bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond Fidelity: Explaining Vulnerability Localization of Learning-Based Detectors
Authors: Cheng Baijun , Zhao Shengming , Wang Kailong , Wang Meizhen , Bai Guangdong , Feng Ruitao , Guo Yao , Ma Lei , Wang Haoyu
Published: February 2024

Vulnerability detectors based on deep learning (DL) models have proven their effectiveness in recent years. However, the shroud of opacity surrounding the decision-making process of these detectors makes it difficult for security analysts to comprehend. To address this, various explanation approaches have been proposed to explain the predictions by highlighting important features, which have been demonstrated effective in domains such as computer vision and natural language processing. Unfortunately, there is still a lack of in-depth evaluation of vulnerability-critical features, such as fine-grained vulnerability-related code lines, learned and understood by these explanation approaches. In this study, we first evaluate the performance of ten explanation approaches for vulnerability detectors based on graph and sequence representations, measured by two quantitative metrics including fidelity and vulnerability line coverage rate. Our results show that fidelity alone is insufficent for evaluating these approaches, as fidelity incurs significant fluctuations across different datasets and detectors. We subsequently check the precision of the vulnerability-related code lines reported by the explanation approaches, and find poor accuracy in this task among all of them. This can be attributed to the inefficiency of explainers in selecting important features and the presence of irrelevant artifacts learned by DL-based detectors.
Activation of farnesoid X receptor retards expansion of renal collecting duct cell-derived cysts via inhibition of CFTR-mediated Cl– secretion
Authors: Srimai Nipitpon , Tonum Kanlayanee , Soodvilai Sunhapas
Published: February 2024

The present study reveals that farnesoid X receptor (FXR) activation reduces microcyst formation and enlargement. This inhibitory effect of FXR activation is involved with decreased cell proliferation and cystic fibrosis transmembrane conductance regulator-mediated Cl– secretion in renal collecting duct cells. FXR might represent a novel target for the treatment of autosomal dominant polycystic kidney disease.
Impact of Transcranial Direct Current Stimulation in Pain, Fatigue, and Health Quality of Life of Patients with Idiopathic Inflammatory Myopathies: A Randomized, Double-Blind, Sham-Controlled Crossover Clinical Trial
Authors: Missé Rafael Giovani , dos Santos Alexandre Moura , Borges Isabela Bruna Pires , Grecco Marcus Vinicius , Faria Marlise Sítima Mendes Simões , da Silva Lorenza Rosa Silvério , Correia Bruna Lindoso , Kim Ana Woo Sook , Tanaka Clarice , Greve Júlia Maria D’Andrea , Baptista Abrahão Fontes , Shinjo Samuel Katsuyuki
Published: February 2024

Objectives. To assess the effectiveness of transcranial direct current stimulation (tDCS) for pain, fatigue, physical function, and health-related quality of life in patients with idiopathic inflammatory myopathy (IIM). Methods. This randomized, double-blind, sham-controlled, crossover clinical trial enrolled IIM patients with fatigue and pain who received tDCS (20 min, 2 mA) or sham stimulation for 10 daily sessions. Electrodes were placed according to the 10/20 EEG system. Both the groups underwent aerobic exercise training during the intervention period. The patients were evaluated for disease perception, pain, and fatigue using uni-multidimensional questionnaires and physical tests in the periods before and after the first and second interventions and after 12 weeks of follow-up. Results. After the tDCS intervention, a reduction in the general score of multidimensional pain of 32.0 (1.5-38.0) vs. 0.0 (0.0-13.4) with effect size (ES) of -0.78 was noted, and after sham intervention, a reduction of 26.0 (0.0-37.0) vs. 5.0 (0.0-19.2) with ES of -0.54 (P=0.047) was also noted. Similar results were evidenced with fatigue (22.5 (15.4-33.2) vs. 5.5 (0.0-14.6) with ES of -0.82) and sham intervention (21.0 (15.8-29.5) vs. 4.0 (4.0-17.5) with ES of -0.80 (P=0.012)). There were no differences in the domains of the fatigue and pain questionnaires. Adherence was observed in 88.8% of the patients without adverse events. Conclusion. The association of tDCS with aerobic training promoted additional effects in relation to the group subjected to placebo stimulation on general pain and fatigue scores, as well as on pain intensity, without changes in the subdomains of the pain and fatigue questionnaire. This trial is registered with NCT04678635.
Molecular Epidemiology of Escherichia coli Resistant to Carbapenems, Fluoroquinolones, and Aminoglycosides Isolated from One of the Largest Hospitals in Vietnam in 2014–2019
Authors: Miyoshi-Akiyama Tohru , Thanh Do Van , Phuong Truong Thai , Huy Nguyen Quang , Thuy Pham Thi Phuong , Kirikae Teruo , Nhung Pham Hong , Ohmagari Norio
Published: February 2024

Introduction. Multidrug-resistant (MDR) Gram-negative bacilli including carbapenem-resistant Gram-negative Enterobacteriaceae (CRE) threaten global health. Little is known, however, about the distribution of antimicrobial resistance genes in MDR isolated from patients in Vietnamese hospitals. In this study, we collected MDR Escherichia coli, defined as E. coli resistance against all fluoroquinolones, aminoglycosides, and carbapenems. Aim. This study was designed to clarify the molecular epidemiology of Escherichia coli isolates resistant to carbapenems, fluoroquinolones, and aminoglycosides isolated from patients admitted to one of the largest hospitals in Vietnam in 2014–2019 based on both whole-genome sequencing (WGS) and phenotypic data. Methodology. Sixty-seven Vietnamese isolates screened by drug resistance by the disk test were subjected to WGS, and their sequences were analyzed to determine their multilocus sequence type (MLST), O-types, H-types, distribution of drug resistance genes, plasmid types, pathogenicity islands (PIs), virulence factor distribution, and phylogenetic evolution using the WGS data. Results. Among the STs detected, ST410 was relatively dominant. Dominant O-types and H-types were O102 and H9 and showed some links, such as those between O102 and H8. The most dominant plasmid type and carbapenemase type were 4 and NDM-5, respectively. MLST, O-types, H-types, plasmid types, and types of carbapenemases were very heterogeneous among the isolates, with no clear correlation between them. Dominant plasmid type carrying drug resistance gene was IncQ1_1. The percentage of isolates positive for drug resistance genes, such as anti-beta-lactams and aminoglycosides, was relatively high because the isolates screened were resistant to carbapenems, fluoroquinolones, and aminoglycosides. Conclusions. MDR E. coli isolates isolated at a high-volume Vietnamese hospital were very heterogeneous, suggesting that they were acquired from different sources, including nosocomial infection, animals, and water. Eradication of MDR E. coli from hospitals and other clinical environments is very challenging because a single measure may be ineffective.
A New Fast and Efficient MPPT Algorithm for Partially Shaded PV Systems Using a Hyperbolic Slime Mould Algorithm
Authors: Belmadani Hamza , Bradai Rafik , Kheldoun Aissa , Mohammed Karam Khairullah , Mekhilef Saad , Belkhier Youcef , Oubelaid Adel
Published: February 2024

The design of new efficient maximum power point tracking (MPPT) techniques has become extremely important due to the rapid expansion of photovoltaic (PV) systems. Because under shading conditions the characteristics of PV devices become multimodal having several power peaks, traditional MPPT techniques provide crappy performance. In turn, metaheuristic algorithms have become massively employed as a typical substitute in maximum power point tracking. In this work, a new optimizer, which was named the hyperbolic slime mould algorithm (HSMA), is designed to be employed as an efficient MPPT algorithm. The hyperbolic tangent function is incorporated into the optimizer framework equations to scale down large perturbations in the tracking stage and boost its convergence trend. Moreover, to provide a strong exploration capability, a new mechanism has been developed in such a way the search process is carried out inside the best two power peak regions along the initial iterations. This region inspection mechanism is the prime hallmark of the designed optimizer in avoiding local power peaks and excessive global search operations. The developed algorithm was examined through diverse complicated partial shading conditions to challenge its global and local search abilities. A comparative analysis was carried out against the well‐regarded PSO, GWO, and the standard slime mould algorithm. In overall, the designed optimizer defeated its contenders in all aspects offering higher efficiency, superior robustness, faster convergence, and fewer fluctuations to the operating point. An experimental setup that consists of the DSpace microcontroller and a PV emulator was employed to validate the algorithm overall performance. The recorded outcomes outline that the developed optimizer can achieve a tracking time of 0.6 seconds and 0.86 seconds on average, with 99.85% average efficiency under complex partial shading conditions.
Comparative Study on the Reinforced Sand‐Bed and the Stone Column in Improving the Clay Deposit Supporting Isolated Footing
Authors: Krishnamurthy Premalatha , Maniam Rajan Priyadharshini
Published: February 2024

The working mechanism of a geotechnical structure can be understood from the deformations and the vertical stresses in the soil media. This article attempts to study the deformation, vertical stress development, and distribution of improved clay deposits carrying a single isolated footing. Through PLAXIS 3D software, numerical analyses were conducted for the ground improvement methods, such as the geogrid reinforced sand‐bed (GRSB) and ordinary and geogrid encased stone column installation (OSC and GESC). In GRSB, the results show that the stresses were maximum at the sand–clay interface at a depth of 0.67 B (B—footing width). It is proposed to place an additional layer of geogrid at the interface, and it must be within the critical depth, i.e., the width of the footing. Furthermore, for the current study, the stiffness of the geogrid in the sand layer greater than 500 kN/m was insignificant in soil improvement, whereas the optimum axial stiffness of the stone column encasement was 1,000 kN/m based on the stress concentration factor. The stone column installation improved the clay layer even below the depth of 0.67 B, improving the capacity of clay to carry higher vertical stresses on par with the stone columns. The GRSB carried higher vertical stresses than the unimproved ground. However, the OSC and GESC could carry vertical stresses higher than the GRSB. This knowledge can allow the practitioners to decide the depth of placement of the reinforcement and also to choose an alternate if one method is not feasible for the site.
Challenges and Advancements in the Health-Related Quality of Life of Older People
Authors: Rony Moustaq Karim Khan , Parvin Mst. Rina , Wahiduzzaman Md. , Akter Khadiza , Ullah Mohammad
Published: February 2024

Background. With the global trend of increasing life expectancy, the health-related quality of life of older people haspersonalised become an area of significant interest. It is crucial to comprehend the advancements and identify the ongoing challenges in this domain for better health management and policy formation. Objectives. This scoping review aimed to comprehensively investigate the existing challenges and recent advancements associated with the quality of health among older people. Methods. We utilized Arksey and O’Malley’s scoping review framework for this study. A systematic literature search was performed across multiple databases, namely, PubMed, Scopus, and Google Scholar, targeting publications from 2018 to 2023. Selected studies were then rigorously examined based on predefined inclusion and exclusion criteria, followed by an in-depth thematic analysis. Results. Of the initial 406 identified studies, 72 were included in the final review. The analysis underscored enduring challenges in physical and medical issues, psychological difficulties, socioeconomic obstacles, and policy-related challenges. Meanwhile, significant advancements were noted in several areas, including technology, medicine, social and societal facets, and policy. Conclusions. Despite noteworthy improvements in the health-related quality of life of older individuals, the continued presence of substantial challenges emphasizes the need for more targeted initiatives. These results suggest an immediate requirement for revising policies and implementing interventions that specifically address identified challenges, with a particular emphasis on ensuring equitable health care access, effectively managing chronic conditions, and enhancing the training of geriatric health care professionals. This comprehensive review serves as a roadmap for guiding future research and shaping policy directions in the health care of older people.
Supplementary Data from Osimertinib Covalently Binds to CD34 and Eliminates Myeloid Leukemia Stem/Progenitor Cells
Authors: Xia Li , Liu Jie-Yang , Yang Meng-Ying , Zhang Xue-Hong , Jiang Yue , Yin Qian-Qian , Luo Chen-Hui , Liu Hong-Chen , Kang Zhi-Jie , Zhang Cheng-Tao , Gao Bei-Bei , Zhou Ai-Wu , Cai Hai-Yan , Waller Edmund K. , Yan Jin-Song , Lu Ying
Published: February 2024

supplementary data
Figure 3 from Deep Learning Enables Spatial Mapping of the Mosaic Microenvironment of Myeloma Bone Marrow Trephine Biopsies
Authors: Hagos Yeman Brhane , Lecat Catherine S.Y. , Patel Dominic , Mikolajczak Anna , Castillo Simon P. , Lyon Emma J. , Foster Kane , Tran Thien-An , Lee Lydia S.H. , Rodriguez-Justo Manuel , Yong Kwee L. , Yuan Yinyin
Published: February 2024

Performance evaluation of MoSaicNet and AwareNet deep learning models: A, The ROC curves and AUC values of the MoSaicNet superpixel classifier. The values in brackets indicate the 95% CI. B, Two-dimensional mapping of superpixels using MoSaicNet learned 200-dimensional features after dimensionality reduction by UMAP. C, The ROC curves and AUC values of single-cell classifier model on separately held test data. The values in brackets indicate the 95% CI. D, UMAP features visualization of deep learned features by AwareNet single-cell classifier CNN. E and F, Validation of AwareNet model using correlation of density of CD8+ (E) and CD4+ (F) cells in panel 1 and panel 2.
Supplementary Figure 3 from A Multiethnic Germline–Somatic Association Database Deciphers Multilayered and Interconnected Genetic Mutations in Cancer
Authors: Xin Junyi , Mo Zongchao , Chai Ruichao , Hua Wei , Wang Jiguang
Published: February 2024

Supplementary Figure 3. Distribution of genome-wide significant SNPs/pairs associated with somatic alterations (P ≤ 5E-06) across different cancer types and ancestry populations.
Supplementary Data from PRMT1 Inhibition Activates the Interferon Pathway to Potentiate Antitumor Immunity and Enhance Checkpoint Blockade Efficacy in Melanoma
Authors: Tao Hongru , Jin Chen , Zhou Liyuan , Deng Zhenzhong , Li Xiao , Dang Wenzhen , Fan Shijie , Li Bing , Ye Fei , Lu Junyan , Kong Xiangqian , Liu Chuanpeng , Luo Cheng , Zhang Yuanyuan
Published: February 2024

This file includes supplementary methods and reagents used in this study.
Supplementary Table S1 from PTEN Lipid Phosphatase Activity Suppresses Melanoma Formation by Opposing an AKT/mTOR/FRA1 Signaling Axis
Authors: Xu Xiaonan , Bok Ilah , Jasani Neel , Wang Kaizhen , Chadourne Manon , Mecozzi Nicol , Deng Ou , Welsh Eric A. , Kinose Fumi , Rix Uwe , Karreth Florian A.
Published: February 2024

Supplementary Table S1
Figure S7 from PTEN Lipid Phosphatase Activity Suppresses Melanoma Formation by Opposing an AKT/mTOR/FRA1 Signaling Axis
Authors: Xu Xiaonan , Bok Ilah , Jasani Neel , Wang Kaizhen , Chadourne Manon , Mecozzi Nicol , Deng Ou , Welsh Eric A. , Kinose Fumi , Rix Uwe , Karreth Florian A.
Published: February 2024

Figure S7
Figure S6 from PTEN Lipid Phosphatase Activity Suppresses Melanoma Formation by Opposing an AKT/mTOR/FRA1 Signaling Axis
Authors: Xu Xiaonan , Bok Ilah , Jasani Neel , Wang Kaizhen , Chadourne Manon , Mecozzi Nicol , Deng Ou , Welsh Eric A. , Kinose Fumi , Rix Uwe , Karreth Florian A.
Published: February 2024

Figure S6
Figure S3 from PTEN Lipid Phosphatase Activity Suppresses Melanoma Formation by Opposing an AKT/mTOR/FRA1 Signaling Axis
Authors: Xu Xiaonan , Bok Ilah , Jasani Neel , Wang Kaizhen , Chadourne Manon , Mecozzi Nicol , Deng Ou , Welsh Eric A. , Kinose Fumi , Rix Uwe , Karreth Florian A.
Published: February 2024

Figure S3
Figure S2 from PTEN Lipid Phosphatase Activity Suppresses Melanoma Formation by Opposing an AKT/mTOR/FRA1 Signaling Axis
Authors: Xu Xiaonan , Bok Ilah , Jasani Neel , Wang Kaizhen , Chadourne Manon , Mecozzi Nicol , Deng Ou , Welsh Eric A. , Kinose Fumi , Rix Uwe , Karreth Florian A.
Published: February 2024

Figure S2
Figure S1 from PTEN Lipid Phosphatase Activity Suppresses Melanoma Formation by Opposing an AKT/mTOR/FRA1 Signaling Axis
Authors: Xu Xiaonan , Bok Ilah , Jasani Neel , Wang Kaizhen , Chadourne Manon , Mecozzi Nicol , Deng Ou , Welsh Eric A. , Kinose Fumi , Rix Uwe , Karreth Florian A.
Published: February 2024

Figure S1
Supplementary Video S1 from Osteoclast Cancer Cell Metabolic Cross-talk Confers PARP Inhibitor Resistance in Bone Metastatic Breast Cancer
Authors: Fan Huijuan , Xu Zhanao , Yao Ke , Zheng Bingxin , Zhang Yuan , Wang Xuxiang , Zhang Tengjiang , Li Xuan , Hu Haitian , Yue Bin , Hu Zeping , Zheng Hanqiu
Published: February 2024

Supplementary Video S1 is related to Figure 5 (Vehicle-only group).
Supplemental Table S1 from Osteoclast Cancer Cell Metabolic Cross-talk Confers PARP Inhibitor Resistance in Bone Metastatic Breast Cancer
Authors: Fan Huijuan , Xu Zhanao , Yao Ke , Zheng Bingxin , Zhang Yuan , Wang Xuxiang , Zhang Tengjiang , Li Xuan , Hu Haitian , Yue Bin , Hu Zeping , Zheng Hanqiu
Published: February 2024

Metabolomics of macrophages vs osteaoclasts
Supplementary Data from SUMOylation-Driven mRNA Circularization Enhances Translation and Promotes Lymphatic Metastasis of Bladder Cancer
Authors: Zhao Yue , Chen Jiancheng , Zheng Hanhao , Luo Yuming , An Mingjie , Lin Yan , Pang Mingrui , Li Yuanlong , Kong Yao , He Wang , Lin Tianxin , Chen Changhao
Published: February 2024

Figure S5
Supplementary Data from SUMOylation-Driven mRNA Circularization Enhances Translation and Promotes Lymphatic Metastasis of Bladder Cancer
Authors: Zhao Yue , Chen Jiancheng , Zheng Hanhao , Luo Yuming , An Mingjie , Lin Yan , Pang Mingrui , Li Yuanlong , Kong Yao , He Wang , Lin Tianxin , Chen Changhao
Published: February 2024

Figure S6
Supplementary Data from RNA Methyltransferase FTSJ3 Regulates the Type I Interferon Pathway to Promote Hepatocellular Carcinoma Immune Evasion
Authors: Zhuang Qiuyu , Dai Zhiguo , Xu Xuechun , Bai Shaoyi , Zhang Yindan , Zheng Youshi , Xing Xiaohua , Hu En , Wang Yingchao , Guo Wuhua , Zhao Bixing , Zeng Yongyi , Liu Xiaolong
Published: February 2024

Fig. S1-S9
Table S1-S4
Data from Deep Learning Enables Spatial Mapping of the Mosaic Microenvironment of Myeloma Bone Marrow Trephine Biopsies
Authors: Hagos Yeman Brhane , Lecat Catherine S.Y. , Patel Dominic , Mikolajczak Anna , Castillo Simon P. , Lyon Emma J. , Foster Kane , Tran Thien-An , Lee Lydia S.H. , Rodriguez-Justo Manuel , Yong Kwee L. , Yuan Yinyin
Published: February 2024

Abstract
Bone marrow trephine biopsy is crucial for the diagnosis of multiple myeloma. However, the complexity of bone marrow cellular, morphologic, and spatial architecture preserved in trephine samples hinders comprehensive evaluation. To dissect the diverse cellular communities and mosaic tissue habitats, we developed a superpixel-inspired deep learning method (MoSaicNet) that adapts to complex tissue architectures and a cell imbalance aware deep learning pipeline (AwareNet) to enable accurate detection and classification of rare cell types in multiplex immunohistochemistry images. MoSaicNet and AwareNet achieved an AUC of >0.98 for tissue and cellular classification on separate test datasets. Application of MoSaicNet and AwareNet enabled investigation of bone heterogeneity and thickness as well as spatial histology analysis of bone marrow trephine samples from monoclonal gammopathies of undetermined significance (MGUS) and from paired newly diagnosed and posttreatment multiple myeloma. The most significant difference between MGUS and newly diagnosed multiple myeloma (NDMM) samples was not related to cell density but to spatial heterogeneity, with reduced spatial proximity of BLIMP1+ tumor cells to CD8+ cells in MGUS compared with NDMM samples. Following treatment of patients with multiple myeloma, there was a reduction in the density of BLIMP1+ tumor cells, effector CD8+ T cells, and regulatory T cells, indicative of an altered immune microenvironment. Finally, bone heterogeneity decreased following treatment of patients with multiple myeloma. In summary, deep learning–based spatial mapping of bone marrow trephine biopsies can provide insights into the cellular topography of the myeloma marrow microenvironment and complement aspirate-based techniques.
Significance:
Spatial analysis of bone marrow trephine biopsies using histology, deep learning, and tailored algorithms reveals the bone marrow architectural heterogeneity and evolution during myeloma progression and treatment.
Data from PRMT1 Inhibition Activates the Interferon Pathway to Potentiate Antitumor Immunity and Enhance Checkpoint Blockade Efficacy in Melanoma
Authors: Tao Hongru , Jin Chen , Zhou Liyuan , Deng Zhenzhong , Li Xiao , Dang Wenzhen , Fan Shijie , Li Bing , Ye Fei , Lu Junyan , Kong Xiangqian , Liu Chuanpeng , Luo Cheng , Zhang Yuanyuan
Published: February 2024

Abstract
Despite the immense success of immune checkpoint blockade (ICB) in cancer treatment, many tumors, including melanoma, exhibit innate or adaptive resistance. Tumor-intrinsic T-cell deficiency and T-cell dysfunction have been identified as essential factors in the emergence of ICB resistance. Here, we found that protein arginine methyltransferase 1 (PRMT1) expression was inversely correlated with the number and activity of CD8+ T cells within melanoma specimen. PRMT1 deficiency or inhibition with DCPT1061 significantly restrained refractory melanoma growth and increased intratumoral CD8+ T cells in vivo. Moreover, PRMT1 deletion in melanoma cells facilitated formation of double-stranded RNA derived from endogenous retroviral elements (ERV) and stimulated an intracellular interferon response. Mechanistically, PRMT1 deficiency repressed the expression of DNA methyltransferase 1 (DNMT1) by attenuating modification of H4R3me2a and H3K27ac at enhancer regions of Dnmt1, and DNMT1 downregulation consequently activated ERV transcription and the interferon signaling. Importantly, PRMT1 inhibition with DCPT1061 synergized with PD-1 blockade to suppress tumor progression and increase the proportion of CD8+ T cells as well as IFNγ+CD8+ T cells in vivo. Together, these results reveal an unrecognized role and mechanism of PRMT1 in regulating antitumor T-cell immunity, suggesting PRMT1 inhibition as a potent strategy to increase the efficacy of ICB.
Significance:
Targeting PRMT1 stimulates interferon signaling by increasing expression of endogenous retroviral elements and double-stranded RNA through repression of DNMT1, which induces antitumor immunity and synergizes with immunotherapy to suppress tumor progression.
Data from PTEN Lipid Phosphatase Activity Suppresses Melanoma Formation by Opposing an AKT/mTOR/FRA1 Signaling Axis
Authors: Xu Xiaonan , Bok Ilah , Jasani Neel , Wang Kaizhen , Chadourne Manon , Mecozzi Nicol , Deng Ou , Welsh Eric A. , Kinose Fumi , Rix Uwe , Karreth Florian A.
Published: February 2024

Abstract
Inactivating mutations in PTEN are prevalent in melanoma and are thought to support tumor development by hyperactivating the AKT/mTOR pathway. Conversely, activating mutations in AKT are relatively rare in melanoma, and therapies targeting AKT or mTOR have shown disappointing outcomes in preclinical models and clinical trials of melanoma. This has led to the speculation that PTEN suppresses melanoma by opposing AKT-independent pathways, potentially through noncanonical functions beyond its lipid phosphatase activity. In this study, we examined the mechanisms of PTEN-mediated suppression of melanoma formation through the restoration of various PTEN functions in PTEN-deficient cells or mouse models. PTEN lipid phosphatase activity predominantly inhibited melanoma cell proliferation, invasion, and tumor growth, with minimal contribution from its protein phosphatase and scaffold functions. A drug screen underscored the exquisite dependence of PTEN-deficient melanoma cells on the AKT/mTOR pathway. Furthermore, activation of AKT alone was sufficient to counteract several aspects of PTEN-mediated melanoma suppression, particularly invasion and the growth of allograft tumors. Phosphoproteomics analysis of the lipid phosphatase activity of PTEN validated its potent inhibition of AKT and many of its known targets, while also identifying the AP-1 transcription factor FRA1 as a downstream effector. The restoration of PTEN dampened FRA1 translation by inhibiting AKT/mTOR signaling, and FRA1 overexpression negated aspects of PTEN-mediated melanoma suppression akin to AKT. This study supports AKT as the key mediator of PTEN inactivation in melanoma and identifies an AKT/mTOR/FRA1 axis as a driver of melanomagenesis.
Significance:
PTEN suppresses melanoma predominantly through its lipid phosphatase function, which when lost, elevates FRA1 levels through AKT/mTOR signaling to promote several aspects of melanomagenesis.
Data from Osteoclast Cancer Cell Metabolic Cross-talk Confers PARP Inhibitor Resistance in Bone Metastatic Breast Cancer
Authors: Fan Huijuan , Xu Zhanao , Yao Ke , Zheng Bingxin , Zhang Yuan , Wang Xuxiang , Zhang Tengjiang , Li Xuan , Hu Haitian , Yue Bin , Hu Zeping , Zheng Hanqiu
Published: February 2024

Abstract
The majority of patients with late-stage breast cancer develop distal bone metastases. The bone microenvironment can affect response to therapy, and uncovering the underlying mechanisms could help identify improved strategies for treating bone metastatic breast cancer. Here, we observed that osteoclasts reduced the sensitivity of breast cancer cells to DNA damaging agents, including cisplatin and the PARP inhibitor (PARPi) olaparib. Metabolic profiling identified elevated glutamine production by osteoclasts. Glutamine supplementation enhanced the survival of breast cancer cells treated with DNA damaging agents, while blocking glutamine uptake increased sensitivity and suppressed bone metastasis. GPX4, the critical enzyme responsible for glutathione oxidation, was upregulated in cancer cells following PARPi treatment through stress-induced ATF4-dependent transcriptional programming. Increased glutamine uptake and GPX4 upregulation concertedly enhanced glutathione metabolism in cancer cells to help neutralize oxidative stress and generate PARPi resistance. Analysis of paired patient samples of primary breast tumors and bone metastases revealed significant induction of GPX4 in bone metastases. Combination therapy utilizing PARPi and zoledronate, which blocks osteoclast activity and thereby reduces the microenvironmental glutamine supply, generated a synergistic effect in reducing bone metastasis. These results identify a role for glutamine production by bone-resident cells in supporting metastatic cancer cells to overcome oxidative stress and develop resistance to DNA-damaging therapies.
Significance:
Metabolic interaction between osteoclasts and tumor cells contributes to resistance to DNA-damaging agents, which can be blocked by combination treatment with PARP and osteoclast inhibitors to reduce bone metastatic burden.
Supplementary Table 2 from Modulating Gut Microbiota Prevents Anastomotic Leak to Reduce Local Implantation and Dissemination of Colorectal Cancer Cells after Surgery
Authors: Hajjar Roy , Oliero Manon , Fragoso Gabriela , Ajayi Ayodeji Samuel , Alaoui Ahmed Amine , Vennin Rendos Hervé , Calvé Annie , Cuisiniere Thibault , Gerkins Claire , Thérien Sophie , Taleb Nassima , Dagbert François , Sebajang Herawaty , Loungnarath Rasmy , Schwenter Frank , Ratelle Richard , Wassef Ramses , De Broux Eric , Richard Carole , Santos Manuela M.
Published: February 2024

Supplementary Table 2. Demographic, clinical, and perioperative data of patients with CRC.
Supplementary Table 1 from Modulating Gut Microbiota Prevents Anastomotic Leak to Reduce Local Implantation and Dissemination of Colorectal Cancer Cells after Surgery
Authors: Hajjar Roy , Oliero Manon , Fragoso Gabriela , Ajayi Ayodeji Samuel , Alaoui Ahmed Amine , Vennin Rendos Hervé , Calvé Annie , Cuisiniere Thibault , Gerkins Claire , Thérien Sophie , Taleb Nassima , Dagbert François , Sebajang Herawaty , Loungnarath Rasmy , Schwenter Frank , Ratelle Richard , Wassef Ramses , De Broux Eric , Richard Carole , Santos Manuela M.
Published: February 2024

Supplementary Table 1. Clinical and demographic data of patients undergoing surgery for CRC between 2011 and 2021.
Supplementary Figure 4 from Modulating Gut Microbiota Prevents Anastomotic Leak to Reduce Local Implantation and Dissemination of Colorectal Cancer Cells after Surgery
Authors: Hajjar Roy , Oliero Manon , Fragoso Gabriela , Ajayi Ayodeji Samuel , Alaoui Ahmed Amine , Vennin Rendos Hervé , Calvé Annie , Cuisiniere Thibault , Gerkins Claire , Thérien Sophie , Taleb Nassima , Dagbert François , Sebajang Herawaty , Loungnarath Rasmy , Schwenter Frank , Ratelle Richard , Wassef Ramses , De Broux Eric , Richard Carole , Santos Manuela M.
Published: February 2024

Supplementary Figure 4. Inulin and 5-ASA were associated with lower circulating levels of pro-inflammatory cytokines in mice with liver metastasis.
Supplementary Figure 1 from Modulating Gut Microbiota Prevents Anastomotic Leak to Reduce Local Implantation and Dissemination of Colorectal Cancer Cells after Surgery
Authors: Hajjar Roy , Oliero Manon , Fragoso Gabriela , Ajayi Ayodeji Samuel , Alaoui Ahmed Amine , Vennin Rendos Hervé , Calvé Annie , Cuisiniere Thibault , Gerkins Claire , Thérien Sophie , Taleb Nassima , Dagbert François , Sebajang Herawaty , Loungnarath Rasmy , Schwenter Frank , Ratelle Richard , Wassef Ramses , De Broux Eric , Richard Carole , Santos Manuela M.
Published: February 2024

Supplementary Figure 1. Recurrent or progressive metastatic tumors in patients with (A) proximal or (B) distal colorectal cancer with and without anastomotic leak (AL).
Supplementary Figure 2 from Selective DNA-PK Inhibition Enhances Chemotherapy and Ionizing Radiation Activity in Soft-Tissue Sarcomas
Authors: Laroche-Clary Audrey , Josensi Coralie , Derieppe Marie-Alix , Belhomme Sarah , Vendrely Véronique , Perret Raul , Cadogan Elaine , Italiano Antoine
Published: February 2024

Supplementary Figure 2: Crispr screen analysis
Supplementary Figure S3 from A Phase Ib First-In-Patient Study Assessing the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ponsegromab in Participants with Cancer and Cachexia
Authors: Crawford Jeffrey , Calle Roberto A. , Collins Susie M. , Weng Yan , Lubaczewski Shannon L. , Buckeridge Clare , Wang Ellen Q. , Harrington Magdalena A. , Tarachandani Anil , Rossulek Michelle I. , Revkin James H.
Published: February 2024

Summary of accelerometry-based monitoring of sedentary activity time (A), light activity time (B), moderate activity time (C), average activity level during the maximum 6 minutes of daily activity (D), total sleep time (E), and gait speed (F) at baseline, week 6 and week 12
Supplementary Data1 from Development of Resistance to Type II JAK2 Inhibitors in MPN Depends on AXL Kinase and Is Targetable
Authors: Codilupi Tamara , Szybinski Jakub , Arunasalam Stefanie , Jungius Sarah , Dunbar Andrew C. , Stivala Simona , Brkic Sime , Albrecht Camille , Vokalova Lenka , Yang Julie L. , Buczak Katarzyna , Ghosh Nilabh , Passweg Jakob R. , Rovo Alicia , Angelillo-Scherrer Anne , Pankov Dmitry , Dirnhofer Stefan , Levine Ross L. , Koche Richard , Meyer Sara C.
Published: February 2024

Codilupi et al, Supplementary figures and methods
Table S2 from Clinical and Immunologic Features of Germline Pathogenic Variant–Positive Patients with Melanoma
Authors: Shen Alan , Arbesman Michelle , Lodha Roshan , Rayman Patricia , Bungo Brandon , Ni Ying , Chan Timothy , Gastman Brian , Ko Jennifer , Diaz-Montero C. Marcela , Arbesman Joshua , Funchain Pauline
Published: February 2024

gPV categories broken up by HRD, Non-HRD, and MMR.
Supplementary Data 1 from Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial
Authors: Wildiers Hans , Armstrong Anne , Cuypere Eveline , Dalenc Florence , Dirix Luc , Chan Steve , Marme Frederik , Schröder Carolina P. , Huober Jens , Duhoux Francois P. , Vuylsteke Peter , Jager Agnes , Brain Etienne , Kuemmel Sherko , Pápai Zsuzsanna , Menke-van der Houven van Oordt Catharina Willemien , Perjesi Luca , Mueller Christian , Brignone Chrystelle , Triebel Frederic
Published: February 2024

Supplement to Methods, Tables S1 to S4, legends to Figures S1 to S7
Figure S7 from Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial
Authors: Wildiers Hans , Armstrong Anne , Cuypere Eveline , Dalenc Florence , Dirix Luc , Chan Steve , Marme Frederik , Schröder Carolina P. , Huober Jens , Duhoux Francois P. , Vuylsteke Peter , Jager Agnes , Brain Etienne , Kuemmel Sherko , Pápai Zsuzsanna , Menke-van der Houven van Oordt Catharina Willemien , Perjesi Luca , Mueller Christian , Brignone Chrystelle , Triebel Frederic
Published: February 2024

. (A) Absolute cell count of CD8+ T cells at baseline and maximal postbaseline by OS status and treatment arm. (B)
Figure S6 from Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial
Authors: Wildiers Hans , Armstrong Anne , Cuypere Eveline , Dalenc Florence , Dirix Luc , Chan Steve , Marme Frederik , Schröder Carolina P. , Huober Jens , Duhoux Francois P. , Vuylsteke Peter , Jager Agnes , Brain Etienne , Kuemmel Sherko , Pápai Zsuzsanna , Menke-van der Houven van Oordt Catharina Willemien , Perjesi Luca , Mueller Christian , Brignone Chrystelle , Triebel Frederic
Published: February 2024

PK concentration to time profiles for 6-mg and 30-mg efti
Figure S5 from Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial
Authors: Wildiers Hans , Armstrong Anne , Cuypere Eveline , Dalenc Florence , Dirix Luc , Chan Steve , Marme Frederik , Schröder Carolina P. , Huober Jens , Duhoux Francois P. , Vuylsteke Peter , Jager Agnes , Brain Etienne , Kuemmel Sherko , Pápai Zsuzsanna , Menke-van der Houven van Oordt Catharina Willemien , Perjesi Luca , Mueller Christian , Brignone Chrystelle , Triebel Frederic
Published: February 2024

Global health status over time as assessed by the EORTC QLQC30-BR23 questionnaire
Figure S3 from Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial
Authors: Wildiers Hans , Armstrong Anne , Cuypere Eveline , Dalenc Florence , Dirix Luc , Chan Steve , Marme Frederik , Schröder Carolina P. , Huober Jens , Duhoux Francois P. , Vuylsteke Peter , Jager Agnes , Brain Etienne , Kuemmel Sherko , Pápai Zsuzsanna , Menke-van der Houven van Oordt Catharina Willemien , Perjesi Luca , Mueller Christian , Brignone Chrystelle , Triebel Frederic
Published: February 2024

Kaplan-Meier plots of PFS by blinded independent central review for AIPAC patient subgroups.
Figure S1 from Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial
Authors: Wildiers Hans , Armstrong Anne , Cuypere Eveline , Dalenc Florence , Dirix Luc , Chan Steve , Marme Frederik , Schröder Carolina P. , Huober Jens , Duhoux Francois P. , Vuylsteke Peter , Jager Agnes , Brain Etienne , Kuemmel Sherko , Pápai Zsuzsanna , Menke-van der Houven van Oordt Catharina Willemien , Perjesi Luca , Mueller Christian , Brignone Chrystelle , Triebel Frederic
Published: February 2024

Immunotherapeutic interventions leading to increased T-cell responses in cancer.
Supplementary Data 1 from Impact of Rare Structural Variant Events in Newly Diagnosed Multiple Myeloma
Authors: Chojnacka Monika , Diamond Benjamin , Ziccheddu Bachisio , Rustad Even , Maclachlan Kylee , Papadimitriou Marios , Boyle Eileen M. , Blaney Patrick , Usmani Saad , Morgan Gareth , Landgren Ola , Maura Francesco
Published: February 2024

Supplementary Data 1
Supplementary Table S8 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

Tumor Types by Elraglusib Dose Level in Part 1
Supplementary Table S10 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

Treatment-Emergent Adverse Events Related to Elraglusib Versus Concomitant Chemotherapy
Supplementary Figure S7 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

Plasma Elraglusib (9-ING-41) Concentrations 3.3 mg/kg Elraglusib plus Nab-Paclitaxel plus Gemcitabine
Supplementary Figure S5 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

Plasma Elraglusib (9-ING-41) Concentrations 5.0 mg/kg Elraglusib PLUS Gemcitabine Regimen
Supplementary Figure S4 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

Plasma Elraglusib (9-ING-41) Concentrations 3.3 mg/kg Elraglusib plus Gemcitabine Regimen
Supplementary Data 1 from First-in-Human Study with Preclinical Data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors
Authors: Lakhani Nehal J. , Rasco Drew , Wang Hengbang , Men Lichuang , Liang Eric , Fu Tommy , Collins Mary C. , Min Ping , Yin Yan , Davids Matthew S. , Yang Dajun , Zhai Yifan
Published: February 2024

Supplementary Tables S1-S3 and Supplementary Figures S1-S4
Supplementary Figure S14 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

Progression to Complete Response with Elraglusib Monotherapy in a Patient with BRAF-mutated Melanoma
Supplementary Table 1 from Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer
Authors: Byrne Katelyn T. , Betts Courtney B. , Mick Rosemarie , Sivagnanam Shamilene , Bajor David L. , Laheru Daniel A. , Chiorean E. Gabriela , O'Hara Mark H. , Liudahl Shannon M. , Newcomb Craig , Alanio Cécile , Ferreira Ana P. , Park Byung S. , Ohtani Takuya , Huffman Austin P. , Väyrynen Sara A. , Dias Costa Andressa , Kaiser Judith C. , Lacroix Andreanne M. , Redlinger Colleen , Stern Martin , Nowak Jonathan A. , Wherry E. John , Cheever Martin A. , Wolpin Brian M. , Furth Emma E. , Jaffee Elizabeth M. , Coussens Lisa M. , Vonderheide Robert H.
Published: February 2024

Table S1 summarizes adverse events associated with selicrelumab administration.
Supplementary Figure 1 from Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer
Authors: Byrne Katelyn T. , Betts Courtney B. , Mick Rosemarie , Sivagnanam Shamilene , Bajor David L. , Laheru Daniel A. , Chiorean E. Gabriela , O'Hara Mark H. , Liudahl Shannon M. , Newcomb Craig , Alanio Cécile , Ferreira Ana P. , Park Byung S. , Ohtani Takuya , Huffman Austin P. , Väyrynen Sara A. , Dias Costa Andressa , Kaiser Judith C. , Lacroix Andreanne M. , Redlinger Colleen , Stern Martin , Nowak Jonathan A. , Wherry E. John , Cheever Martin A. , Wolpin Brian M. , Furth Emma E. , Jaffee Elizabeth M. , Coussens Lisa M. , Vonderheide Robert H.
Published: February 2024

Figure S1 shows the CONSORT diagram.
Data from Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer
Authors: Byrne Katelyn T. , Betts Courtney B. , Mick Rosemarie , Sivagnanam Shamilene , Bajor David L. , Laheru Daniel A. , Chiorean E. Gabriela , O'Hara Mark H. , Liudahl Shannon M. , Newcomb Craig , Alanio Cécile , Ferreira Ana P. , Park Byung S. , Ohtani Takuya , Huffman Austin P. , Väyrynen Sara A. , Dias Costa Andressa , Kaiser Judith C. , Lacroix Andreanne M. , Redlinger Colleen , Stern Martin , Nowak Jonathan A. , Wherry E. John , Cheever Martin A. , Wolpin Brian M. , Furth Emma E. , Jaffee Elizabeth M. , Coussens Lisa M. , Vonderheide Robert H.
Published: February 2024

AbstractPurpose:
CD40 activation is a novel clinical opportunity for cancer immunotherapy. Despite numerous active clinical trials with agonistic CD40 monoclonal antibodies (mAb), biological effects and treatment-related modulation of the tumor microenvironment (TME) remain poorly understood.
Patients and Methods:
Here, we performed a neoadjuvant clinical trial of agonistic CD40 mAb (selicrelumab) administered intravenously with or without chemotherapy to 16 patients with resectable pancreatic ductal adenocarcinoma (PDAC) before surgery followed by adjuvant chemotherapy and CD40 mAb.
Results:
The toxicity profile was acceptable, and overall survival was 23.4 months (95% confidence interval, 18.0–28.8 months). Based on a novel multiplexed immunohistochemistry platform, we report evidence that neoadjuvant selicrelumab leads to major differences in the TME compared with resection specimens from treatment-naïve PDAC patients or patients given neoadjuvant chemotherapy/chemoradiotherapy only. For selicrelumab-treated tumors, 82% were T-cell enriched, compared with 37% of untreated tumors (P = 0.004) and 23% of chemotherapy/chemoradiation-treated tumors (P = 0.012). T cells in both the TME and circulation were more active and proliferative after selicrelumab. Tumor fibrosis was reduced, M2-like tumor-associated macrophages were fewer, and intratumoral dendritic cells were more mature. Inflammatory cytokines/sec CXCL10 and CCL22 increased systemically after selicrelumab.
Conclusions:
This unparalleled examination of CD40 mAb therapeutic mechanisms in patients provides insights for design of subsequent clinical trials targeting CD40 in cancer.
Data from A Phase Ib First-In-Patient Study Assessing the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ponsegromab in Participants with Cancer and Cachexia
Authors: Crawford Jeffrey , Calle Roberto A. , Collins Susie M. , Weng Yan , Lubaczewski Shannon L. , Buckeridge Clare , Wang Ellen Q. , Harrington Magdalena A. , Tarachandani Anil , Rossulek Michelle I. , Revkin James H.
Published: February 2024

AbstractPurpose:
Cachexia is common in patients with advanced cancer and is associated with elevated serum growth differentiation factor 15 (GDF-15) concentrations. This first-in-patient (phase Ib), 24-week study assessed use of ponsegromab, a mAb against GDF-15, in adults with advanced cancer, cachexia, and elevated GDF-15 serum concentration.
Patients and Methods:
Participants (n = 10) received open-label ponsegromab subcutaneous 200 mg every 3 weeks for 12 weeks in addition to standard-of-care anticancer treatment. Ponsegromab safety, tolerability, and pharmacokinetics were assessed in addition to serum GDF-15 concentrations and exploratory measures of efficacy.
Results:
No treatment-related treatment-emergent adverse events, injection site reactions, or adverse trends in clinical laboratory tests, vital signs, or electrocardiogram parameters attributable to ponsegromab were identified. Median serum unbound GDF-15 concentration at baseline was 2.269 ng/mL. Following initiation of study treatment, median unbound GDF-15 concentrations were below the lower limit of quantification (0.0424 ng/mL) from day 1 (3 hours postdose) through week 15. Increases in body weight were observed at all time points during the treatment and follow-up periods. A least-squares mean (SE) increase of 4.63 (1.98) kg was observed at week 12, an increase of approximately 6.6% relative to baseline. Ponsegromab-mediated improvements in actigraphy-based assessments of physical activity and in quality of life, including appetite as assessed by Functional Assessment of Anorexia-Cachexia Therapy total and subscale scores, were also observed.
Conclusions:
Ponsegromab was well tolerated, suppressed serum GDF-15 concentrations, and demonstrated preliminary evidence of efficacy. These findings support the continued development of ponsegromab for the treatment of cachexia.