bluuebunny/crossref_metadata_2025 huggingface dataset:
FDA and EMA Approvals of New Breast Cancer Drugs—A Comparative Regulatory Analysis
Authors: Leo Chandra P. , Hentschel Bettina , Szucs Thomas D. , Leo Cornelia
Published: February 2020

Breast cancer is the most common cancer in women worldwide and the solid tumor type for which the highest number of drugs have been approved to date. This study examines new drug approvals for breast cancer by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), based on an analysis of regulatory documents from both agencies for the period from 1995 to 2018. Of the 29 breast cancer drugs approved over this time span, 17 received positive decisions from both the FDA and EMA, including all drugs licensed after 2008. Nineteen of the 25 FDA-approved drugs, but none of the EMA approvals, benefited from special regulatory pathways (such as fast track, breakthrough therapy, or priority review). In the U.S.A., four accelerated approvals were granted (of which one, for bevacizumab, was later revoked), while only two drugs received provisional approvals following EMA review. New breast cancer drugs were approved approximately twelve months earlier in the United States than in Europe. These results suggest that a broader use of special regulatory pathways by EMA could help to accelerate access to novel drugs for European breast cancer patients.
Targeting Melanoma Hypoxia with the Food-Grade Lactic Acid Bacterium Lactococcus Lactis
Authors: Garza-Morales Rodolfo , Rendon Beatriz E. , Malik Mohammad Tariq , Garza-Cabrales Jeannete E. , Aucouturier Anne , Bermúdez-Humarán Luis G. , McMasters Kelly M. , McNally Lacey R. , Gomez-Gutierrez Jorge G.
Published: February 2020

Melanoma is the most aggressive form of skin cancer. Hypoxia is a feature of the tumor microenvironment that reduces efficacy of immuno- and chemotherapies, resulting in poor clinical outcomes. Lactococcus lactis is a facultative anaerobic gram-positive lactic acid bacterium (LAB) that is Generally Recognized as Safe (GRAS). Recently, the use of LAB as a delivery vehicle has emerged as an alternative strategy to deliver therapeutic molecules; therefore, we investigated whether L. lactis can target and localize within melanoma hypoxic niches. To simulate hypoxic conditions in vitro, melanoma cells A2058, A375 and MeWo were cultured in a chamber with a gas mixture of 5% CO2, 94% N2 and 1% O2. Among the cell lines tested, MeWo cells displayed greater survival rates when compared to A2058 and A375 cells. Co-cultures of L. lactis expressing GFP or mCherry and MeWo cells revealed that L. lactis efficiently express the transgenes under hypoxic conditions. Moreover, multispectral optoacoustic tomography (MSOT), and near infrared (NIR) imaging of tumor-bearing BALB/c mice revealed that the intravenous injection of either L. lactis expressing β-galactosidase (β-gal) or infrared fluorescent protein (IRFP713) results in the establishment of the recombinant bacteria within tumor hypoxic niches. Overall, our data suggest that L. lactis represents an alternative strategy to target and deliver therapeutic molecules into the tumor hypoxic microenvironment.
Patient-Derived Xenograft Models in Urological Malignancies: Urothelial Cell Carcinoma and Renal Cell Carcinoma
Authors: Tracey Andrew T. , Murray Katie S. , Coleman Jonathan A. , Kim Kwanghee
Published: February 2020

The engraftment of human tumor tissues into immunodeficient host mice to generate patient-derived xenograft (PDX) models has become increasingly utilized for many types of cancers. By capturing the unique genomic and molecular properties of the parental tumor, PDX models enable analysis of patient-specific clinical responses. PDX models are an important platform to address the contribution of inter-tumoral heterogeneity to therapeutic sensitivity, tumor evolution, and the mechanisms of treatment resistance. With the increasingly important role played by targeted therapies in urological malignancies, the establishment of representative PDX models can contribute to improved facilitation and adoption of precision medicine. In this review of the evolving role of the PDX in urothelial cancer and kidney cancer, we discuss the essential elements of successful graft development, effective translational application, and future directions for clinical models.
Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit?
Authors: Wojcicki Anna V. , Kadapakkam Meena , Frymoyer Adam , Lacayo Norman , Chae Hee-Don , Sakamoto Kathleen M.
Published: February 2020

Acute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive and leads to a number of secondary effects with varying results by patient population. Due to the high cost of discovery and an unmet need for new targeted therapies that are well tolerated, alternative drug development strategies have become increasingly attractive. Repurposing existing drugs is one approach to identify new therapies with fewer financial and regulatory hurdles. In this review, we provide an overview of previously U.S. Food and Drug Administration (FDA) approved non-chemotherapy drugs under investigation for the treatment of AML.
Pre-Analytical and Analytical Variables of Label-Independent Enrichment and Automated Detection of Circulating Tumor Cells in Cancer Patients
Authors: Koch Claudia , Joosse Simon A. , Schneegans Svenja , Wilken Okka J. W. , Janning Melanie , Loreth Desiree , Müller Volkmar , Prieske Katharina , Banys-Paluchowski Malgorzata , Horst Ludwig J. , Loges Sonja , Peine Sven , Wikman Harriet , Gorges Tobias M. , Pantel Klaus
Published: February 2020

Circulating tumor cells (CTCs) are promising tools for risk prediction and the monitoring of response to therapy in cancer patients. Within the EU/IMI CANCER-ID consortium, we validated CTC enrichment systems for future inclusion into clinical trials. Due to the known heterogeneity of markers expressed on CTCs, we tested the Parsortix® system (ANGLE plc) which enables label-independent CTC enrichment from whole blood based on increased size and deformability of these tumor cells compared to leukocytes. We performed extensive comparisons both with spiked-in blood models (i.e., MDA-MB-468 tumor cell line cells spiked at very low concentration into blood from healthy donors) and validated the protocol on actual clinical samples from breast, lung, and gastrointestinal cancer patients to define optimal conditions for CTC enrichment. Multiple parameters including cassette gap, separation pressure, and cell fixatives were compared in parallel. Also, the compatibility of blood collection tubes with whole genome amplification of isolated tumor cells was demonstrated and we furthermore established a workflow for semi-automated CTC detection using a quantitative cell imager. The established workflow will contribute to supporting the use of size-based CTC enrichment platforms in clinical trials testing the clinical validity and utility of CTCs for personalized medicine.
Nuclear Lamins and Emerin Are Differentially Expressed in Osteosarcoma Cells and Scale with Tumor Aggressiveness
Authors: Urciuoli Enrica , Petrini Stefania , D’Oria Valentina , Leopizzi Martina , Della Rocca Carlo , Peruzzi Barbara
Published: February 2020

The nuclear lamina is essential for the maintenance of nuclear shape and mechanics. Mutations in lamin genes have been identified in a heterogeneous spectrum of human diseases known as “laminopathies” associated with nuclear envelope defects and deregulation of cellular functions. Interestingly, osteosarcoma is the only neoplasm described in the literature in association with laminopathies. This study aims characterized the expression of A-type and B-type lamins and emerin in osteosarcoma, revealing a higher percentage of dysmorphic nuclei in osteosarcoma cells in comparison to normal osteoblasts and all the hallmarks of laminopathic features. Both lamins and emerin were differentially expressed in osteosarcoma cell lines in comparison to normal osteoblasts and correlated with tumor aggressiveness. We analysed lamin A/C expression in a tissue-microarray including osteosarcoma samples with different prognosis, finding a positive correlation between lamin A/C expression and the overall survival of osteosarcoma patients. An inefficient MKL1 nuclear shuttling and actin depolymerization, as well as a reduced expression of pRb and a decreased YAP nuclear content were observed in A-type lamin deficient 143B cells. In conclusion, we described for the first time laminopathic nuclear phenotypes in osteosarcoma cells, providing evidence for an altered lamins and emerin expression and a deregulated nucleoskeleton architecture of this tumor.
Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer
Authors: Kim Seok-Mo , Kim Soo Young , Park Cheong Soo , Chang Hang-Seok , Park Ki Cheong
Published: February 2020

The incidence of papillary thyroid carcinoma (PTC) has been increasing worldwide. PTC is the most common type of differentiated thyroid cancer and usually shows good prognosis. However, some PTC is driven to advanced stage by epithelial-mesenchymal transition (EMT)-mediated drug resistance, which is particularly noticeable in pediatric patients. There are limited options for systemic treatment, necessitating development of new clinical approaches. Here, we aimed to clarify genetic differences due to age of patients with PTC, and thereby aid in developing novel therapeutics. Patients with biochemically and histologically confirmed PTC were included in this study. PTC cells were acquired from young and older patients showing drug resistance, and were compared via microarray analysis. Cellular proliferation and other properties were determined after treatments with lenvatinib and sorafenib. In vivo, tumor volume and other properties were examined using a mouse xenograft model. Lenvatinib-treated group showed obvious suppression of markers of anti-apoptosis, EMT, and the FGFR signaling pathway, compared with control and Sorafenib-treated group. In the xenograft models, lenvatinib treatment induced significant tumor shrinkage and blocked the proto-oncogene Bcl-2 (B cell lymphoma/leukemia gene-2) and FGFR signaling pathway, along with reduced levels of EMT markers, compared with control and Sorafenib-treated group. Our findings clarify the age-dependent characteristics of pediatric PTC, giving insights into the relationship between young age and poor prognosis. Furthermore, it provides a basis for developing novel therapeutics tailored to the age at diagnosis.
Bioactive Phenolic Compounds in the Modulation of Central and Peripheral Nervous System Cancers: Facts and Misdeeds
Authors: Perrone Lorena , Sampaolo Simone , Melone Mariarosa Anna Beatrice
Published: February 2020

Efficacious therapies are not available for the cure of both gliomas and glioneuronal tumors, which represent the most numerous and heterogeneous primary cancers of the central nervous system (CNS), and for neoplasms of the peripheral nervous system (PNS), which can be divided into benign tumors, mainly represented by schwannomas and neurofibromas, and malignant tumors of the peripheral nerve sheath (MPNST). Increased cellular oxidative stress and other metabolic aspects have been reported as potential etiologies in the nervous system tumors. Thus polyphenols have been tested as effective natural compounds likely useful for the prevention and therapy of this group of neoplasms, because of their antioxidant and anti-inflammatory activity. However, polyphenols show poor intestinal absorption due to individual intestinal microbiota content, poor bioavailability, and difficulty in passing the blood–brain barrier (BBB). Recently, polymeric nanoparticle-based polyphenol delivery improved their gastrointestinal absorption, their bioavailability, and entry into defined target organs. Herein, we summarize recent findings about the primary polyphenols employed for nervous system tumor prevention and treatment. We describe the limitations of their application in clinical practice and the new strategies aimed at enhancing their bioavailability and targeted delivery.
Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines
Authors: Weißbach Susann , Heredia-Guerrero Sofia Catalina , Barnsteiner Stefanie , Großhans Lukas , Bodem Jochen , Starz Hanna , Langer Christian , Appenzeller Silke , Knop Stefan , Steinbrunn Torsten , Rost Simone , Einsele Hermann , Bargou Ralf Christian , Rosenwald Andreas , Stühmer Thorsten , Leich Ellen
Published: February 2020

Approximately 20% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRASp.G12C entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRASp.G12A and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRASWT, KRASp.G12A, KRASp.A146T, and KRASp.A146V were overexpressed in HEK293 cells and the KRASWT MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.
An Epitope on EGFR Loading Catastrophic Internalization Serve as a Novel Oncotarget for Hepatocellular Carcinoma Therapy
Authors: Huang Dianshuai , Fan Qingjie , Liu Zhiyi , Zhang Shuqin , Huang Wei , Li Hongrui , Liang Chongyang , Sun Fei
Published: February 2020

The precise role of Epidermal Growth Factor Receptor (EGFR) in Hepatocellular carcinoma (HCC) cells is unknown and EGFR inhibitors have not achieved positive clinical results. The rapid and drastic internalization of EGFR has been proved to successfully treat EGFR inhibitor-resistant patients in recent clinical trials. Here, the anti-tumor efficacy of a protein (rLZ-8) from Ganoderma lucidum was evaluated, it was demonstrated that rLZ-8 could bind to EGFR specifically, drastically enter into Hepatoma cells, abrogate endosomal recycling and induce HCC cell death. Surprisingly, we screened a monoclonal antibody which possesses competitive binding site with rLZ-8, it also trigger catastrophic EGFR internalization. This result suggests that it is necessary to investigate the interface of EGFR and rLZ-8 complex. An internalization related epitope (S222/K269) was identified on the dimerization arm of EGFR extracellular domain (ECD). These results suggest vulnerability of HCC cells to catastrophic EGFR internalization that can be targeted by a novel epitope and point to the possible exploitation in the design of anti-EGFR therapeutic biologics for HCC therapy.
CXCL1/CXCR2 Paracrine Axis Contributes to Lung Metastasis in Osteosarcoma
Authors: Chao Chia-Chia , Lee Chiang-Wen , Chang Tsung-Ming , Chen Po-Chun , Liu Ju-Fang
Published: February 2020

Osteosarcoma, the most common of all bone malignancies, has a high likelihood of lung metastasis. Up until now, the molecular mechanisms involved in osteosarcomas with lung metastases are not clearly understood. Recent observations have shown that the chemokine CXCL1 and its receptor CXCR2 assist with the homing of neutrophils into the tumor microenvironment. Here, we show that the CXCL1/CXCR2 paracrine axis is crucial for lung metastasis in osteosarcoma. In an in vivo lung metastasis model of osteosarcoma, lung blood vessels expressed CXCL1 and osteosarcoma cells expressed the CXCR2 receptor. CXCR2 expression was higher in osteosarcoma cell lines than in normal osteoblast cells. Immunohistochemistry staining of clinical osteosarcoma specimens revealed positive correlations between CXCR2 expression and pathology stage and also vascular cell adhesion molecule 1 (VCAM-1) expression. High levels of CXCL1 secreted by human pulmonary artery endothelial cells (HPAECs) promoted osteosarcoma cell mobility, which was mediated by the upregulation of VCAM-1 expression. When HPAECs-conditioned media was incubated in osteosarcoma cells, we observed that the CXCR2 receptor and FAK/PI3K/Akt/NF-κB signaling cascade were required for VCAM-1 expression. Our findings illustrate a molecular mechanism of lung metastasis in osteosarcoma and indicate that CXCL1/CXCR2 is worth targeting in treatment schemas.
Non-Coding RNAs in Adrenocortical Cancer: From Pathogenesis to Diagnosis
Authors: Decmann Abel , Perge Pál , Turai Peter Istvan , Patócs Attila , Igaz Peter
Published: February 2020

Non-coding RNA molecules including microRNAs and long non-coding RNAs (lncRNA) have been implicated in the pathogenesis of several tumors and numerous data support their applicability in diagnosis as well. Despite recent advances, the pathogenesis of adrenocortical cancer still remains elusive and there are no reliable blood-borne markers of adrenocortical malignancy, either. Several findings show the potential applicability of microRNAs as biomarkers of malignancy and prognosis, and there are some data on lncRNA as well. In this review, we present a synopsis on the potential relevance of non-coding RNA molecules in adrenocortical pathogenesis and their applicability in diagnosis from tissue and blood.
Changes in Functional Outcome and Quality of Life in Soft Tissue Sarcoma Patients within the First Year after Surgery: A Prospective Observational Study
Authors: Saebye Casper , Amidi Ali , Keller Johnny , Andersen Henning , Baad-Hansen Thomas
Published: February 2020

Soft tissue sarcoma (STS) patients undergoing surgery may experience reduced functional outcome (FO) and quality of life (QoL) compared to the general population. The aim of this study was to evaluate the development of FO and QoL in patients with STS in the extremities within the first year after first-time limb-sparing surgery. Twenty-nine out of 40 eligible patients were included in the present study. QoL and FO were evaluated by questionnaires while FO was also evaluated by objective tests. Patients were assessed before surgery and at fixed time points within the first year after surgery. Patients with STS in the extremities had an average strength of 82.34% (95% CI: 68.57–96.11) of the expected strength at one year post surgery. Multivariate, repeated ANOVA showed statistically significant reductions in strength in the disease-affected extremity when compared with the healthy side after surgery. Multivariate, repeated ANOVA showed a statistically significant improvement in FO and QoL within the first year post surgery. Limb-sparing surgery for STS significantly reduced strength in the disease-affected extremity and generally reduced FO and QoL in the first months after surgery. Improvements were observed for FO and QoL at one year after surgery.
Melanoma-Derived Exosomal miR-125b-5p Educates Tumor Associated Macrophages (TAMs) by Targeting Lysosomal Acid Lipase A (LIPA)
Authors: Gerloff Dennis , Lützkendorf Jana , Moritz Rose K.C. , Wersig Tom , Mäder Karsten , Müller Lutz P. , Sunderkötter Cord
Published: February 2020

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, promoting tumor initiation, growth, progression, metastasis, and immune evasion. Recently it was shown that cancer cell-derived exosomes induce a tumor-promoting phenotype in TAMs. Exosome-loaded proteins, DNA, and RNAs may contribute to the macrophage reprogramming. However, the exact mediators and mechanisms, particularly in melanoma, are not known. In this study we examined the effects of cutaneous melanoma-derived exosomes on macrophage function and the underlying mechanisms. First, we showed that exposure to melanoma exosomes induces a tumor-promoting TAM phenotype in macrophages. Sequencing revealed enrichment for several miRNAs including miR-125b-5p in cutaneous melanoma exosomes. We showed that miR-125b-5p is delivered to macrophages by melanoma exosomes and partially induces the observed tumor-promoting TAM phenotype. Finally, we showed that miR-125b-5p targets the lysosomal acid lipase A (LIPA) in macrophages, which in turn contributes to their phenotype switch and promotes macrophage survival. Thus, our data show for the first time that miR-125b-5p transferred by cutaneous melanoma-derived exosomes induces a tumor-promoting TAM phenotype in macrophages.
Venetoclax, a BCL-2 Inhibitor, Enhances the Efficacy of Chemotherapeutic Agents in Wild-Type ABCG2-Overexpression-Mediated MDR Cancer Cells
Authors: Wang Jing-Quan , Li Jonathan Y. , Teng Qiu-Xu , Lei Zi-Ning , Ji Ning , Cui Qingbin , Zeng Leli , Pan Yihang , Yang Dong-Hua , Chen Zhe-Sheng
Published: February 2020

Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This study showed that, at a non-toxic concentration, venetoclax at 10 µM significantly reversed multidrug resistance (MDR) mediated by wild-type ABCG2, without significantly affecting MDR mediated by mutated ABCG2 (R482G and R482T) and ABCB1, while moderate or no reversal effects were observed at lower concentrations (0.5 to 1 µM). The results showed that venetoclax increased the intracellular accumulation of chemotherapeutic agents, which was the result of directly blocking the wild-type ABCG2 efflux function and inhibiting the ATPase activity of ABCG2. Our study demonstrated that venetoclax potentiates the efficacy of wild-type ABCG2 substrate drugs. These findings may provide useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice.
Association of TGF-β1 Polymorphisms with Breast Cancer Risk: A Meta-Analysis of Case–Control Studies
Authors: Krishna B. , Jana Samir , Panda Aditya , Horne David , Awasthi Sanjay , Salgia Ravi , Singhal Sharad
Published: February 2020

Reports on the association of TGF-β1 polymorphisms with breast cancer (BC) have been conflicting, inconsistent, inconclusive, and controversial. PubMed, EMBASE, and Google Scholar were used to identify studies on TGF-β1 polymorphisms and BC risk. Data were extracted independently, and of the initial 3043 studies, 39 case-control studies were eligible for inclusion in the meta-analysis. Information from these studies was extracted, and the overall associations of three TGF-β1 polymorphisms (TGF-β1 29>T/C, TGF-β1-509 C/T, and TGF-β1*6A) with BC risk were analyzed using overall allele, homozygous, heterozygous, recessive, and dominant models. None of the three TGF-β1 polymorphisms studied had a significant influence on the development of BC. However, stratified analysis revealed a positive correlation between the TGF-β1 29T>C polymorphism and BC risk according to a heterozygous model of the Asian population (odds ratio (OR) = 1.115, 95% confidence interval (CI) = 1.006–1.237, p = 0.039). Interestingly, this polymorphism was associated with lower odds of BC according to a heterozygous model of the Middle Eastern population (OR = 0.602, 95% CI = 0.375–0.966, p = 0.035). Thus, our analysis of large datasets indicates that the TGF-β1 29T>C polymorphism is significantly associated with BC risk in the Asian population. In contrast, the TGF-β1*6A and TGF-β1-509 C/T polymorphisms failed to show an association with BC.
Effect of Diphtheria Toxin-Based Gene Therapy for Hepatocellular Carcinoma
Authors: Kamimura Kenya , Yokoo Takeshi , Abe Hiroyuki , Sakai Norihiro , Nagoya Takuro , Kobayashi Yuji , Ohtsuka Masato , Miura Hiromi , Sakamaki Akira , Kamimura Hiroteru , Miyamura Norio , Nishina Hiroshi , Terai Shuji
Published: February 2020

Hepatocellular carcinoma (HCC) is a major global malignancy, responsible for >90% of primary liver cancers. Currently available therapeutic options have poor performances due to the highly heterogeneous nature of the tumor cells; recurrence is highly probable, and some patients develop resistances to the therapies. Accordingly, the development of a novel therapy is essential. We assessed gene therapy for HCC using a diphtheria toxin fragment A (DTA) gene-expressing plasmid, utilizing a non-viral hydrodynamics-based procedure. The antitumor effect of DTA expression in HCC cell lines (and alpha-fetoprotein (AFP) promoter selectivity) is assessed in vitro by examining HCC cell growth. Moreover, the effect and safety of the AFP promoter-selective DTA expression was examined in vivo using an HCC mice model established by the hydrodynamic gene delivery of the yes-associated protein (YAP)-expressing plasmid. The protein synthesis in DTA transfected cells is inhibited by the disappearance of tdTomato and GFP expression co-transfected upon the delivery of the DTA plasmid; the HCC cell growth is inhibited by the expression of DTA in HCC cells in an AFP promoter-selective manner. A significant inhibition of HCC occurrence and the suppression of the tumor marker of AFP and des-gamma-carboxy prothrombin can be seen in mice groups treated with hydrodynamic gene delivery of DTA, both 0 and 2 months after the YAP gene delivery. These results suggest that DTA gene therapy is effective for HCC.
Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses
Authors: Dubot Patricia , Astudillo Leonardo , Therville Nicole , Sabourdy Frédérique , Stirnemann Jérôme , Levade Thierry , Andrieu-Abadie Nathalie
Published: February 2020

The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to β-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of β-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of β-glucosylceramide. The previously described mechanistic links between lysosomal β-glucosylceramidase, β-glucosylceramide and/or β-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the β-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed.
Plasma-activated Ringer’s Lactate Solution Displays a Selective Cytotoxic Effect on Ovarian Cancer Cells
Authors: Bisag Alina , Bucci Cristiana , Coluccelli Sara , Girolimetti Giulia , Laurita Romolo , De Iaco Pierandrea , Perrone Anna Myriam , Gherardi Matteo , Marchio Lorena , Porcelli Anna Maria , Colombo Vittorio , Gasparre Giuseppe
Published: February 2020

Epithelial Ovarian Cancer (EOC) is one of the leading causes of cancer-related deaths among women and is characterized by the diffusion of nodules or plaques from the ovary to the peritoneal surfaces. Conventional therapeutic options cannot eradicate the disease and show low efficacy against resistant tumor subclones. The treatment of liquids via cold atmospheric pressure plasma enables the production of plasma-activated liquids (PALs) containing reactive oxygen and nitrogen species (RONS) with selective anticancer activity. Thus, the delivery of RONS to cancer tissues by intraperitoneal washing with PALs might be an innovative strategy for the treatment of EOC. In this work, plasma-activated Ringer’s Lactate solution (PA-RL) was produced by exposing a liquid substrate to a multiwire plasma source. Subsequently, PA-RL dilutions are used for the treatment of EOC, non-cancer and fibroblast cell lines, revealing a selectivity of PA-RL, which induces a significantly higher cytotoxic effect in EOC with respect to non-cancer cells.
Bone and Soft-Tissue Sarcoma: A New Target for Telomerase-Specific Oncolytic Virotherapy
Authors: Tazawa Hiroshi , Hasei Joe , Yano Shuya , Kagawa Shunsuke , Ozaki Toshifumi , Fujiwara Toshiyoshi
Published: February 2020

Adenovirus serotype 5 (Ad5) is widely and frequently used as a virus vector in cancer gene therapy and oncolytic virotherapy. Oncolytic virotherapy is a novel antitumor treatment for inducing lytic cell death in tumor cells without affecting normal cells. Based on the Ad5 genome, we have generated three types of telomerase-specific replication-competent oncolytic adenoviruses: OBP-301 (Telomelysin), green fluorescent protein (GFP)-expressing OBP-401 (TelomeScan), and tumor suppressor p53-armed OBP-702. These viruses drive the expression of the adenoviral E1A and E1B genes under the control of the hTERT (human telomerase reverse transcriptase-encoding gene) promoter, providing tumor-specific virus replication. This review focuses on the therapeutic potential of three hTERT promoter-driven oncolytic adenoviruses against bone and soft-tissue sarcoma cells with telomerase activity. OBP-301 induces the antitumor effect in monotherapy or combination therapy with chemotherapeutic drugs via induction of autophagy and apoptosis. OBP-401 enables visualization of sarcoma cells within normal tissues by serving as a tumor-specific labeling reagent for fluorescence-guided surgery via induction of GFP expression. OBP-702 exhibits a profound antitumor effect in OBP-301-resistant sarcoma cells via activation of the p53 signaling pathway. Taken together, telomerase-specific oncolytic adenoviruses are promising antitumor reagents that are expected to provide novel therapeutic options for the treatment of bone and soft-tissue sarcomas.
ARH1 in Health and Disease
Authors: Ishiwata-Endo Hiroko , Kato Jiro , Stevens Linda A. , Moss Joel
Published: February 2020

Arginine-specific mono-adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD)+-dependent, reversible post-translational modification involving the transfer of an ADP-ribose from NAD+ by bacterial toxins and eukaryotic ADP-ribosyltransferases (ARTs) to arginine on an acceptor protein or peptide. ADP-ribosylarginine hydrolase 1 (ARH1) catalyzes the cleavage of the ADP-ribose-arginine bond, regenerating (arginine)protein. Arginine-specific mono-ADP-ribosylation catalyzed by bacterial toxins was first identified as a mechanism of disease pathogenesis. Cholera toxin ADP-ribosylates and activates the α subunit of Gαs, a guanine nucleotide-binding protein that stimulates adenylyl cyclase activity, increasing cyclic adenosine monophosphate (cAMP), and resulting in fluid and electrolyte loss. Arginine-specific mono-ADP-ribosylation in mammalian cells has potential roles in membrane repair, immunity, and cancer. In mammalian tissues, ARH1 is a cytosolic protein that is ubiquitously expressed. ARH1 deficiency increased tumorigenesis in a gender-specific manner. In the myocardium, in response to cellular injury, an arginine-specific mono-ADP-ribosylation cycle, involving ART1 and ARH1, regulated the level and cellular distribution of ADP-ribosylated tripartite motif-containing protein 72 (TRIM72). Confirmed substrates of ARH1 in vivo are Gαs and TRIM72, however, more than a thousand proteins, ADP-ribosylated on arginine, have been identified by proteomic analysis. This review summarizes the current understanding of the properties of ARH1, e.g., bacterial toxin action, myocardial membrane repair following injury, and tumorigenesis.
Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma: A Review of the Current Status of Literature
Authors: Hull Ashleigh , Li Yanrui , Bartholomeusz Dylan , Hsieh William , Allen Barry , Bezak Eva
Published: February 2020

Pancreatic ductal adenocarcinoma (PDAC) has long been associated with low survival rates. A lack of accurate diagnostic tests and limited treatment options contribute to the poor prognosis of PDAC. Radioimmunotherapy using α- or β-emitting radionuclides has been identified as a potential treatment for PDAC. By harnessing the cytotoxicity of α or β particles, radioimmunotherapy may overcome the anatomic and physiological factors which traditionally make PDAC resistant to most conventional treatments. Appropriate selection of target receptors and the development of selective and cytotoxic radioimmunoconjugates are needed to achieve the desired results of radioimmunotherapy. The aim of this review is to examine the growing preclinical and clinical trial evidence regarding the application of α and β radioimmunotherapy for the treatment of PDAC. A systematic search of MEDLINE® and Scopus databases was performed to identify 34 relevant studies conducted on α or β radioimmunotherapy of PDAC. Preclinical results demonstrated α and β radioimmunotherapy provided effective tumour control. Clinical studies were limited to investigating β radioimmunotherapy only. Phase I and II trials observed disease control rates of 11.2%–57.9%, with synergistic effects noted for combination therapies. Further developments and optimisation of treatment regimens are needed to improve the clinical relevance of α and β radioimmunotherapy in PDAC.
Current Advances in the Treatment of BRAF-Mutant Melanoma
Authors: Patel Hima , Yacoub Nour , Mishra Rosalin , White Aaron , Yuan Long , Alanazi Samar , Garrett Joan T.
Published: February 2020

Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.
Nerve Sparing Radical Hysterectomy: Short-Term Oncologic, Surgical, and Functional Outcomes
Authors: Muallem Mustafa Zelal , Armbrust Robert , Neymeyer Jörg , Miranda Andrea , Muallem Jumana
Published: February 2020

There is an obvious prevalence of disparity in opinions concerning the technique of nerve-sparing radical hysterectomy and its application, despite agreement on the need to spare the pelvic autonomic nerve system during such a radical operation. Understanding the precise three-dimensional anatomy of paracolpium and its close anatomical relationship to the components of the pelvic autonomic nervous system is the key in performing the nerve-sparing radical hysterectomy. A total of 42 consecutive patients with primary cervical cancers, who were operated upon in our institution between January 2017 and June 2019, were analyzed, concerning surgical, urinary functional, and short-term oncologic outcomes. Two thirds of the patients had locally advanced tumors (T > 40 mm or pT ≥ IIA2) with a median tumor size of 44.1 mm. The nerve-sparing radical hysterectomy was combined with the complete recovery of bladder function in 90% of patients directly after surgery and in 97% of patients in the first 2 weeks. The recurrence rate in a median follow-up time of 18 months was 9.5%. The nerve-sparing radical hysterectomy approach, which depends on the comprehensive understanding of the precise entire anatomy of paracolpium, was found to be feasible and applicable, even in locally advanced tumors, with good functional results and convincing short-term oncologic outcomes.
Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation
Authors: Huang Duen-Yi , Chen Wei-Yu , Chen Chi-Long , Wu Nan-Lin , Lin Wan-Wan
Published: February 2020

Syk is a non-receptor tyrosine kinase involved in the signalling of immunoreceptors and growth factor receptors. Previously, we reported that Syk mediates epidermal growth factor receptor (EGFR) signalling and plays a negative role in the terminal differentiation of keratinocytes. To understand whether Syk is a potential therapeutic target of cancer cells, we further elucidated the role of Syk in disease progression of squamous cell carcinoma (SCC), which is highly associated with EGFR overactivation, and determined the combined effects of Syk and PARP1 inhibitors on SCC viability. We found that pharmacological inhibition of Syk could attenuate the EGF-induced phosphorylation of EGFR, JNK, p38 MAPK, STAT1, and STAT3 in A431, CAL27 and SAS cells. In addition, EGF could induce a Syk-dependent IL-8 gene and protein expression in SCC. Confocal microscopic data demonstrated the ability of the Syk inhibitor to change the subcellular distribution patterns of EGFR after EGF treatment in A431 and SAS cells. Moreover, according to Kaplan-Meier survival curve analysis, higher Syk expression is correlated with poorer patient survival rate and prognosis. Notably, both Syk and EGFR inhibitors could induce PARP activation, and synergistic cytotoxic actions were observed in SCC cells upon the combined treatment of the PARP1 inhibitor olaparib with Syk or the EGFR inhibitor. Collectively, we reported Syk as an important signalling molecule downstream of EGFR that plays crucial roles in SCC development. Combining Syk and PARP inhibition may represent an alternative therapeutic strategy for treating SCC.
Depth of Remission Following First-Line Treatment Is an Independent Prognostic Marker for Progression-Free Survival in Gastric Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma
Authors: Kiesewetter Barbara , Simonitsch-Klupp Ingrid , Dolak Werner , Mayerhoefer Marius E. , Raderer Markus
Published: February 2020

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma responding to upfront treatment has an excellent outcome and no further therapy is recommended, even in the presence of residual disease. However, no data exist on the influence of initial depth of remission on progression-free survival (PFS). Methods: We investigated a correlation between PFS and depth of response, categorizing them as complete remission (CR), partial remission (PR) and stable disease (SD) in 137 consecutive patients at the Medical University Vienna. Results: All patients with Helicobacter pylori (H. pylori)-positive, localized disease received H. pylori eradication (70%, 96/137), while the remaining patients were treated with various modalities. The response rate was 67% for the entire collective and 58% for eradication only, with corresponding CR-rates of 48% and 38%. At a median follow-up of 56.2 months, the estimated PFS for the entire cohort was 34.2 months (95% Confidence Interval 16.0–52.4). Responding patients (=CR/PR) had a significantly longer PFS compared to SD (68.3 vs. 17.3 months, p < 0.001). This was also applicable to the eradication only cohort (49.0 vs. 17.3 months, p < 0.001) and remained significant after correction for MALT-IPI. Furthermore, CR significantly prolonged PFS over PR (p = 0.007 entire cohort, p = 0.020 eradication). Conclusions: Remission status correlated significantly with PFS, suggesting depth of remission as prognostic marker for long-term relapse-free survival.
Selective Oxidation of Benzyl Alcohol by Ag/Pd/m-BiVO4 Microspheres under Visible Light Irradiation
Authors: Yu Xiujuan , Li Haiying , Hao Xueli , Zhang Zhiying , Wang Yan , Li Jingyi , Wang Kai
Published: February 2020

A series of Ag/Pd/m-BiVO4 (monoclinic) bimetallic photocatalytic materials with different loading amounts and different mass ratios of Ag and Pd were synthesized by a hydrothermal method and an NaBH4 reduction method. The Ag/Pd/m-BiVO4 photocatalyst with a total Ag and Pd loading of 2 wt% and an Ag-to-Pd mass ratio of 2:1 can selectively oxidize benzyl alcohol to benzaldehyde under visible light irradiation, the conversion rate was up to 89.9%, and the selectivity was greater than 99%. The conversion rate on Ag/Pd/m-BiVO4 was higher than those on Ag/m-BiVO4 and Pd/m-BiVO4. The photocatalysts were characterized by X-ray powder diffraction (XRD), ultraviolet-visible diffuse reflection spectroscopy (UV-vis DRS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), photoluminescence (PL) spectroscopy, N2 adsorption-desorption isothermal curves (BET) and other means. The effects of different light wavelengths and light intensities were compared. Then, the effects of different alcohol derivatives on the reactions were explored. The cycle experiments proved that the Ag/Pd/m-BiVO4 photocatalyst had good light stability and thermal stability. In addition, the capturing experiment of active species shows that the selective oxidation of benzyl alcohol is mainly accomplished through the synergistic action of h+, e−, •OH and •O2−.
Serial Crystallography: Preface
Authors: Spence John C. H.
Published: February 2020

The history of serial crystallography (SC) has its origins in the earliest attempts to merge data from several crystals. This preface provides an overview of some recent work, with a survey of the rapid advances made over the past decade in both sample delivery and data analysis.
Spin Glasses in a Field Show a Phase Transition Varying the Distance among Real Replicas (And How to Exploit It to Find the Critical Line in a Field)
Authors: Dilucca Maddalena , Leuzzi Luca , Parisi Giorgio , Ricci-Tersenghi Federico , Ruiz-Lorenzo Juan J.
Published: February 2020

We discuss a phase transition in spin glass models that have been rarely considered in the past, namely, the phase transition that may take place when two real replicas are forced to be at a larger distance (i.e., at a smaller overlap) than the typical one. In the first part of the work, by solving analytically the Sherrington-Kirkpatrick model in a field close to its critical point, we show that, even in a paramagnetic phase, the forcing of two real replicas to an overlap small enough leads the model to a phase transition where the symmetry between replicas is spontaneously broken. More importantly, this phase transition is related to the de Almeida-Thouless (dAT) critical line. In the second part of the work, we exploit the phase transition in the overlap between two real replicas to identify the critical line in a field in finite dimensional spin glasses. This is a notoriously difficult computational problem, because of considerable finite size corrections. We introduce a new method of analysis of Monte Carlo data for disordered systems, where the overlap between two real replicas is used as a conditioning variate. We apply this analysis to equilibrium measurements collected in the paramagnetic phase in a field, h > 0 and T c ( h ) < T < T c ( h = 0 ) , of the d = 1 spin glass model with long range interactions decaying fast enough to be outside the regime of validity of the mean field theory. We thus provide very reliable estimates for the thermodynamic critical temperature in a field.
Phylogenetic Analysis of HIV-1 Genomes Based on the Position-Weighted K-mers Method
Authors: Ma Yuanlin , Yu Zuguo , Tang Runbin , Xie Xianhua , Han Guosheng , Anh Vo V.
Published: February 2020

HIV-1 viruses, which are predominant in the family of HIV viruses, have strong pathogenicity and infectivity. They can evolve into many different variants in a very short time. In this study, we propose a new and effective alignment-free method for the phylogenetic analysis of HIV-1 viruses using complete genome sequences. Our method combines the position distribution information and the counts of the k-mers together. We also propose a metric to determine the optimal k value. We name our method the Position-Weighted k-mers (PWkmer) method. Validation and comparison with the Robinson–Foulds distance method and the modified bootstrap method on a benchmark dataset show that our method is reliable for the phylogenetic analysis of HIV-1 viruses. PWkmer can resolve within-group variations for different known subtypes of Group M of HIV-1 viruses. This method is simple and computationally fast for whole genome phylogenetic analysis.
Evaluation of the Potential of Biomass to Energy in Portugal—Conclusions from the CONVERTE Project
Authors: Abreu Mariana , Reis Alberto , Moura Patrícia , Fernando Ana Luisa , Luís António , Quental Lídia , Patinha Pedro , Gírio Francisco
Published: February 2020

The main objective of the Portuguese project “CONVERTE-Biomass Potential for Energy” is to support the transition to a low-carbon economy, identifying biomass typologies in mainland Portugal, namely agri-forest waste, energy crops and microalgae. Therefore, the aim was to design and construct a georeferenced (mapping) database for mainland Portugal, to identify land availability for the implementation of energy crops and microalgae cultures, and to locate agricultural and forestry production areas (including their residues) with potential for sustainable exploitation for energy. The ArcGIS software was used as a Geographic Information System (GIS) tool, introducing the data corresponding to the type of soil, water needs and edaphoclimatic conditions in shapefile and raster data type, to assess the areas for the implantation of the biomass of interest. After analysing the data of interest in each map in ArcGIS, the intersection of all maps is presented, suggesting adequate areas and predicting biomass productions for the implementation of each culture in mainland Portugal. Under the conditions of the study, cardoon (72 kha, 1085 kt), paulownia (81 kha, 26 kt) and microalgae (29 kha, 1616 kt) presented the greater viability to be exploited as biomass to energy in degraded and marginal soils.