 with model parameters, and Figure S2 graphing cellular clearance.
Supplementary Figure Legend from Inhibition of Tumor Growth and Angiogenesis by SP-2, an Anti–Lectin, Galactoside-Binding Soluble 3 Binding Protein (LGALS3BP) Antibody
Authors: Traini Sara , Piccolo Enza , Tinari Nicola , Rossi Cosmo , La Sorda Rossana , Spinella Francesca , Bagnato Anna , Lattanzio Rossano , D'Egidio Maurizia , Di Risio Annalisa , Tomao Federica , Grassadonia Antonino , Piantelli Mauro , Natoli Clara , Iacobelli Stefano
Published: April 2023

PDF file - 67KB
Supplementary Figure 4 from 1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling
Authors: Chen Ping-Tsung , Hsieh Ching-Chuan , Wu Chun-Te , Yen Tzu-Chen , Lin Paul-Yang , Chen Wen-Cheng , Chen Miao-Fen
Published: April 2023

Supplementary Figure 4. Effects of Calcitriol on IL-6/STAT3 signaling in esophageal SCC
Supplementary Methods from Phosphoproteomics of MAPK Inhibition in BRAF-Mutated Cells and a Role for the Lethal Synergism of Dual BRAF and CK2 Inhibition
Authors: Parker Robert , Clifton-Bligh Roderick , Molloy Mark P.
Published: April 2023

PDF file - 89K
Supplementary Figure 3 from Phosphoproteomics of MAPK Inhibition in BRAF-Mutated Cells and a Role for the Lethal Synergism of Dual BRAF and CK2 Inhibition
Authors: Parker Robert , Clifton-Bligh Roderick , Molloy Mark P.
Published: April 2023

PDF file - 207K, Response to combinatorial Vandetanib/CK2 inhibition in TPC1 thyroid cell line.
Supplementary Methods, Figures 1 - 10, Table 1 from Dual Targeting of Integrin αvβ3 and Matrix Metalloproteinase-2 for Optical Imaging of Tumors and Chemotherapeutic Delivery
Authors: Crisp Jessica L. , Savariar Elamprakash N. , Glasgow Heather L. , Ellies Lesley G. , Whitney Michael A. , Tsien Roger Y.
Published: April 2023

PDF file - 5319K, Supplementary Materials and Methods. Supplemental Table 1: List of peptides and synthetic intermediates with corresponding molecular weights. Supplemental Figure 1: Chemical Structure of dual targeted peptides. Supplemental Figure 2: Gel images for MMP-2 cleavage assay. Supplemental Figure 3: Peptide SUVs (MDA-MB-231 tumors). Supplemental Figure 4: Injection of cyclic-RGD-PLGC(Me)AG-ACPP with excess of unlabeled cyclic-RGD. Supplemental Figure 5: Dual targeting of PLGC(Me)AG-ACPP with folate does not improve tumor uptake in SK-OV-3 tumors. Supplemental Figure 6: No primary antibody control for IHC. Supplemental Figure 7: Plasma stability and blood clearance of cyclic-RGDPLGC(Me)AG-ACPP. Supplemental Figure 8: Tumor growth curve corresponding to Figure 5B and animal body weights corresponding to Figure 5 B&C. Supplemental Figure 9: Animal body weight and tumor growth curves for therapy studies at 1.2mg/kg (~40nmol) and 0.6mg/kg (~20nmol). Supplemental Figure 10: Targeting of MMAE in Py230 syngeneic tumor model.
Supplementary Figure Legend from Downregulation of Hepatoma-Derived Growth Factor Contributes to Retarded Lung Metastasis via Inhibition of Epithelial–Mesenchymal Transition by Systemic POMC Gene Delivery in Melanoma
Authors: Tsai Han-En , Liu Guei-Sheung , Kung Mei-Lang , Liu Li-Feng , Wu Jian-Ching , Tang Chia-Hua , Huang Ching-Hui , Chen San-Cher , Lam Hing-Chung , Wu Chieh-Shan , Tai Ming-Hong
Published: April 2023

PDF file - 26K
Supplementary Figure Legend from Combined Targeting of mTOR and AKT Is an Effective Strategy for Basal-like Breast Cancer in Patient-Derived Xenograft Models
Authors: Xu Siguang , Li Shunqiang , Guo Zhanfang , Luo Jingqin , Ellis Matthew J. , Ma Cynthia X.
Published: April 2023

PDF file - 6K
Supplementary Figure 8 from Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways
Authors: Basu Dipanjan , Lettan Robert , Damodaran Krishnan , Strellec Susan , Reyes-Mugica Miguel , Rebbaa Abdelhadi
Published: April 2023

PDF - 253K, Effect of degradation refractory TAZ on activity of the Hippo reporter, autophagy and cell migration.
Supplementary Figure Legend from Identification and Characterization of a Small-Molecule Inhibitor of Wnt Signaling in Glioblastoma Cells
Authors: De Robertis Alessandra , Valensin Silvia , Rossi Marco , Tunici Patrizia , Verani Margherita , De Rosa Antonella , Giordano Cinzia , Varrone Maurizio , Nencini Arianna , Pratelli Carmela , Benicchi Tiziana , Bakker Annette , Hill Jeffrey , Sangthongpitag Kanda , Pendharkar Vishal , Liu Boping , Mee Ng Fui , Wen Then Siew , Jing Tai Shi , Cheong Seong-Moon , He Xi , Caricasole Andrea , Salerno Massimiliano
Published: April 2023

PDF file - 81K
Supplementary Figure S2 from Selective Delivery of PEGylated Compounds to Tumor Cells by Anti-PEG Hybrid Antibodies
Authors: Tung Hsin-Yi , Su Yu-Cheng , Chen Bing-Mae , Burnouf Pierre-Alain , Huang Wei-Chiao , Chuang Kuo-Hsiang , Yan Yu-Ting , Cheng Tian-Lu , Roffler Steve R.
Published: April 2023

Comparison of the binding of mouse anti-PEG antibodies to different PEG molecules.
Supplementary Data from p53 Pathway Inactivation Drives SMARCB1-deficient p53-wildtype Epithelioid Sarcoma Onset Indicating Therapeutic Vulnerability Through MDM2 Inhibition
Authors: Oppel Felix , Shao Senyao , Gendreizig Sarah , Zimmerman Mark W. , Schürmann Matthias , Flavian Viyof Ful , Goon Peter , Chi Susan N. , Aster Jon C. , Sudhoff Holger , Look A. Thomas
Published: April 2023

Supplementary Data from p53 Pathway Inactivation Drives SMARCB1-deficient p53-wildtype Epithelioid Sarcoma Onset Indicating Therapeutic Vulnerability Through MDM2 Inhibition
BET Inhibition Sensitizes Immunologically Cold Rb-Deficient Prostate Cancer to Immune Checkpoint Blockade
Authors: Olson Brian M. , Chaudagar Kiranj , Bao Riyue , Saha Sweta Sharma , Hong Christina , Li Marguerite , Rameshbabu Srikrishnan , Chen Raymond , Thomas Alison , Patnaik Akash
Published: April 2023

Non–T-cell–inflamed immunologically “cold” tumor microenvironments (TME) are associated with poor responsiveness to immune checkpoint blockade (ICB) and can be sculpted by tumor cell genomics. Here, we evaluated how retinoblastoma (Rb) tumor-suppressor loss-of-function (LOF), one of the most frequent alterations in human cancer and associated with lineage plasticity, poor prognosis, and therapeutic outcomes, alters the TME, and whether therapeutic strategies targeting the molecular consequences of Rb loss enhance ICB efficacy. We performed bioinformatics analysis to elucidate the impact of endogenous Rb LOF on the immune TME in human primary and metastatic tumors. Next, we used isogenic murine models of Rb-deficient prostate cancer for in vitro and in vivo mechanistic studies to examine how Rb loss and bromodomain and extraterminal (BET) domain inhibition (BETi) reprograms the immune landscape, and evaluated in vivo therapeutic efficacy of BETi, singly and in combination with ICB and androgen deprivation therapy. Rb loss was enriched in non–T-cell–inflamed tumors, and Rb-deficient murine tumors demonstrated decreased immune infiltration in vivo. The BETi JQ1 increased immune infiltration into the TME through enhanced tumor cell STING/NF-κB activation and type I IFN signaling within tumor cells, resulting in differential macrophage and T-cell–mediated tumor growth inhibition and sensitization of Rb-deficient prostate cancer to ICB. BETi can reprogram the immunologically cold Rb-deficient TME via STING/NF-κB/IFN signaling to sensitize Rb-deficient prostate cancer to ICB. These data provide the mechanistic rationale to test combinations of BETi and ICB in clinical trials of Rb-deficient prostate cancer.
Abstract 4066: Lipid nanoparticle library towards development next generation genomic medicines
Authors: Thomas Anitha , Jain Nikita , Nazaripour Sedigheh , Higgins Rehan , Chen Zhengyu , Abraham Suraj , Yee Leanna , Abbina Srinivas , Namala Gayatri Mehar , Son Helena , Sadat Sams , Chemmannur Sijo , Anantha Malathi , Sharma Ruchi , Tickner Kobe , Boyer Eve , Tsai Shannon , Thambatti Seetalakshmi , Mayya Vinay , Soon Emily , Paquette Jay
Published: April 2023

Ionizable amino lipids are a major constituent of the lipid nanoparticles for delivering nucleic acid therapeutics (e.g., DLin-MC3-DMA in ONPATTRO®, ALC-0315 in Comirnaty®, SM-102 in Spikevax®). Scarcity of lipids that are suitable for cell therapy, vaccination, and gene therapies continue to be a problem in advancing many potential diagnostic/therapeutic/vaccine candidates to the clinic.

Herein, we describe the development of novel ionizable lipids to be used as functional excipients for designing vehicles for nucleic acid therapeutics/vaccines in vivo or ex vivo use in cell therapy applications. We first studied the transfection efficiency (TE) of LNP-based mRNA formulations of these ionizable lipid candidates in primary human T cells and established a workflow for engineering of primary immune T cells. We then adapted this workflow towards bioengineering of CAR constructs to T cells towards non-viral CAR T therapy. Lipids were also tested in rodents for vaccine applications using self-amplifying RNA (saRNA) encoding various antigens. We have then evaluated various ionizable lipid candidates and their biodistribution along with the mRNA/DNA translation exploration using various LNP compositions. Further, using ionizable lipids from the library, we have shown gene editing of various targets in rodents.

We believe that these studies will pave the path to the advancement in nucleic acid based therapeutics and vaccines, or cell & gene therapy agents for early diagnosis and detection of cancer, and for targeted genomic medicines towards cancer treatment and diagnosis.

Citation Format: Anitha Thomas, Nikita Jain, Sedigheh Nazaripour, Rehan Higgins, Zhengyu Chen, Suraj Abraham, Leanna Yee, Srinivas Abbina, Gayatri Mehar Namala, Helena Son, Sams Sadat, Sijo Chemmannur, Malathi Anantha, Ruchi Sharma, Kobe Tickner, Eve Boyer, Shannon Tsai, Seetalakshmi Thambatti, Vinay Mayya, Emily Soon, Jay Paquette. Lipid nanoparticle library towards development next generation genomic medicines. [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 4066.
Abstract 4086: Mitigating the CD5 CAR-CD5 interaction enhances the functionality of CD5 CAR-T cells by alleviating the T-cell fratricide
Authors: Ho Lee Young , Yu Seung Rok , Jeong Jeong Hoon , Lee Hyeong Ji , Cho Hyeon Jeong , Kim Hyung Cheol
Published: April 2023

Chimeric antigen receptor (CAR) T-cell therapy has been used with unprecedented clinical responses in relapsed/refractory B-ALL or B-NHL, MM patients. However, CAR-T therapy has not yet been proven effective in other hematological malignancies, such as T cell lymphoma and leukemia (T-NHL/T-ALL) and acute myeloid leukemia (AML). Developing CAR-T cells for patients with T-cell malignancies remains challenging as most CARs targeting T-lineage antigens, such as CD5, CD7, and CD3, target themselves, potentially resulting in fratricide of CAR-T cells. Thus, there is a need for technical approaches to alleviate the fratricide of CAR-T to treat T-cell malignancies successfully. As part of the approach, we studied whether the affinity of CAR and cognate antigen expression of CAR-T cells influence the intensity of CAR-T`s fratricide and hypothesized that if a single chain Fragment variable (scFv) with a low intensity of fratricide is applied to T-lineage antigen-downregulated CAR-T cells, the effector function of CAR-T cell targeting T cell antigen can be maximized. For this, we screened full human scFvs targeting CD5, a pan T-cell marker, tested the affinity of scFvs for CD5 antigen, and generated anti-CD5 CAR-T cells (CAR5). We evaluated the intensity of in vitro fratricide in CAR5 based on cell expansion and cytokine secretion in vitro and tested their anti-tumor activity in a CD5+ T-ALL xenograft model (Jurkat). In addition, to minimize CAR recognition to a cognate antigen expressed in CAR-T cells, we also generated CD5-downregulated CAR5s (CD5-KD CAR5) using a short hairpin RNA cassette integrated into an anti-CD5 CAR vector to test if the downregulation of CD5 in CAR5s can reduce the fratricide. We found that a CAR5 clone (C7CAR5) with the lowest level of fratricide in vitro, showed superior anti-tumor activity compared to other CAR5s in vivo and that CD5-downregulated C7 CAR5 (CD5-KD C7CAR5) further reduced the fratricide, maximizing the anti-tumor activity. In conclusion, we demonstrate that high-affinity CAR may not always show superior functionality in T cell malignancy CAR-T therapy, explaining one or more strategies to alleviate the fratricide are required. These studies provide the foundation for developing CD5 CART products to treat relapsed T-cell malignancies.

Citation Format: Lee Young Ho, Seung Rok Yu, Jeong Hoon Jeong, Hyeong Ji Lee, Hyeon Jeong Cho, Hyung Cheol Kim. Mitigating the CD5 CAR-CD5 interaction enhances the functionality of CD5 CAR-T cells by alleviating the T-cell fratricide. [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 4086.
Abstract 4494: Multi-specific cMet x EGFR x VEGF antibody for difficult to treat cancers
Authors: Chiu Mark
Published: April 2023

Cancers such as TNBC, pancreatic, and gastric are difficult to treat due to diverse etiologies. Several subtypes of these cancers are driven by abnormal EGFR signaling, increased cMET activation, and VEGF linked angiogenesis which are responsible for tumor growth and metastasis. TAVO412, a humanized multi-specific antibody with two distinct anti-EGFR nanobody domains, an anti-cMet Fab arm, and an anti-VEGF ScFv domain, was designed to treat patients with these unmet medical needs. In addition, the Fc domain allows for the heterodimerization, antibody-like pharmacokinetic profile, and additional mutations that enhance the Fc effector functional activity. In preclinical xenograft models, TAVO412 demonstrated strong tumor growth inhibition effects on TNBC, PDAC, GC or NSCLC cell line-derived tumors. The mechanisms of action included selective and potent binding to EGFR, cMet, and VEGF at lower pH values found in the solid tumor environment; effective blocking of EGFR and cMet pathways that drove cancer cell growth and proliferation; shutdown of VEGF mediated angiogenesis; and potent and efficacious Fc effector function that enhanced ADCC, ADCP, and CDC. TAVO412 had better TGI than analogous molecules. TAVO412 also demonstrated strong tumor growth inhibition against NSCLC patient derived xenograft (PDX) models with mutant EGFR and cMet genotypes. Each of the binding arms had cross reactivity with the cynomolgus monkey orthologues allowing the cyno model to be a relevant toxicology model. In the pivotal GLP toxicology study in cynomolgus monkeys, TAVO412 was well tolerated, had no major organ toxicities, observations were mostly consistent with EGFR-related effects and recoverable. In conclusion, TAVO412 was successfully discovered and developed for hard-to-treat solid tumors. This drug is expected to be safe and efficacious in cancer patients. The IND application was approved by the US FDA in October 2022. A first-in-human, 2-Part Phase 1 study to examine the preliminary efficacy, safety, tolerability, pharmacokinetic/pharmacodynamic parameters; maximum tolerated dose/recommended phase 2 dose of TAVO412 will be starting in the first quarter of 2023.

Citation Format: Mark Chiu. Multi-specific cMet x EGFR x VEGF antibody for difficult to treat cancers. [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 4494.
Abstract 4724: Single cell multiomic profiling of high-grade serous carcinoma
Authors: Sandoval Leticia Assad Maia , Ismail Wazim Mohammed , Mazzone Amelia , Munankarmy Amik , Kaur Jagneet , Tashi Tsering , Hou Xiaonan , Kannan Nagarajan , Oberg Ann , Kaufmann Scott H. , Weroha Saravut John , Gaspar-Maia Alexandre
Published: April 2023

Ovarian cancer is one of the most common gynecologic malignancies, with high-grade serous carcinoma (HGSC) as the most frequent and deadliest type of ovarian cancer (OC). With the recent advances in cancer epigenomic profiling, it has become clear that intra-tumor heterogeneity driven by genetic and epigenetic factors may be the basis of resistance, where current treatments could efficiently target sub-populations of cells while a sub-group may be resistant, or prone to develop resistance. With epigenomic profiling and single cell sequencing technology, we aim to characterize cell signatures that translate as prognostic markers and novel drug targets. We have mapped the epigenomic landscape of HGSC in 12 patient-derived xenografts (PDX), and their metastatic counterparts (circulating tumor cells and ascites present in the PDX models) using an assay for transposase-accessible chromatin (or ATAC-seq) and compared it with normal fallopian tube organoids to identify tumor and metastatic-specific regulatory elements. We also performed RNA-seq to validate potential transcriptional dependencies associated with resistance to chemotherapy. In order to identify potentially chemotherapy-resistant subpopulations and further validate the activity of some of the transcription factors that can be driving resistance, we performed single cell multiomic profiling using the 10x Multiome sequencing platform (scRNA+scATAC from the same nuclei) in HGSC patient samples and PDX. Finally, we performed immunohistochemistry of patient tissue slides for target markers and correlated it with overall survival in OC patients. As previously suggested, a subset of cancer clonal cells can drive treatment resistance and metastasis and result in poor patient outcomes. Data derived from PDX ATAC-seq showed a cancer stem cell signature driven by SOX2 in metastatic samples compared to the paired PDX primary tumor, suggesting a role for SOX2 in disease progression. Interestingly, SOX2 expression in epithelial cells in the Multiome analysis is more patient-specific than other stem cell markers, like CD133. We also observed that SOX2 expression negatively correlated with prognosis. These data, taken together, point out the promising role of SOX2 as a prognostic and targetable marker for HGSC.

Citation Format: Leticia Assad Maia Sandoval, Wazim Mohammed Ismail, Amelia Mazzone, Amik Munankarmy, Jagneet Kaur, Tsering Tashi, Xiaonan Hou, Nagarajan Kannan, Ann Oberg, Scott H. Kaufmann, Saravut John Weroha, Alexandre Gaspar-Maia. Single cell multiomic profiling of high-grade serous carcinoma. [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 4724.
Abstract 7: AGS3 depletion promotes tumorigenesis in a murine model of lung cancer
Authors: Adekoya Timothy O. , Smith Nikia , Richardson Ricardo M.
Published: April 2023

Activator of G-protein Signaling 3 (AGS3/GPSM1) is a receptor independent activator of G-protein signaling that couples to Gα subunits of the heterotrimeric G-protein to mediate cellular functions. It was previously shown that AGS3 modulates prostate tumor development. In this study we investigate the role of AGS3 in the onset of lung cancer. To that end, we used a murine model of Lung Lewis Carcinoma (LLC) in mice deficient in AGS3 expression (AGS3-/-) relative to wild-type animals (AGS3+/+). AGS3-/- mice exhibited a significant increase in LLC tumor growth relative to AGS3+/+ mice. Immunohistochemical analysis of the tumors also revealed a significant increase in microvessels density in AGS3-/- tumors. FACS analysis of tumor infiltrating leukocytes also showed a significant decrease in lymphocyte recruitment in AGS3-/- tumor microenvironment (TME) relative to AGS3+/+ mice. The decrease leukocytes recruitment in AGS3-/- xenografts correlated with a marked decrease in chemokines expression in the TME. Taken together, these results indicate that AGS3 modulates LLC tumor development and progression.

Citation Format: Timothy O. Adekoya, Nikia Smith, Ricardo M. Richardson. AGS3 depletion promotes tumorigenesis in a murine model of lung cancer [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 7.
Abstract 99: Apoptotic DNase DFFB mediates cancer persister cell mutagenesis and acquired drug resistance
Authors: Williams August Finley , Gervasio David , Turkal Claire , Stuhlfire Anna , Wang Michael , Mauch Brandon , West Ariel , Paw Michelle , Hairani Mehrshad , Lathrop Cooper , Harris Sophie , Page Jennifer , Hangauer Matthew
Published: April 2023

Tumors frequently acquire resistance to therapy resulting in disease relapse and patient mortality. Therapeutic approaches to overcome acquired resistance are hindered by limited treatment options and the presence of multiple parallel resistance mechanisms. Rather than treating resistance after it emerges, it may possible to prevent it by inhibiting the adaptive processes which initiate resistance. However, these processes and the genes which control them are poorly understood. Here we report that drug-tolerant cancer persister cells, which constitute residual disease and seed relapse, undergo drug stress-induced sublethal apoptotic signaling resulting in activation of apoptotic DNase DFFB without cell death. DFFB induces DNA damage and mutagenesis in persister cells, revealing DFFB as a key regulator of stress-induced mutagenesis in persister cells. Furthermore, we found in multiple tumor types that DFFB is required for acquired resistance to targeted therapies. Mechanistically, DFFB induces multiple putative resistance mutations and may also promote epigenetic changes which result in resistance. These results reveal DFFB as a promising potential therapeutic target to prevent acquired resistance. In addition, this stress-sensing mutagenic mechanism may promote mutagenesis in other contexts including normal tissues because sublethal apoptotic signaling may result from a variety of physiological stresses.

Citation Format: August Finley Williams, David Gervasio, Claire Turkal, Anna Stuhlfire, Michael Wang, Brandon Mauch, Ariel West, Michelle Paw, Mehrshad Hairani, Cooper Lathrop, Sophie Harris, Jennifer Page, Matthew Hangauer. Apoptotic DNase DFFB mediates cancer persister cell mutagenesis and acquired drug 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 99.
Supplemental Figures from PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions
Authors: Wang Jin , Xie Tongxin , Wang Bingbing , William William N. , Heymach John V. , El-Naggar Adel K. , Myers Jeffrey N. , Caulin Carlos
Published: April 2023

SupplementaryFigureS1. Quantification of the immunohistochemistry shown in Figure 3A. The graphs represent comparative analyses of the staining for the indicated proteins between low-and high-grade lesions in the control and anti-PD1 treatment groups. Supplementary Figure S2. Quantification of the immunohistochemistry shown in Figure 3B. The graphs represent comparative analyses of the staining for the indicated proteins between low-and high-grade lesions in the control and anti-PD1 treatment groups. Supplementary Figure S3. Quantification o fthe (A-C) immunohistochemistry and (D) TUNEL assay shown in Figure 4.
Supplementary Tables 1-6 from Circulating RANKL and RANKL/OPG and Breast Cancer Risk by ER and PR Subtype: Results from the EPIC Cohort
Authors: Sarink Danja , Schock Helena , Johnson Theron , Overvad Kim , Holm Marianne , Tjønneland Anne , Boutron-Ruault Marie-Christine , His Mathilde , Kvaskoff Marina , Boeing Heiner , Lagiou Pagona , Papatesta Eleni-Maria , Trichopoulou Antonia , Palli Domenico , Pala Valeria , Mattiello Amalia , Tumino Rosario , Sacerdote Carlotta , Bueno-de-Mesquita H.B(as). , van Gils Carla H. , Peeters Petra H. , Weiderpass Elisabete , Agudo Antonio , Sánchez Maria-José , Chirlaque Maria-Dolores , Ardanaz Eva , Amiano Pilar , Khaw Kay Tee , Travis Ruth , Dossus Laure , Gunter Mark , Rinaldi Sabina , Merritt Melissa , Riboli Elio , Kaaks Rudolf , Fortner Renée T.
Published: April 2023

Supplementary table 1. Correlations of sRANKL and the sRANKL/OPG ratio with select hormones among controls: EPIC cohort nested case-control study. Supplementary table 2. Distribution of covariates by quintiles of sRANKL. Supplementary table 3. Circulating concentrations of sRANKL and breast cancer risk by hormone-receptor subtype and menopausal status at blood collection. Supplementary table 4. The sRANKL/OPG ratio and breast cancer risk by hormone-receptor subtype and menopausal status at blood collection. Supplementary table 5. sRANKL additionally adjusted for continuous (log2) OPG and breast cancer risk by hormone-receptor subtype: EPIC nested case-control study. Supplementary table 6. sRANKL/OPG cross-classification based on median split of sRANKL and OPG and breast cancer risk by hormone-receptor subtype: EPIC nested case-control study.
Supplemental Materials from Sex-Specific Association between Family History of Diabetes and Risk of Colorectal Cancer: Two Prospective Cohort Studies
Authors: Ma Wenjie , Song Mingyang , Kværner Ane Sørlie , Prescott Jennifer , Chan Andrew , Giovannucci Edward , Zhang Xuehong
Published: April 2023

Supplemental Methods
Supplementary Figure from Analgesic Use and Circulating Estrogens, Androgens, and Their Metabolites in the Women's Health Initiative Observational Study
Authors: Hurwitz Lauren M. , Shadyab Aladdin H. , Tabung Fred K. , Anderson Garnet L. , Saquib Nazmus , Wallace Robert B. , Wild Robert A. , Pfeiffer Ruth M. , Xu Xia , Trabert Britton
Published: April 2023

Supplementary Figure from Analgesic Use and Circulating Estrogens, Androgens, and Their Metabolites in the Women's Health Initiative Observational Study
Figure S1 from Simultaneous Measurement of 92 Serum Protein Biomarkers for the Development of a Multiprotein Classifier for Ovarian Cancer Detection
Authors: Skubitz Amy P.N. , Boylan Kristin L.M. , Geschwind Kate , Cao Qing , Starr Timothy K. , Geller Melissa A. , Celestino Joseph , Bast Robert C. , Lu Karen H. , Koopmeiners Joseph S.
Published: April 2023

Supplemental Figure S1
Supplementary Figure Legends from Baseline Oral Microbiome and All-cancer Incidence in a Cohort of Nonsmoking Mexican American Women
Authors: Zhang Xiaotao , Hoffman Kristi L. , Wei Peng , Elhor Gbito Kplola Y. , Joseph Reji , Li Fangyu , Scheet Paul , Chang Shine , Petrosino Joseph F. , Daniel Carrie R.
Published: April 2023

Legends for supplemental figures
Supplemental Figures from Vitamin D Signaling Suppresses Early Prostate Carcinogenesis in TgAPT121 Mice
Authors: Fleet James C. , Kovalenko Pavlo L. , Li Yan , Smolinski Justin , Spees Colleen , Yu Jun-Ge , Thomas-Ahner Jennifer M. , Cui Min , Neme Antonio , Carlberg Carsten , Clinton Steven K.
Published: April 2023

Figures 1S and 2S