bluuebunny/crossref_metadata_2025 huggingface dataset:
Flexible Cyclic Immunofluorescence (cyCIF) Using Oligonucleotide Barcoded Antibodies
Authors: McMahon Nathan P. , Jones Jocelyn A. , Anderson Ashley N. , Dietz Matthew S. , Wong Melissa H. , Gibbs Summer L.
Published: January 2023

Advances in our understanding of the complex, multifaceted interactions between tumor epithelia, immune infiltrate, and tumor microenvironmental cells have been driven by highly multiplexed imaging technologies. These techniques are capable of labeling many more biomarkers than conventional immunostaining methods. However, multiplexed imaging techniques suffer from low detection sensitivity, cell loss—particularly in fragile samples—, and challenges with antibody labeling. Herein, we developed and optimized an oligonucleotide antibody barcoding strategy for cyclic immunofluorescence (cyCIF) that can be amplified to increase the detection efficiency of low-abundance antigens. Stained fluorescence signals can be readily removed using ultraviolet light treatment, preserving tissue and fragile cell sample integrity. We also extended the oligonucleotide barcoding strategy to secondary antibodies to enable the inclusion of difficult-to-label primary antibodies in a cyCIF panel. Using both the amplification oligonucleotides to label DNA barcoded antibodies and in situ hybridization of multiple fluorescently labeled oligonucleotides resulted in signal amplification and increased signal-to-background ratios. This procedure was optimized through the examination of staining parameters including staining oligonucleotide concentration, staining temperature, and oligonucleotide sequence design, resulting in a robust amplification technique. As a proof-of-concept, we demonstrate the flexibility of our cyCIF strategy by simultaneously imaging with the original oligonucleotide conjugated antibody (Ab-oligo) cyCIF strategy, the novel Ab-oligo cyCIF amplification strategy, as well as direct and indirect immunofluorescence to generate highly multiplexed images.
The Risk of Endometrial Cancer and Uterine Sarcoma Following Endometriosis or Pelvic Inflammatory Disease
Authors: Huang Jing-Yang , Ma Kevin Sheng-Kai , Wang Li-Tzu , Chiang Cho-Han , Yang Shun-Fa , Wang Chun-Hao , Wang Po-Hui
Published: January 2023

The relationship between uterine corpus cancer and endometriosis was conflicting. We aimed to determine the risk of uterine cancer in patients with endometriosis or pelvic inflammatory disease (PID). In this population-based cohort study, a total of 135,236 females with endometriosis (n = 20,510) or PID (n = 114,726), as well as 135,236 age-matched controls, were included. Cox regression models estimated the risk of uterine cancer in each group. Sub-outcomes of risk for uterine corpus cancer included endometrial cancer and uterine sarcoma were analyzed. An age subgroup analysis was performed to determine the moderator effect of age. A landmark analysis depicted the time varying effect of endometriosis and PID. A propensity score matching analysis was conducted to validate the findings. Patients with endometriosis had significantly higher risk of endometrial cancer (adjusted hazard ratio, aHR = 2.92; 95% CI = 2.12–4.03) and uterine sarcoma (aHR = 5.83; 95% CI = 2.02–16.89), while PID was not associated with the risk of uterine cancer. The increased risk of uterine cancer in patients with endometriosis persisted after propensity score matching (aHR = 2.83, 95%CI = 1.70–4.71). The greatest risk of endometrial cancer occurred in patients who had endometriosis for 37 to 60 months (adjusted relative risk, aRR = 9.15, 95% CI = 4.40–19.02). Females aged 12 to 35 years were at the greatest risk of endometriosis-associated uterine cancer (RR = 6.97, 95% CI = 3.41–14.26). In conclusion, patients with endometriosis were at great risk of uterine cancer, including endometrial cancer and uterine sarcoma, compared with propensity score-matched populations and compared with patients of PID. Younger females with endometriosis and patients who had endometriosis for three to five years were at the greatest risk of endometriosis-associated uterine cancer.
The Immunology of DLBCL
Authors: Takahara Taishi , Nakamura Shigeo , Tsuzuki Toyonori , Satou Akira
Published: January 2023

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and is the most common type of malignant lymphoid neoplasm. While some DLBCLs exhibit strong cell-autonomous survival and proliferation activity, others depend on interactions with non-malignant cells for their survival and proliferation. Recent next-generation sequencing studies have linked these interactions with the molecular classification of DLBCL. For example, germinal center B-cell-like DLBCL tends to show strong associations with follicular T cells and epigenetic regulation of immune recognition molecules, whereas activated B-cell-like DLBCL shows frequent genetic aberrations affecting the class I major histocompatibility complex. Single-cell technologies have also provided detailed information about cell–cell interactions and the cell composition of the microenvironment of DLBCL. Aging-related immunological deterioration, i.e., immunosenescence, also plays an important role in DLBCL pathogenesis, especially in Epstein-Barr virus-positive DLBCL. Moreover, DLBCL in “immune-privileged sites”—where multiple immune-modulating mechanisms exist—shows unique biological features, including frequent down-regulation of immune recognition molecules and an immune-tolerogenic tumor microenvironment. These advances in understanding the immunology of DLBCL may contribute to the development of novel therapies targeting immune systems.
Exploratory Assessment of Nutritional Evaluation Tools as Predictors of Complications and Sarcopenia in Patients with Colorectal Cancer
Authors: Vegas-Aguilar Isabel M. , Guirado-Peláez Patricia , Fernández-Jiménez Rocío , Boughanem Hatim , Tinahones Francisco J. , Garcia-Almeida Jose Manuel
Published: January 2023

Background: Patients with colorectal cancer (CRC) are largely malnourished, which decreases overall survival and treatment efficacy and increases mortality rates. We hypothesize that angle phase might be associated with the risk of sarcopenia as well as cancer complications in patients with CRC. The inclusion of various nutritional status indicators and clinical cancer outcomes can result in significant variability. Therefore, the objective of this study was to perform an exploratory analysis of nutritional evaluation tools used to assess body composition and muscle quality in patients with CRC, in order to predict cancer complications and survival rate. Methods: A total of 127 patients with CRC were included in this study. Bioelectrical impedance analysis and body composition were performed, which we used to obtain phase angle (PhA) values. Muscle function was assessed by hand-grip strength (HGS) and muscle quality and adipose tissue depot were performed using ultrasound techniques. Results: This study showed that there were significant differences in body composition between females and males, as well as in muscle quantity and quality. PhA was highly correlated with quadriceps rectus femoris of cross-sectional area (RF-CSA), circumference of quadriceps rectus femoris (RF-CIR), superficial subcutaneous abdominal fat (S-SAT), as well as HGS (p < 0.05). PhA was also correlated with water content in females, and with muscle mass and quality in males (p < 0.05). Specifically, we found that PhA was a good predictor for cancer complications in women and the risk of sarcopenia in men. In the linear model controlled for age and body mass index (BMI), high PhA value was associated with a decreased risk of complications in females (Odds Ratio (OR) = 0.15, 95% CI: 0.03–0.81, p < 0.05). High PhA value was associated with a decreased risk of sarcopenia in males (OR = 0.42, 95% CI: 0.19–0.95, p < 0.05). In addition, Receiving Operating Characteristics (ROC) curve analysis showed that PhA had a good diagnostic accuracy for detecting cancer complications in females (Area under curve (AUC) = 0.894, 95% CI: 0.88–0.89, p < 0.05) and the risk of sarcopenia in males (AUC = 0.959, 95% CI: 0.91–0.92, p < 0.05). Conclusions: PhA can accurately predict oncological complications in women and sarcopenia in men. These differences are relevant to understanding the nutritional status of patients with CRC and their personalized nutritional treatment.
Real-World Effectiveness of Sorafenib versus Lenvatinib Combined with PD-1 Inhibitors in Unresectable Hepatocellular Carcinoma
Authors: Chiang Hsueh-Chien , Lee Yang-Cheng , Chang Ting-Tsung , Lin Yih-Jyh , Wu Hung-Tsung , Wang Chung-Teng , Chen Chiung-Yu , Chen Po-Jun , Hsieh Ming-Tsung , Lin Sheng-Hsiang , Chen Shang-Hung , Chuang Chiao-Hsiung , Wu I-Chin , Hong Tzu-Chun , Wu Juei-Seng , Han Meng-Zhi , Chen Wei-Ting , Chiang Chien-Ming , Hung Kuan-Kai , Kuo Hsin-Yu
Published: January 2023

Immune checkpoint inhibitors (ICIs) combined with multitarget tyrosine kinase inhibitors (MTKIs) exert a synergistic effect and are effective in unresectable hepatocellular carcinoma (uHCC). However, precise data regarding the real-world clinical applications of these combination therapies in uHCC are lacking. This study compared the treatment efficacy of sorafenib versus lenvatinib in combination with programmed cell death protein-1 (PD-1) inhibitors in patients with uHCC in a clinical setting. Among 208 patients with uHCC treated with PD-1 inhibitors, 88 were administered with ICIs in combination with sorafenib or lenvatinib. The treatment response and survival outcomes were evaluated. Predictors of survival were assessed by multivariate analysis. A total of 49 patients were treated with PD-1 inhibitors combined with sorafenib, and 39 patients were treated with PD-1 inhibitors combined with lenvatinib. The lenvatinib group exhibited a stronger objective response rate (ORR) (20.51% vs. 16.33%) and had a higher disease control rate (41.03% vs. 28.57%) than did the sorafenib group. The median overall survival was longer in the lenvatinib group than the sorafenib group (13.1 vs. 7.8 months; hazard ratio = 0.39, p = 0.017). The incidence of treatment-related adverse events was similar. PD-1 inhibitors combined with lenvatinib can be a feasible treatment strategy for HCC patients receiving MTKI-based combination therapy. PD-1 inhibitors combined with lenvatinib resulted in more favorable survival outcomes without increased toxic effects compared with PD-1 inhibitors with sorafenib. Additional larger-scale and prospective studies should be conducted to verify the study results.
The Association of Nevus-Associated Melanoma with Common or Dysplastic Melanocytic Nevus: A Systematic Review and Meta-Analysis
Authors: Dessinioti Clio , Befon Aggeliki , Stratigos Alexander J.
Published: January 2023

Background: Cutaneous melanoma has an adjacent nevus remnant upon histological examination in 30% of cases (nevus-associated melanoma, NAM), while it appears de novo for 70% of tumors. Regarding NAM arising in acquired melanocytic nevus, currently there is no evidence on whether NAM more frequently develops in association with a dysplastic or common melanocytic nevus. Objectives: To conduct a systematic review and meta-analysis to investigate the proportion of dysplastic or common melanocytic nevus in NAM associated with acquired nevus. Methods: A systematic literature search is conducted using PubMed, Scopus, and the Cochrane Library. The PRISMA checklist is used. Studies reporting patients diagnosed with NAM arising in an acquired common or dysplastic melanocytic nevus are included. A meta-analysis of proportions is performed using the random-effects model. The magnitude of heterogeneity is assessed with the I2 statistic. Results: A total of 22 studies with 2174 NAMs with an acquired nevus (dysplastic or common) are included. The proportion of dysplastic nevus in NAM varies considerably in the included studies, ranging from 0% to 100%. In the meta-analysis, the overall estimate of the proportion of having a dysplastic nevus in NAM is 51% (95% CI: 39–63%) with high heterogeneity at I2: 95.8% (p < 0.01). A sensitivity meta-analysis of 12 studies that included 30 or more acquired nevus-NAMs (2023 cases) shows that 65% of the NAMs developed in a dysplastic nevus (95% CI: 51–77%). In a meta-analysis of 4 studies reporting invasive-only acquired nevus-NAMs (764 cases), the proportion of dysplastic nevus is 56% (95% CI: 36–75%). Only 2 studies are found reporting in situ NAMs with an acquired nevus, and the pooled estimated proportion of dysplastic nevus is 71% (95% CI: 63–78%). Conclusions: The results of this meta-analysis suggest a higher proportion of dysplastic nevus in acquired nevus-NAM; however, there is considerable uncertainty and high heterogeneity, highlighting the need for future well-designed studies with uniform histopathological definitions for dysplastic nevus remnants which report the type of nevus in NAM separately for invasive melanomas, thin tumors, and by histological subtype.
Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy with Intra-Operative Radiotherapy for Patients with Locally Advanced or Locally Recurrent Rectal Cancer and Peritoneal Metastases
Authors: van de Vlasakker Vincent C. J. , van den Heuvel Teun B. M. , Rijken Anouk , Nienhuijs Simon W. , Ketelaers Stijn H. J. , Verrijssen An-Sofie E. , Rutten Harm J. , Nieuwenhuijzen Grard A. P. , Burger Jacobus W. A. , de Hingh Ignace H. J. T.
Published: January 2023

Purpose: To assess the safety and long-term outcome of a multimodality treatment consisting of radical surgery, intra-operative radiotherapy (IORT), and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for patients with locally advanced rectal cancer (LARC) or locally recurrent rectal carcinoma (LRRC) and peritoneal metastases (PM). Methods: The present study was a single-center cohort study, including all consecutive patients undergoing this treatment in a tertiary referral center for LARC, LRRC, and PM. Postoperative complications, intensive care stay (ICU stay), and re-admission rates were assessed as well as disease-free survival (DFS) and overall survival (OS). Results: A total of 14 LARC and 16 LRRC patients with PM were included in the study. The median ICU stay was 1 day, and 57% of patients developed a severe postoperative complication. No 90-day mortality was observed. Median DFS was 10.0 months (Interquartile Range 7.1–38.7), and median OS was 31.0 months (Interquartile Range 15.9–144.3). Conclusions: As postoperative complications and survival were in line with treatments that are accepted for LARC or LRRC and PM as separate procedures, we conclude that combined treatment with IORT and CRS-HIPEC should be considered as a treatment option for selected patients with LARC or LRRC and peritoneal metastases in tertiary referral centers.
Green Tea in Reproductive Cancers: Could Treatment Be as Simple?
Authors: Parish Maclaine , Massoud Gaelle , Hazimeh Dana , Segars James , Islam Md Soriful
Published: January 2023

Green tea originates from the tea plant Camellia sinensis and is one of the most widely consumed beverages worldwide. Green tea polyphenols, commonly known as catechins, are the major bioactive ingredients and account for green tea’s unique health benefits. Epigallocatechin-3-gallate (EGCG), is the most potent catechin derivative and has been widely studied for its pro- and anti-oxidative effects. This review summarizes the chemical and chemopreventive properties of green tea in the context of female reproductive cancers. A comprehensive search of PubMed and Google Scholar up to December 2022 was conducted. All original and review articles related to green tea or EGCG, and gynecological cancers published in English were included. The findings of several in vitro, in vivo, and epidemiological studies examining the effect of green tea on reproductive cancers, including ovarian, cervical, endometrial, and vulvar cancers, are presented. Studies have shown that this compound targets specific receptors and intracellular signaling pathways involved in cancer pathogenesis. The potential benefits of using green tea in the treatment of reproductive cancers, alone or in conjunction with chemotherapeutic agents, are examined, shedding light on new therapeutic strategies for the management of female reproductive cancers.
Cumulative UV Exposure or a Modified SCINEXA™-Skin Aging Score Do Not Play a Substantial Role in Predicting the Risk of Developing Keratinocyte Cancers after Solid Organ Transplantation—A Case Control Study
Authors: Borik-Heil Liliane , Endler Georg , Parson Walther , Zuckermann Andreas , Schnaller Lisa , Uyanik-Ünal Keziban , Jaksch Peter , Böhmig Georg , Cejka Daniel , Staufer Katharina , Hielle-Wittmann Elisabeth , Rasoul-Rockenschaub Susanne , Wolf Peter , Sunder-Plassmann Raute , Geusau Alexandra
Published: January 2023

The risk of keratinocyte cancer is determined by intrinsic and extrinsic factors, which also influence skin aging. Few studies have linked skin aging and UV exposure with the incidence of non-melanoma skin cancer (NMSC). We evaluated signs of actinic skin damage and aging, individual UV burden, and melanocortin-1 receptor (MC1R) variants. A total of 194 organ transplant recipients (OTR) who suffered from NMSC were compared to 194 tumor-free controls matched for gender, age, type of transplanted organ, post-transplantation (TX) period, and immunosuppressive therapy. Compared with the cases, the controls scored higher in all skin aging scores and there were no differences in UV burden except for intentional whole-body UV exposure for specific UV scenarios and periods of life in favor of cases. The number of NMSCs correlated with all types of skin aging scores, the extent of intentional sun exposure, older age, longer post-TX period, shorter interval from TX to first NMSC, and specific MC1R risk groups. Multivariable models revealed a 7.5-fold risk of developing NMSC in individuals with actinic keratosis; 4.1- or 3.6-fold in those with green or blue eyes, respectively; and a 1.9-fold increased risk in the MC1R medium- + high-risk group. In the absence of skin aging contributing to NMSC development, certain MC1R risk types may identify OTR at risk for high tumor burden.
Hydrothermal Co-Crystallization of Novel Copper Tungstate-Strontium Titanate Crystal Composite for Enhanced Photocatalytic Activity and Increased Electron–Hole Recombination Time
Authors: Ágoston Áron , Janovák László
Published: January 2023

The development of catalysts continues to have a significant influence on science today since we can utilize them to efficiently destroy some contaminants. A study in this field is justified because there is a dearth of comprehensive literature on the creation of SrTiO3-based photocatalysts. Related to this topic, here we report the facile preparation of a structure-modified SrTiO3 photocatalyst, by incorporating CuWO4. Within the case of the CuWO4-modified samples (0.5–3 wt% nominal CuWO4 content), the photo-oxidation of phenol, as a contaminant, was more than two times higher than the initial SrTiO3. However, the photocatalytic activity does not change linearly with increasing CuWO4 content, and the CWS2.5 (2.5 wt% nominal CuWO4 content and 4.25 wt% measured content) has the highest photo-activity under the applied conditions. The reason for the better activity was the increased recombination time of charge separation on the catalyst surface. Slower recombination can result in more water being oxidized to hydroxyl radicals, leading to the faster decomposition of the phenol.
Photocatalytically Active Semiconductor Cu3P Unites with Flocculent TiN for Efficient Removal of Sulfamethoxazole
Authors: Shi Huancong , Yao Xulei , Lu Shijian , Zuo Yuanhui , Zheng Tao , Jia Liangquan
Published: January 2023

Sulfamethoxazole is a widely—used antibiotic with high water solubility and low biodegradability, which was considered a refractory environmental pollutant. Hence, a series of functionalized hybrids uniting Cu3P with TiN were prepared. The Cu3P/TiN—x composites remarkably removed the sulfamethoxazole in solution compared with Cu3P and TiN alone. All the as—prepared Cu3P/TiN—x hybrids integrated the advantages of strong adsorption and photocatalysis and achieved removal rates above 70% of sulfamethoxazole. Among the composites, the Cu3P/TiN—2 with a 1:1 molar ratio of Cu: Ti reached a 90% removal rate under dark adsorption for 30 min and subsequent photodegradation for 120 min. The enhanced performance of the Cu3P/TiN—x composites is attributed to the introduced flocculent TiN with a large specific surface area and high conductivity that provide more reactive sites and high electron transferability. Meanwhile, the strong corrosion resistance and chemical stability were also beneficial to the improved performance. Cycling experiments further demonstrate the stability and reliability of the composites. In addition, the capture experiments indicated that the superoxide radical (·O2−) and hydroxyl radical (·OH) played a major role in sulfamethoxazole degradation.
Impact of 5-HT6 Receptor Subcellular Localization on Its Signaling and Its Pathophysiological Roles
Authors: Chaumont-Dubel Séverine , Galant Sonya , Prieur Matthieu , Bouschet Tristan , Bockaert Joël , Marin Philippe
Published: January 2023

The serotonin (5-HT)6 receptor still raises particular interest given its unique spatio-temporal pattern of expression among the serotonin receptor subtypes. It is the only serotonin receptor specifically expressed in the central nervous system, where it is detected very early in embryonic life and modulates key neurodevelopmental processes, from neuronal migration to brain circuit refinement. Its predominant localization in the primary cilium of neurons and astrocytes is also unique among the serotonin receptor subtypes. Consistent with the high expression levels of the 5-HT6 receptor in brain regions involved in the control of cognitive processes, it is now well-established that the pharmacological inhibition of the receptor induces pro-cognitive effects in several paradigms of cognitive impairment in rodents, including models of neurodevelopmental psychiatric disorders and neurodegenerative diseases. The 5-HT6 receptor can engage several signaling pathways in addition to the canonical Gs signaling, but there is still uncertainty surrounding the signaling pathways that underly its modulation of cognition, as well as how the receptor’s coupling is dependent on its cellular compartmentation. Here, we describe recent findings showing how the proper subcellular localization of the receptor is achieved, how this peculiar localization determines signaling pathways engaged by the receptor, and their pathophysiological influence.
Development of a Laser Microdissection-Coupled Quantitative Shotgun Lipidomic Method to Uncover Spatial Heterogeneity
Authors: Varga-Zsíros Vanda , Migh Ede , Marton Annamária , Kóta Zoltán , Vizler Csaba , Tiszlavicz László , Horváth Péter , Török Zsolt , Vígh László , Balogh Gábor , Péter Mária
Published: January 2023

Lipid metabolic disturbances are associated with several diseases, such as type 2 diabetes or malignancy. In the last two decades, high-performance mass spectrometry-based lipidomics has emerged as a valuable tool in various fields of biology. However, the evaluation of macroscopic tissue homogenates leaves often undiscovered the differences arising from micron-scale heterogeneity. Therefore, in this work, we developed a novel laser microdissection-coupled shotgun lipidomic platform, which combines quantitative and broad-range lipidome analysis with reasonable spatial resolution. The multistep approach involves the preparation of successive cryosections from tissue samples, cross-referencing of native and stained images, laser microdissection of regions of interest, in situ lipid extraction, and quantitative shotgun lipidomics. We used mouse liver and kidney as well as a 2D cell culture model to validate the novel workflow in terms of extraction efficiency, reproducibility, and linearity of quantification. We established that the limit of dissectible sample area corresponds to about ten cells while maintaining good lipidome coverage. We demonstrate the performance of the method in recognizing tissue heterogeneity on the example of a mouse hippocampus. By providing topological mapping of lipid metabolism, the novel platform might help to uncover region-specific lipidomic alterations in complex samples, including tumors.
Brain Macro-Structural Alterations in Aging Rats: A Longitudinal Lifetime Approach
Authors: Gull Sidra , Gaser Christian , Herrmann Karl-Heinz , Urbach Anja , Boehme Marcus , Afzal Samia , Reichenbach Jürgen R. , Witte Otto W. , Schmidt Silvio
Published: January 2023

Aging is accompanied by macro-structural alterations in the brain that may relate to age-associated cognitive decline. Animal studies could allow us to study this relationship, but so far it remains unclear whether their structural aging patterns correspond to those in humans. Therefore, by applying magnetic resonance imaging (MRI) and deformation-based morphometry (DBM), we longitudinally screened the brains of male RccHan:WIST rats for structural changes across their average lifespan. By combining dedicated region of interest (ROI) and voxel-wise approaches, we observed an increase in their global brain volume that was superimposed by divergent local morphologic alterations, with the largest aging effects in early and middle life. We detected a modality-dependent vulnerability to shrinkage across the visual, auditory, and somato-sensory cortical areas, whereas the piriform cortex showed partial resistance. Furthermore, shrinkage emerged in the amygdala, subiculum, and flocculus as well as in frontal, parietal, and motor cortical areas. Strikingly, we noticed the preservation of ectorhinal, entorhinal, retrosplenial, and cingulate cortical regions, which all represent higher-order brain areas and extraordinarily grew with increasing age. We think that the findings of this study will further advance aging research and may contribute to the establishment of interventional approaches to preserve cognitive health in advanced age.
RHOA Therapeutic Targeting in Hematological Cancers
Authors: Santos Juliana Carvalho , Profitós-Pelejà Núria , Sánchez-Vinces Salvador , Roué Gaël
Published: January 2023

Primarily identified as an important regulator of cytoskeletal dynamics, the small GTPase Ras homolog gene family member A (RHOA) has been implicated in the transduction of signals regulating a broad range of cellular functions such as cell survival, migration, adhesion and proliferation. Deregulated activity of RHOA has been linked to the growth, progression and metastasis of various cancer types. Recent cancer genome-wide sequencing studies have unveiled both RHOA gain and loss-of-function mutations in primary leukemia/lymphoma, suggesting that this GTPase may exert tumor-promoting or tumor-suppressive functions depending on the cellular context. Based on these observations, RHOA signaling represents an attractive therapeutic target for the development of selective anticancer strategies. In this review, we will summarize the molecular mechanisms underlying RHOA GTPase functions in immune regulation and in the development of hematological neoplasms and will discuss the current strategies aimed at modulating RHOA functions in these diseases.
Genetic and Chemical Controls of Sperm Fate and Spermatocyte Dedifferentiation via PUF-8 and MPK-1 in Caenorhabditis elegans
Authors: Park Youngyong , Gaddy Matthew , Hyun Moonjung , Jones Mariah E. , Aslam Hafiz M. , Lee Myon Hee
Published: January 2023

Using the nematode C. elegans germline as a model system, we previously reported that PUF-8 (a PUF RNA-binding protein) and LIP-1 (a dual-specificity phosphatase) repress sperm fate at 20 °C and the dedifferentiation of spermatocytes into mitotic cells (termed “spermatocyte dedifferentiation”) at 25 °C. Thus, double mutants lacking both PUF-8 and LIP-1 produce excess sperm at 20 °C, and their spermatocytes return to mitotically dividing cells via dedifferentiation at 25 °C, resulting in germline tumors. To gain insight into the molecular competence for spermatocyte dedifferentiation, we compared the germline phenotypes of three mutant strains that produce excess sperm—fem-3(q20gf), puf-8(q725); fem-3(q20gf), and puf-8(q725); lip-1(zh15). Spermatocyte dedifferentiation was not observed in fem-3(q20gf) mutants, but it was more severe in puf-8(q725); lip-1(zh15) than in puf-8(q725); fem-3(q20gf) mutants. These results suggest that MPK-1 (the C. elegans ERK1/2 MAPK ortholog) activation in the absence of PUF-8 is required to promote spermatocyte dedifferentiation. This idea was confirmed using Resveratrol (RSV), a potential activator of MPK-1 and ERK1/2 in C. elegans and human cells, respectively. Notably, spermatocyte dedifferentiation was significantly enhanced by RSV treatment in the absence of PUF-8, and its effect was blocked by mpk-1 RNAi. We, therefore, conclude that PUF-8 and MPK-1 are essential regulators for spermatocyte dedifferentiation and tumorigenesis. Since these regulators are broadly conserved, we suggest that similar regulatory circuitry may control cellular dedifferentiation and tumorigenesis in other organisms, including humans.
Placental Galectins in Cancer: Why We Should Pay More Attention
Authors: Fuselier Camille , Dumoulin Alyssa , Paré Alex , Nehmé Rita , Ajarrag Samy , Granger Joly de Boissel Philippine , Chatenet David , Doucet Nicolas , St-Pierre Yves
Published: January 2023

The first studies suggesting that abnormal expression of galectins is associated with cancer were published more than 30 years ago. Today, the role of galectins in cancer is relatively well established. We know that galectins play an active role in many types of cancer by regulating cell growth, conferring cell death resistance, or inducing local and systemic immunosuppression, allowing tumor cells to escape the host immune response. However, most of these studies have focused on very few galectins, most notably galectin-1 and galectin-3, and more recently, galectin-7 and galectin-9. Whether other galectins play a role in cancer remains unclear. This is particularly true for placental galectins, a subgroup that includes galectin-13, -14, and -16. The role of these galectins in placental development has been well described, and excellent reviews on their role during pregnancy have been published. At first sight, it was considered unlikely that placental galectins were involved in cancer. Yet, placentation and cancer progression share several cellular and molecular features, including cell invasion, immune tolerance and vascular remodeling. The development of new research tools and the concomitant increase in database repositories for high throughput gene expression data of normal and cancer tissues provide a new opportunity to examine the potential involvement of placental galectins in cancer. In this review, we discuss the possible roles of placental galectins in cancer progression and why they should be considered in cancer studies. We also address challenges associated with developing novel research tools to investigate their protumorigenic functions and design highly specific therapeutic drugs.
Deciphering Interactions between Phosphorus Status and Toxic Metal Exposure in Plants and Rhizospheres to Improve Crops Reared on Acid Soil
Authors: Wang Xiurong , Ai Shaoying , Liao Hong
Published: January 2023

Acid soils are characterized by deficiencies in essential nutrient elements, oftentimes phosphorus (P), along with toxicities of metal elements, such as aluminum (Al), manganese (Mn), and cadmium (Cd), each of which significantly limits crop production. In recent years, impressive progress has been made in revealing mechanisms underlying tolerance to high concentrations of Al, Mn, and Cd. Phosphorus is an essential nutrient element that can alleviate exposure to potentially toxic levels of Al, Mn, and Cd. In this review, recent advances in elucidating the genes responsible for the uptake, translocation, and redistribution of Al, Mn, and Cd in plants are first summarized, as are descriptions of the mechanisms conferring resistance to these toxicities. Then, literature highlights information on interactions of P nutrition with Al, Mn, and Cd toxicities, particularly possible mechanisms driving P alleviation of these toxicities, along with potential applications for crop improvement on acid soils. The roles of plant phosphate (Pi) signaling and associated gene regulatory networks relevant for coping with Al, Mn, and Cd toxicities, are also discussed. To develop varieties adapted to acid soils, future work needs to further decipher involved signaling pathways and key regulatory elements, including roles fulfilled by intracellular Pi signaling. The development of new strategies for remediation of acid soils should integrate the mechanisms of these interactions between limiting factors in acid soils.
C1q and Tumor Necrosis Factor Related Protein 9 Protects from Diabetic Cardiomyopathy by Alleviating Cardiac Insulin Resistance and Inflammation
Authors: Haustein Ricarda , Trogisch Felix A. , Keles Merve , Hille Susanne , Fuhrmann Manuela , Weinzierl Nina , Hemanna Shruthi , Thackeray James , Dou Yanliang , Zwadlo Carolin , Froese Natali , Cordero Julio , Bengel Frank , Müller Oliver J. , Bauersachs Johann , Dobreva Gergana , Heineke Joerg
Published: January 2023

(1) Background: Diabetic cardiomyopathy is a major health problem worldwide. CTRP9, a secreted glycoprotein, is mainly expressed in cardiac endothelial cells and becomes downregulated in mouse models of diabetes mellitus; (2) Methods: In this study, we investigated the impact of CTRP9 on early stages of diabetic cardiomyopathy induced by 12 weeks of high-fat diet; (3) Results: While the lack of CTRP9 in knock-out mice aggravated insulin resistance and triggered diastolic left ventricular dysfunction, AAV9-mediated cardiac CTRP9 overexpression ameliorated cardiomyopathy under these conditions. At this early disease state upon high-fat diet, no fibrosis, no oxidative damage and no lipid deposition were identified in the myocardium of any of the experimental groups. Mechanistically, we found that CTRP9 is required for insulin-dependent signaling, cardiac glucose uptake in vivo and oxidative energy production in cardiomyocytes. Extensive RNA sequencing from myocardial tissue of CTRP9-overexpressing and knock-out as well as respective control mice revealed that CTRP9 acts as an anti-inflammatory mediator in the myocardium. Hence, CTRP9 knock-out exerted more, while CTRP9-overexpressing mice showed less leukocytes accumulation in the heart during high-fat diet; (4) Conclusions: In summary, endothelial-derived CTRP9 plays a prominent paracrine role to protect against diabetic cardiomyopathy and might constitute a therapeutic target.
The Role of the Plasminogen/Plasmin System in Inflammation of the Oral Cavity
Authors: Yatsenko Tetiana , Skrypnyk Maksym , Troyanovska Olga , Tobita Morikuni , Osada Taro , Takahashi Satoshi , Hattori Koichi , Heissig Beate
Published: January 2023

The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major salivary glands that open into the oral cavity. The cavity is constantly exposed to viral and microbial pathogens. Recent studies indicate that components of the plasminogen (Plg)/plasmin (Pm) system are expressed in tissues of the oral cavity, such as the salivary gland, and contribute to microbial infection and inflammation, such as periodontitis. The Plg/Pm system fulfills two major functions: (a) the destruction of fibrin deposits in the bloodstream or damaged tissues, a process called fibrinolysis, and (b) non-fibrinolytic actions that include the proteolytic modulation of proteins. One can observe both functions during inflammation. The virus that causes the coronavirus disease 2019 (COVID-19) exploits the fibrinolytic and non-fibrinolytic functions of the Plg/Pm system in the oral cavity. During COVID-19, well-established coagulopathy with the development of microthrombi requires constant activation of the fibrinolytic function. Furthermore, viral entry is modulated by receptors such as TMPRSS2, which is necessary in the oral cavity, leading to a derailed immune response that peaks in cytokine storm syndrome. This paper outlines the significance of the Plg/Pm system for infectious and inflammatory diseases that start in the oral cavity.
Effects of Fatty Acid Metabolites on Adipocytes Britening: Role of Thromboxane A2
Authors: Colson Cécilia , Batrow Pierre-Louis , Dieckmann Sebastian , Contu Laura , Roux Christian H. , Balas Laurence , Vigor Claire , Fourmaux Baptiste , Gautier Nadine , Rochet Nathalie , Bernoud-Hubac Nathalie , Durand Thierry , Langin Dominique , Klingenspor Martin , Amri Ez-Zoubir
Published: January 2023

Obesity is a complex disease highly related to diet and lifestyle and is associated with low amount of thermogenic adipocytes. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to fight overweight and associated comorbidities. Recent studies suggest a role for several fatty acids and their metabolites, called lipokines, in the control of thermogenesis. The purpose of this work was to analyze the role of several lipokines in the control of brown/brite adipocyte formation. We used a validated human adipocyte model, human multipotent adipose-derived stem cell model (hMADS). In the absence of rosiglitazone, hMADS cells differentiate into white adipocytes, but convert into brite adipocytes upon rosiglitazone or prostacyclin 2 (PGI2) treatment. Gene expression was quantified using RT-qPCR and protein levels were assessed by Western blotting. We show here that lipokines such as 12,13-diHOME, 12-HEPE, 15dPGJ2 and 15dPGJ3 were not able to induce browning of white hMADS adipocytes. However, both fatty acid esters of hydroxy fatty acids (FAHFAs), 9-PAHPA and 9-PAHSA potentiated brown key marker UCP1 mRNA levels. Interestingly, CTA2, the stable analog of thromboxane A2 (TXA2), but not its inactive metabolite TXB2, inhibited the rosiglitazone and PGI2-induced browning of hMADS adipocytes. These results pinpoint TXA2 as a lipokine inhibiting brown adipocyte formation that is antagonized by PGI2. Our data open new horizons in the development of potential therapies based on the control of thromboxane A2/prostacyclin balance to combat obesity and associated metabolic disorders.
Advances of Wnt Signalling Pathway in Colorectal Cancer
Authors: Zhu Yaoyao , Li Xia
Published: January 2023

Colorectal cancer (CRC) represents one of the most common cancers worldwide, with a high mortality rate despite the decreasing incidence and new diagnostic and therapeutic strategies. CRC arises from both epidemiologic and molecular backgrounds. In addition to hereditary factor and genetic mutations, the strongly varying incidence of CRC is closely linked to chronic inflammatory disorders of the intestine and terrible dietary habits. The Wnt signalling pathway is a complex regulatory network that is implicated in many CRC physiological processes, including cancer occurrence, development, prognosis, invasion, and metastasis. It is currently believed to include classical Wnt/β-catenin, Wnt/PCP, and Wnt/Ca2+. In this review, we summarise the recent mechanisms and potential regulators of the three branches of the Wnt signalling pathway in CRC.
Novel Local “Off-the-Shelf” Immunotherapy for the Treatment of Myeloma Bone Disease
Authors: Charvátová Sandra , Motais Benjamin , Czapla Justyna , Cichoń Tomasz , Smolarczyk Ryszard , Walek Zuzana , Giebel Sebastian , Hájek Roman , Bagó Juli R.
Published: January 2023

Myeloma bone disease (MBD) is one of the major complications in multiple myeloma (MM)—the second most frequent hematologic malignancy. It is characterized by the formation of bone lesions due to the local action of proliferating MM cells, and to date, no effective therapy has been developed. In this study, we propose a novel approach for the local treatment of MBD with a combination of natural killer cells (NKs) and mesenchymal stem cells (MSCs) within a fibrin scaffold, altogether known as FINM. The unique biological properties of the NKs and MSCs, joined to the injectable biocompatible fibrin, permitted to obtain an efficient “off-the-shelf” ready-to-use composite for the local treatment of MBD. Our in vitro analyses demonstrate that NKs within FINM exert a robust anti-tumor activity against MM cell lines and primary cells, with the capacity to suppress osteoclast activity (~60%) within in vitro 3D model of MBD. Furthermore, NKs’ post-thawing cytotoxic activity is significantly enhanced (~75%) in the presence of MSCs, which circumvents the decrease of NKs cytotoxicity after thawing, a well-known issue in the cryopreservation of NKs. To reduce the tumor escape, we combined FINM with other therapeutic agents (bortezomib (BZ), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)), observing a clear therapeutic synergistic effect in vitro. Finally, the therapeutic efficacy of FINM in combination with BZ and TRAIL was assessed in a mouse model of MM, achieving 16-fold smaller tumors compared to the control group without treatment. These results suggest the potential of FINM to serve as an allogeneic “off-the-shelf” approach to improve the outcomes of patients suffering from MBD.
Novel Molecular Therapies and Genetic Landscape in Selected Rare Diseases with Hematologic Manifestations: A Review of the Literature
Authors: Ręka Gabriela , Stefaniak Martyna , Lejman Monika
Published: January 2023

Rare diseases affect less than 1 in 2000 people and are characterized by a serious, chronic, and progressive course. Among the described diseases, a mutation in a single gene caused mastocytosis, thrombotic thrombocytopenic purpura, Gaucher disease, and paroxysmal nocturnal hemoglobinuria (KIT, ADAMTS13, GBA1, and PIG-A genes, respectively). In Castleman disease, improper ETS1, PTPN6, TGFBR2, DNMT3A, and PDGFRB genes cause the appearance of symptoms. In histiocytosis, several mutation variants are described: BRAF, MAP2K1, MAP3K1, ARAF, ERBB3, NRAS, KRAS, PICK1, PIK3R2, and PIK3CA. Genes like HPLH1, PRF1, UNC13D, STX11, STXBP2, SH2D1A, BIRC4, ITK, CD27, MAGT1, LYST, AP3B1, and RAB27A are possible reasons for hemophagocytic lymphohistiocytosis. Among novel molecular medicines, tyrosine kinase inhibitors, mTOR inhibitors, BRAF inhibitors, interleukin 1 or 6 receptor antagonists, monoclonal antibodies, and JAK inhibitors are examples of drugs expanding therapeutic possibilities. An explanation of the molecular basis of rare diseases might lead to a better understanding of the pathogenesis and prognosis of the disease and may allow for the development of new molecularly targeted therapies.
Analysis of the Chloroplast Genome of Ficus simplicissima Lour Collected in Vietnam and Proposed Barcodes for Identifying Ficus Plants
Authors: Vu Thuy Thi Thu , Vu Lien Thi Kim , Le Lam Tung , Lo Thu Thi Mai , Chu Mau Hoang
Published: January 2023

Ficus simplicissima Lour. is an Asian species of fig tree in the family Moraceae. The chloroplast (cp) genome of F. simplicissima m3 was sequenced using the Pacbio sequel platform. The F. simplicissima cpDNA has a size of 160,321 bp in length, of which GC content accounts for 36.13%. The cp genome of F. simplicissima consists of a single large copy (LSC) with a size of 91,346 bp, a single small copy (SSC) with a size of 20,131 bp, and a pair of inverted repeats with a size of 24,421 to 24,423 bp. The cp genome of F. simplicissima has 127 genes, including 85 protein-coding genes, eight rRNA genes, and 34 tRNA genes; 92 simple sequence repeats and 39 long repeats were detected in the cpDNA of F. simplicissim. A comparative cp genome analysis among six species in the Ficus genus indicated that the genome structure and gene content were highly conserved. The non-coding regions show more differentiation than the coding regions, and the LSC and SSC regions show more differences than the inverted repeat regions. Phylogenetic analysis supported that F. simplicissima m3 had a close relationship with F. hirta. The complete cp genome of F. simplicissima was proposed as a chloroplast DNA barcoding for genus-level in the Moraceae family and the psbA-trnH gene region for species-level identification.
Metabolites and Plant Hormones Related to the Resistance Response to Feeding Stimulation and Leaf Clipping Control in Chinese Pine (Pinus tabuliformis Carr.)
Authors: Zhao Yanan , Zhou Guona , Sun Tianhua , Wang Lifeng , Xu Qiang , Liu Junxia , Gao Baojia
Published: January 2023

This experiment was conducted to define changes in metabolic pathways in response to mandibulate insect feeding and to provide a reference for further investigation of the molecular mechanisms underlying the development of conifer resistance. Chinese pine (Pinus tabuliformis Carr.) in good growth status in natural condition was chosen for stimulation by 10 pine caterpillars (Dendrolimus tabulaefomis Tsai et Liu) as feeding stimulation (FS), leaf clipping control (LCC) as mechanical damage, and CK group (with no treatment) (recorded as 0 h). The metabolome and total flavonoid content were measured in the needles at 0, 2, and 8 h after treatment. Plant hormones were measured with needles at 0, 0.5, 1, 1.5, 2, 4, 6, and 8 h after different treatments. The results show that a total of 30.8% flavonoids are identified by metabolomics analysis. Compared with leaf clipping control, feeding stimulation of Chinese pine caterpillars significantly induced the upregulation of metabolites in the flavonoid pathway in Chinese pine, and the plant hormones JA and IAA showed expression trends consistent with those of the metabolome. According to the biological processes of the four plant hormones involved, JA and SA are mostly involved in resistance formation, and in this study, both of them also have fluctuating expressions influenced by feeding stimulation, while the expressions of the growth-related hormones IAA and ABA have no significant changes at other time points except for 1 h after treatment. Thus, the flavonoid pathway is one of the main pathways involved in resistance formation in conifers, and JA and IAA are involved in the formation of resistance.
The Use of Biomaterials in Three-Dimensional Culturing of Cancer Cells
Authors: Hanasti Novia , Faridah Lia , Fibriani Azzania , Wiraswati Hesti Lina , Kusumawaty Diah , Ekawardhani Savira
Published: January 2023

Cell culture is an important tool in biological research. Most studies use 2D cell culture, but cells grown in 2D cell culture have drawbacks, including limited cell and cell-extracellular matrix interactions, which make it inaccurate to model conditions in vivo. Anticancer drug screening is an important research and development process for developing new drugs. As an experiment to mimic the cancer environment in vivo, several studies have been carried out on 3-dimensional (3D) cell cultures with added biomaterials. The use of hydrogel in 3D culture cells is currently developing. The type of hydrogel used might influence cell morphology, viability, and drug screening outcome. Therefore, this review discusses 3D cell culture research regarding the addition of biomaterials.