bluuebunny/crossref_metadata_2025 huggingface dataset:
Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells
Authors: Galofré Claudia , Gönül Geyik Öykü , Asensio Elena , Wangsa Darawalee , Hirsch Daniela , Parra Carolina , Saez Jordi , Mollà Meritxell , Yüce Zeynep , Castells Antoni , Ried Thomas , Camps Jordi
Published: May 2020

Tetraploidy, or whole-genome duplication, is a common phenomenon in cancer and preludes chromosome instability, which strongly correlates with disease progression, metastasis, and treatment failure. Therefore, it is reasonable to hypothesize that tetraploidization confers multidrug resistance. Nevertheless, the contribution of whole-genome duplication to chemo-radiotherapy resistance remains unclear. Here, using isogenic diploid and near-tetraploid clones from three colorectal cancer cell lines and one non-transformed human epithelial cell line, we show a consistent growth impairment but a divergent tumorigenic potential of near-tetraploid cells. Next, we assessed the effects of first-line chemotherapeutic drugs, other commonly used agents and ionizing radiation, and found that whole-genome duplication promoted increased chemotherapy resistance and also conferred protection against irradiation. When testing the activation of apoptosis, we observed that tetraploid cells were less prone to caspase 3 activation after treatment with first-line chemotherapeutic agents. Furthermore, we found that pre-treatment with ataxia telangiectasia and Rad3 related (ATR) inhibitors, which targets response to replication stress, significantly enhanced the sensitivity of tetraploid cells to first-line chemotherapeutic agents as well as to ionizing radiation. Our findings provide further insight into how tetraploidy results in greater levels of tolerance to chemo-radiotherapeutic agents and, moreover, we show that ATR inhibitors can sensitize near-tetraploid cells to commonly used chemo-radiotherapy regimens.
Warburg and Beyond: The Power of Mitochondrial Metabolism to Collaborate or Replace Fermentative Glycolysis in Cancer
Authors: Cassim Shamir , Vučetić Milica , Ždralević Maša , Pouyssegur Jacques
Published: May 2020

A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has been crucial for the development of clinical imaging modalities, it has become now evident that in contrast to prior beliefs, mitochondria play a key role in tumorigenesis. Recent findings demonstrated that a full genetic disruption of the Warburg effect of aggressive cancers does not suppress but instead reduces tumor growth. Tumor growth then relies exclusively on functional mitochondria. Besides having fundamental bioenergetic functions, mitochondrial metabolism indeed provides appropriate building blocks for tumor anabolism, controls redox balance, and coordinates cell death. Hence, mitochondria represent promising targets for the development of novel anti-cancer agents. Here, after revisiting the long-standing Warburg effect from a historic and dynamic perspective, we review the role of mitochondria in cancer with particular attention to the cancer cell-intrinsic/extrinsic mechanisms through which mitochondria influence all steps of tumorigenesis, and briefly discuss the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.
The Role of lncRNAs TAPIR-1 and -2 as Diagnostic Markers and Potential Therapeutic Targets in Prostate Cancer
Authors: Friedrich Maik , Wiedemann Karolin , Reiche Kristin , Puppel Sven-Holger , Pfeifer Gabriele , Zipfel Ivonne , Binder Stefanie , Köhl Ulrike , Müller Gerd A. , Engeland Kurt , Aigner Achim , Füssel Susanne , Fröhner Michael , Peitzsch Claudia , Dubrovska Anna , Rade Michael , Christ Sabina , Schreiber Stephan , Hackermüller Jörg , Lehmann Jörg , Toma Marieta I. , Muders Michael H. , Sommer Ulrich , Baretton Gustavo B. , Wirth Manfred , Horn Friedemann
Published: May 2020

In search of new biomarkers suitable for the diagnosis and treatment of prostate cancer, genome-wide transcriptome sequencing was carried out with tissue specimens from 40 prostate cancer (PCa) and 8 benign prostate hyperplasia patients. We identified two intergenic long non-coding transcripts, located in close genomic proximity, which are highly expressed in PCa. Microarray studies on a larger cohort comprising 155 patients showed a profound diagnostic potential of these transcripts (AUC~0.94), which we designated as tumor associated prostate cancer increased lncRNA (TAPIR-1 and -2). To test their therapeutic potential, knockdown experiments with siRNA were carried out. The knockdown caused an increase in the p53/TP53 tumor suppressor protein level followed by downregulation of a large number of cell cycle- and DNA-damage repair key regulators. Furthermore, in radiation therapy resistant tumor cells, the knockdown leads to a renewed sensitization of these cells to radiation treatment. Accordingly, in a preclinical PCa xenograft model in mice, the systemic application of nanoparticles loaded with siRNA targeting TAPIR-1 significantly reduced tumor growth. These findings point to a crucial role of TAPIR-1 and -2 in PCa.
Identifying Therapies to Combat Epithelial Mesenchymal Plasticity-Associated Chemoresistance to Conventional Breast Cancer Therapies Using An shRNA Library Screen
Authors: Bhatia Sugandha , Blick Tony , Pinto Cletus , Waltham Mark , Monkman James , Ivanova Ekaterina , Pollock Pamela M. , Nagaraj Shivashankar H. , Wiegmans Adrian P. , Haviv Izhak , Simpson Kaylene J. , Thompson Erik W.
Published: May 2020

Background: Breast cancer (BC) is a heterogeneous disease for which the commonly used chemotherapeutic agents primarily include the anthracyclines (doxorubicin, epirubicin), microtubule inhibitors (paclitaxel, docetaxel, eribulin), and alkylating agents (cyclophosphamide). While these drugs can be highly effective, metastatic tumours are frequently refractory to treatment or become resistant upon tumour relapse. Methods: We undertook a cell polarity/epithelial mesenchymal plasticity (EMP)-enriched short hairpin RNA (shRNA) screen in MDA-MB-468 breast cancer cells to identify factors underpinning heterogeneous responses to three chemotherapeutic agents used clinically in breast cancer: Doxorubicin, docetaxel, and eribulin. shRNA-transduced cells were treated for 6 weeks with the EC10 of each drug, and shRNA representation assessed by deep sequencing. We first identified candidate genes with depleted shRNA, implying that their silencing could promote a response. Using the Broad Institute’s Connectivity Map (CMap), we identified partner inhibitors targeting the identified gene families that may induce cell death in combination with doxorubicin, and tested them with all three drug treatments. Results: In total, 259 shRNAs were depleted with doxorubicin treatment (at p < 0.01), 66 with docetaxel, and 25 with eribulin. Twenty-four depleted hairpins overlapped between doxorubicin and docetaxel, and shRNAs for TGFB2, RUNX1, CCDC80, and HYOU1 were depleted across all the three drug treatments. Inhibitors of MDM/TP53, TGFBR, and FGFR were identified by CMap as the top pharmaceutical perturbagens and we validated the combinatorial benefits of the TGFBR inhibitor (SB525334) and MDM inhibitor (RITA) with doxorubicin treatment, and also observed synergy between the inhibitor SB525334 and eribulin in MDA-MB-468 cells. Conclusions: Taken together, a cell polarity/EMP-enriched shRNA library screen identified relevant gene products that could be targeted alongside current chemotherapeutic agents for the treatment of invasive BC.
Usefulness of Two Independent DNA and RNA Tissue-Based Multiplex Assays for the Routine Care of Advanced NSCLC Patients
Authors: Marin Elba , Teixido Cristina , Carmona-Rocha Elena , Reyes Roxana , Arcocha Ainara , Viñolas Nuria , Rodríguez-Mues MªCarmen , Cabrera Carlos , Sánchez Marcelo , Vollmer Ivan , Castillo Sergi , Muñoz Silvia , Sullivan Ivana G. , Rodriguez Adela , Garcia Mireia , Alos Silvia , Jares Pedro , Martinez Antonio , Prat Aleix , Molina-Vila Miguel Ángel , Reguart Noemi
Published: May 2020

Personalized medicine is nowadays a paradigm in lung cancer management, offering important benefits to patients. This study aimed to test the feasibility and utility of embedding two multiplexed genomic platforms as the routine workup of advanced non-squamous non-small cell lung cancer (NSCLC) patients. Two parallel multiplexed approaches were performed based on DNA sequencing and direct digital detection of RNA with nCounter® technology to evaluate gene mutations and fusions. The results were used to guide genotype-directed therapies and patient outcomes were collected. A total of 224 advanced non-squamous NSCLC patients were prospectively included in the study. Overall, 85% of samples were successfully characterized at DNA and RNA levels and oncogenic drivers were found in 68% of patients, with KRAS, EGFR, METΔex14, BRAF, and ALK being the most frequent (31%, 19%, 5%, 4%, and 4%, respectively). Among all patients with complete genotyping results and follow-up data (n = 156), the median overall survival (OS) was 1.90 years (confidence interval (CI) 95% 1.69–2.10) for individuals harbouring an actionable driver treated with a matched therapy, compared with 0.59 years (CI 95% 0.39–0.79) in those not eligible for any targeted therapy and 0.61 years (CI 95% 0.12–1.10) in patients with no drivers identified (p < 0.001). Integrating DNA and RNA multiplexing technologies into the routine molecular testing of advanced NSCLC patients is feasible and useful and highlights the necessity of widespread integrating comprehensive molecular diagnosis into lung cancer care.
Precision Medicine for NSCLC in the Era of Immunotherapy: New Biomarkers to Select the Most Suitable Treatment or the Most Suitable Patient
Authors: Rossi Giovanni , Russo Alessandro , Tagliamento Marco , Tuzi Alessandro , Nigro Olga , Vallome Giacomo , Sini Claudio , Grassi Massimiliano , Dal Bello Maria Giovanna , Coco Simona , Longo Luca , Zullo Lodovica , Tanda Enrica Teresa , Dellepiane Chiara , Pronzato Paolo , Genova Carlo
Published: May 2020

In recent years, the evolution of treatments has made it possible to significantly improve the outcomes of patients with non-small cell lung cancer (NSCLC). In particular, while molecular targeted therapies are effective in specific patient sub-groups, immune checkpoint inhibitors (ICIs) have greatly influenced the outcomes of a large proportion of NSCLC patients. While nivolumab activity was initially assessed irrespective of predictive biomarkers, subsequent pivotal studies involving other PD-1/PD-L1 inhibitors in pre-treated advanced NSCLC (atezolizumab within the OAK study and pembrolizumab in the Keynote 010 study) reported the first correlations between clinical outcomes and PD-L1 expression. However, PD-L1 could not be sufficient on its own to select patients who may benefit from immunotherapy. Many studies have tried to discover more precise markers that are derived from tumor tissue or from peripheral blood. This review aims to analyze any characteristics of the immunogram that could be used as a predictive biomarker for response to ICIs. Furthermore, we describe the most important genetic alteration that might predict the activity of immunotherapy.
Evaluation of Anti-Tumor Effects of Whole-Body Low-Dose Irradiation in Metastatic Mouse Models
Authors: Song Kyung-Hee , Jung Seung-Youn , Park Jeong-In , Ahn Jiyeon , Park Jong-Kuk , Hwang Sang-Gu , Kim Eun-Ho , Nam Seon Young , Park Seungwoo , Ha Hunjoo , Song Jie-Young
Published: May 2020

Low-dose irradiation (LDI) has recently been shown to have various beneficial effects on human health, such as on cellular metabolic activities, DNA repair, antioxidant activity, homeostasis potency, and immune activation. Although studies on the immunogenic effects of LDI are rapidly accumulating, clinical trials for cancer treatment are considered premature owing to the lack of available preclinical results and protocols. Here, we aim to investigate anti-tumor and anti-metastatic effects of whole-body LDI in several tumor-bearing mouse models. Mice were exposed to single or fractionated whole-body LDI prior to tumor transplantation, and tumor growth and metastatic potential were determined, along with analysis of immune cell populations and expression of epithelial–mesenchymal transition (EMT) markers. Whole-body fractionated-LDI decreased tumor development and lung metastasis not only by infiltration of CD4+, CD8+ T-cells, and dendritic cells (DCs) but also by attenuating EMT. Moreover, a combination of whole-body LDI with localized high-dose radiation therapy reduced the non-irradiated abscopal tumor growth and increased infiltration of effector T cells and DCs. Therefore, whole-body LDI in combination with high-dose radiation therapy could be a potential therapeutic strategy for treating cancer.
Survival of Patients with Hepatocellular Carcinoma in Renal Insufficiency: Prognostic Role of Albumin-Bilirubin Grade
Authors: Ho Shu-Yein , Hsu Chia-Yang , Liu Po-Hong , Ko Chih-Chieh , Huang Yi-Hsiang , Su Chien-Wei , Lee Rheun-Chuan , Hou Ming-Chih , Huo Teh-Ia
Published: May 2020

Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). The prognostic role of albumin-bilirubin (ALBI) grade in this special setting is unclear. We aimed to investigate the role of ALBI grade associated with the impact of RI on HCC. A prospective cohort of 3690 HCC patients between 2002 and 2016 were retrospectively analyzed. The Kaplan–Meier method and multivariate Cox proportional hazards model were used to determine survival and independent prognostic predictors. Of all patients, RI was an independent predictor associated with decreased survival. In multivariate Cox analysis for patients with RI, α-fetoprotein level ≥20 ng/mL, tumor size >3 cm, vascular invasion, distant metastasis, presence of ascites, performance status 1–2, performance status 3–4, and ALBI grade 2 and grade 3 were independent predictors of decreased survival (all p < 0.05). In subgroup analysis of patients with RI undergoing curative and non-curative treatments, the ALBI grade remained a significant prognostic predictor associated with decreased survival (p < 0.001). In summary, HCC patients with RI have decreased survival compared to those without RI. The ALBI grade can discriminate the survival in patients with RI independent of treatment strategy and is a feasible prognostic tool in this special patient population.
Multicenter Retrospective Analysis of Second-Line Therapy after Gemcitabine Plus Nab-Paclitaxel in Advanced Pancreatic Cancer Patients
Authors: Merz Valeria , Cavaliere Alessandro , Messina Carlo , Salati Massimiliano , Zecchetto Camilla , Casalino Simona , Milella Michele , Caffo Orazio , Melisi Davide
Published: May 2020

Pancreatic cancer is one of the most lethal solid tumors. In many European countries gemcitabine plus nab-paclitaxel is the preferred first-line treatment. An increasing number of patients are eligible for second-line therapy, but the best regimen is still controversial. This study aimed to evaluate the efficacy of oxaliplatin-based compared to irinotecan-based therapies in this setting. 181 advanced pancreatic cancer patients consecutively treated in three centers with a second-line therapy progressed on gemcitabine plus nab-paclitaxel were retrospectively enrolled. OS and PFS were calculated using the Kaplan-Meier method and survival of the two groups was compared using the log-rank test. The median PFS and OS were respectively 3.5 (95%CI 3.2–3.8) and 8.8 months (95%CI 7.9–9.8) from second-line therapy in the overall population. The median PFS and OS were respectively 3.3 (95%CI 3.1–3.5) and 8.2 months (95%CI 7.24–9.34) with an irinotecan-based combination compared to 4.0 (95%CI 2.4–5.7) and 10.3 months (95%CI 8.62–12.02) in patients receiving an oxaliplatin-based combination. We observed a clear trend for longer survival outcomes with platinum-based doublet compared to regimens including irinotecan or nal-IRI. Head-to-head trials are still lacking. The neutrophil-to-lymphocyte ratio and the presence of liver metastases could drive physicians in tailoring the treatment strategy.
Cytoskeletal Disruption after Electroporation and Its Significance to Pulsed Electric Field Therapies
Authors: Graybill Philip M. , Davalos Rafael V.
Published: May 2020

Pulsed electric fields (PEFs) have become clinically important through the success of Irreversible Electroporation (IRE), Electrochemotherapy (ECT), and nanosecond PEFs (nsPEFs) for the treatment of tumors. PEFs increase the permeability of cell membranes, a phenomenon known as electroporation. In addition to well-known membrane effects, PEFs can cause profound cytoskeletal disruption. In this review, we summarize the current understanding of cytoskeletal disruption after PEFs. Compiling available studies, we describe PEF-induced cytoskeletal disruption and possible mechanisms of disruption. Additionally, we consider how cytoskeletal alterations contribute to cell–cell and cell–substrate disruption. We conclude with a discussion of cytoskeletal disruption-induced anti-vascular effects of PEFs and consider how a better understanding of cytoskeletal disruption after PEFs may lead to more effective therapies.
Multi-Gene Prognostic Signatures and Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in ER-Positive, HER2-Negative Breast Cancer Patients
Authors: Mazo Claudia , Barron Stephen , Mooney Catherine , Gallagher William M.
Published: May 2020

Determining which patients with early-stage breast cancer should receive chemotherapy is an important clinical issue. Chemotherapy has several adverse side effects, impacting on quality of life, along with significant economic consequences. There are a number of multi-gene prognostic signatures for breast cancer recurrence but there is less evidence that these prognostic signatures are predictive of therapy benefit. Biomarkers that can predict patient response to chemotherapy can help avoid ineffective over-treatment. The aim of this work was to assess if the OncoMasTR prognostic signature can predict pathological complete response (pCR) to neoadjuvant chemotherapy, and to compare its predictive value with other prognostic signatures: EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes. Gene expression datasets from ER-positive, HER2-negative breast cancer patients that had pre-treatment biopsies, received neoadjuvant chemotherapy and an assessment of pCR were obtained from the Gene Expression Omnibus repository. A total of 813 patients with 66 pCR events were included in the analysis. OncoMasTR, EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes numeric risk scores were approximated by applying the gene coefficients to the corresponding mean probe expression values. OncoMasTR, EndoPredict and Oncotype DX prognostic scores were moderately well correlated according to the Pearson’s correlation coefficient. Association with pCR was estimated using logistic regression. The odds ratio for a 1 standard deviation increase in risk score, adjusted for cohort, were similar in magnitude for all four signatures. Additionally, the four signatures were significant predictors of pCR. OncoMasTR added significant predictive value to Tumor Infiltrating Leukocytes signatures as determined by bivariable and trivariable analysis. In this in silico analysis, OncoMasTR, EndoPredict, Oncotype DX, and Tumor Infiltrating Leukocytes were significantly predictive of pCR to neoadjuvant chemotherapy in ER-positive and HER2-negative breast cancer patients.
Increased Level of Long Non-Coding RNA MALAT1 Is a Common Feature of Amoeboid Invasion
Authors: Merta Ladislav , Gandalovičová Aneta , Čermák Vladimír , Dibus Michal , Gutschner Tony , Diederichs Sven , Rösel Daniel , Brábek Jan
Published: May 2020

The ability of cancer cells to adopt various migration modes (the plasticity of cancer cell invasiveness) is a substantive obstacle in the treatment of metastasis, yet still an incompletely understood process. We performed a comparison of publicly available transcriptomic datasets from various cell types undergoing a switch between the mesenchymal and amoeboid migration modes. Strikingly, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was one of three genes that were found upregulated in all amoeboid cells analyzed. Accordingly, downregulation of MALAT1 in predominantly amoeboid cell lines A375m2 and A2058 resulted in decrease of active RhoA (Ras homolog family member A) and was accompanied by the amoeboid-mesenchymal transition in A375m2 cells. Moreover, MALAT1 downregulation in amoeboid cells led to increased cell proliferation. Our work is the first to address the role of MALAT1 in MAT/AMT (mesenchymal to amoeboid transition/amoeboid to mesenchymal transition) and suggests that increased MALAT1 expression is a common feature of amoeboid cells.
Expanding the Spectrum of Adenoviral Vectors for Cancer Therapy
Authors: Gao Jian , Zhang Wenli , Ehrhardt Anja
Published: May 2020

Adenoviral vectors (AdVs) have attracted much attention in the fields of vaccine development and treatment for diseases such as genetic disorders and cancer. In this review, we discuss the utility of AdVs in cancer therapies. In recent years, AdVs were modified as oncolytic AdVs (OAs) that possess the characteristics of cancer cell-specific replication and killing. Different carriers such as diverse cells and extracellular vesicles are being explored for delivering OAs into cancer sites after systemic administration. In addition, there are also various strategies to improve cancer-specific replication of OAs, mainly through modifying the early region 1 (E1) of the virus genome. It has been documented that oncolytic viruses (OVs) function through stimulating the immune system, resulting in the inhibition of cancer progression and, in combination with classical immune modulators, the anti-cancer effect of OAs can be even further enforced. To enhance the cancer treatment efficacy, OAs are also combined with other standard treatments, including surgery, chemotherapy and radiotherapy. Adenovirus type 5 (Ad5) has mainly been explored to develop vectors for cancer treatment with different modulations. Only a limited number of the more than 100 identified AdV types were converted into OAs and, therefore, the construction of an adenovirus library for the screening of potential novel OA candidates is essential. Here, we provide a state-of-the-art overview of currently performed and completed clinic trials with OAs and an adenovirus library, providing novel possibilities for developing innovative adenoviral vectors for cancer treatment.
SNAI1-Driven Sequential EMT Changes Attributed by Selective Chromatin Enrichment of RAD21 and GRHL2
Authors: Sundararajan Vignesh , Tan Ming , Zea Tan Tuan , Pang Qing You , Ye Jieru , Chung Vin Yee , Huang Ruby Yun-Ju
Published: May 2020

Over two decades of research on cancer-associated epithelial-mesenchymal transition (EMT) led us to ascertain the occurrence of transitional intermediate states (collectively referred to as the EMT spectrum). Among the molecular factors that drive EMT, SNAI1 plays an indispensable role in regulating other core transcription factors, and this regulation is highly context-dependent. However, molecular investigation on this context-dependent regulation is still lacking. Using two ovarian cancer cell lines, we show that SNAI1 regulation on other core EMT-TFs switches from a repressive control in highly epithelial cells to an activation signaling in intermediate epithelial cells. Upon further scrutiny, we identify that the expression of early epithelial genes PERP and ERBB3 are differentially regulated in SNAI1-induced sequential EMT changes. Mechanistically, we show that changes in PERP and ERBB3 transcript levels could be correlated to the selective enrichment loss of RAD21, a cohesin component, at the distal enhancer sites of PERP and ERBB3, which precedes that of the proximal promoter-associated sites. Furthermore, the RAD21 enrichment at the distal enhancer sites is dependent on GRHL2 expression. In a nutshell, the alteration of GRHL2-associated RAD21 enrichment in epithelial genes is crucial to redefine the transition of cellular states along the EMT spectrum.
Molecular Signatures of JMJD10/MINA53 in Gastric Cancer
Authors: Aziz Nur , Hong Yo Han , Jo Min Kyeong , Kim Jin Kyeong , Kim Kyung-Hee , Ashktorab Hassan , Smoot Duane T. , Hur Hoon , Yoo Byong Chul , Cho Jae Youl
Published: May 2020

The JMJD10 gene and its encoded protein MYC-induced nuclear antigen (MINA53) are associated with multiple cancers. Besides having both an oncogenic and tumor suppressor function, the intricate role of JMJD10 in cancer is complex as it depends on the cancer type. In particular, the functional role of JMJD10/MINA53 in gastric cancer has been poorly understood. In this study, we have unraveled the molecular signatures and functional roles of JMJD10/MINA53 in gastric cancer by multiple approaches, i.e., multi-omics bioinformatics study, analysis of human gastric cancer tissues, and studies in vitro using knockdown or overexpression strategies in gastric cancer cell lines. The results indicated that the JMJD10 gene and MINA53 protein are commonly overexpressed in cancer patients. JMJD10/MINA53 is involved in the regulation of proliferation and survival of gastric cancer by controlling cell cycle gene expression. These processes are highly associated with MINA53 enzymatic activity in the regulation of H3K9me3 methylation status and controlling activation of AP-1 signaling pathways. This highlights the oncogenic role of JMJD10/MINA53 in gastric cancer and opens the opportunity to develop therapeutic targeting of JMJD10/MINA53 in gastric cancer.
Integrative Analysis of Fecal Metagenomics and Metabolomics in Colorectal Cancer
Authors: Clos-Garcia Marc , Garcia Koldo , Alonso Cristina , Iruarrizaga-Lejarreta Marta , D’Amato Mauro , Crespo Anais , Iglesias Agueda , Cubiella Joaquín , Bujanda Luis , Falcón-Pérez Juan Manuel
Published: May 2020

Although colorectal cancer (CRC) is the second leading cause of death in developed countries, current diagnostic tests for early disease stages are suboptimal. We have performed a combination of UHPLC-MS metabolomics and 16S microbiome analyses on 224 feces samples in order to identify early biomarkers for both advanced adenomas (AD) and CRC. We report differences in fecal levels of cholesteryl esters and sphingolipids in CRC. We identified Fusobacterium, Parvimonas and Staphylococcus to be increased in CRC patients and Lachnospiraceae family to be reduced. We finally described Adlercreutzia to be more abundant in AD patients’ feces. Integration of metabolomics and microbiome data revealed tight interactions between bacteria and host and performed better than FOB test for CRC diagnosis. This study identifies potential early biomarkers that outperform current diagnostic tools and frame them into the stablished gut microbiota role in CRC pathogenesis.
Direct Oral Anticoagulants in Cancer Patients. Time for a Change in Paradigm
Authors: Wojtukiewicz Marek Z. , Skalij Piotr , Tokajuk Piotr , Politynska Barbara , Wojtukiewicz Anna M. , Tucker Stephanie C. , Honn Kenneth V.
Published: May 2020

Thrombosis is a more common occurrence in cancer patients compared to the general population and is one of the main causes of death in these patients. Low molecular weight heparin (LMWH) has been the recognized standard treatment for more than a decade, both in cancer-related thrombosis and in its prevention. Direct oral anticoagulants (DOACs) are a new option for anticoagulation therapy. Recently published results of large randomized clinical trials have confirmed that DOAC may be a reasonable alternative to LMWH in cancer patients. The following review summarizes the current evidence on the safety and efficacy of DOAC in the treatment and prevention of cancer-related thrombosis. It also draws attention to the limitations of this group of drugs, knowledge of which will facilitate the selection of optimal therapy.
Establishment and Validation of an Individualized Cell Cycle Process-Related Gene Signature to Predict Cancer-Specific Survival in Patients with Bladder Cancer
Authors: Shi Run , Bao Xuanwen , Rogowski Paul , Schäfer Christian , Schmidt-Hegemann Nina-Sophie , Unger Kristian , Lu Shun , Sun Jing , Buchner Alexander , Stief Christian , Belka Claus , Li Minglun
Published: May 2020

More accurate models are essential to identify high-risk bladder cancer (BCa) patients who will benefit from adjuvant therapies and thus helpful to facilitate personalized management of BCa. Among various cancer-related hallmarks and pathways, cell cycle process (CCP) was identified as a dominant risk factor for cancer-specific survival (CSS) in BCa. Using a series of bioinformatic and statistical approaches, a CCP-related gene signature was established, and the prognostic value was validated in other independent BCa cohorts. In addition, the risk score derived from the gene signature serves as a promising marker for therapeutic resistance. In combination with clinicopathological features, a nomogram was constructed to provide more accurate prediction for CSS, and a decision tree was built to identify high-risk subgroup of muscle invasive BCa patients. Overall, the gene signature could be a useful tool to predict CSS and help to identify high-risk subgroup of BCa patients, which may benefit from intensified adjuvant therapy.
Leveraging Advances in Artificial Intelligence to Improve the Quality and Timing of Palliative Care
Authors: Windisch Paul , Hertler Caroline , Blum David , Zwahlen Daniel , Förster Robert
Published: May 2020

In recent years, research on artificial intelligence (AI) in medicine has seen great advances, especially with regards to the detection of diseases [...]
Cytoplasmic Increase in Hsp70 Protein: A Potential New Biomarker of Early Infiltration of Cutaneous Squamous Cell Carcinoma Arising from Actinic Keratosis
Authors: Fernández-Guarino Montserrat , Zamorano León José Javier , López Farré Antonio José , González Morales Maria Luisa , Sánchez Adrada Ana Isabel , Barrio Garde José , Arias Navalon Jose Antonio , Jaén Olasolo Pedro
Published: May 2020

Background: Cutaneous squamous skin cell carcinoma (SCC) is the second most frequent type of non-melanoma skin cancer and is the second leading cause of death by skin cancer in Caucasian populations. However, at present it is difficult to predict patients with poor SCC prognosis. Objective: To identify proteins with expression levels that could predict SCC infiltration in SCC arising from actinic keratosis (SCC-AK). Methods: A total of 20 biopsies from 20 different patients were studied; 10 were SCC-AK samples and 10 were taken from normal skin. Early infiltrated SCC-AK samples were selected based on histological examination, and to determine the expression of proteins, fresh skin samples were processed by two-dimensional electrophoresis. Results: The expression levels of three proteins, namely alpha hemoglobin and heat shock proteins 27 and 70 (Hsp27 and Hsp70, respectively) were significantly increased in SCC-AK samples with respect to normal control skin. However, only the expression level of Hsp70 protein positively correlated with the level of SCC-AK dermis infiltration. Immunohistological examination suggested that increased expression of Hsp70 proteins seemed to mainly occur in the cytoplasm of keratinocytes. The increased cytoplasmic Hsp70 expression in SCC-AK was confirmed by Western blot experiments. Conclusion: Cytoplasmic expression of Hsp70 could be a potential biomarker of early infiltration of SCC arising from AK.
Pediatric Low-Grade Gliomas
Authors: Collins Kelly L. , Pollack Ian F.
Published: May 2020

Brain tumors constitute the largest source of oncologic mortality in children and low-grade gliomas are among most common pediatric central nervous system tumors. Pediatric low-grade gliomas differ from their counterparts in the adult population in their histopathology, genetics, and standard of care. Over the past decade, an increasingly detailed understanding of the molecular and genetic characteristics of pediatric brain tumors led to tailored therapy directed by integrated phenotypic and genotypic parameters and the availability of an increasing array of molecular-directed therapies. Advances in neuroimaging, conformal radiation therapy, and conventional chemotherapy further improved treatment outcomes. This article reviews the current classification of pediatric low-grade gliomas, their histopathologic and radiographic features, state-of-the-art surgical and adjuvant therapies, and emerging therapies currently under study in clinical trials.
Metabolism and Immune Modulation in Patients with Solid Tumors: Systematic Review of Preclinical and Clinical Evidence
Authors: Mirabile Aurora , Rivoltini Licia , Daveri Elena , Vernieri Claudio , Mele Roberto , Porcu Luca , Lazzari Chiara , Bulotta Alessandra , Viganò Maria Grazia , Cascinu Stefano , Gregorc Vanesa
Published: May 2020

Several immunotherapy agents are the standard of care of many solid malignancies. Nevertheless, the majority of patients do not benefit from the currently available immunotherapies. It is therefore of paramount importance to identify the prognostic and predictive factors of tumor response/resistance and to design effective therapeutic strategies to overcome primary resistance and improve the efficacy of immunotherapy. The aim of this review is to underline the influence of the tumor and host metabolism on the antitumor immune response and to discuss possible strategies to improve the efficacy of available treatments by targeting the specific metabolic pathways in tumors or immune cells and by modifying patients’ nutritional statuses. A systematic search of the Medline and EMBASE databases was carried out to identify scientific papers published until February 2020, which reported original research articles on the influence of tumor or host metabolism on antitumor immune response. The literature data showed the key role of glycolysis and mitochondrial oxidative phosphorylation, arginine, tryptophan, glutamine, lipid metabolism and microbiome on immune cell function. Moreover, specific nutritional behaviors, such as a low dietary intake of vitamin C, low glycemic index and alpha-linolenic acid, eicosapentenoic acid, docosahexaenoic acid, ornithine ketoglutarate, tryptophan and probiotic supplementation were associated with the potential clinical benefits from the currently available immunotherapies.
MHC Class I Regulation: The Origin Perspective
Authors: Sznarkowska Alicja , Mikac Sara , Pilch Magdalena
Published: May 2020

Viral-derived elements and non-coding RNAs that build up “junk DNA” allow for flexible and context-dependent gene expression. They are extremely dense in the MHC region, accounting for flexible expression of the MHC I, II, and III genes and adjusting the level of immune response to the environmental stimuli. This review brings forward the viral-mediated aspects of the origin and evolution of adaptive immunity and aims to link this perspective with the MHC class I regulation. The complex regulatory network behind MHC expression is largely controlled by virus-derived elements, both as binding sites for immune transcription factors and as sources of regulatory non-coding RNAs. These regulatory RNAs are imbalanced in cancer and associate with different tumor types, making them promising targets for diagnostic and therapeutic interventions.
Impact and Diagnostic Gaps of Comprehensive Genomic Profiling in Real-World Clinical Practice
Authors: Singh Aditi P. , Shum Elaine , Rajdev Lakshmi , Cheng Haiying , Goel Sanjay , Perez-Soler Roman , Halmos Balazs
Published: May 2020

Purpose: next-generation sequencing based comprehensive genomic profiling (CGP) is becoming common practice. Although numerous studies have shown its feasibility to identify actionable genomic alterations in most patients, its clinical impact as part of routine management across all cancers in the community remains unknown. Methods: we conducted a retrospective study of all patients that underwent CGP as part of routine cancer management from January 2013 to June 2017 at an academic community-based NCI-designated cancer center. CGP was done in addition to established first tier reflex molecular testing as per national guidelines (e.g., EGFR/ALK for non-small cell lung cancer (NSCLC) and extended-RAS for colorectal cancer). Results: 349 tests were sent for CGP from 333 patients and 95% had at least one actionable genomic alteration reported. According to the reported results, 23.2% had a Food and Drug Administration (FDA) approved therapy available, 61.3% had an off-label therapy available and 77.9% were potentially eligible for a clinical trial. Treatment recommendations were also reviewed within the OncoKB database and 47% of them were not clinically validated therapies. The CGP results led to treatment change in only 35 patients (10%), most commonly in NSCLC. Nineteen of these patients (54% of those treated and 5% of total) had documented clinical benefit with targeted therapy. Conclusion: we demonstrate that routine use of CGP in the community across all cancer types detects potentially actionable genomic alterations in a majority of patients, however has modest clinical impact enriched in the NSCLC subset.
Targeting GSK3 and Associated Signaling Pathways Involved in Cancer
Authors: Duda Przemysław , Akula Shaw M. , Abrams Stephen L. , Steelman Linda S. , Martelli Alberto M. , Cocco Lucio , Ratti Stefano , Candido Saverio , Libra Massimo , Montalto Giuseppe , Cervello Melchiorre , Gizak Agnieszka , Rakus Dariusz , McCubrey James A.
Published: May 2020

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.
Environmental Restrictions: A New Concept Governing HIV-1 Spread Emerging from Integrated Experimental-Computational Analysis of Tissue-Like 3D Cultures
Authors: Sid Ahmed Samy , Bundgaard Nils , Graw Frederik , Fackler Oliver
Published: May 2020

HIV-1 can use cell-free and cell-associated transmission modes to infect new target cells, but how the virus spreads in the infected host remains to be determined. We recently established 3D collagen cultures to study HIV-1 spread in tissue-like environments and applied iterative cycles of experimentation and computation to develop a first in silico model to describe the dynamics of HIV-1 spread in complex tissue. These analyses (i) revealed that 3D collagen environments restrict cell-free HIV-1 infection but promote cell-associated virus transmission and (ii) defined that cell densities in tissue dictate the efficacy of these transmission modes for virus spread. In this review, we discuss, in the context of the current literature, the implications of this study for our understanding of HIV-1 spread in vivo, which aspects of in vivo physiology this integrated experimental–computational analysis takes into account, and how it can be further improved experimentally and in silico.
How Diffusion Impacts Cortical Protein Distribution in Yeasts
Authors: Moran Kyle D. , Lew Daniel J.
Published: May 2020

Proteins associated with the yeast plasma membrane often accumulate asymmetrically within the plane of the membrane. Asymmetric accumulation is thought to underlie diverse processes, including polarized growth, stress sensing, and aging. Here, we review our evolving understanding of how cells achieve asymmetric distributions of membrane proteins despite the anticipated dissipative effects of diffusion, and highlight recent findings suggesting that differential diffusion is exploited to create, rather than dissipate, asymmetry. We also highlight open questions about diffusion in yeast plasma membranes that remain unsolved.
Interleukin-6 Treatment Results in GLUT4 Translocation and AMPK Phosphorylation in Neuronal SH-SY5Y Cells
Authors: Marko Daniel M. , Foran Gregory , Vlavcheski Filip , Baron David C. , Hayward Grant C. , Baranowski Bradley J. , Necakov Aleksander , Tsiani Evangelia , MacPherson Rebecca E. K.
Published: May 2020

Interleukin-6 (IL-6) is a pleiotropic cytokine that can be released from the brain during prolonged exercise. In peripheral tissues, exercise induced IL-6 can result in GLUT4 translocation and increased glucose uptake through AMPK activation. GLUT4 is expressed in the brain and can be recruited to axonal plasma membranes with neuronal activity through AMPK activation. The aim of this study is to examine if IL-6 treatment: (1) results in AMPK activation in neuronal cells, (2) increases the activation of proteins involved in GLUT4 translocation, and (3) increases neuronal glucose uptake. Retinoic acid was used to differentiate SH-SY5Y neuronal cells. Treatment with 100 nM of insulin increased the phosphorylation of Akt and AS160 (p < 0.05). Treatment with 20 ng/mL of IL-6 resulted in the phosphorylation of STAT3 at Tyr705 (p ≤ 0.05) as well as AS160 (p < 0.05). Fluorescent Glut4GFP imaging revealed treatment with 20ng/mL of IL-6 resulted in a significant mobilization towards the plasma membrane after 5 min until 30 min. There was no difference in GLUT4 mobilization between the insulin and IL-6 treated groups. Importantly, IL-6 treatment increased glucose uptake. Our findings demonstrate that IL-6 and insulin can phosphorylate AS160 via different signaling pathways (AMPK and PI3K/Akt, respectively) and promote GLUT4 translocation towards the neuronal plasma membrane, resulting in increased neuronal glucose uptake in SH-SY5Y cells.
IAP-Mediated Protein Ubiquitination in Regulating Cell Signaling
Authors: Dumétier Baptiste , Zadoroznyj Aymeric , Dubrez Laurence
Published: May 2020

Over the last decade, the E3-ubiquitine ligases from IAP (Inhibitor of Apoptosis) family have emerged as potent regulators of immune response. In immune cells, they control signaling pathways driving differentiation and inflammation in response to stimulation of tumor necrosis factor receptor (TNFR) family, pattern-recognition receptors (PRRs), and some cytokine receptors. They are able to control the activity, the cellular fate, or the stability of actors of signaling pathways, acting at different levels from components of receptor-associated multiprotein complexes to signaling effectors and transcription factors, as well as cytoskeleton regulators. Much less is known about ubiquitination substrates involved in non-immune signaling pathways. This review aimed to present IAP ubiquitination substrates and the role of IAP-mediated ubiquitination in regulating signaling pathways.
Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity
Authors: Gupte Manisha , Umbarkar Prachi , Singh Anand Prakash , Zhang Qinkun , Tousif Sultan , Lal Hind
Published: May 2020

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.
Human Induced Pluripotent Stem Cell-Derived 3D-Neurospheres Are Suitable for Neurotoxicity Screening
Authors: Kobolak Julianna , Teglasi Annamaria , Bellak Tamas , Janstova Zofia , Molnar Kinga , Zana Melinda , Bock Istvan , Laszlo Lajos , Dinnyes Andras
Published: May 2020

We present a hiPSC-based 3D in vitro system suitable to test neurotoxicity (NT). Human iPSCs-derived 3D neurospheres grown in 96-well plate format were characterized timewise for 6-weeks. Changes in complexity and homogeneity were followed by immunocytochemistry and transmission electron microscopy. Transcriptional activity of major developmental, structural, and cell-type-specific markers was investigated at weekly intervals to present the differentiation of neurons, astrocytes, and oligodendrocytes. Neurospheres were exposed to different well-known toxicants with or without neurotoxic effect (e.g., paraquat, acrylamide, or ibuprofen) and examined at various stages of the differentiation with an ATP-based cell viability assay optimized for 3D-tissues. Concentration responses were investigated after acute (72 h) exposure. Moreover, the compound-specific effect of rotenone was investigated by a panel of ER-stress assay, TUNEL assay, immunocytochemistry, electron microscopy, and in 3D-spheroid based neurite outgrowth assay. The acute exposure to different classes of toxicants revealed distinct susceptibility profiles in a differentiation stage-dependent manner, indicating that hiPSC-based 3D in vitro neurosphere models could be used effectively to evaluate NT, and can be developed further to detect developmental neurotoxicity (DNT) and thus replace or complement the use of animal models in various basic research and pharmaceutical applications.