bluuebunny/crossref_metadata_2025 huggingface dataset:
Preservation of the Hypoxic Transcriptome in Glioblastoma Patient-Derived Cell Lines Maintained at Lowered Oxygen Tension
Authors: Gozdz Agata , Wojtaś Bartosz , Szpak Patrycja , Szadkowska Paulina , Czernicki Tomasz , Marchel Andrzej , Wójtowicz Katarzyna , Kaspera Wojciech , Ladzinski Piotr , Szopa Wojciech , Niedbala Marcin , Nawrocki Sergiusz , Kaminska Bozena , Kalaszczynska Ilona
Published: October 2022

Despite numerous efforts aiming to characterise glioblastoma pathology (GBM) and discover new therapeutic strategies, GBM remains one of the most challenging tumours to treat. Here we propose the optimisation of in vitro culturing of GBM patient-derived cells, namely the establishment of GBM-derived cultures and their maintenance at oxygen tension mimicking oxygenation conditions occurring within the tumour. To globally analyse cell states, we performed the transcriptome analysis of GBM patient-derived cells kept as spheroids in serum-free conditions at the reduced oxygen tension (5% O2), cells cultured at atmospheric oxygen (20% O2), and parental tumour. Immune cells present in the tumour were depleted, resulting in the decreased expression of the immune system and inflammation-related genes. The expression of genes promoting cell proliferation and DNA repair was higher in GBM cell cultures when compared to the relevant tumour sample. However, lowering oxygen tension to 5% did not affect the proliferation rate and expression of cell cycle and DNA repair genes in GBM cell cultures. Culturing GBM cells at 5% oxygen was sufficient to increase the expression of specific stemness markers, particularly the PROM1 gene, without affecting neural cell differentiation markers. GBM spheroids cultured at 5% oxygen expressed higher levels of hypoxia-inducible genes, including those encoding glycolytic enzymes and pro-angiogenic factors. The genes up-regulated in cells cultured at 5% oxygen had higher expression in parental GBMs compared to that observed in 20% cell cultures, suggesting the preservation of the hypoxic component of GBM transcriptome at 5% oxygen and its loss in standard culture conditions. Evaluation of expression of those genes in The Cancer Genome Atlas dataset comprising samples of normal brain tissue, lower-grade gliomas and GBMs indicated the expression pattern of the indicated genes was specific for GBM. Moreover, GBM cells cultured at 5% oxygen were more resistant to temozolomide, the chemotherapeutic used in GBM therapy. The presented comparison of GBM cultures maintained at high and low oxygen tension together with analysis of tumour transcriptome indicates that lowering oxygen tension during cell culture may more allegedly reproduce tumour cell behaviour within GBM than standard culture conditions (e.g., atmospheric oxygen tension). Low oxygen culture conditions should be considered as a more appropriate model for further studies on glioblastoma pathology and therapy.
Should the Splenic Vein Be Preserved—Fate of Sinistral Portal Hypertension after Pancreatoduodenectomy with Vascular Re-Section for Pancreatic Cancer
Authors: Kim Sung Hyun , Kim Seung-Seob , Hwang Ho Kyoung , Lee Woo Jung , Kang Chang Moo
Published: October 2022

Background: This study aims to evaluate sinistral portal hypertension (SPH) development and its clinical impact on the long-term outcomes of patients with pancreatic cancer who underwent surgical resection with splenic vein (SV) ligation. Methods: Data from 94 consecutive patients who underwent pancreatoduodenectomy (PD) with vascular resection for pancreatic cancer from 2008 to 2019 were retrospectively collected. The patients were divided into two groups according to whether the SV was preserved or ligated during the surgery. Their computed tomography images were serially reviewed (preoperative, 6-, 12-, and 24-months postoperative) with clinical parameters. The degree of variceal formation (variceal score) and splenomegaly were assessed, and the oncologic outcomes were compared between the two groups. Variceal score in the SV ligation group was significantly higher than that in the SV saving group at the same postoperative periods (SV saving vs. ligation: 12 months, 0.9 ± 1.3 vs. 3.5 ± 2.2, p < 0.001; 24 months, 1.4 ± 1.8 vs. 4.0 ± 3.4, p = 0.009). Clinically relevant variceal bleeding was noted in one patient from the SV ligation group (SV saving vs. ligation: 0.0% vs. 3.1%, p = 0.953). In survival analysis, there was no significant difference between the two groups (DFS; SV saving vs. ligation: 13.0 (11.1–14.9) months vs. 13.0 (10.4–15.6) months, p = 0.969, OS; SV saving vs. ligation: 35.0 (19.9–50.1) months vs. 27.0 (11.6–42.4) months, p = 0.417). Although SV ligation induced SPH during PD for pancreatic cancer, it did not lead to clinically significant long-term complications. In addition, it did not impact the long-term survival of patients with resected pancreatic head cancer.
Anti-Apoptotic c-FLIP Reduces the Anti-Tumour Activity of Chimeric Antigen Receptor T Cells
Authors: Tan Grace Min Yi , Poudel Aarati , Ali Hosseini Rad Seyed Mohammad , McLellan Alexander Donald
Published: October 2022

CAR T cell treatment of solid tumours is limited by poor persistence partly due to CD95 ligand (CD95L)-induced apoptosis. Both T cells and cells within the tumour microenvironment (TME) may express CD95L, triggering apoptosis in CD95-receptor-positive CAR T cells. Tonic signalling of CAR T cells may also increase CD95-dependent AICD. Because the intracellular protein c-FLIP protects T cells from AICD, we expressed c-FLIPp43 within a Her-2 targeted CAR cassette and evaluated the potential of c-FLIPp43 through in vitro functional assays and in vivo tumour-bearing xenograft model. cFLIP expression protected against CD95L-induced cell death in the Jurkat T cell lines. However, in primary human CAR T cells containing CAR-CD28 domains, c-FLIPp43 overexpression had minimal additional impact on resistance to CD95L-induded cell death. In vitro cytotoxicity against a breast cancer tumour cell line was not altered by c-FLIPp43 expression, but the expression of c-FLIPp43 in Her2-CAR T cells lowered interferon-γ secretion, without markedly affecting IL-2 levels, and c-FLIPp43-Her2-CAR T cells showed reduced anti-tumour activity in immunodeficient mice with breast cancer. The findings of this study provide a new understanding of the effects of controlling extrinsic apoptosis pathway suppression in CAR T cells, suggesting that c-FLIPp43 expression reduces anti-tumour immunity through the modulation of effector T cell pathways.
Large Improvements in Health-Related Quality of Life and Physical Fitness during Multidisciplinary Inpatient Rehabilitation for Pediatric Cancer Survivors
Authors: Riedl David , Licht Thomas , Nickels Alain , Rothmund Maria , Rumpold Gerhard , Holzner Bernhard , Grote Vincent , Fischer Michael J. , Fischmeister Gustav
Published: October 2022

Rehabilitation is a key element in improving health-related quality of life (HRQOL) for pediatric cancer survivors. The aim of this study was to present data from a multidisciplinary inpatient rehabilitation treatment. Children took part in a four-week multidisciplinary family-oriented inpatient rehabilitation. A total of 236 children (>5–21 years) and 478 parents routinely completed electronic patient-reported outcomes (ePROs), performance-based assessments, and clinician-rated assessments before (T1) and at the end (T2) of rehabilitation. HRQOL was assessed with the PedsQL generic core and PedsQL cancer module. Data were analyzed using repeated measures analysis of variance (ANOVA). Statistically significant improvements with medium to large effect sizes were observed for most HRQOL scales (η2 = 0.09–0.31), as well as performance-based and clinician-rated assessments for physical activity and functional status (η2 > 0.28). Agreement between children’s PROs and parents’ proxy ratings was lower before (rICC = 0.72) than after (rICC = 0.86) rehabilitation. While the concordance between children and parents’ assessment of changes during rehab was low to moderate (r = 0.19–0.59), the use of the performance score led to substantially increased scores (r = 0.29–0.68). The results of this naturalistic observational study thus highlight the benefits of multidisciplinary pediatric inpatient rehabilitation for childhood cancer survivors. The use of the performance score is recommended in this field.
Spatial Transcriptomic Analysis Reveals Associations between Genes and Cellular Topology in Breast and Prostate Cancers
Authors: Alsaleh Lujain , Li Chen , Couetil Justin L. , Ye Ze , Huang Kun , Zhang Jie , Chen Chao , Johnson Travis S.
Published: October 2022

Background: Cancer is the leading cause of death worldwide with breast and prostate cancer the most common among women and men, respectively. Gene expression and image features are independently prognostic of patient survival; but until the advent of spatial transcriptomics (ST), it was not possible to determine how gene expression of cells was tied to their spatial relationships (i.e., topology). Methods: We identify topology-associated genes (TAGs) that correlate with 700 image topological features (ITFs) in breast and prostate cancer ST samples. Genes and image topological features are independently clustered and correlated with each other. Themes among genes correlated with ITFs are investigated by functional enrichment analysis. Results: Overall, topology-associated genes (TAG) corresponding to extracellular matrix (ECM) and Collagen Type I Trimer gene ontology terms are common to both prostate and breast cancer. In breast cancer specifically, we identify the ZAG-PIP Complex as a TAG. In prostate cancer, we identify distinct TAGs that are enriched for GI dysmotility and the IgA immunoglobulin complex. We identified TAGs in every ST slide regardless of cancer type. Conclusions: These TAGs are enriched for ontology terms, illustrating the biological relevance to our image topology features and their potential utility in diagnostic and prognostic models.
Lysine Methyltransferase NSD1 and Cancers: Any Role in Melanoma?
Authors: Krossa Imène , Strub Thomas , Aplin Andrew E. , Ballotti Robert , Bertolotto Corine
Published: October 2022

Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of NSD1 in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or promoter functions according to the tissue context and we discuss the role of NSD1 in melanoma. Finally, we examine the ongoing efforts to target NSD1 signaling in cancers.
Targeting the DNA Damage Response and DNA Repair Pathways to Enhance Radiosensitivity in Colorectal Cancer
Authors: Deng Siyao , Vlatkovic Tijana , Li Moying , Zhan Tianzuo , Veldwijk Marlon R. , Herskind Carsten
Published: October 2022

Radiotherapy is an important component of current treatment options for colorectal cancer (CRC). It is either applied as neoadjuvant radiotherapy to improve local disease control in rectal cancers or for the treatment of localized metastatic lesions of CRC. DNA double-strand breaks (DSBs) are the major critical lesions contributing to ionizing radiation (IR)-induced cell death. However, CRC stem cells promote radioresistance and tumor cell survival through activating cell-cycle checkpoints to trigger the DNA damage response (DDR) and DNA repair after exposure to IR. A promising strategy to overcome radioresistance is to target the DDR and DNA repair pathways with drugs that inhibit activated cell-cycle checkpoint proteins, thereby improving the sensitivity of CRC cells to radiotherapy. In this review, we focus on the preclinical studies and advances in clinical trials of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related kinase (ATR), checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2), WEE1 and poly (ADP-ribose) polymerase 1 (PARP1) kinase inhibitors in CRC. Importantly, we also discuss the selective radiosensitization of CRC cells provided by synthetic lethality of these inhibitors and the potential for widening the therapeutic window by targeting the DDR and DNA repair pathways in combination with radiotherapy and immunotherapy.
PTTG1/ZEB1 Axis Regulates E-Cadherin Expression in Human Seminoma
Authors: Teveroni Emanuela , Di Nicuolo Fiorella , Vergani Edoardo , Bianchetti Giada , Bruno Carmine , Maulucci Giuseppe , De Spirito Marco , Cenci Tonia , Pierconti Francesco , Gulino Gaetano , Bassi Pierfrancesco , Pontecorvi Alfredo , Milardi Domenico , Mancini Francesca
Published: October 2022

(1) Background: PTTG1 sustains the EMT process and the invasiveness of several neoplasms. We previously showed the role of nuclear PTTG1 in promoting invasiveness, through its transcriptional target MMP2, in seminoma in vitro models. Here, we investigated the key players involved in PTTG1-mediated EMT in human seminoma. (2) Methods: Two seminoma cell lines and four human seminoma tumor specimens were used. E-Cadherin gene regulation was investigated using Western blot, real-time PCR, and luciferase assay. Immunoprecipitation, ChIP, RE-ChIP, and confocal microscopy analysis were performed to evaluate the interplay between PTTG1 and ZEB1. Matrigel invasion and spheroid formation assays were applied to functionally investigate PTTG1 involvement in the EMT of seminoma cell lines. RNA depletion and overexpression experiments were performed to verify the role of PTTG1/ZEB1 in E-Cadherin repression and seminoma invasiveness. E-Cadherin and ZEB1 levels were analyzed in human testicular tumors from the Atlas database. (3) Results: PTTG1 transcriptionally represses E-Cadherin in seminoma cell lines through ZEB1. The cooperation of PTTG1 with ZEB1 has a significant impact on cell growth/invasion properties involving the EMT process. Analysis of the Atlas database of testicular tumors showed significantly lower E-Cadherin levels in seminoma, where PTTG1 showed nuclear staining. Finally, PTTG1 and ZEB1 strongly localize together in the periphery of the tumors. (4) Conclusions: These results strengthen the evidence for a role of PTTG1 in the EMT process in human seminomas through its cooperation with the transcriptional repressor ZEB1 on the E-Cadherin gene. Our data enrich the molecular characterization of seminoma, suggesting that PTTG1 is a prognostic factor in seminoma clinical management.
The Crucial Role of AR-V7 in Enzalutamide-Resistance of Castration-Resistant Prostate Cancer
Authors: Zheng Zeyuan , Li Jinxin , Liu Yankuo , Shi Zhiyuan , Xuan Zuodong , Yang Kunao , Xu Chunlan , Bai Yang , Fu Meiling , Xiao Qiaohong , Sun Huimin , Shao Chen
Published: October 2022

Prostate cancer (PCa) has the second highest incidence of malignancies occurring in men worldwide. The first-line therapy of PCa is androgen deprivation therapy (ADT). Nonetheless, most patients progress to castration-resistant prostate cancer (CRPC) after being treated by ADT. As a second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ) is the current mainstay of new endocrine therapies for CRPC in clinical use. However, almost all patients develop resistance during AR antagonist therapy due to various mechanisms. At present, ENZ resistance (ENZR) has become challenging in the clinical treatment of CRPC. AR splice variant 7 (AR-V7) refers to a ligand-independent and constitutively active variant of the AR and is considered a key driver of ENZR in CRPC. In this review, we summarize the mechanisms and biological behaviors of AR-V7 in ENZR of CRPC to contribute novel insights for CRPC therapy.
Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast Cancer
Authors: Huo Yang , Shao Shuai , Liu Enze , Li Jin , Tian Zhen , Wu Xue , Zhang Shijun , Stover Daniel , Wu Huanmei , Cheng Lijun , Li Lang
Published: October 2022

Chemoresistance has been a major challenge in the treatment of patients with breast cancer. The diverse omics platforms and small sample sizes reported in the current studies of chemoresistance in breast cancer limit the consensus regarding the underlying molecular mechanisms of chemoresistance and the applicability of these study findings. Therefore, we built two transcriptome datasets for patients with chemotherapy-resistant breast cancers—one comprising paired transcriptome samples from 40 patients before and after chemotherapy and the second including unpaired samples from 690 patients before and 45 patients after chemotherapy. Subsequent conventional pathway analysis and new subpathway analysis using these cohorts uncovered 56 overlapping upregulated genes (false discovery rate [FDR], 0.018) and 36 downregulated genes (FDR, 0.016). Pathway analysis revealed the activation of several pathways in the chemotherapy-resistant tumors, including those of drug metabolism, MAPK, ErbB, calcium, cGMP-PKG, sphingolipid, and PI3K-Akt, as well as those activated by Cushing’s syndrome, human papillomavirus (HPV) infection, and proteoglycans in cancers, and subpathway analysis identified the activation of several more, including fluid shear stress, Wnt, FoxO, ECM-receptor interaction, RAS signaling, Rap1, mTOR focal adhesion, and cellular senescence (FDR < 0.20). Among these pathways, those associated with Cushing’s syndrome, HPV infection, proteoglycans in cancer, fluid shear stress, and focal adhesion have not yet been reported in breast cancer chemoresistance. Pathway and subpathway analysis of a subset of triple-negative breast cancers from the two cohorts revealed activation of the identical chemoresistance pathways.
In Silico Strategies for Designing of Peptide Inhibitors of Oncogenic K-Ras G12V Mutant: Inhibiting Cancer Growth and Proliferation
Authors: Ghufran Mehreen , Khan Haider Ali , Ullah Mehran , Ghufran Sabreen , Ayaz Muhammad , Siddiq Muhammad , Hassan Syed Shams ul , Bungau Simona
Published: October 2022

Ras plays a pivotal function in cell proliferation and is an important protein in signal transduction pathways. Mutations in genes encoding the Ras protein drive the signaling cascades essential for malignant transformation, tumour angiogenesis, and metastasis and are responsible for above 30% of all human cancers. There is evidence that N-Ras, K-Ras, and H-Ras play significant roles in human cancer. The mutated K-Ras protein is typically observed in malignant growths. Mutant K-Ras is the most common in lung, colon, and pancreatic cancers. The purpose of this research was to create peptides that inhibit K-Ras G12V. The crystal structure of the mutant K-Ras G12V-H-REV107 complex was obtained from a protein data bank. Further, we used a residue scan approach to create unique peptides from the reference peptide (H-REV107). AMBER molecular dynamics simulations were used to test the stability of the top four proposed peptides (based on binding free energies). Our findings showed that the top four selected peptides had stronger interactions with K-Ras than the reference peptide and have the ability to block the activation function of K-Ras. Our extensive analyses of binding affinities showed that our designed peptide possesses the potential to inhibit K-Ras and to reduce the progression of cancer.
Multiplexed In Situ Spatial Protein Profiling in the Pursuit of Precision Immuno-Oncology for Patients with Breast Cancer
Authors: Massa Davide , Tosi Anna , Rosato Antonio , Guarneri Valentina , Dieci Maria Vittoria
Published: October 2022

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many solid tumors. In breast cancer (BC), immunotherapy is currently approved in combination with chemotherapy, albeit only in triple-negative breast cancer. Unfortunately, most patients only derive limited benefit from ICIs, progressing either upfront or after an initial response. Therapeutics must engage with a heterogeneous network of complex stromal–cancer interactions that can fail at imposing cancer immune control in multiple domains, such as in the genomic, epigenomic, transcriptomic, proteomic, and metabolomic domains. To overcome these types of heterogeneous resistance phenotypes, several combinatorial strategies are underway. Still, they can be predicted to be effective only in the subgroups of patients in which those specific resistance mechanisms are effectively in place. As single biomarker predictive performances are necessarily suboptimal at capturing the complexity of this articulate network, precision immune-oncology calls for multi-omics tumor microenvironment profiling in order to identify unique predictive patterns and to proactively tailor combinatorial treatments. Multiplexed single-cell spatially resolved tissue analysis, through precise epitope colocalization, allows one to infer cellular functional states in view of their spatial organization. In this review, we discuss—through the lens of the cancer-immunity cycle—selected, established, and emerging markers that may be evaluated in multiplexed spatial protein panels to help identify prognostic and predictive patterns in BC.
Bacterial Involvement in Progression and Metastasis of Adenocarcinoma of the Stomach
Authors: Morgan Amanda D. , Seely Kevin D. , Hagenstein Lauren D. , Florey Garrett M. , Small James M.
Published: October 2022

Gastric cancer metastasis is a process in which the tumor microenvironment may carry significant influence. Helicobacter pylori (H. pylori) infection is well-established as a contributor to gastric carcinoma. However, the role that these bacteria and others may play in gastric carcinoma metastasis is a current focus of study. A review of the literature was conducted to elucidate the process by which gastric adenocarcinoma metastasizes, including its ability to utilize both the lymphatic system and the venous system to disseminate. Studies that investigate the tumor microenvironment at both the primary and secondary sites were assessed in detail. H. pylori and Mycoplasma hyorhinis (M. hyorhinis) were found to be important drivers of the pathogenesis of gastric adenocarcinoma by modifying various steps in cell metastasis, including epithelial–mesenchymal transition, cell migration, and cell invasion. H. pylori is also a known driver of MALT lymphoma, which is often reversible simply with the eradication of infection. M. hyorhinis has been implicated in gastric neoplasia via β-catenin stabilization and subsequent activation of the WNT-signaling pathway, promoting gastric cancer cell motility and inciting cancer progression. Fusobacterium nucleatum (F. nucleatum) and its association with worse prognosis in diffuse-type gastric adenocarcinoma are also reviewed. Recognition of the roles that bacteria play within the metastatic cascade is vital in gastrointestinal adenocarcinoma treatment and potential reoccurrence. Further investigation is needed to establish potential treatment for metastatic gastric carcinoma by targeting the tumor microenvironment.
Chloride Intracellular Channel Proteins (CLICs) and Malignant Tumor Progression: A Focus on the Preventive Role of CLIC2 in Invasion and Metastasis
Authors: Ozaki Saya , Mikami Kanta , Kunieda Takeharu , Tanaka Junya
Published: October 2022

CLICs are the dimorphic protein present in both soluble and membrane fractions. As an integral membrane protein, CLICs potentially possess ion channel activity. However, it is not fully clarified what kinds of roles CLICs play in physiological and pathological conditions. In vertebrates, CLICs are classified into six classes: CLIC1, 2, 3, 4, 5, and 6. Recently, in silico analyses have revealed that the expression level of CLICs may have prognostic significance in cancer. In this review, we focus on CLIC2, which has received less attention than other CLICs, and discuss its role in the metastasis and invasion of malignant tumor cells. CLIC2 is expressed at higher levels in benign tumors than in malignant ones, most likely preventing tumor cell invasion into surrounding tissues. CLIC2 is also expressed in the vascular endothelial cells of normal tissues and maintains their intercellular adhesive junctions, presumably suppressing the hematogenous metastasis of malignant tumor cells. Surprisingly, CLIC2 is localized in secretory granules and secreted into the extracellular milieu. Secreted CLIC2 binds to MMP14 and inhibits its activity, leading to suppressed MMP2 activity. CLIC4, on the other hand, promotes MMP14 activity. These findings challenge the assumption that CLICs are ion channels, implying that they could be potential new targets for the treatment of malignant tumors.
Histological Subtypes Drive Distinct Prognostic Immune Signatures in Classical Hodgkin Lymphoma
Authors: Lamaison Claire , Ferrant Juliette , Gravelle Pauline , Traverse-Glehen Alexandra , Ghesquières Hervé , Tosolini Marie , Rossi Cédric , Ysebaert Loic , Brousset Pierre , Laurent Camille , Syrykh Charlotte
Published: October 2022

Despite the success of standard front-line chemotherapy, 20% of classical Hodgkin lymphoma (cHL) patients still relapse or have refractory disease (r/r), and a subset of them die due to disease progression. There is a critical lack of predictive factors for early identification of those r/r patients who may benefit from new therapeutic strategies. This study aimed to evaluate the dynamic expression of 586 immune-related genes in a cohort of 42 cHL patients including 30 r/r cHL after first-line chemotherapy. Gene expression profiling (GEP) using NanoString technology identified a 19-gene immune signature at diagnosis predictive of cHL relapse, but dependent on histological subtypes. Genes related to tumor survival were found upregulated while genes related to B-lineage were downregulated at diagnosis in r/r nodular sclerosis cHL. In contrast to the mixed-cellularity subtype, comparative GEP analyses between paired diagnosis/relapse biopsies of nodular sclerosis cHL showed 118 differentially expressed genes, supporting an immune contexture switch at relapse with upregulation of immunosuppressive cytokines, such as LGALS1 and TGFB1, and downregulation of the T-cell co-stimulatory receptor ICOS. These results indicate that the predictive value of immune signature in cHL is strongly influenced by histological subtype which should be considered when assessing new immunotherapy target strategies.
Efficacy and Safety of Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Combination Therapy as First-Line Treatment for Patients with Advanced EGFR-Mutated, Non-Small Cell Lung Cancer: A Systematic Review and Bayesian Network Meta-Analysis
Authors: Xue Jianchao , Li Bowen , Wang Yadong , Huang Zhicheng , Liu Xinyu , Guo Chao , Zheng Zhibo , Liang Naixin , Le Xiuning , Li Shanqing
Published: October 2022

(1) Background: Several randomized controlled trials (RCTs) have been conducted in combination with Efficacy and Safety of Epidermal Growth Factor Receptor(EGFR)-Tyrosine Kinase Inhibitor (TKI) for the first-line treatment of patients with advanced non-small cell lung cancer; however, head-to-head comparisons of combination therapies are still lacking. Therefore, this study aims to compare the efficacy and safety of various combination treatments. (2) Methods: We conducted a systematic review and Bayesian network meta-analysis by searching MEDLINE, EMBASE, and COCHRANE for relevant RCTs. (3) Results: TKI combined with antiangiogenic therapy, chemotherapy, or radiation achieved a significant benefit compared with TKI alone for progression free survival (PFS). A combination with radiation yielded better benefits in PFS than any other treatment. In terms of overall survival (OS), only the combination with pemetrexed and carboplatin (HR = 0.63, 95% credible interval 0.43–0.86)/radiation (0.44, 0.23–0.83) was superior to TKI alone. All of the combination therapies may increase the incidence of ≥Grade 3 AEs, as the pooled RRs are over 1; different toxicity spectrums were revealed for individual treatments. (4) Conclusions: The TKI combination of radiation/pemetrexed and carboplatin could provide the best antitumor effects among the first generation TKI-based treatments. Considering safety, ramucirumab and bevacizumab may be the ideal additions to TKIs (systematic review registration: PROSPERO CRD42022350474).
Regulation of Metastasis in Ewing Sarcoma
Authors: Li Mingli , Chen Chunwei
Published: October 2022

Ewing sarcoma (EwS) is a type of bone and soft tissue tumor in children and adolescents. Over 85% of cases are caused by the expression of fusion protein EWSR1-FLI1 generated by chromosome translocation. Acting as a potent chimeric oncoprotein, EWSR1-FLI1 binds to chromatin, changes the epigenetic states, and thus alters the expression of a large set of genes. Several studies have revealed that the expression level of EWSR1-FLI1 is variable and dynamic within and across different EwS cell lines and primary tumors, leading to tumoral heterogeneity. Cells with high EWSR1-FLI1 expression (EWSR1-FLI1-high) proliferate in an exponential manner, whereas cells with low EWSR1-FLI1 expression (EWSR1-FLI1-low) tend to have a strong propensity to migrate, invade, and metastasize. Metastasis is the leading cause of cancer-related deaths. The continuous evolution of EwS research has revealed some of the molecular underpinnings of this dissemination process. In this review, we discuss the molecular signatures that contribute to metastasis.
In Vivo MRI-CEST Tumor pH Imaging Detects Resistance to Proton Pump Inhibitors in Human Prostate Cancer Murine Models
Authors: Irrera Pietro , Consolino Lorena , Roberto Miriam , Capozza Martina , Dhakan Chetan , Carella Antonella , Corrado Alessia , Villano Daisy , Anemone Annasofia , Navarro-Tableros Victor , Bracesco Martina , Dastrù Walter , Aime Silvio , Longo Dario Livio
Published: October 2022

The tumor microenvironment acidification confers treatment resistance; therefore, the interference with pH regulating systems is considered a new therapeutic strategy. In this study, two human prostate cancer cell lines, PC3 and LNCaP, have been treated in vitro with proton pump inhibitors (PPIs), namely Lansoprazole, Esomeprazole (V-ATPases-inhibitors), Cariporide, and Amiloride (NHE1-inhibitors). The cell viability and pH were assessed at several drug concentrations either at normoxic or hypoxic conditions. Since Esomeprazole showed the highest toxicity towards the PC3 cancer cells compared to LNCaP ones, athymic nude mice bearing subcutaneous or orthotopic PC3 tumors were treated with Esomeprazole (dose: 2.5 mg/kg body weight) for a period of three weeks—and tumor growth was monitored. MRI-CEST tumor pH imaging with Iopamidol was performed upon treatment at 3 h, 1 week (in combination with FDG-PET), and after 2 weeks for evaluating acute, early, and late responses. Although acute tumor pH changes were observed in vivo, long-term studies on both PC3 prostate cancer models did not provide any significant change in tumor acidosis or tumor growth. In conclusion, this work shows that MRI-CEST tumor pH imaging is a valuable tool for assessing the in vivo treatment response to PPIs.
CD20 Expression as a Possible Novel Prognostic Marker in CLL: Application of EuroFlow Standardization Technique and Normalization Procedures in Flow Cytometric Expression Analysis
Authors: Schilhabel Anke , Walter Peter Jonas , Cramer Paula , von Tresckow Julia , Kohlscheen Saskia , Szczepanowski Monika , Laqua Anna , Fischer Kirsten , Eichhorst Barbara , Böttcher Sebastian , Schneider Christof , Tausch Eugen , Brüggemann Monika , Kneba Michael , Hallek Michael , Ritgen Matthias
Published: October 2022

Background: CD20 expression is a controversial issue regarding response prediction to anti-CD20 therapy in chronic lymphocytic leukemia (CLL). Methods: Median fluorescence intensities (MFIs) of standard fluorescence beads from the daily calibration of flow cytometers according to EuroFlow protocols were used to establish a normalization approach to study CD20 expression on CLL cells. CD20 MFI was retrospectively assessed prior to and during treatment from flow cytometric measurements of peripheral blood in patients with different depths of molecular response in the four phase-II CLL2-BXX trials (BIG; BAG; BIO; BCG; N = 194) administering either Obinutuzumab or Ofatumumab in combination with targeted agents. Results: No significant difference was observed between the normalized and measured MFIs of CD19 and CD20 on CLL cells. During treatment, CD20 expression levels on CLL cells did not significantly differ between the four investigated different treatment schemes, but a strong molecular response to Ofatumumab seemed to correlate with higher CD20 expression prior to therapy. Conclusions: Standardized staining and instrument monitoring enable a robust assessment of longitudinal biological variations of marker expression based on MFI values. Obinutuzumab showed a higher proportion of patients with a strong MRD response independent from initial CD20 expression, whereas high pre-therapeutic CD20 expression levels seem to correlate with a profound response to Ofatumumab.
Identifying the Metallic State of Rh Catalyst on Boron Nitride during Partial Oxidation of Methane by Using the Product Molecule as the Infrared Probe
Authors: Yao Jikang , Xu Yuanjie , Yang Hua , Ren Zhuangzhuang , Wu Lizhi , Tang Yu
Published: October 2022

The partial oxidation of methane (POM) is a promising method for converting methane to syngas. The transition metal supported on boron nitride (BN) has recently been studied as part of a catalog of emerging catalysts. However, the chemical state of the metal supported on BN during methane reforming is still in debate. In this work, we report a rhodium catalyst on boron nitride (Rh/BN) for the POM, with exceptional activity and long-term stability at 600 °C for 230 h. The Rh/BN catalyst was investigated by X-ray diffraction, X-ray photoelectron spectroscopy, Raman spectroscopy, transmission electron microscopy, and diffuse reflectance infrared Fourier transformed spectroscopy (DRIFTS). As revealed by in situ DRIFTS, the infrared band (2020 cm−1) of the product molecule, CO, adsorbed on the Rh, as the probe confirms the metallic state of Rh during the POM reaction. In addition, the results of in situ DRIFTS indicate that the reactive gaseous environment would react with the catalyst to form B-OH and B-H, which synergistically boost the POM activity.
Enhanced Performance and Stability of a Trimetallic CuZnY/SiBEA Catalyst in Ethanol to Butadiene Reaction by Introducing Copper to Optimize Acid/Base Ratio
Authors: Dai Haowen , Ye Tian , Wang Kewei , Zhang Meng , Wu Li-Ming , Ouyang Gangfeng
Published: October 2022

Bioethanol to butadiene is currently the most promising non-oil-based butadiene production route. Here, copper is introduced into the conventional bimetallic zeolite catalyst to partially substitute for zinc; the isolated tetracoordinated Cu(II) species are formed, with weak and strong basic sites transformed into medium acid sites in trimetallic CuZnY/SiBEA catalyst. A partial substitution of zinc by copper increases the dispersion of metal, reduces the formation of ZnO clusters, decreases the pore blockage, and enhances the total pore volume of catalyst. The Cu1Zn2Y5/SiBEA catalyst with an appropriate 0.33 Cu/(Cu + Zn) mass ratio, a highest medium acid sites/(weak + strong) basic sites value of 6.17, and largest total pore volume of 0.251 cm3/g in all samples presents excellent catalytic performance in the ethanol to butadiene reaction: 99.01% ethanol conversion and 73.36% butadiene selectivity, higher than most reported ethanol to butadiene catalysts. The isolated tetracoordinated Cu(II) structure is stable, which is beneficial to the stability of trimetallic catalyst; when the reaction time is 60 h, the butadiene selectivity is 45.95%, 14% higher than corresponding bimetallic catalyst. The butadiene productivity of Cu1Zn2Y5/SiBEA catalyst reaches up to 1.68 gBD·gcat−1·h−1 at WHSV = 6 h−1 and time-on-stream = 8 h. Increasing reaction temperature could linearly increase the ethanol conversion, while the butadiene selectivity increases first and then decreases, the suitable temperature is 375 ℃ for the highest butadiene yield.
Accelerated Removal of Acid Orange 7 by Natural Iron Ore Activated Peroxymonosulfate System with Hydroxylamine for Promoting Fe(III)/Fe(II) Cycle
Authors: Li Haibo , Wang Linfeng , He Dingyuan , Cai Jie , He Wenjie , Liu Fuzhen , Chen Hanxiao , Zhang Hui , Xu Yin
Published: October 2022

In this study, peroxymonosulfate (PMS) was activated by cheap and readily available natural iron ore to remove Acid Orange 7 (AO7) in water with the assistance of hydroxylamine (HA). Results show that the presence of HA could accelerate the Fe(II)/Fe(III) cycle on the ore surface, promoting the activation of PMS to generate reactive oxidative species. The effects of ore dosage, PMS dosage, HA dosage and initial pH on the degradation of AO7 were investigated in the HA/Ore/PMS system. Under the optimal conditions, the removal of AO7 could reach 93.1% during 30 min, which was 41.4% higher than the ore/PMS system. The AO7 removal increased with the increase of HA, PMS and ore dosage, but was unaffected by the initial solution pH. Based on radical scavenging experiments and EPR tests, the dominant reactive species in the HA/Ore/PMS system were revealed to be the sulfate radical (SO4•−), singlet oxygen (1O2), superoxide radical (O2•−) and hydroxyl radical (•OH), which were responsible for the AO7 degradation. Furthermore, the possible reaction mechanism of PMS activation was proposed. This study provides an efficient technique for the removal of azo dye organic contaminant in water, which has great practical significance.
Efficient Catalysts of Ethanol Steam Reforming Based on Perovskite-Fluorite Nanocomposites with Supported Ni: Effect of the Synthesis Methods on the Activity and Stability
Authors: Arapova Marina , Naurzkulova Symbat , Krieger Tamara , Rogov Vladimir , Sadykov Vladislav
Published: October 2022

Catalysts based on perovskite—fluorite nanocomposites with supported nickel 5%Ni/[Pr0.15Sm0.15Ce0.35Zr0.35O2 + LaMn0.9Ru0.1O3] were synthesized by three different methods. Structural and surface features of as-prepared samples were elucidated by N2 adsorption, XRD, HR TEM with EDX; reducibility and reactivity were estimated by H2-TPR, and catalytic properties were studied in ethanol steam reforming in the 500–700 °C temperature range. The best catalytic activity without coke accumulation was demonstrated for the 5%Ni/[Pr0.15Sm0.15Ce0.35Zr0.35O2+ LaMn0.9Ru0.1O3] catalyst with nanocomposite support obtained by a simple sequential polymeric preparation method. Highly dispersed particles of metallic nickel strongly fixed on the support after the reaction were shown by the HR-TEM and H2 –TPR data. The catalyst provides stable full conversion of ethanol and hydrogen yield above 60% at 600 °C for at least 6 h.
Effect of Hydrogen-Donor of Heavy Crude Oil Catalytic Aquathermolysis in the Presence of a Nickel-Based Catalyst
Authors: Urazov Khoshim Kh. , Sviridenko Nikita N. , Iovik Yuliya A. , Kolobova Ekaterina N. , Grabchenko Maria V. , Kurzina Irina A. , Mukhamatdinov Irek I.
Published: October 2022

The transformations of oil components from the Zyuzeevskoye field during catalytic aquathermolysis in the presence of a nickel-containing catalyst precursor and hydrogen donors were studied. It was found that the yield of gasoline and diesel fractions increased by more than 36% in the case of catalytic aquathermolysis in the presence of tetralin. The maximum conversion of asphaltenes was achieved with a simultaneous slowing down of coke formation by four times. The calculation of the structural-group parameters of initial asphaltenes and the products of thermal cracking and catalytic aquathermolysis was made, and the hypothetical construction of their molecular structures was proposed. It was established that the phase composition, ratio, and morphology of nickel catalysts after catalytic aquathermolysis (CA) and catalytic aquathermolysis with tetralin (CA+T) depend on the amount of “free” hydrogen and are represented by Ni0.96S and Ni9S8.
The Effects of AlPO-n Additives as Catalytic Support on Pd-Catalytic Hydrogenation of 2-Amylanthraquinone Process
Authors: Li Dawei , Su Hongjiu , Yan Hua , Yang Xiaoye , Zhou Junhong , Wang Shudong
Published: October 2022

The Pd-catalyzed hydrogenation of anthraquinone to synthesize hydrogen peroxide is an important process in the chemical industry. A Pd catalyst with high dispersion is the key to hydrogenation activity and selectivity. For the first time, this team introduced the AlPO-5 zeolite to SiO2 powder to prepare a finely dispersed Pd catalyst with higher efficiency than the conventional Pd/SiO2 catalyst. Based on previous research, other aluminophosphate molecular sieves (AlPO-n) with different properties from AlPO-5 were introduced to the SiO2 support, and then the synthesized hydrogenation catalysts were characterized by the BET, XRD, H2-TPR, NH3-TPD, H2-TPD, XPS and HRTEM methods and then tested for the hydrogenation of 2-amylanthraquinone in a continuous stirred tank reactor (CSTR). It was demonstrated that the Pd-AlPO-31/SiO2 catalyst exhibits superior H2O2 yield (8.4 g·L−1) and selectivity (96%) among all prepared Pd-AlPO-n/SiO2 and Pd/SiO2 catalysts. The characterization results suggest that the dimensions and structure of AlPO-31 micropore channels are responsible for highly dispersing Pd particles, preventing the accumulation of Pd particles, and intensifying H2 adsorption in its micropore channels, which is significant for the catalytic activity.
Engineering of Microbial Substrate Promiscuous CYP105A5 for Improving the Flavonoid Hydroxylation
Authors: Subedi Pradeep , Park Jong Kook , Oh Tae-Jin
Published: October 2022

Bacterial cytochrome P450 (CYP) enzymes are versatile biocatalysts that are responsible for the biotransformation of diverse endogenous substances. CYP105A5 from Streptomyces sp. showed substrate flexibility with different flavonoids and was able to catalyze O-demethylation of biochanin A, regioselective C3′-hydroxylation of daidzein, genistein, and naringenin, and additional C8-hydroxylation for daidzein using heterologous redox partners putidaredoxin and putidaredoxin reductase. By rational design of substrate-binding pocket based on experimental data, homology modeling, and molecular docking analysis, we enhanced the product formation rate of flavonoids. The double mutant L100A/I302A and L100A/I408N exhibited greatly enhanced in vivo conversion rates for flavonoid hydroxylation. Particularly, the L100A/I302A mutant’s kcat/Km values and in vivo conversion rate increased by 1.68-fold and 2.57-fold, respectively, for naringenin. Overall, our result might facilitate the potential use of CYP105A5 for future modification and application in whole-cell biocatalysts for the production of valuable polyphenols.
Evaluation of Enzymatic Hydrolysis of Sugarcane Bagasse Using Combination of Enzymes or Co-Substrate to Boost Lytic Polysaccharide Monooxygenases Action
Authors: Balaguer Moya Eva , Cunha Maria Laura Silva , Prado Carina Aline , Turella Simone , da Silva Silvio Silvério , Abou-Hachem Maher , Dragone Giuliano , dos Santos Júlio César , Mussatto Solange Inês
Published: October 2022

This study evaluated innovative approaches for the enzymatic hydrolysis of lignocellulosic biomass. More specifically, assays were performed to evaluate the supplementation of the commercial cellulolytic cocktail Cellic® CTec2 (CC2) with LPMO (GcLPMO9B), H2O2, or cello-oligosaccharide dehydrogenase (CelDH) FgCelDH7C in order to boost the LPMO action and improve the saccharification efficiency of biomass into monosaccharides. The enzymatic hydrolysis was carried out using sugarcane bagasse pretreated by hydrodynamic cavitation-assisted oxidative process, 10% (w/w) solid loading, and 30 FPU CC2/g dry biomass. The results were compared in terms of sugars release and revealed an important influence of the supplementations at the initial 6 h of hydrolysis. While the addition of CelDH led to a steady increase in glucose production to reach 101.1 mg of glucose/g DM, accounting for the highest value achieved after 72 h of hydrolysis, boosting the LPMOs activity by the supplementation of pure LPMOs or the LPMO co-substrate H2O2 were also effective to improve the cellulose conversion, increasing the initial reaction rate of the hydrolysis. These results revealed that LPMOs play an important role on enzymatic hydrolysis of cellulose and boosting their action can help to improve the reaction rate and increase the hydrolysis yield. LPMOs-CelDH oxidative pairs represent a novel potent combination for use in the enzymatic hydrolysis of lignocellulose biomass. Finally, the strategies presented in this study are promising approaches for application in lignocellulosic biorefineries, especially using sugarcane bagasse as a feedstock.
Construction of the Photocatalytic Film of the Recyclable TaON/Nickel Foam with Ohmic Junction for Efficient Wastewater Treatment
Authors: Wang Shaomang , Wang Jie , Liu Rui , Zheng Zhiqian , Guan Yuan , Shen Juan
Published: October 2022

A recyclable photocatalytic film of TaON/Ni foam with ohmic junction is prepared by the electrophoretic deposition technology. The photocatalytic film of 60 mg TaON/Ni foam demonstrates excellent photocatalytic activity and recycling performance for the degradation of basic fuchsin from water. Around 80% of basic fuchsin (50 mL, 10 mg L−1) is removed over 60 mg TaON/Ni foam under irradiation of 72 W LED white light for 5 h. The photocatalytic activity of the film does not significantly decrease after three rounds of use. The active species for the photocatalytic degradation of basic fuchsin are ·O2−, h+ and ·OH.
Natural Polymer-Based Iron Oxide (Fe3O4) Synthesis, Characterization and Its Application for 1-Amino-Nitrobenzene Degradation in Assistance with Oxidants
Authors: Balachandramohan Jayachandrabal , Kumar Mithun , Sivasankar Thirugnanasambandam , Sivakumar Manickam
Published: October 2022

A natural polymer-based iron oxide (Fe3O4) nanocomposite was prepared through a sonochemical-assisted precipitation method. Characterization studies such as X-ray diffractometer, scanning electron microscopy, and transmission electron microscopy have revealed that the synthesized nanocomposites are homogenously distributed, having an average size of ~49 nm with a cubical spinel structure. The toxic 1-amino-nitrobenzene was initially treated with a sonophotochemical process in the presence of synthesized nanocomposites, resulting in lower efficiency, whereas with the addition of oxidants, the efficiency enhanced significantly. The parametric effects with respect to the initial solution pH, nanocomposites dose, 1-amino-nitrobenzene concentration, and oxidant concentration were studied, and it was found that an approximately 75% removal efficiency of 1-amino-nitrobenzene was achieved within 120 min. Further, the performance of the catalyst on the oxidation of 1-amino-nitrobenzene with sodium persulfate was also investigated, and it was found that a 95% removal efficiency was attained.