bluuebunny/crossref_metadata_2025 huggingface dataset:
Low Absolute Lymphocyte Counts in the Peripheral Blood Predict Inferior Survival and Improve the International Prognostic Index in Testicular Diffuse Large B-Cell Lymphoma
Authors: Vähämurto Pauli , Pollari Marjukka , Clausen Michael R. , d’Amore Francesco , Leppä Sirpa , Mannisto Susanna
Published: July 2020

Low absolute lymphocyte counts (ALC) and high absolute monocyte counts (AMC) are associated with poor survival in patients with diffuse large B-cell lymphoma (DLBCL). We studied the prognostic impact of the ALC and AMC in patients with testicular DLBCL (T-DLBCL). T-DLBCL patients were searched using Southern Finland University Hospital databases and the Danish lymphoma registry. The progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. We identified 178 T-DLBCL patients, of whom 78 (44%) had a low ALC at diagnosis. The ALC did not correlate with survival in the whole cohort. However, among the patients treated with rituximab (R) containing regimen, a pre-therapeutic low ALC was associated with an increased risk of progression (HR 1.976, 95% CI 1.267–3.086, p = 0.003). Conversely, intravenous (iv) CNS directed chemotherapy translated to favorable outcome. In multivariate analyses, the advantage of an iv CNS directed chemotherapy was sustained (PFS, HR 0.364, 95% CI 0.175–0.757, p = 0.007). The benefit of R and intravenous CNS directed chemotherapy was observed only in non-lymphopenic patients. The AMC did not correlate with survival. A low ALC is an adverse prognostic factor in patients with T-DLBCL. Alternative treatment options for lymphopenic patients are needed.
Co-Expression of IL-7 Improves NKG2D-Based CAR T Cell Therapy on Prostate Cancer by Enhancing the Expansion and Inhibiting the Apoptosis and Exhaustion
Authors: He Cong , Zhou Ying , Li Zhenlong , Farooq Muhammad Asad , Ajmal Iqra , Zhang Hongmei , Zhang Li , Tao Lei , Yao Jie , Du Bing , Liu Mingyao , Jiang Wenzheng
Published: July 2020

Chimeric antigen receptor (CAR) T-cell therapy is a promising approach in treating solid tumors but the therapeutic effect is limited. Prostate cancer is a typical solid malignancy with invasive property and a highly immunosuppressive microenvironment. Ligands for the NKG2D receptor are primarily expressed on many cancer cells, including prostate cancer. In this study, we utilized NKG2D-based CAR to treat prostate cancer, and improved the therapeutic effect by co-expression of IL-7. The results showed that NKG2D-CAR T cells performed significantly increased cytotoxicity against prostate cancer compared to non-transduced T cells in vitro and in vivo. Moreover, the introduction of the IL-7 gene into the NKG2D-CAR backbone enhanced the production of IL-7 in an antigen-dependent manner. NKG2DIL7-CAR T cells exhibited better antitumor efficacy at 16 h and 72 h in vitro, and inhibited tumor growth in xenograft models more effectively. In mechanism, enhanced proliferation and Bcl-2 expression in CD8+ T cells, decreased apoptosis and exhaustion, and increased less-differentiated cell phenotype may be the reasons for the improved persistence and survival of NKG2DIL7-CAR T cells. In conclusion, these findings demonstrated that NKG2D is a promising option for CAR T-cell therapy on prostate cancer, and IL-7 has enhanced effect on NKG2D-based CAR T-cell immunotherapy, providing a novel adoptive cell therapy for prostate cancer either alone or in combination with IL-7.
JAK-STAT Signalling Pathway in Cancer
Authors: Brooks Andrew J. , Putoczki Tracy
Published: July 2020

n/a
Reconstitution of T Cell Subsets Following Allogeneic Hematopoietic Cell Transplantation
Authors: Dekker Linde , de Koning Coco , Lindemans Caroline , Nierkens Stefan
Published: July 2020

Allogeneic (allo) hematopoietic cell transplantation (HCT) is the only curative treatment option for patients suffering from chemotherapy-refractory or relapsed hematological malignancies. The occurrence of morbidity and mortality after allo-HCT is still high. This is partly correlated with the immunological recovery of the T cell subsets, of which the dynamics and relations to complications are still poorly understood. Detailed information on T cell subset recovery is crucial to provide tools for better prediction and modulation of adverse events. Here, we review the current knowledge regarding CD4+ and CD8+ T cells, γδ T cells, iNKT cells, Treg cells, MAIT cells and naive and memory T cell reconstitution, as well as their relations to outcome, considering different cell sources and immunosuppressive therapies. We conclude that the T cell subsets reconstitute in different ways and are associated with distinct adverse and beneficial events; however, adequate reconstitution of all the subsets is associated with better overall survival. Although the exact mechanisms involved in the reconstitution of each T cell subset and their associations with allo-HCT outcome need to be further elucidated, the data and suggestions presented here point towards the development of individualized approaches to improve their reconstitution. This includes the modulation of immunotherapeutic interventions based on more detailed immune monitoring, aiming to improve overall survival changes.
Treatment of Patients with Advanced Biliary Tract Cancer with Either Oxaliplatin, Gemcitabine, and Capecitabine or Cisplatin and Gemcitabine—A Randomized Phase II Trial
Authors: Markussen Alice , Jensen Lars Henrik , Diness Laura Vittrup , Larsen Finn Ole
Published: July 2020

This study is an investigator-initiated randomized phase II trial focusing on the treatment of advanced biliary tract cancer with either oxaliplatin 50 mg/m2 and gemcitabine 1000 mg/m2 on day 1 in a two-week cycle with capecitabine 650 mg/m2 twice-daily continuously or cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and day 8 in a three-week cycle. One-hundred patients were included. Forty-seven patients received oxaliplatin, gemcitabine, and capecitabine with a median progression-free survival (mPFS) of 5.7 months (95% CI 3.0–7.8) and a median overall survival (mOS) of 8.7 months (95% CI 6.5–11.2). Forty-nine patients received cisplatin and gemcitabine with a mPFS of 7.3 months (95% CI 6.0–8.7) and a mOS of 12.0 months (95% CI 8.3–16.7). This trial confirms a mOS of 12 months with cisplatin and gemcitabine, as found in earlier trials. With a superior tumor control rate of 79% vs. 60% (p = 0.045), a difference in the mPFS of 1.6 months (HR = 0.721, p = 0.1), and a difference in the mOS of 3.3 months (HR = 0.731, p = 0.1), cisplatin and gemcitabine should still be considered the standard first-line treatment for advanced biliary tract cancer.
Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model
Authors: Koch Maximilian , Reinartz Sebastian , Saggau Julia , Knittel Gero , Rosen Natascha , Fedorchenko Oleg , Thelen Lisa , Barthel Romy , Reinart Nina , Seeger-Nukpezah Tamina , Reinhardt Hans Christian , Hallek Michael , Nguyen Phuong-Hien
Published: July 2020

The Eµ-TCL1 transgenic mouse model represents the most widely and extensively used animal model for chronic lymphocytic leukemia (CLL). In this report, we performed a meta-analysis of leukemia progression in over 300 individual Eµ-TCL1 transgenic mice and discovered a significantly accelerated disease progression in females compared to males. This difference is also reflected in an aggressive CLL mouse model with additional deletion of Tp53 besides the TCL1 transgene. Moreover, after serial adoptive transplantation of murine CLL cells, female recipients also succumbed to CLL earlier than male recipients. This sex-related disparity in the murine models is markedly contradictory to the human CLL condition. Thus, due to our observation we urge both careful consideration in the experimental design and accurate description of the Eµ-TCL1 transgenic cohorts in future studies.
High-Throughput Sequencing of Gastric Cancer Patients: Unravelling Genetic Predispositions Towards an Early-Onset Subtype
Authors: Machlowska Julita , Kapusta Przemysław , Baj Jacek , Morsink Folkert H. M. , Wołkow Paweł , Maciejewski Ryszard , Offerhaus G. Johan A. , Sitarz Robert
Published: July 2020

Background: Gastric cancer is the fourth most common cause of cancer-related death. Currently, it is broadly accepted that the molecular complexity and heterogeneity of gastric cancer, both inter- and intra-tumor, display important barriers for finding specific biomarkers for the early detection and diagnosis of this malignancy. Early-onset gastric cancer is not as prevalent as conventional gastric carcinoma, but it is a preferable model for studying the genetic background, as young patients are less exposed to environmental factors, which influence cancer development. Aim: The main objective of this study was to reveal age-dependent genotypic characteristics of gastric cancer subtypes, as well as conduct mutation profiling for the most frequent alterations in gastric cancer development, using targeted next-generation sequencing technology. Patients and methods: The study group included 53 patients, consisting of 18 patients with conventional gastric cancer and 35 with an early-onset subtype. The DNA of all index cases was used for next-generation sequencing, employing a panel of 94 genes and 284 single nucleotide polymorphisms (SNPs) (TruSight Cancer Panel, Illumina), which is characteristic for common and rare types of cancer. Results: From among the 53 samples processed for sequencing, we were able to identify seven candidate genes (STK11, RET, FANCM, SLX4, WRN, MEN1, and KIT) and nine variants among them: one splice_acceptor, four synonymous, and four missense variants. These were selected for the age-dependent differentiation of gastric cancer subtypes. We found four variants with C-Score ≥ 10, as 10% of the most deleterious substitutions: rs1800862 (RET), rs10138997 (FANCM), rs2230009 (WRN), and rs2959656 (MEN1). We identified 36 different variants, among 24 different genes, which were the most frequent genetic alterations among study subjects. We found 16 different variants among the genes that were present in 100% of the total cohort: SDHB (rs2746462), ALK (rs1670283), XPC (rs2958057), RECQL4 (rs4925828; rs11342077, rs398010167; rs2721190), DDB2 (rs326212), MEN1 (rs540012), AIP (rs4930199), ATM (rs659243), HNF1A (rs1169305), BRCA2 (rs206075; rs169547), ERCC5 (rs9514066; rs9514067), and FANCI (rs7183618). Conclusions: The technology of next-generation sequencing is a useful tool for studying the development and progression of gastric carcinoma in a high-throughput way. Our study revealed that early-onset gastric cancer has a different mutation frequency profile in certain genes compared to conventional subtype.
The Biological Role of Sponge Circular RNAs in Gastric Cancer: Main Players or Coadjuvants?
Authors: Pereira Adenilson Leão , Magalhães Leandro , Pantoja Rafael Pompeu , Araújo Gilderlanio , Ribeiro-dos-Santos Ândrea , Vidal Amanda Ferreira
Published: July 2020

Circular RNAs (circRNAs) are a new class of long noncoding RNAs able to perform multiple functions, including sponging microRNAs (miRNAs) and RNA-Binding Proteins (RBPs). They play an important role in gastric carcinogenesis, but its involvement during gastric cancer (GC) development and progression are not well understood. We gathered miRNA and/or RBPs sponge circRNAs present in GC, and accessed their biological roles through functional enrichment of their target genes or ligand RBPs. We identified 54 sponge circRNAs in GC that are able to sponge 51 miRNAs and 103 RBPs. Then, we evaluated their host gene expression using The Cancer Genome Atlas (TCGA) database and observed that COL1A2 is the most overexpressed gene, which may be due to circHIPK3/miR-29b-c/COL1A2 axis dysregulation. We identified 27 GC-related pathways that may be affected mainly by circPVT1, circHIPK3 and circNF1. Our results indicate that circHIPK3/miR-107/BDNF/LIN28 axis may mediate chemoresistance in GC, and that circPVT1, circHIPK3, circNF1, ciRS-7 and circ_0000096 appear to be involved in gastrointestinal cancer development. Lastly, circHIPK3, circNRIP1 and circSMARCA5 were identified in different ethnic populations and may be ubiquitous modulators of gastric carcinogenesis. Overall, the studied sponge circRNAs are part of a complex RBP-circRNA-miRNA-mRNA interaction network, and are involved in the establishment, chemoresistance and progression of GC.
Hypoalbuminemia Reflects Nutritional Risk, Body Composition and Systemic Inflammation and Is Independently Associated with Survival in Patients with Colorectal Cancer
Authors: Almasaudi Arwa S. , Dolan Ross D. , Edwards Christine A. , McMillan Donald C.
Published: July 2020

It has long been recognized that albumin has prognostic value in patients with cancer. However, although the Global Leadership Initiative on Malnutrition GLIM criteria (based on five diagnostic criteria, three phenotypic criteria and two etiologic criteria) recognize inflammation as an important etiologic factor in malnutrition, there are limited data regarding the association between albumin, nutritional risk, body composition and systemic inflammation, and whether albumin is associated with mortality independent of these parameters. The aim of this study was to examine the relationship between albumin, nutritional risk, body composition, systemic inflammation, and outcomes in patients with colorectal cancer (CRC). A retrospective cohort study (n = 795) was carried out in which patients were divided into normal and hypoalbuminaemic groups (albumin  < 35 g/L) in the presence and absence of a systemic inflammatory response C-reactive protein (CRP > 10 and <10 mg/L, respectively). Post-operative complications, severity of complications and mortality were considered as outcome measures. Categorical variables were analyzed using Chi-square test χ2 or linear-by-linear association. Survival data were analyzed using univariate and multivariate Cox regression. In the presence of a systemic inflammatory response, hypoalbuminemia was directly associated with Malnutrition Universal Screening Tool MUST (p < 0.001) and inversely associated with Body Mass Index BMI (p < 0.001), subcutaneous adiposity (p < 0.01), visceral obesity (p < 0.01), skeletal muscle index (p < 0.001) and skeletal muscle density (p < 0.001). There was no significant association between hypoalbuminemia and either the presence of complications or their severity. In the absence of a systemic inflammatory response (n = 589), hypoalbuminemia was directly associated with MUST (p < 0.05) and inversely associated with BMI (p < 0.01), subcutaneous adiposity (p < 0.05), visceral adiposity (p < 0.05), skeletal muscle index (p < 0.01) and skeletal muscle density (p < 0.001). Hypoalbuminemia was, independently of inflammatory markers, associated with poorer cancer-specific and overall survival (both p < 0.001). The results suggest that hypoalbuminemia in patients with CRC reflects both increased nutritional risk and greater systemic inflammatory response and was independently associated with poorer survival in patients with CRC.
Tumor-Associated Macrophage Status in Cancer Treatment
Authors: Malfitano Anna Maria , Pisanti Simona , Napolitano Fabiana , Di Somma Sarah , Martinelli Rosanna , Portella Giuseppe
Published: July 2020

Tumor-associated macrophages (TAMs) represent the most abundant innate immune cells in tumors. TAMs, exhibiting anti-inflammatory phenotype, are key players in cancer progression, metastasis and resistance to therapy. A high TAM infiltration is generally associated with poor prognosis, but macrophages are highly plastic cells that can adopt either proinflammatory/antitumor or anti-inflammatory/protumor features in response to tumor microenvironment stimuli. In the context of cancer therapy, many anticancer therapeutics, apart from their direct effect on tumor cells, display different effects on TAM activation status and density. In this review, we aim to evaluate the indirect effects of anticancer therapies in the modulation of TAM phenotypes and pro/antitumor activity.
Role of Mitochondria in Cancer Stem Cell Resistance
Authors: García-Heredia José Manuel , Carnero Amancio
Published: July 2020

Cancer stem cells (CSC) are associated with the mechanisms of chemoresistance to different cytotoxic drugs or radiotherapy, as well as with tumor relapse and a poor prognosis. Various studies have shown that mitochondria play a central role in these processes because of the ability of this organelle to modify cell metabolism, allowing survival and avoiding apoptosis clearance of cancer cells. Thus, the whole mitochondrial cycle, from its biogenesis to its death, either by mitophagy or by apoptosis, can be targeted by different drugs to reduce mitochondrial fitness, allowing for a restored or increased sensitivity to chemotherapeutic drugs. Once mitochondrial misbalance is induced by a specific drug in any of the processes of mitochondrial metabolism, two elements are commonly boosted: an increment in reactive nitrogen/oxygen species and, subsequently, activation of the intrinsic apoptotic pathway.
What Have In Vitro Co-Culture Models Taught Us about the Contribution of Epithelial-Mesenchymal Interactions to Airway Inflammation and Remodeling in Asthma?
Authors: Osei Emmanuel Twumasi , Booth Steven , Hackett Tillie-Louise
Published: July 2020

As the lung develops, epithelial-mesenchymal crosstalk is essential for the developmental processes that drive cell proliferation, differentiation, and extracellular matrix (ECM) production within the lung epithelial-mesenchymal trophic unit (EMTU). In asthma, a number of the lung EMTU developmental signals have been associated with airway inflammation and remodeling, which has led to the hypothesis that aberrant activation of the asthmatic EMTU may lead to disease pathogenesis. Monoculture studies have aided in the understanding of the altered phenotype of airway epithelial and mesenchymal cells and their contribution to the pathogenesis of asthma. However, 3-dimensional (3D) co-culture models are needed to enable the study of epithelial-mesenchymal crosstalk in the setting of the in vivo environment. In this review, we summarize studies using 3D co-culture models to assess how defective epithelial-mesenchymal communication contributes to chronic airway inflammation and remodeling within the asthmatic EMTU.
Regulation of Histone Ubiquitination in Response to DNA Double Strand Breaks
Authors: Aquila Lanni , Atanassov Boyko S.
Published: July 2020

Eukaryotic cells are constantly exposed to both endogenous and exogenous stressors that promote the induction of DNA damage. Of this damage, double strand breaks (DSBs) are the most lethal and must be efficiently repaired in order to maintain genomic integrity. Repair of DSBs occurs primarily through one of two major pathways: non-homologous end joining (NHEJ) or homologous recombination (HR). The choice between these pathways is in part regulated by histone post-translational modifications (PTMs) including ubiquitination. Ubiquitinated histones not only influence transcription and chromatin architecture at sites neighboring DSBs but serve as critical recruitment platforms for repair machinery as well. The reversal of these modifications by deubiquitinating enzymes (DUBs) is increasingly being recognized in a number of cellular processes including DSB repair. In this context, DUBs ensure proper levels of ubiquitin, regulate recruitment of downstream effectors, dictate repair pathway choice, and facilitate appropriate termination of the repair response. This review outlines the current understanding of histone ubiquitination in response to DSBs, followed by a comprehensive overview of the DUBs that catalyze the removal of these marks.
Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy
Authors: Böckmann Sabine , Hinz Burkhard
Published: July 2020

Cannabidiol (CBD), a non-psychoactive cannabinoid, has been reported to mediate antioxidant, anti-inflammatory, and anti-angiogenic effects in endothelial cells. This study investigated the influence of CBD on the expression of heme oxygenase-1 (HO-1) and its functional role in regulating metabolic, autophagic, and apoptotic processes of human umbilical vein endothelial cells (HUVEC). Concentrations up to 10 µM CBD showed a concentration-dependent increase of HO-1 mRNA and protein and an increase of the HO-1-regulating transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). CBD-induced HO-1 expression was not decreased by antagonists of cannabinoid-activated receptors (CB1, CB2, transient receptor potential vanilloid 1), but by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC). The incubation of HUVEC with 6 µM CBD resulted in increased metabolic activity, while 10 µM CBD caused decreased metabolic activity and an induction of apoptosis, as demonstrated by enhanced caspase-3 cleavage. In addition, CBD triggered a concentration-dependent increase of the autophagy marker LC3A/B-II. Both CBD-induced LC3A/B-II levels and caspase-3 cleavage were reduced by NAC. The inhibition of autophagy by bafilomycin A1 led to apoptosis induction by 6 µM CBD and a further increase of the proapoptotic effect of 10 µM CBD. On the other hand, the inhibition of HO-1 activity with tin protoporphyrin IX (SnPPIX) or knockdown of HO-1 expression by Nrf2 siRNA was associated with a decrease in CBD-mediated autophagy and apoptosis. In summary, our data show for the first time ROS-mediated HO-1 expression in endothelial cells as a mechanism by which CBD mediates protective autophagy, which at higher CBD concentrations, however, can no longer prevent cell death inducing apoptosis.
The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients
Authors: Zamai Loris
Published: July 2020

The article describes the rationale for inhibition of the renin-angiotensin system (RAS) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent positive feedback-loop mechanisms. Based purely on experimental studies in which RAS pathway inhibitors were administered in vivo to humans/rodents, a reasonable hypothesis of using inhibitors that block both ACE and ACE2 zinc metalloproteases and their downstream pathways in COVID-19 patients will be proposed. In particular, metal (zinc) chelators and renin inhibitors may work alone or in combination to inhibit the positive feedback loops (initially triggered by SARS-CoV-2 and subsequently sustained by hypoxia independently on viral trigger) as both arms of renin-angiotensin system are upregulated, leading to critical, advanced and untreatable stages of the disease.
Experimental Models for Fungal Keratitis: An Overview of Principles and Protocols
Authors: Montgomery Micaela L. , Fuller Kevin K.
Published: July 2020

Fungal keratitis is a potentially blinding infection of the cornea that afflicts diverse patient populations worldwide. The development of better treatment options requires a more thorough understanding of both microbial and host determinants of pathology, and a spectrum of experimental models have been developed toward this end. In vivo (animal) models most accurately capture complex pathological outcomes, but protocols may be challenging to implement and vary widely across research groups. In vitro models allow for the molecular dissection of specific host cell–fungal interactions, but they do so without the appropriate environmental/structural context; ex vivo (corneal explant) models provide the benefits of intact corneal tissue, but they do not provide certain pathological features, such as inflammation. In this review, we endeavor to outline the key features of these experimental models as well as describe key technical variations that could impact study design and outcomes.
Regulation of Neurogenesis in Mouse Brain by HMGB1
Authors: Zhao Xiang , Rouhiainen Ari , Li Zhilin , Guo Su , Rauvala Heikki
Published: July 2020

The High Mobility Group Box 1 (HMGB1) is the most abundant nuclear nonhistone protein that is involved in transcription regulation. In addition, HMGB1 has previously been found as an extracellularly acting protein enhancing neurite outgrowth in cultured neurons. Although HMGB1 is widely expressed in the developing central nervous system of vertebrates and invertebrates, its function in the developing mouse brain is poorly understood. Here, we have analyzed developmental defects of the HMGB1 null mouse forebrain, and further examined our findings in ex vivo brain cell cultures. We find that HMGB1 is required for the proliferation and differentiation of neuronal stem cells/progenitor cells. Enhanced apoptosis is also found in the neuronal cells lacking HMGB1. Moreover, HMGB1 depletion disrupts Wnt/β-catenin signaling and the expression of transcription factors in the developing cortex, including Foxg1, Tbr2, Emx2, and Lhx6. Finally, HMGB1 null mice display aberrant expression of CXCL12/CXCR4 and reduced RAGE signaling. In conclusion, HMGB1 plays a critical role in mammalian neurogenesis and brain development.
The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses
Authors: Campillo-Davo Diana , Flumens Donovan , Lion Eva
Published: July 2020

Over the past decades, adoptive transfer of T cells has revolutionized cancer immunotherapy. In particular, T-cell receptor (TCR) engineering of T cells has marked important milestones in developing more precise and personalized cancer immunotherapies. However, to get the most benefit out of this approach, understanding the role that TCR affinity, avidity, and functional avidity play on how TCRs and T cells function in the context of tumor-associated antigen (TAA) recognition is vital to keep generating improved adoptive T-cell therapies. Aside from TCR-related parameters, other critical factors that govern T-cell activation are the effect of TCR co-receptors on TCR–peptide-major histocompatibility complex (pMHC) stabilization and TCR signaling, tumor epitope density, and TCR expression levels in TCR-engineered T cells. In this review, we describe the key aspects governing TCR specificity, T-cell activation, and how these concepts can be applied to cancer-specific TCR redirection of T cells.
The Secretome Analysis of Activated Human Renal Fibroblasts Revealed Beneficial Effect of the Modulation of the Secreted Peptidyl-Prolyl Cis-Trans Isomerase A in Kidney Fibrosis
Authors: Dihazi Gry H. , Eltoweissy Marwa , Jahn Olaf , Tampe Björn , Zeisberg Michael , Wülfrath Hauke S. , Müller Gerhard A. , Dihazi Hassan
Published: July 2020

The secretome is an important mediator in the permanent process of reciprocity between cells and their environment. Components of secretome are involved in a large number of physiological mechanisms including differentiation, migration, and extracellular matrix modulation. Alteration in secretome composition may therefore trigger cell transformation, inflammation, and diseases. In the kidney, aberrant protein secretion plays a central role in cell activation and transition and in promoting renal fibrosis onset and progression. Using comparative proteomic analyses, we investigated in the present study the impact of cell transition on renal fibroblast cells secretome. Human renal cell lines were stimulated with profibrotic hormones and cytokines, and alterations in secretome were investigated using proteomic approaches. We identified protein signatures specific for the fibrotic phenotype and investigated the impact of modeling secretome proteins on extra cellular matrix accumulation. The secretion of peptidyl-prolyl cis-trans isomerase A (PPIA) was demonstrated to be associated with fibrosis phenotype. We showed that the in-vitro inhibition of PPIA with ciclosporin A (CsA) resulted in downregulation of PPIA and fibronectin (FN1) expression and significantly reduced their secretion. Knockdown studies of PPIA in a three-dimensional (3D) cell culture model significantly impaired the secretion and accumulation of the extracellular matrix (ECM), suggesting a positive therapeutic effect on renal fibrosis progression.
The Functionality of Endothelial-Colony-Forming Cells from Patients with Diabetes Mellitus
Authors: Lyons Caomhán J. , O'Brien Timothy
Published: July 2020

Endothelial-colony-forming cells (ECFCs) are a population of progenitor cells which have demonstrated promising angiogenic potential both in vitro and in vivo. However, ECFCs from diabetic patients have been shown to be dysfunctional compared to ECFCs from healthy donors. Diabetes mellitus itself presents with many vascular co-morbidities and it has been hypothesized that ECFCs may be a potential cell therapy option to promote revascularisation in these disorders. While an allogeneic cell therapy approach would offer the potential of an ‘off the shelf’ therapeutic product, to date little research has been carried out on umbilical cord-ECFCs in diabetic models. Alternatively, autologous cell therapy using peripheral blood-ECFCs allows the development of a personalised therapeutic approach to medicine; however, autologous diabetic ECFCs are dysfunctional and need to be repaired so they can effectively treat diabetic co-morbidities. Many different groups have modified autologous diabetic ECFCs to improve their function using a variety of methods including pre-treatment with different factors or with genetic modification. While the in vitro and in vivo data from the literature is promising, no ECFC therapy has proceeded to clinical trials to date, indicating that more research is needed for a potential ECFC therapy in the future to treat diabetic complications.
Blocking Notch-Signaling Increases Neurogenesis in the Striatum after Stroke
Authors: Santopolo Giuseppe , Magnusson Jens P. , Lindvall Olle , Kokaia Zaal , Frisén Jonas
Published: July 2020

Stroke triggers neurogenesis in the striatum in mice, with new neurons deriving in part from the nearby subventricular zone and in part from parenchymal astrocytes. The initiation of neurogenesis by astrocytes within the striatum is triggered by reduced Notch-signaling, and blocking this signaling pathway by deletion of the gene encoding the obligate Notch coactivator Rbpj is sufficient to activate neurogenesis by striatal astrocytes in the absence of an injury. Here we report that blocking Notch-signaling in stroke increases the neurogenic response to stroke 3.5-fold in mice. Deletion of Rbpj results in the recruitment of a larger number of parenchymal astrocytes to neurogenesis and over larger areas of the striatum. These data suggest inhibition of Notch-signaling as a potential translational strategy to promote neuronal regeneration after stroke.
Human Cardiac Organoids for Modeling Genetic Cardiomyopathy
Authors: Filippo Buono Michele , von Boehmer Lisa , Strang Jaan , P. Hoerstrup Simon , Y. Emmert Maximilian , Nugraha Bramasta
Published: July 2020

Genetic cardiomyopathies are characterized by changes in the function and structure of the myocardium. The development of a novel in vitro model could help to better emulate healthy and diseased human heart conditions and may improve the understanding of disease mechanisms. In this study, for the first time, we demonstrated the generation of cardiac organoids using a triculture approach of human induced pluripotent stem-cell-derived cardiomyocytes (hiPS-CMs)—from healthy subjects and cardiomyopathy patients—human cardiac microvascular endothelial cells (HCMECs) and human cardiac fibroblasts (HCFs). We assessed the organoids’ suitability as a 3D cellular model for the representation of phenotypical features of healthy and cardiomyopathic hearts. We observed clear differences in structure and beating behavior between the organoid groups, depending on the type of hiPS-CMs (healthy versus cardiomyopathic) used. Organoids may thus prove a promising tool for the design and testing of patient-specific treatments as well as provide a platform for safer and more efficacious drug development.
Interplay of TRIM2 E3 Ubiquitin Ligase and ALIX/ESCRT Complex: Control of Developmental Plasticity During Early Neurogenesis
Authors: Lokapally Ashwin , Neuhaus Herbert , Herfurth Juliane , Hollemann Thomas
Published: July 2020

Tripartite motif 2 (TRIM2) drives neurite outgrowth and polarization, is involved in axon specification, and confers neuroprotective functions during rapid ischemia. The mechanisms controlling neuronal cell fate determination and differentiation are fundamental for neural development. Here, we show that in Xenopus, trim2 knockdown affects primary neurogenesis and neural progenitor cell survival. Embryos also suffer from severe craniofacial malformation, a reduction in brain volume, and the loss of motor sensory function. Using a high-throughput LC-MS/MS approach with GST-Trim2 as bait, we pulled down ALG-2 interacting protein X (Alix) from Xenopus embryonic lysates. We demonstrate that the expression of trim2/TRIM2 and alix/ALIX overlap during larval development and on a cellular level in cell culture. Interestingly, trim2 morphants showed a clustering and apoptosis of neural progenitors, which are phenotypic hallmarks that are also observed in Alix KO mice. Therefore, we propose that the interaction of Alix and Trim2 plays a key role in the determination and differentiation of neural progenitors via the modulation of cell proliferation/apoptosis during neurogenesis.
The Leukemic Fly: Promises and Challenges
Authors: Al Outa Amani , Abubaker Dana , Madi Joelle , Nasr Rihab , Shirinian Margret
Published: July 2020

Leukemia involves different types of blood cancers, which lead to significant mortality and morbidity. Murine models of leukemia have been instrumental in understanding the biology of the disease and identifying therapeutics. However, such models are time consuming and expensive in high throughput genetic and drug screening. Drosophila melanogaster has emerged as an invaluable in vivo model for studying different diseases, including cancer. Fruit flies possess several hematopoietic processes and compartments that are in close resemblance to their mammalian counterparts. A number of studies succeeded in characterizing the fly’s response upon the expression of human leukemogenic proteins in hematopoietic and non-hematopoietic tissues. Moreover, some of these studies showed that these models are amenable to genetic screening. However, none were reported to be tested for drug screening. In this review, we describe the Drosophila hematopoietic system, briefly focusing on leukemic diseases in which fruit flies have been used. We discuss myeloid and lymphoid leukemia fruit fly models and we further highlight their roles for future therapeutic screening. In conclusion, fruit fly leukemia models constitute an interesting area which could speed up the process of integrating new therapeutics when complemented with mammalian models.
3-D Multi-Tubular Reactor Model Development for the Oxidative Dehydrogenation of Butene to 1,3-Butadiene
Authors: Moon Jiyoung , Gbadago Dela Quarme , Hwang Sungwon
Published: July 2020

The oxidative dehydrogenation (ODH) of butene has been recently developed as a viable alternative for the synthesis of 1,3-butadiene due to its advantages over other conventional methods. Various catalytic reactors for this process have been previously studied, albeit with a focus on lab-scale design. In this study, a multi-tubular reactor model for the butadiene synthesis via ODH of butene was developed using computational fluid dynamics (CFD). For this, the 3D multi-tubular model, which combines complex reaction kinetics with a shell-side coolant fluid over a series of individual reactor tubes, was generated using OpenFOAM®. Then, the developed model was validated and analyzed with the experimental results, which gave a maximum error of 7.5%. Finally, parametric studies were conducted to evaluate the effect of thermodynamic conditions (isothermal, non-isothermal and adiabatic), feed temperature, and gas velocity on reactor performance. The results showed the formation of a hotspot at the reactor exit, which necessitates an efficient temperature control at that section of the reactor. It was also found that as the temperature increased, the conversion and yield increased whilst the selectivity decreased. The converse was found for increasing velocities.
Erratum: Chakraborty, P. et al. Macrophages from Susceptible and Resistant Chicken Lines have Different Transcriptomes following Marek’s Disease Virus Infection. Genes 2019, 10, 74
Authors: Chakraborty Pankaj , Kuo Richard , Vervelde Lonneke , Dutia Bernadette , Kaiser Pete , Smith Jacqueline
Published: July 2020

The authors wish to make the following correction to their paper published in Genes [...]
Salmonella enterica’s “Choice”: Itaconic Acid Degradation or Bacteriocin Immunity Genes
Authors: Joerger Rolf D.
Published: July 2020

Itaconic acid is an immunoregulatory metabolite produced by macrophages in response to pathogen invasion. It also exhibits antibacterial activity because it is an uncompetitive inhibitor of isocitrate lyase, whose activity is required for the glyoxylate shunt to be operational. Some bacteria, such as Yersinia pestis, encode enzymes that can degrade itaconic acid and therefore eliminate this metabolic inhibitor. Studies, primarily with Salmonella enterica subspecies enterica serovar Typhimurium, have demonstrated the presence of similar genes in this pathogen and the importance of these genes for the persistence of the pathogen in murine hosts. This minireview demonstrates that, based on Blast searches of 1063 complete Salmonella genome sequences, not all Salmonella serovars possess these genes. It is also shown that the growth of Salmonella isolates that do not possess these genes is sensitive to the acid under glucose-limiting conditions. Interestingly, most of the serovars without the three genes, including serovar Typhi, harbor DNA at the corresponding genomic location that encodes two open reading frames that are similar to bacteriocin immunity genes. It is hypothesized that these genes could be important for Salmonella that finds itself in strong competition with other Enterobacteriacea in the intestinal tract—for example, during inflammation.
Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations
Authors: Suszynska Malwina , Kozlowski Piotr
Published: July 2020

Over the last two decades, numerous BARD1 mutations/pathogenic variants (PVs) have been found in patients with breast cancer (BC) and ovarian cancer (OC). However, their role in BC and OC susceptibility remains controversial, and strong evidence-based guidelines for carriers are not yet available. Herein, we present a comprehensive catalog of BARD1 PVs identified in large cumulative cohorts of ~48,700 BC and ~20,800 OC cases (retrieved from 123 studies examining the whole coding sequence of BARD1). Using these resources, we compared the frequency of BARD1 PVs in the cases and ~134,100 controls from the gnomAD database and estimated the effect of the BARD1 PVs on BC and OC risks. The analysis revealed that BARD1 is a BC moderate-risk gene (odds ratio (OR) = 2.90, 95% CIs:2.25–3.75, p < 0.0001) but not an OC risk gene (OR = 1.36, 95% CIs:0.87–2.11, p = 0.1733). In addition, the BARD1 mutational spectrum outlined in this study allowed us to determine recurrent PVs and evaluate the variant-specific risk for the most frequent PVs. In conclusion, these precise estimates improve the understanding of the role of BARD1 PVs in BC and OC predisposition and support the need for BARD1 diagnostic testing in BC patients.
De Novo Assembly-Based Analysis of RPGR Exon ORF15 in an Indigenous African Cohort Overcomes Limitations of a Standard Next-Generation Sequencing (NGS) Data Analysis Pipeline
Authors: Maggi Jordi , Roberts Lisa , Koller Samuel , Rebello George , Berger Wolfgang , Ramesar Rajkumar
Published: July 2020

RPGR exon ORF15 variants are one of the most frequent causes for inherited retinal disorders (IRDs), in particular retinitis pigmentosa. The low sequence complexity of this mutation hotspot makes it prone to indels and challenging for sequence data analysis. Whole-exome sequencing generally fails to provide adequate coverage in this region. Therefore, complementary methods are needed to avoid false positives as well as negative results. In this study, next-generation sequencing (NGS) was used to sequence long-range PCR amplicons for an IRD cohort of African ancestry. By developing a novel secondary analysis pipeline based on de novo assembly, we were able to avoid the miscalling of variants generated by standard NGS analysis tools. We identified pathogenic variants in 11 patients (13% of the cohort), two of which have not been reported previously. We provide a novel and alternative end-to-end secondary analysis pipeline for targeted NGS of ORF15 that is less prone to false positive and negative variant calls.
Genome-Wide Characterization and Expression Analysis of NHX Gene Family under Salinity Stress in Gossypium barbadense and Its Comparison with Gossypium hirsutum
Authors: Akram Umar , Song Yuhan , Liang Chengzhen , Abid Muhammad Ali , Askari Muhammad , Myat Aye Aye , Abbas Mubashir , Malik Waqas , Ali Zulfiqar , Guo Sandui , Zhang Rui , Meng Zhigang
Published: July 2020

Cotton is an important economic crop affected by different abiotic stresses at different developmental stages. Salinity limits the growth and productivity of crops worldwide. Na+/H+ antiporters play a key role during the plant development and in its tolerance to salt stress. The aim of the present study was a genome-wide characterization and expression pattern analysis under the salinity stress of the sodium-proton antiporter (NHX) of Gossypium barbadense in comparison with Gossypium hirsutum. In G. barbadense, 25 NHX genes were identified on the basis of the Na+_H+ exchanger domain. All except one of the G. barbadense NHX transporters have an Amiloride motif that is a known inhibitor of Na+ ions in plants. A phylogenetic analysis inferred three classes of GbNHX genes—viz., Vac (GbNHX1, 2 and 4), Endo (GbNHX6), and PM (GbNHX7). A high number of the stress-related cis-acting elements observed in promoters show their role in tolerance against abiotic stresses. The Ka/Ks values show that the majority of GbNHX genes are subjected to strong purifying selection under the course of evolution. To study the functional divergence of G. barbadense NHX transporters, the real-time gene expression was analyzed under salt stress in the root, stem, and leaf tissues. In G. barbadense, the expression was higher in the stem, while in G. hirsutum the leaf and root showed a high expression. Moreover, our results revealed that NHX2 homologues in both species have a high expression under salinity stress at higher time intervals, followed by NHX7. The protein-protein prediction study revealed that GbNHX7 is involved in the CBL-CIPK protein interaction pathway. Our study also provided valuable information explaining the molecular mechanism of Na+ transport for the further functional study of Gossypium NHX genes.
Shedding the Light on Litopenaeus vannamei Differential Muscle and Hepatopancreas Immune Responses in White Spot Syndrome Virus (WSSV) Exposure
Authors: Santos Camilla A. , Andrade Sónia C. S. , Fernandes Jorge M. O. , Freitas Patrícia D.
Published: July 2020

White Spot Syndrome Virus (WSSV) is one of the main threats to farming Litopenaeus vannamei, the most important crustacean commercialized in aquaculture worldwide. Here, we performed RNA-seq analyses in hepatopancreas and muscle from WSSV-negative (healthy) and WSSV-positive (unhealthy) L. vannamei, previously exposed to the virus, to obtain new insights about the molecular basis of resistance to WSSV. We detected 71% of our reads mapped against the recently described L. vannamei genome. This is the first report mapping RNA-seq transcripts from shrimps exposed to WSSV against the species reference genome. Differentially expressed gene (DEG) analyses were performed for four independent comparisons, and 13,338 DEGs were identified. When the redundancies and isoforms were disregarded, we observed 8351 and 6514 DEGs, respectively. Interestingly, after crossing the data, we detected a common set of DEGs for hepatopancreas and healthy shrimps, as well as another one for muscle and unhealthy shrimps. Our findings indicate that genes related to apoptosis, melanization, and the Imd pathway are likely to be involved in response to WSSV, offering knowledge about WSSV defense in shrimps exposed to the virus but not infected. These data present potential to be applied in further genetic studies in penaeids and other farmed shrimp species.
Genetic Diversity of C4 Photosynthesis Pathway Genes in Sorghum bicolor (L.)
Authors: Tao Yongfu , George-Jaeggli Barbara , Bouteillé-Pallas Marie , Tai Shuaishuai , Cruickshank Alan , Jordan David , Mace Emma
Published: July 2020

C4 photosynthesis has evolved in over 60 different plant taxa and is an excellent example of convergent evolution. Plants using the C4 photosynthetic pathway have an efficiency advantage, particularly in hot and dry environments. They account for 23% of global primary production and include some of our most productive cereals. While previous genetic studies comparing phylogenetically related C3 and C4 species have elucidated the genetic diversity underpinning the C4 photosynthetic pathway, no previous studies have described the genetic diversity of the genes involved in this pathway within a C4 crop species. Enhanced understanding of the allelic diversity and selection signatures of genes in this pathway may present opportunities to improve photosynthetic efficiency, and ultimately yield, by exploiting natural variation. Here, we present the first genetic diversity survey of 8 known C4 gene families in an important C4 crop, Sorghum bicolor (L.) Moench, using sequence data of 48 genotypes covering wild and domesticated sorghum accessions. Average nucleotide diversity of C4 gene families varied more than 20-fold from the NADP-malate dehydrogenase (MDH) gene family (θπ = 0.2 × 10−3) to the pyruvate orthophosphate dikinase (PPDK) gene family (θπ = 5.21 × 10−3). Genetic diversity of C4 genes was reduced by 22.43% in cultivated sorghum compared to wild and weedy sorghum, indicating that the group of wild and weedy sorghum may constitute an untapped reservoir for alleles related to the C4 photosynthetic pathway. A SNP-level analysis identified purifying selection signals on C4 PPDK and carbonic anhydrase (CA) genes, and balancing selection signals on C4 PPDK-regulatory protein (RP) and phosphoenolpyruvate carboxylase (PEPC) genes. Allelic distribution of these C4 genes was consistent with selection signals detected. A better understanding of the genetic diversity of C4 pathway in sorghum paves the way for mining the natural allelic variation for the improvement of photosynthesis.
Intestinal Microbiota Influences DNA Methylome and Susceptibility to Colorectal Cancer
Authors: Zouggar Aïcha , Haebe Joshua R. , Benoit Yannick D.
Published: July 2020

In a recent publication, Ansari et al. identified gut microbiota as a critical mediator of the intestinal inflammatory response through epigenetic programming of host intestinal epithelium. Exposure to the microbiota induces Ten-Eleven-Translocation (TET)-dependent hypomethylation of genomic elements regulating genes associated with inflammatory response and colorectal cancer. Here, we discuss the impact of such a discovery on the understanding of how the intestinal microbiota may contribute to epigenetic reprogramming and influence the onset of colorectal tumorigenesis. Finally, we examine the prospect of TET inhibition strategies as a therapeutic and/or preventive approach for colorectal cancer in patients afflicted by inflammatory bowel disease.