bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring Precise Medication Strategies for OSCC Based on Single-Cell Transcriptome Analysis from a Dynamic Perspective
Authors: Meng Qingkang , Wu Feng , Li Guoqi , Xu Fei , Liu Lei , Zhang Denan , Lu Yangxu , Xie Hongbo , Chen Xiujie
Published: October 2022

At present, most patients with oral squamous cell carcinoma (OSCC) are in the middle or advanced stages at the time of diagnosis. Advanced OSCC patients have a poor prognosis after traditional therapy, and the complex heterogeneity of OSCC has been proven to be one of the main reasons. Single-cell sequencing technology provides a powerful tool for dissecting the heterogeneity of cancer. However, most of the current studies at the single-cell level are static, while the development of cancer is a dynamic process. Thus, understanding the development of cancer from a dynamic perspective and formulating corresponding therapeutic measures for achieving precise treatment are highly necessary, and this is also one of the main study directions in the field of oncology. In this study, we combined the static and dynamic analysis methods based on single-cell RNA-Seq data to comprehensively dissect the complex heterogeneity and evolutionary process of OSCC. Subsequently, for clinical practice, we revealed the association between cancer heterogeneity and the prognosis of patients. More importantly, we pioneered the concept of pseudo-time score of patients, and we quantified the levels of heterogeneity based on the dynamic development process to evaluate the relationship between the score and the survival status at the same stage, finding that it is closely related to the prognostic status. The pseudo-time score of patients could not only reflect the tumor status of patients but also be used as an indicator of the effects of drugs on the patients so that the medication strategy can be adjusted on time. Finally, we identified candidate drugs and proposed precision medication strategies to control the condition of OSCC in two respects: treatment and blocking.
Microglia-Based Gene Expression Signature Highly Associated with Prognosis in Low-Grade Glioma
Authors: Schaafsma Evelien , Jiang Chongming , Nguyen Thinh , Zhu Kenneth , Cheng Chao
Published: October 2022

Gliomas make up ~80% of malignant brain tumors in adults and are responsible for the majority of deaths from primary brain tumors. The glioma tumor microenvironment (TME) is a dynamic, heterogeneous mixture of extracellular matrix and malignant and non-malignant cells. Several ongoing clinical trials are evaluating the efficacy of therapies that target non-malignant cells, particularly immune cells. Consequently, a better understanding of the TME in glioma is pertinent. We utilized several gene expression datasets to evaluate the relationship between immune-related genes (IRGs) and patient prognosis. We generated microglia signatures using single-cell RNAseq data from human and mouse glioma cells to infer microglia abundance. Lastly, we built a LASSO Cox regression model that predicts patient survival. We found that 428 IRGs were negatively associated with survival in glioma patients. Overall survival was significantly lower in those with a high level of microglia infiltration. In addition, we also found that microglia abundance was significantly associated with several common genomic aberrations, including IDH2 and TP53 mutations. Furthermore, we found that patients with high risk scores had significantly worse overall survival than those with low risk scores in several independent datasets. Altogether, we characterized immune features predictive of overall survival in glioma and found that microglia abundance is negatively associated with survival. We developed a 23-gene risk score that can significantly stratify patients into low- and high-risk categories.
Current Immune Checkpoint Inhibitor Genetic Biomarker Exploration in Gastrointestinal Tumors
Authors: Rogers Jane E. , Yamashita Kohei , Sewastjanow Silva Matheus , Ajani Jaffer A.
Published: October 2022

Immune checkpoint inhibitors have revolutionized cancer management. Some patients with gastrointestinal (GI) tract malignancy have experienced remarkable results. Here, in our review, we discuss predictive/prognostic GI tumor biomarkers that appear to correlate with benefits with this strategy. Remarkable progress has been made in certain subsets of patients including the potential for solid tumor patients to avoid local therapies such as radiation and/or surgery (organ preservation), which come with acute and chronic risks that have historically been the only curable strategies for these GI tumors. These results provide new and exciting strategies for solid tumor management. Unfortunately, immune checkpoint inhibitors can correlate with biomarkers, but benefits occur in a small subset of patients with GI malignancies. Most frequently, immune checkpoint inhibitors fail to induce response in GI malignancies due to the “cold” tumor microenvironment that protects cancer. Translational strategies are needed to develop effective combination strategies and novel biomarkers to overcome the intrinsic resistance.
Dickkopf-Related Protein 1 as Response Marker for Transarterial Chemoembolization of Hepatocellular Carcinomas
Authors: Olbrich Anne , Gros Olga , Ebel Sebastian , Denecke Timm , Gößmann Holger , Linder Nicolas , Lordick Florian , Forstmeyer Dirk , Seehofer Daniel , Sucher Robert , Rademacher Sebastian , Niemeyer Johannes , Matz-Soja Madlen , Berg Thomas , Bömmel Florian van
Published: October 2022

Background and Aims: In the treatment of hepatocellular carcinoma (HCC), response prediction to transarterial chemoembolization (TACE) based on serum biomarkers is not established. We have studied the association of circulating Dickkopf-related protein 1 (DKK-1) with baseline characteristics and response to TACE in European HCC patients. Methods: Patients with HCC treated with TACE from 2010 to 2018 at a tertiary referral hospital were retrospectively enrolled. Levels of DKK-1 were measured in serum samples collected before TACE. Response was assessed according to mRECIST criteria at week 12 after TACE. Results: Ninety-seven patients were enrolled, including seventy-nine responders and eighteen refractory. Before TACE, median DKK-1 serum levels were 922 [range, 199–4514] pg/mL. DKK-1 levels were lower in patients with liver cirrhosis (p = 0.002) and showed a strong correlation with total radiologic tumor size (r = 0.593; p < 0.001) and with Barcelona Clinic Liver Cancer stages (p = 0.032). Median DKK-1 levels were significantly higher in refractory patients as compared to responders (1471 pg/mL [range, 546–2492 pg/mL] versus 837 pg/mL [range, 199–4515 pg/mL]; p < 0.001), and DKK-1 could better identify responders than AFP (AUC = 0.798 vs. AUC = 0.679; p < 0.001). A DKK-1 cutoff of ≤1150 pg/mL was defined to identify responders to TACE with a sensitivity of 78% and specificity of 77%. DKK-1 levels were suitable to determine response to TACE in patients with low AFP serum levels (AFP levels < 20 ng/mL; AUC = 0.843; 95% CI [0.721–0.965]; p = 0.003). Conclusion: DKK-1 levels in serum are strongly associated tumor size and with response to TACE in European HCC patients, including those patients with low AFP levels.
FOLFOXIRI Resistance Induction and Characterization in Human Colorectal Cancer Cells
Authors: Ramzy George M. , Boschung Laura , Koessler Thibaud , Delucinge-Vivier Céline , Docquier Mylène , McKee Thomas A. , Rubbia-Brandt Laura , Nowak-Sliwinska Patrycja
Published: October 2022

FOLFOXIRI, i.e., the combination of folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan, is a first-line treatment for colorectal carcinoma (CRC), yet non-personalized and aggressive. In this study, to mimic the clinical situation of patients diagnosed with advanced CRC and exposed to a chronic treatment with FOLFOXIRI, we have generated the CRC cell clones chronically treated with FOLFOXIRI. A significant loss in sensitivity to FOLFOXIRI was obtained in all four cell lines, compared to their treatment-naïve calls, as shown in 2D cultures and heterotypic 3D co-cultures. Acquired drug resistance induction was observed through morphometric changes in terms of the organization of the actin filament. Bulk RNA sequencing revealed important upregulation of glucose transporter family 5 (GLUT5) in SW620 resistant cell line, while in the LS174T-resistant cell line, a significant downregulation of protein tyrosine phosphatase receptor S (PTPRS) and oxoglutarate dehydrogenase-like gene (OGDHL). This acquired resistance to FOLFOXIRI was overcome with optimized low-dose synergistic drug combinations (ODCs) acting via the Ras-Raf-MEK-ERK pathway. The ODCs inhibited the cell metabolic activity in SW620 and LS174T 3Dcc, respectively by up to 82%.
Radiogenomic System for Non-Invasive Identification of Multiple Actionable Mutations and PD-L1 Expression in Non-Small Cell Lung Cancer Based on CT Images
Authors: Shao Jun , Ma Jiechao , Zhang Shu , Li Jingwei , Dai Hesen , Liang Shufan , Yu Yizhou , Li Weimin , Wang Chengdi
Published: October 2022

Purpose: Personalized treatments such as targeted therapy and immunotherapy have revolutionized the predominantly therapeutic paradigm for non-small cell lung cancer (NSCLC). However, these treatment decisions require the determination of targetable genomic and molecular alterations through invasive genetic or immunohistochemistry (IHC) tests. Numerous previous studies have demonstrated that artificial intelligence can accurately predict the single-gene status of tumors based on radiologic imaging, but few studies have achieved the simultaneous evaluation of multiple genes to reflect more realistic clinical scenarios. Methods: We proposed a multi-label multi-task deep learning (MMDL) system for non-invasively predicting actionable NSCLC mutations and PD-L1 expression utilizing routinely acquired computed tomography (CT) images. This radiogenomic system integrated transformer-based deep learning features and radiomic features of CT volumes from 1096 NSCLC patients based on next-generation sequencing (NGS) and IHC tests. Results: For each task cohort, we randomly split the corresponding dataset into training (80%), validation (10%), and testing (10%) subsets. The area under the receiver operating characteristic curves (AUCs) of the MMDL system achieved 0.862 (95% confidence interval (CI), 0.758–0.969) for discrimination of a panel of 8 mutated genes, including EGFR, ALK, ERBB2, BRAF, MET, ROS1, RET and KRAS, 0.856 (95% CI, 0.663–0.948) for identification of a 10-molecular status panel (previous 8 genes plus TP53 and PD-L1); and 0.868 (95% CI, 0.641–0.972) for classifying EGFR / PD-L1 subtype, respectively. Conclusions: To the best of our knowledge, this study is the first deep learning system to simultaneously analyze 10 molecular expressions, which might be utilized as an assistive tool in conjunction with or in lieu of ancillary testing to support precision treatment options.
A Novel Bayesian Framework Infers Driver Activation States and Reveals Pathway-Oriented Molecular Subtypes in Head and Neck Cancer
Authors: Liu Zhengping , Cai Chunhui , Ma Xiaojun , Liu Jinling , Chen Lujia , Lui Vivian Wai Yan , Cooper Gregory F. , Lu Xinghua
Published: October 2022

Head and neck squamous cell cancer (HNSCC) is an aggressive cancer resulting from heterogeneous causes. To reveal the underlying drivers and signaling mechanisms of different HNSCC tumors, we developed a novel Bayesian framework to identify drivers of individual tumors and infer the states of driver proteins in cellular signaling system in HNSCC tumors. First, we systematically identify causal relationships between somatic genome alterations (SGAs) and differentially expressed genes (DEGs) for each TCGA HNSCC tumor using the tumor-specific causal inference (TCI) model. Then, we generalize the most statistically significant driver SGAs and their regulated DEGs in TCGA HNSCC cohort. Finally, we develop machine learning models that combine genomic and transcriptomic data to infer the protein functional activation states of driver SGAs in tumors, which enable us to represent a tumor in the space of cellular signaling systems. We discovered four mechanism-oriented subtypes of HNSCC, which show distinguished patterns of activation state of HNSCC driver proteins, and importantly, this subtyping is orthogonal to previously reported transcriptomic-based molecular subtyping of HNSCC. Further, our analysis revealed driver proteins that are likely involved in oncogenic processes induced by HPV infection, even though they are not perturbed by genomic alterations in HPV+ tumors.
Validation of MRI-Based Models to Predict MGMT Promoter Methylation in Gliomas: BraTS 2021 Radiogenomics Challenge
Authors: Kim Byung-Hoon , Lee Hyeonhoon , Choi Kyu Sung , Nam Ju Gang , Park Chul-Kee , Park Sung-Hye , Chung Jin Wook , Choi Seung Hong
Published: October 2022

O6-methylguanine-DNA methyl transferase (MGMT) methylation prediction models were developed using only small datasets without proper external validation and achieved good diagnostic performance, which seems to indicate a promising future for radiogenomics. However, the diagnostic performance was not reproducible for numerous research teams when using a larger dataset in the RSNA-MICCAI Brain Tumor Radiogenomic Classification 2021 challenge. To our knowledge, there has been no study regarding the external validation of MGMT prediction models using large-scale multicenter datasets. We tested recent CNN architectures via extensive experiments to investigate whether MGMT methylation in gliomas can be predicted using MR images. Specifically, prediction models were developed and validated with different training datasets: (1) the merged (SNUH + BraTS) (n = 985); (2) SNUH (n = 400); and (3) BraTS datasets (n = 585). A total of 420 training and validation experiments were performed on combinations of datasets, convolutional neural network (CNN) architectures, MRI sequences, and random seed numbers. The first-place solution of the RSNA-MICCAI radiogenomic challenge was also validated using the external test set (SNUH). For model evaluation, the area under the receiver operating characteristic curve (AUROC), accuracy, precision, and recall were obtained. With unexpected negative results, 80.2% (337/420) and 60.0% (252/420) of the 420 developed models showed no significant difference with a chance level of 50% in terms of test accuracy and test AUROC, respectively. The test AUROC and accuracy of the first-place solution of the BraTS 2021 challenge were 56.2% and 54.8%, respectively, as validated on the SNUH dataset. In conclusion, MGMT methylation status of gliomas may not be predictable with preoperative MR images even using deep learning.
Biomarkers in Metastatic Colorectal Cancer: Status Quo and Future Perspective
Authors: Puccini Alberto , Seeber Andreas , Berger Martin D.
Published: October 2022

Colorectal cancer (CRC) is the third most frequent cancer worldwide, and its incidence is steadily increasing. During the last two decades, a tremendous improvement in outcome has been achieved, mainly due to the introduction of novel drugs, targeted treatment, immune checkpoint inhibitors (CPIs) and biomarker-driven patient selection. Moreover, progress in molecular diagnostics but also improvement in surgical techniques and local ablative treatments significantly contributed to this success. However, novel therapeutic approaches are needed to further improve outcome in patients diagnosed with metastatic CRC. Besides the established biomarkers for mCRC, such as microsatellite instability (MSI) or mismatch repair deficiency (dMMR), RAS/BRAF, sidedness and HER2 amplification, new biomarkers have to be identified to better select patients who derive the most benefit from a specific treatment. In this review, we provide an overview about therapeutic relevant and established biomarkers but also shed light on potential promising markers that may help us to better tailor therapy to the individual mCRC patient in the near future.
Durable Responses to Anti-PD1 and Anti-CTLA4 in a Preclinical Model of Melanoma Displaying Key Immunotherapy Response Biomarkers
Authors: Shklovskaya Elena , Pedersen Bernadette , Stewart Ashleigh , Simpson Jack O. G. , Ming Zizhen , Irvine Mal , Scolyer Richard A. , Long Georgina V. , Rizos Helen
Published: October 2022

Immunotherapy has transformed the management of patients with advanced melanoma, with five-year overall survival rates reaching 52% for combination immunotherapies blocking the cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) and programmed cell death-1 (PD1) immune axes. Yet, our understanding of local and systemic determinants of immunotherapy response and resistance is restrained by the paucity of preclinical models, particularly those for anti-PD1 monotherapy. We have therefore generated a novel murine model of melanoma by integrating key immunotherapy response biomarkers into the model development workflow. The resulting YUMM3.3UVRc34 (BrafV600E; Cdkn2a–/–) model demonstrated high mutation burden and response to interferon (IFN)γ, including induced expression of antigen-presenting molecule MHC-I and the principal PD1 ligand PD-L1, consistent with phenotypes of human melanoma biopsies from patients subsequently responding to anti-PD1 monotherapy. Syngeneic immunosufficient mice bearing YUMM3.3UVRc34 tumors demonstrated durable responses to anti-PD1, anti-CTLA4, or combined treatment. Immunotherapy responses were associated with early on-treatment changes in the tumor microenvironment and circulating T-cell subsets, and systemic immunological memory underlying protection from tumor recurrence. Local and systemic immunological landscapes associated with immunotherapy response in the YUMM3.3UVRc34 melanoma model recapitulate immunotherapy responses observed in melanoma patients and identify discrete immunological mechanisms underlying the durability of responses to anti-PD1 and anti-CTLA4 treatments.
Preclinical Three-Dimensional Vibrational Shear Wave Elastography for Mapping of Tumour Biomechanical Properties In Vivo
Authors: Parasaram Vaideesh , Civale John , Bamber Jeffrey C. , Robinson Simon P. , Jamin Yann , Harris Emma
Published: October 2022

Preclinical investigation of the biomechanical properties of tissues and their treatment-induced changes are essential to support drug-discovery, clinical translation of biomarkers of treatment response, and studies of mechanobiology. Here we describe the first use of preclinical 3D elastography to map the shear wave speed (cs), which is related to tissue stiffness, in vivo and demonstrate the ability of our novel 3D vibrational shear wave elastography (3D-VSWE) system to detect tumour response to a therapeutic challenge. We investigate the use of one or two vibrational sources at vibrational frequencies of 700, 1000 and 1200 Hz. The within-subject coefficients of variation of our system were found to be excellent for 700 and 1000 Hz and 5.4 and 6.2%, respectively. The relative change in cs measured with our 3D-VSWE upon treatment with an anti-vascular therapy ZD6126 in two tumour xenografts reflected changes in tumour necrosis. U-87 MG drug vs vehicle: Δcs = −24.7 ± 2.5 % vs 7.5 ± 7.1%, (p = 0.002) and MDA-MB-231 drug vs vehicle: Δcs = −12.3 ± 2.7 % vs 4.5 ± 4.7%, (p = 0.02). Our system enables rapid (<5 min were required for a scan length of 15 mm and three vibrational frequencies) 3D mapping of quantitative tumour viscoelastic properties in vivo, allowing exploration of regional heterogeneity within tumours and speedy recovery of animals from anaesthesia so that longitudinal studies (e.g., during tumour growth or following treatment) may be conducted frequently.
c-MYC Protein Stability Is Sustained by MAPKs in Colorectal Cancer
Authors: Lepore Signorile Martina , Grossi Valentina , Fasano Candida , Forte Giovanna , Disciglio Vittoria , Sanese Paola , De Marco Katia , La Rocca Francesca , Armentano Raffaele , Valentini Anna , Giannelli Gianluigi , Simone Cristiano
Published: October 2022

c-MYC is one of the most important factors involved in colorectal cancer (CRC) initiation and progression; indeed, it is found to be upregulated in up to 80% of sporadic cases. During colorectal carcinogenesis, c-MYC is maintained upregulated through β-catenin-mediated transcriptional activation and ERK-mediated post-translational stabilization. Our data demonstrate that p38α, a kinase involved in CRC metabolism and survival, contributes to c-Myc protein stability. Moreover, we show that p38α, like ERK, stabilizes c-MYC protein levels by preventing its ubiquitination. Of note, we found that p38α phosphorylates c-MYC and interacts with it both in vitro and in cellulo. Extensive molecular analyses in the cellular and in vivo models revealed that the p38α kinase inhibitors, SB202190 and ralimetinib, affect c-MYC protein levels. Ralimetinib also exhibited a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Overall, our findings identify p38α as a promising therapeutic target, acting directly on c-MYC, with potential implications for countering c-MYC-mediated CRC proliferation, metastatic dissemination, and chemoresistance.
Neoadjuvant Chemotherapy before Nephroureterectomy in High-Risk Upper Tract Urothelial Cancer: A Systematic Review and Meta-Analysis
Authors: Oswald David , Pallauf Maximilian , Deininger Susanne , Törzsök Peter , Sieberer Manuela , Eiben Christian
Published: October 2022

Neoadjuvant chemotherapy is a well-established concept in muscle-invasive bladder cancer with known advantages in overall survival. Phase II trials show encouraging response rates for neoadjuvant immunotherapy before radical surgery in urothelial cancer. There is no recommendation for neoadjuvant therapy in upper tract urothelial carcinoma before nephroureterectomy. Our aim was to assess the available data on neoadjuvant chemotherapy and immunotherapy before nephroureterectomy in patients with high-risk upper tract urothelial carcinoma in terms of pathological downstaging and oncological outcomes. Two investigators screened PubMed/Medline for comparative trials in the English language. We identified 368 studies and included eleven investigations in a systematic review and meta-analysis for neoadjuvant chemotherapy and control groups. There were no comparative trials investigating immunotherapy in this setting. All 11 studies reported on overall pathological downstaging with a significant effect in favor of neoadjuvant chemotherapy (OR 5.17; 95%CI 3.82; 7.00). Pathological complete response and non-muscle invasive disease were significantly higher in patients receiving neoadjuvant chemotherapy (OR 12.07; 95%CI 4.16; 35.03 and OR 1.62; 95%CI 1.05; 2.49). Overall survival and progression-free survival data analysis showed a slight benefit for neoadjuvant chemotherapy. Our results show that neoadjuvant chemotherapy is effective in downstaging in upper urinary tract urothelial carcinoma. The selection of patients and chemotherapy regimens are unclear.
Prognostic and Predictive Significance of Stromal Tumor-Infiltrating Lymphocytes (sTILs) in ER-Positive/HER2−Negative Postmenopausal Breast Cancer Patients
Authors: Pousette Jenny , Johansson Annelie , Jönsson Carolin , Fornander Tommy , Lindström Linda S. , Olsson Hans , Perez-Tenorio Gizeh
Published: October 2022

The clinical impact of tumor-infiltrating lymphocytes (TILs) is less known for breast cancer patients with the estrogen receptor-positive (ER+)/human epidermal growth factor receptor-negative (HER−) subtype. Here, we explored the prognostic and predictive value of TILs regarding distant recurrence-free interval (DRFI) and breast cancer-specific survival (BCSS) in 763 postmenopausal patients randomized to receive tamoxifen vs. no systemic treatment. TILs were assessed in whole section tumor samples stained with H&E and divided into low (<10%), intermediate (10–39%), or high (≥40%). High TILs were associated with poor prognostic variables and good prognoses for all patients, but not within the ER+/HER2− group. Within the ER+/HER2− group, high gene expression of CD19 and PD-L1 and high IMMUNE1 score indicated good prognosis in multivariable analysis while high CD8 and CD19 gene expression and high IMMUNE1 score were associated with less tamoxifen benefit. These results indicate that within the ER+/HER2− subtype there could be subsets of patients where expression of specific TIL markers might be used to reveal candidates for immune therapy interventions upon failure of the endocrine therapy.
Cytotoxic Mechanism of Momilactones A and B against Acute Promyelocytic Leukemia and Multiple Myeloma Cell Lines
Authors: Anh La Hoang , Lam Vu Quang , Takami Akiyoshi , Khanh Tran Dang , Quan Nguyen Van , Xuan Tran Dang
Published: October 2022

This is the first study clarifying the cytotoxic mechanism of momilactones A (MA) and B (MB) on acute promyelocytic leukemia (APL) HL-60 and multiple myeloma (MM) U266 cell lines. Via the MTT test, MB and the mixture MAB (1:1, w/w) exhibit a potent cytotoxicity on HL-60 (IC50 = 4.49 and 4.61 µM, respectively), which are close to the well-known drugs doxorubicin, all-trans retinoic acid (ATRA), and the mixture of ATRA and arsenic trioxide (ATRA/ATO) (1:1, w/w) (IC50 = 5.22, 3.99, and 3.67 µM, respectively). Meanwhile MB, MAB, and the standard suppressor doxorubicin substantially inhibit U266 (IC50 = 5.09, 5.59, and 0.24 µM, respectively). Notably, MB and MAB at 5 µM may promote HL-60 and U266 cell apoptosis by activating the phosphorylation of p-38 in the mitogen-activated protein kinase (MAPK) pathway and regulating the relevant proteins (BCL-2 and caspase-3) in the mitochondrial pathway. Besides, these compounds may induce G2 phase arrest in the HL-60 cell cycle through the activation of p-38 and disruption of CDK1 and cyclin B1 complex. Exceptionally, momilactones negligibly affect the non-cancerous cell line MeT-5A. This finding provides novel insights into the anticancer property of momilactones, which can be a premise for future studies and developments of momilactone-based anticancer medicines.
Intestinal Microbiota Influence Doxorubicin Responsiveness in Triple-Negative Breast Cancer
Authors: Bawaneh Alaa , Wilson Adam S. , Levi Nicole , Howard-McNatt Marissa M. , Chiba Akiko , Soto-Pantoja David R. , Cook Katherine L.
Published: October 2022

Triple-negative breast cancer (TNBC) is highly aggressive with a poor 5-year survival rate. Targeted therapy options are limited and most TNBC patients are treated with chemotherapy. This study aimed to determine whether doxorubicin (Dox) shifts the gut microbiome and whether gut microbiome populations influence chemotherapeutic responsiveness. Female BALB/c mice (n = 115) were injected with 4T1-luciferase cells (a murine syngeneic TNBC model) and treated with Dox and/or antibiotics, high-fat diet-derived fecal microbiota transplant (HFD-FMT), or exogenous lipopolysaccharide (LPS). Metagenomic sequencing was performed on fecal DNA samples. Mice that received Dox were stratified into Dox responders or Dox nonresponders. Mice from the Dox responders and antibiotics + Dox groups displayed reduced tumor weight and metastatic burden. Metagenomic analysis showed that Dox was associated with increased Akkermansia muciniphila proportional abundance. Moreover, Dox responders showed an elevated proportional abundance of Akkermansia muciniphila prior to Dox treatment. HFD-FMT potentiated tumor growth and decreased Dox responsiveness. Indeed, lipopolysaccharide, a structural component of Gram-negative bacteria, was increased in the plasma of Dox nonresponders and FMT + Dox mice. Treatment with exogenous LPS increases intestinal inflammation, reduces Dox responsiveness, and increases lung metastasis. Taken together, we show that modulating the gut microbiota through antibiotics, HFD-FMT, or by administering LPS influenced TNBC chemotherapy responsiveness, lung metastasis, and intestinal inflammation.
Cholesterol-Inulin Conjugates for Efficient SN38 Nuclear Delivery: Nanomedicines for Precision Cancer Therapy
Authors: Mauro Nicolò , Utzeri Mara Andrea , Cillari Roberta , Scialabba Cinzia , Giammona Gaetano , Cavallaro Gennara
Published: October 2022

An amphiphilic inulin-thiocholesterol conjugate (INU-Cys-TC) was strategically designed as a biodegradable core-shell nanocarrier of 7-ethyl-10-hydroxy-camptothecin (SN38) to enhance its solubility and stability in aqueous media, thus exploiting its brilliant anticancer effect. INU-Cys-TC was designed to have the hydrophilic inulin backbone (external shell) partially functionalized with hydrophobic thiocholesterol moieties (internal core) through a biodegradable disulfide bond due to cysteamine bridges. Thiocholesterol moieties impair redox-sensitive self-assembling abilities, yielding to nano-sized micelles in aqueous media capable of efficiently encapsulating a high amount of SN38 (DL = 8.1%). Micelles (INU-Cys-TC@SN38) were widely characterized, demonstrating an effective and stable delivery strategy to overcome the poor water-solubility of SN38. SN38-loaded micelles showed a gradual and prolonged release of SN38 over time, and a cell- and time-dependent cytotoxicity. In particular, we show that micelles efficiently deliver SN38 inside cell nuclei, and, compared to normal cell lines, they can also enter cancer cells by endo-lysosomes, where a complete degradation can occur releasing the drug payload. Overall, the proposed micelles appear potentially effective as nanomedicines for precision cancer therapies of colorectal and breast cancer, thus improving the SN38 therapeutic index and extending its use in a huge plethora of cancers.
Development of a High-Affinity Antibody against the Tumor-Specific and Hyperactive 611-p95HER2 Isoform
Authors: Dorraji Esmaeil , Borgen Elin , Segura-Peña Dario , Rawat Puneet , Smorodina Eva , Dunn Claire , Greiff Victor , Sekulić Nikolina , Russnes Hege , Kyte Jon Amund
Published: October 2022

The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for aggressive disease and confers resistance to therapy. Contrary to full-length HER2, 611-p95HER2 has negligible normal tissue expression. There is currently no approved diagnostic assay to identify this subgroup and no therapy targeting this mechanism of tumor escape. The purpose of this study was to develop a monoclonal antibody (mAb) against 611-CTF-p95HER2. Hybridomas were generated from rats immunized with cells expressing 611-CTF. A hybridoma producing a highly specific Ab was identified and cloned further as a mAb. This mAb, called Oslo-2, gave strong staining for 611-CTF and no binding to full-length HER2, as assessed in cell lines and tissues by flow cytometry, immunohistochemistry and immunofluorescence. No cross-reactivity against HER2 negative controls was detected. Surface plasmon resonance analysis demonstrated a high binding affinity (equilibrium dissociation constant 2 nM). The target epitope was identified at the N-terminal end, using experimental alanine scanning. Further, the mAb paratope was identified and characterized with hydrogen-deuterium-exchange, and a molecular model for the (Oslo-2 mAb:611-CTF-p95HER2) complex was generated by an experimental-information-driven docking approach. We conclude that the Oslo-2 mAb has a high affinity and is highly specific for 611-CTF-p95HER2. The Ab may be used to develop potent and safe therapies, overcoming p95HER2-mediated tumor escape, as well as for developing diagnostic assays.
Systematic Review of Parotid Gland Sarcomas: Multi-Variate Analysis of Clinicopathologic Findings, Therapeutic Approaches and Oncological Outcomes That Affect Survival Rate
Authors: Colizza Andrea , Di Stadio Arianna , Ralli Massimo , De Luca Pietro , Cavaliere Carlo , Gilardi Antonio , Zoccali Federica , Riminucci Mara , Greco Antonio , Corsi Alessandro , de Vincentiis Marco
Published: October 2022

The aim of this study was to systematically review the literature of sarcoma of the parotid gland in order to analyze the main factors affecting survival rate. A systematic literature review was performed between January 1990 to November 2021, and 88 patients affected by parotid gland sarcomas were included. The most common histological types were Rhabdomyosarcoma and Synovial Sarcoma. From our review, it emerges that primary sarcomas of the parotid glands are locally aggressive but show low tendency to metastasize to the lymph nodes of the neck and that surgery (i.e., total or radical parotidectomy) is the main approach for their treatment. The global overall survival (OS) is 52% at 5 years and 34.1% at 10 years. The OS for T1, T2, T3, T4 tumor at 5 years of follow up is 80.0%, 66.5%, 56.7% and 33.3%, respectively. Size/extension at the diagnosis and the sarcoma’s histotype are the most important prognostic factors. Multivariate analysis showed that surgery (total or radical parotidectomy) performed on the tumor (p = 0.0008) was the only parameter that significantly affected the OS. Among the other variables, age (younger), use of adjuvant therapy and lymph node metastasis showed borderline significative values (p = 0.05). Our analysis suggests that, when a primitive parotid sarcoma is diagnosed, total or radical parotidectomy should be performed at any age independent of tumor histology. Because regional lymph node metastases from parotid sarcomas are uncommon, alternative strategies (e.g., close follow-up by imaging and evaluation of sentinel lymph nodes) should be pursued before lymph node (selective/radical) dissection.
BRAF Inhibitors in Non-Small Cell Lung Cancer
Authors: Sforza Vincenzo , Palumbo Giuliano , Cascetta Priscilla , Carillio Guido , Manzo Anna , Montanino Agnese , Sandomenico Claudia , Costanzo Raffaele , Esposito Giovanna , Laudato Francesca , Damiano Simona , Forte Cira , Frosini Giulia , Farese Stefano , Piccirillo Maria , Pascarella Giacomo , Normanno Nicola , Morabito Alessandro
Published: October 2022

RAF family proteins are serine–threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5–3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.
Novel Insights into Redox-Based Mechanisms for Auranofin-Induced Rapid Cancer Cell Death
Authors: Hatem Elie , El Banna Nadine , Heneman-Masurel Amélie , Baïlle Dorothée , Vernis Laurence , Riquier Sylvie , Golinelli-Cohen Marie-Pierre , Guittet Olivier , Vallières Cindy , Camadro Jean-Michel , Qiu Xue , Hildebrandt Niko , Lepoivre Michel , Huang Meng-Er
Published: October 2022

Auranofin (Ridaura®, AUF) is a gold complex originally approved as an antirheumatic agent that has emerged as a potential candidate for multiple repurposed therapies. The best-studied anticancer mechanism of AUF is the inhibition of thioredoxin reductase (TrxR). However, a number of reports indicate a more complex and multifaceted mode of action for AUF that could be cancer cell type- and dose-dependent. In this study, we observed that AUF displayed variable cytotoxicity in five triple-negative breast cancer cell lines. Using representative MDA-MB-231 cells treated with moderate and cytotoxic doses of AUF, we evidenced that an AUF-mediated TrxR inhibition alone may not be sufficient to induce cell death. Cytotoxic doses of AUF elicited rapid and drastic intracellular oxidative stress affecting the mitochondria, cytoplasm and nucleus. A “redoxome” proteomics investigation revealed that a short treatment with a cytotoxic dose AUF altered the redox state of a number of cysteines-containing proteins, pointing out that the cell proliferation/cell division/cell cycle and cell–cell adhesion/cytoskeleton structure were the mostly affected pathways. Experimentally, AUF treatment triggered a dose-dependent S-phase arrest and a rapid disintegration of the actin cytoskeleton structure. Our study shows a new spectrum of AUF-induced early effects and should provide novel insights into the complex redox-based mechanisms of this promising anticancer molecule.
Glycosaminoglycan Analysis of FFPE Tissues from Prostate Cancer and Benign Prostate Hyperplasia Patients Reveals Altered Regulatory Functions and Independent Markers for Survival
Authors: Tóth Gábor , Sugár Simon , Pál Domonkos , Fügedi Kata Dorina , Drahos László , Schlosser Gitta , Oláh Csilla , Reis Henning , Kovalszky Ilona , Szarvas Tibor , Turiák Lilla
Published: October 2022

Prostate cancer is one of the most frequent cancer types among men. Several biomarkers and risk assessment methods are already available; however, enhancing their selectivity and sensitivity is still necessary. For improving therapeutic decisions, both basic and clinical research studies are still ongoing for a better understanding of the underlying molecular mechanisms. The enzymatic digests of heparan sulfate (HS) and chondroitin sulfate (CS) chains were investigated in tissue samples taken from patients with prostate cancer (PCa) and benign prostate hyperplasia (BPH) with the HPLC–MS methodology. None of the HS species analyzed showed correlating alterations with currently used markers such as clinical stage, Gleason score, or prostate-specific antigen (PSA) level. The total quantity and sulfation motifs of CS were both significantly different among BPH and different risk groups of PCa. Furthermore, the cancer-specific survival of patients can be predicted based on the levels of non-sulfated and doubly sulfated CS disaccharides as well as the total HS content and the doubly and triply sulfated HS disaccharide ratios. These disaccharide ratios proved to be independent markers from clinical parameters. Further investigations of glycosaminoglycan motifs were proposed for the validation of the results on independent patient cohorts as well.
Neuraminidase-1: A Sialidase Involved in the Development of Cancers and Metabolic Diseases
Authors: Toussaint Kévin , Appert-Collin Aline , Morjani Hamid , Albrecht Camille , Sartelet Hervé , Romier-Crouzet Béatrice , Maurice Pascal , Duca Laurent , Blaise Sébastien , Bennasroune Amar
Published: October 2022

Sialidases or neuraminidases (NEU) are glycosidases which cleave terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides. Four types of mammalian sialidases, which are encoded by different genes, have been described with distinct substrate specificity and subcellular localization: NEU-1, NEU-2, NEU-3 and NEU-4. Among them, NEU-1 regulates many membrane receptors through desialylation which results in either the activation or inhibition of these receptors. At the plasma membrane, NEU-1 also associates with the elastin-binding protein and the carboxypeptidase protective protein/cathepsin A to form the elastin receptor complex. The activation of NEU-1 is required for elastogenesis and signal transduction through this receptor, and this is responsible for the biological effects that are mediated by the elastin-derived peptides (EDP) on obesity, insulin resistance and non-alcoholic fatty liver diseases. Furthermore, NEU-1 expression is upregulated in hepatocellular cancer at the mRNA and protein levels in patients, and this sialidase regulates the hepatocellular cancer cells’ proliferation and migration. The implication of NEU-1 in other cancer types has also been shown notably in the development of pancreatic carcinoma and breast cancer. Altogether, these data indicate that NEU-1 plays a key role not only in metabolic disorders, but also in the development of several cancers which make NEU-1 a pharmacological target of high potential in these physiopathological contexts.
The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment
Authors: Bartoszewska Sylwia , Collawn James F. , Bartoszewski Rafal
Published: October 2022

Despite our understanding of the unfolded protein response (UPR) pathways, the crosstalk between the UPR and the complex signaling networks that different cancers utilize for cell survival remains to be, in most cases, a difficult research barrier. A major problem is the constant variability of different cancer types and the different stages of cancer as well as the complexity of the tumor microenvironments (TME). This complexity often leads to apparently contradictory results. Furthermore, the majority of the studies that have been conducted have utilized two-dimensional in vitro cultures of cancer cells that were exposed to continuous hypoxia, and this approach may not mimic the dynamic and cyclic conditions that are found in solid tumors. Here, we discuss the role of intermittent hypoxia, one of inducers of the UPR in the cellular component of TME, and the way in which intermittent hypoxia induces high levels of reactive oxygen species, the activation of the UPR, and the way in which cancer cells modulate the UPR to aid in their survival. Although the past decade has resulted in defining the complex, novel non-coding RNA-based regulatory networks that modulate the means by which hypoxia influences the UPR, we are now just to beginning to understand some of the connections between hypoxia, the UPR, and the TME.
The Clinical Impact of Hepatic Arterial Infusion Chemotherapy New-FP for Hepatocellular Carcinoma with Preserved Liver Function
Authors: Iwamoto Hideki , Niizeki Takashi , Nagamatsu Hiroaki , Ueshima Kazuomi , Tani Joji , Kuzuya Teiji , Kasai Kazuhiro , Kooka Youhei , Hiraoka Atsushi , Sugimoto Rie , Yonezawa Takehiro , Tanaka Satoshi , Deguchi Akihiro , Shimose Shigeo , Shirono Tomotake , Sakai Miwa , Suzuki Hiroyuki , Moriyama Etsuko , Koga Hironori , Torimura Takuji , Kawaguchi Takumi ,   New FP Study Group,   Kurume Liver Cancer Study Group of Japan
Published: October 2022

Background: Systemic treatments are recommended for advanced hepatocellular carcinoma (HCC) in preserved liver function. However, their effects are unsatisfactory in some tumor conditions, particularly macrovascular invasion (MVI) including major portal vein tumor thrombus (PVTT). We compared the efficacy of hepatic arterial infusion chemotherapy (HAIC) regimens New-FP and sorafenib for various tumor conditions in preserved liver function. Methods: We retrospectively collected the data of 1709 patients with HCC who were treated with New-FP or sorafenib. Survival was assessed after propensity score matching. Subgroup analyses were conducted: cohort 1 (no MVI or extrahepatic spread (EHS)), cohort 2 (MVI only), cohort 3 (EHS only), cohort 4 (MVI and EHS), and cohort 5 (major PVTT). Results: The New-FP group had a longer median survival time (MST) than the sorafenib in the whole analysis (18 vs. 9 months; p < 0.0001). New-FP demonstrated a longer MST compared with sorafenib in cohort 2 and cohort 4. In cohort 5, the MST of the New-FP group was 16 months, while that of sorafenib was 6 months (p < 0.0001). For major PVTT-HCC, the response rate of New-FP was 73.0%. The MST of patients who achieved complete response with New-FP was 59 months. Conclusions: HAIC using New-FP is promising for patients with MVI- and major PVTT-HCC in preserved liver function.
Oncogenic Role of HMGB1 as An Alarming in Robust Prediction of Immunotherapy Response in Colorectal Cancer
Authors: Lu Huijiao , Zhu Mengyi , Qu Lin , Shao Hongwei , Zhang Rongxin , Li Yan
Published: October 2022

Objective: To assess the correlation between HMGB1 expression and the patient prognosis in a multicancer context. Methods: The potential oncogenic role of HMGB1 was explored in forty tumors through the TCGA, GEO, and Oncomine datasets. We analyzed the clinical prognostic value and antitumor immunotherapy of HMGB1 in a multicancer context using GEO (GSE111636). Results: High expression of HMGB1 is present in multicancer cases, and its low expression is closely associated with the prognostic survival of patients, in terms of both overall and disease-free survival in ACC and LUAD. Further investigation revealed that the high expression of gastric and lung cancer is closely associated with low risk and better prognosis of patients based on COX and Kaplan–Meier analysis of OS, FP and PPS. HMGB1 expression was found to be significantly correlated with cancer-associated fibroblast and CD8+ T cell infiltration in the TME. The analysis of GO functional annotation/KEGG pathways indicates that HMGB1 may regulate tumor immunity-related pathways, such as the tumor immunotherapy response in colorectal cancer. The function of four genes as hubs are confirmed by in vitro HMGB1 knockdown which led to inhibition of cell proliferation and metastasis in SW620 and SW480 cells. Conclusion: HMGB1 is a potential novel biomarker for improving clinical prognosis and antitumor immunotherapy efficacy. CDK1, HMGB2, SSRP1, and H2AFV may serve as key nodes for HMGB1 in colorectal cancer.
Multiphasic Heterogeneity of Fibroblasts in the Microenvironment of Pancreatic Ductal Adenocarcinoma: Dissection and the Sum of the Dynamics
Authors: Ijichi Hideaki
Published: October 2022

Pancreatic cancer is still the most intractable cancer, with a 5-year survival of around 10%. To conquer the most common type, pancreatic ductal adenocarcinoma (PDAC), we need to understand its pathobiology, especially the tumor microenvironment (TME) that characteristically contains abundant stromal components, with marked fibrosis. In this Special Issue, “Tumor Microenvironment and Pancreatic Cancer”, various aspects of TME were discussed, most frequently including articles related to cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM). CAFs and ECM have been considered in favor of PDAC cells; however, surprisingly, depleting CAFs or reducing the stromal components in PDAC-model mice induced aggressive PDAC and worsened the prognosis. Subsequently, accumulating studies have elucidated evidence of the heterogeneity of CAFs and the plasticity between the subtypes. Possible cancer-promoting and -restraining properties of the CAF subtypes have been suggested, but these are yet to be fully elucidated. Here, in addition to the extensive reviews on the heterogeneity of CAFs in this Special Issue, I refer to another insight from a recent integrative study of PDAC TME, that PDAC TME can be divided into three distinct sub-tumor microenvironments (subTMEs), and the co-existence of the distinct subTMEs is associated with poor prognosis. In the subTME, the heterogeneity of each component, including CAFs, can be changed transiently through various interactions in the TME, and the sum of the transient change and dynamic plasticity might be timely tuned in the co-existence of distinct subTMEs to contribute to the poor prognosis. Thus, understanding the more detailed underlying mechanisms in this heterogeneity of TME, as well as how to control the sum of multiphasic heterogeneity, might lead to the establishment of a more desirable therapeutic strategy to conquer intractable PDAC.