bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Potential Key Genes and Prognostic Biomarkers of Lung Cancer Based on Bioinformatics
Authors: Cai Kaier , Xie Zhilong , Liu Yingao , Wu Junfeng , Song Hao , Liu Wang , Wang Xinyi , Xiong Yinghuan , Gan Siyuan , Sun Yanqin
Published: January 2023

Objective. To analyze and identify the core genes related to the expression and prognosis of lung cancer including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) by bioinformatics technology, with the aim of providing a reference for clinical treatment. Methods. Five sets of gene chips, GSE7670, GSE151102, GSE33532, GSE43458, and GSE19804, were obtained from the Gene Expression Omnibus (GEO) database. After using GEO2R to analyze the differentially expressed genes (DEGs) between lung cancer and normal tissues online, the common DEGs of the five sets of chips were obtained using a Venn online tool and imported into the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database for Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The protein–protein interaction (PPI) network was constructed by STRING online software for further study, and the core genes were determined by Cytoscape software and KEGG pathway enrichment analysis. The clustering heat map was drawn by Excel software to verify its accuracy. In addition, we used the University of Alabama at Birmingham Cancer (UALCAN) website to analyze the expression of core genes in P53 mutation status, confirmed the expression of crucial core genes in lung cancer tissues with Gene Expression Profiling Interactive Analysis (GEPIA) and GEPIA2 online software, and evaluated their prognostic value in lung cancer patients with the Kaplan–Meier online plotter tool. Results. CHEK1, CCNB1, CCNB2, and CDK1 were selected. The expression levels of these four genes in lung cancer tissues were significantly higher than those in normal tissues. Their increased expression was negatively correlated with lung cancer patients (including LUAD and LUSC) prognosis and survival rate. Conclusion. CHEK1, CCNB1, CCNB2, and CDK1 are the critical core genes of lung cancer and are highly expressed in lung cancer. They are negatively correlated with the prognosis of lung cancer patients (including LUAD and LUSC) and closely related to the formation and prediction of lung cancer. They are valuable predictors and may be predictive biomarkers of lung cancer.
Ultrasound-Based Three-Dimensional Microangiography for Repeated Noninvasive Imaging of Neovascularization
Authors: Guldbæk-Svensson Fredrik K. E. , Thygesen Mathias M. , Nielsen Teresa H. , Mikkelsen Trine W. , Ding Ming , Pedersen Michael , Lauridsen Henrik
Published: January 2023

Neovascularization plays an essential part in the progression of several diseases as well as recovery processes such as angiogenesis-guided neurogenesis after a spinal cord injury. To visualize and quantify neovascularization in an experimental setup, it is desirable to apply a noninvasive, repeatable, and harmless technique. Here, we apply a newly developed ultrasound-based technique to construct angiographies and quantify neovascularization in the regenerating spinal cord of a regeneration competent animal model, the Mexican axolotl. We measured vessel volume fraction prior to the induction of contusion and transection spinal cord injury and repeated this measurement directly after injury and at 3, 6, 12, and 63 days after injury. Although neither of the injury types resulted in statistically significant differences in vessel volume fraction relative to sham-operated animals, there was a statistically significant increase in neovascularization over time in all groups. Additionally, vessel volume fraction at the final time point (63 days after injury) was quantified with micro-CT imaging after vascular perfusion with a contrast agent, confirming no statistically significant difference in neovascularization between injury types. Ex vivo vessel volume fraction measured by micro-CT was significantly different from the in vivo ultrasound-based measurement at the same time point. This is likely a result of incomplete vascular perfusion with the contrast agent before micro-CT imaging, which was supported by subsequent histological evaluation. In summary, the results suggest that the ultrasound-based angiographic procedure, we demonstrate here, is applicable to visualize and quantify neovascularization in a noninvasive and harmless fashion in longitudinal experiments circumventing the limitations of contrast agent-dependent techniques.
A Novel Cuproptosis‐Associated Gene Signature to Predict Prognosis in Patients with Pancreatic Cancer
Authors: Du Yan , Jiang Wenkai , Hou Shuang , Chen Zhou , Zhou Wence
Published: January 2023

Background. Pancreatic cancer (PAAD) is a malignant tumor with a poor prognosis and lacks sensitive biomarkers for diagnosis and targeted therapy. Cuproptosis, a recently proposed form of cell death based on cellular copper ion concentration, plays a key role in cancer biology. This study is aimed at constructing a risk model for predicting the prognosis of PAAD patients based on cuproptosis‐related genes. Methods. Pancreatic‐related data from UCSC‐TCGA and UCSC‐GTEx databases were extracted for analysis, and TCGA‐PAAD samples were randomly divided into the training and validation groups. Pearson correlation analysis was used to obtain cuproptosis‐related genes coexpressed with 19 copper death genes. Univariate Cox and Lasso regression analyses were used to obtain cuproptosis‐related prognostic genes. Multivariate Cox regression analysis was used to construct the final prognostic risk model. The risk score curve, Kaplan‐Meier survival curves, and ROC curve were used to evaluate the predictive ability of the Cox risk model. Finally, the functional annotation of the risk model was obtained through enrichment analysis. Results. The Cox risk model has an eight prognostic cuproptosis‐related gene signature. Kaplan‐Meier survival curves demonstrated that the high‐risk group had a shorter survival time. The ROC curve of the risk score was well created to predict one‐, three‐, and five‐year survival rates, and AUC of the risk score was higher than other clinical characteristics. Cox regression analysis revealed that the risk score has an independent prognostic value for PAAD. GSEA reveals specific tumor pathways associated with the risk model (Myc targets v1, mTORC1 signaling, and E2F targets). Conclusions. We constructed a prognostic model containing eight cuproptosis‐related genes (AKR1B10, KLHL29, PROM2, PIP5K1C, KIF18B, AMIGO2, MRPL3, and PI4KB) that can accurately predict the prognosis of PAAD patients. The results will provide new perspectives for individualized outcome prediction and new therapy development for PAAD patients.
CEACAM1 Is a Prognostic Biomarker and Correlated with Immune Cell Infiltration in Clear Cell Renal Cell Carcinoma
Authors: Yang Lu , Liu Yun , Zhang Boke , Yu Mengsi , Huang Fen , Zeng Jiangzheng , Lu Yanda , Yang Changcheng
Published: January 2023

Background. CEACAM1 has been shown to be aberrantly expressed in a variety of tumors, and modulation of CEACAM1-related signaling pathways has been suggested as a novel approach for cancer immunotherapy in recent years. However, its role in clear cell renal cell carcinoma (ccRCC) is unclear. Methods. The relationship between CEACAM1 and ccRCC was demonstrated based on data from TCGA, GEO, and HPA databases. And the relationship between clinicopathological features and CEACAM1 expression was also assessed. Survival curve analysis was performed to analyze the prognostic relationship between CEACAM1 expression and ccRCC. Protein interaction network analysis was used to analyze the relationship between CEACAM1 and microenvironment-related proteins. In addition, the immunomodulatory role of CEACAM1 in ccRCC was assessed by analyzing CEACAM1 and immune cell infiltration. Results. The expression of CEACAM1 was lower in ccRCC tissues than in adjacent normal tissues, and its expression level was negatively correlated with tumor size status (

P
<
0.001

), metastasis status (

P
=
0.009

), pathological stage (

P
=
0.002

), gender (

P
<
0.001

), histological grade (

P
<
0.001

), and primary therapy outcome (

P
=
0.045

) of ccRCC. Survival curve analysis showed that ccRCC patients with lower CEACAM1 expression exhibited shorter overall survival (

P
<
0.001

), and CEACAM1 interacted with microenvironmental molecules such as fibronectin and integrins. Furthermore, immune infiltration analysis showed that CEACAM1 expression correlated with CD8+ and CD4+ T cells, macrophage, neutrophil, and dendritic cell infiltration in ccRCC. Conclusions. CEACAM1 expression correlates with progression, prognosis, and immune cell infiltration in ccRCC patients, and it may be a promising prognostic biomarker and therapeutic target for ccRCC.
Evaluation of Biodegradable Alloy Fe30Mn0.6N in Rabbit Femur and Cartilage through Detecting Osteogenesis and Autophagy
Authors: Hao Shimin , Yang Tianyu , Zhang Ao , Wang Penghao , Jiang Hua , Shen Dianlin , Guo Lei , Ye Mao
Published: January 2023

Biodegradable iron alloy implants have become one of the most ideal possible candidates because of their biocompatibility and comprehensive mechanical properties. Iron alloy’s impact on chondrocytes is still unknown, though. This investigation looked at the biocompatibility and degradation of the Fe30Mn0.6N alloy as well as how it affected bone formation and chondrocyte autophagy. In vivo implantation of Fe30Mn0.6N and Ti6Al4V rods into rabbit femoral cartilage and femoral shaft was carried out to evaluate the degradation of the alloy and the cartilage and bone response at different intervals. After 8 weeks of implantation, the cross‐sectional area of the Fe30Mn0.6N alloys lowered by 50.79 ± 9.59%. More Ca and P element deposition was found on the surface Fe30Mn0.6N rods by using energy dispersive spectroscopy (EDS) and scanning electron microscopy (P < 0.05). After 2, 4, and 8 weeks of implantation, no evident inflammatory infiltration was seen in peri‐implant cartilage and bone tissue of Fe30Mn0.6N and Ti6Al4V alloys. Also, implantation of Fe30Mn0.6N alloy promoted autophagy in cartilage by detecting expression of LC3‐II compared with Ti6Al4V after implantation (P < 0.05). Fe30Mn0.6N alloy also stimulated early osteogenesis at the peri‐implant interface compared with Ti6Al4V after implantation (P < 0.05). In the in vitro test, we found that low concentrations of Fe30Mn0.6N extracts had no influence on cell viability. 15% and 30% extracts of Fe30Mn0.6N could upregulate autophagy compared to the control group by detecting beclin‐1, LC3, Atg3, and P62 on the basis of WB and IHC (P < 0.05). Also, the PI3K‐AKT‐mTOR signaling pathway mediated in the upregulation of autophagy of chondrocytes resulting in exposure to extract of Fe30Mn0.6N alloy. It is concluded that Fe30Mn0.6N showed degradability and biocompatibility in vivo and upregulated autophagy activity in chondrocytes.
TRIM72 Alleviates Muscle Inflammation in mdx Mice via Promoting Mitophagy-Mediated NLRP3 Inflammasome Inactivation
Authors: Wu Mengli , Li Huan , He Juanjuan , Liang Jiahui , Liu Yanmei , Zhang Weixi
Published: January 2023

Chronic muscle inflammation exacerbates the pathogenesis of Duchenne muscular dystrophy (DMD), which is characterized by progressive muscle degeneration and weakness. NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome plays a key role in the inflammatory process, and its abnormal activation leads to a variety of inflammatory or immune diseases. TRIM72 (MG53) is a protective myokine for tissue repair and regeneration. However, little is known about the potential impact of TRIM72 in the crosstalk between mitophagy and inflammatory process of DMD. Here, 10-week-old male mdx mice were injected intramuscularly with adeno-associated virus (AAV-TRIM72) to overexpress TRIM72 protein for 6 weeks. Then, skeletal muscle samples were collected, and relevant parameters were measured by histopathological analysis and molecular biology techniques. C2C12 cell line was transfected with lentivirus (LV-TRIM72) to overexpress or siRNA (si-TRIM72) to suppress the TRIM72 expression for the following experiment. Our data firstly showed that the TRIM72 expression was decreased in skeletal muscles of mdx mice. Then, we observed the increased NLRP3 inflammasome and impaired mitophagy in mdx mice compared with wild type mice. In mdx mice, administration of AAV-TRIM72 alleviated the accumulation of NLRP3 inflammasome and the consequent IL-18 and IL1β maturation by inducing autophagy, while this protective effect was reversed by chloroquine. Mitochondrial reactive oxygen species (mtROS), as a recognized activator for NLRP3 inflammasome, was attenuated by TRIM72 through the induction of mitophagy in C2C12 cells. Additionally, we proposed that the TRIM72 overexpression might promote mitophagy through both the early stage by PI3K-AKT pathway and the late stage by autolysosome fusion. In conclusion, the current study suggests that TRIM72 prevents DMD inflammation via decreasing NLRP3 inflammasomes and enhancing mitophagy. Collectively, our study provides insight into TRIM72 as a promising target for therapeutic intervention for DMD.
Inference on the Genetic Architecture of Breast Cancer Risk
Authors: Yasui Yutaka , Letsou William , Wang Fan , Im Cindy , Sapkota Yadav , Wang Zhaoming , Salehabadi Sedigheh Mirzaei , Baedke Jessica L. , Moon Won Jong , Liu Qi , Robison Leslie L. , Martinez Jose Miguel
Published: January 2023

Background:

What are the major determinants of women's breast cancer risk? Rare mutations such as those in the BRCA1/2 genes, polygenic scores of common alleles identified by genome-wide association studies, or nongenetic factors?

Methods:

The population-based Nordic Twin Study of Cancer, with 3,933 breast cancer cases among 21,054 monozygotic (MZ) and 30,939 dizygotic (DZ) female twin pairs, provides three key clues to this question: (i) the average lifetime risk, approximately 8%, does not differ by twin zygosity; (ii) the mean time interval between diagnoses when both twins develop disease (i.e., disease concordance) also does not differ by zygosity; but, (iii) conditioning on one twin having developed disease, the incidence rate in the co-twin is approximately 1% per year if the pair is MZ and 0.5% per year if DZ.

Results:

Assuming that nongenetic risk factors are shared similarly between twins regardless of zygosity, we can draw two conclusions from (i) to (iii).

Conclusions:

First, (i) and (iii) imply that the chief determinant of risk is in the germline DNA, because the conditional incidence rate is several-fold higher than the average risk (8% lifetime) in MZ twins but only half as much in DZ twins. Second, the seeming inconsistency between the two-fold conditional incidence rate (iii) and the equality of the mean inter-twin disease intervals in disease concordance (ii) can be resolved if the risk factors in the germline DNA are rare variants, not common variants.

Impact:

This paper details simple deductive reasoning for these conclusions and draws a critical inference regarding breast cancer etiology.

See related In the Spotlight, p. 1477
Abstract B009: A liver-tropic BCL-xL PROTAC effectively clears senescent hepatocytes and prevents NASH-driven HCC in mice
Authors: Yang Yang , Jn-Simon Natacha , Hu Wanyi , Zhang Peiyi , Zheng Guangrong , Pi Liya , He Yonghan , Zhou Daohong
Published: January 2023

Accumulation of senescent cells (SnCs) plays a causative role in many age-related diseases and has been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Senolytics that can selectively kill SnCs have the potential to be developed as therapeutics for these diseases. Here we reported the discovery of 753b, a BCL-xL proteolysis targeting chimera (PROTAC), as a potent and liver-tropic senolytic. We found that 753b can selectively clear senescent hepatocytes in aged mice and the STAM mice even though it can potently kill various SnCs in vitro. This is in part because 753b is enriched in the liver after its administration by ip injection. Moreover, 753b treatment can effectively reduce the development of non-alcoholic steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma (HCC) in the STAM mice. These findings suggest that 753b has the potential to be developed as a novel therapeutic for NAFLD and NASH-driven HCC.

Citation Format: Yang Yang, Natacha Jn-Simon, Wanyi Hu, Peiyi Zhang, Guangrong Zheng, Liya Pi, Yonghan He, Daohong Zhou. A liver-tropic BCL-xL PROTAC effectively clears senescent hepatocytes and prevents NASH-driven HCC in mice [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B009.
Abstract B020: Pre-malignant plasma cells exhibit a senescence-like phenotype and accumulation of transposable elements
Authors: Borges Gabriel Alvares , Guilatco Angelo Jose , Hachfeld Christine M. , Ruan Ming , Royzenblat Sonya , Xu Ming , Edwards Claire M. , Diaz-delCastillo Marta , Andersen Thomas L. , Kourelis Taxiarchis , Tchkonia Tamar , Kirkland James L. , Drake Matthew T. , Weivoda Megan
Published: January 2023

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR012) of the Conference Proceedings.

Citation Format: Gabriel Alvares Borges, Angelo Jose Guilatco, Christine M. Hachfeld, Ming Ruan, Sonya Royzenblat, Ming Xu, Claire M. Edwards, Marta Diaz-delCastillo, Thomas L. Andersen, Taxiarchis Kourelis, Tamar Tchkonia, James L. Kirkland, Matthew T. Drake, Megan Weivoda. Pre-malignant plasma cells exhibit a senescence-like phenotype and accumulation of transposable elements [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B020.
Abstract IA012: Age related changes in the tumor microenvironment drive tumor progression
Authors: Stewart Sheila A.
Published: January 2023

The stromal compartment plays a pivotal role in tumor progression. This is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells and its expression levels correlate with poor prognosis. Using clinically relevant breast cancer metastasis models, we show that orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase, MK2, each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. Further we found that this effect is mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, we also found that these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity for cancer patients that drastically impacts their quality of life. Mechanistic studies revealed that p38MAPKα’s ability to limit tumor growth within the bone is dependent on CD4 T cells and macrophages. To determine which cell types within the bone contribute to tumor growth and bone loss, we carried out single cell RNA-sequencing of stromal cells located within the bone metastatic lesion and cells outside the lesion. We found numerous differences that could explain how the stromal compartment contributes to tumor progression and bone loss and how inhibition of p38MAPKα or MK2 contribute. These data underscore the vital role stromal-derived factors play in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss.

Citation Format: Sheila A. Stewart. Age related changes in the tumor microenvironment drive tumor progression [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA012.
Abstract A023: OGT/CDK5/ACSS2 axis regulates breast cancer brain metastatic growth
Authors: Esquea Emily , Ciraku Lorela , Minh Giang Le , Reginato Mauricio
Published: January 2023

Brain metastases (BMs) in breast cancer patients is considered an end-stage event, with no effective drug treatment and a median survival after diagnosis measured in months. Currently, there are no effective drug treatment for BM patients, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to lack of lipid availability in the brain environment and are highly dependent on fatty acid synthesis for growth and survival. However, the signaling pathways that regulate precursors of fatty acid synthesis and lipid metabolism in breast cancer brain metastatic (BCBM) tumors are not known. Here, we show that BCBM cells can generate acetyl-CoA, a major metabolite feeding lipid biosynthesis, via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinse-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Breast cancer cells selected to metastasize to the brain contain higher levels of O-GlcNAcylation, OGT. and ACSS2-Ser267 phosphorylation compared to parental cells, and we show that human breast cancer brain metastatic patient samples contain elevated ACSS2-Ser-267 levels. Additionally, overexpression of the OGT, CDK5, or ACSS2-S267D phospho-mimetic mutant confers a growth advantage of breast cancer cells in the brain in vivo. Importantly, we show that ACSS2 is required for breast cancer growth in the brain but not in the mammary fat pad. Transcriptome analysis shows that ACSS2 regulates E2F-regulated genes and E2F1 protein levels in breast cancer cells. Pharmacologically targeting the CDK5 or ACSS2 with respective small molecule inhibitors reduces tumor growth in orthotopic ex vivo brain slice model. These results suggest a crucial role for OGT/CDK5/ACSS2 signaling axis to regulate lipid metabolism in BCBM cells and identify CDK5 and ACSS2 as novel therapeutic targets for treatment of breast cancer brain metastatic growth.

Citation Format: Emily Esquea, Lorela Ciraku, Giang Le Minh, Mauricio Reginato. OGT/CDK5/ACSS2 axis regulates breast cancer brain metastatic growth [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A023.
Abstract A037: PROTACs as emergent treatment modality of metastatic prostate cancer. [R
Authors: Bhavar Prashant Kashinath , Surampudi Uday Kumar , Sarma Partha Pratim , Katike Satish , Gandham Adilakshmi
Published: January 2023

Prostate cancer is one of the most commonly diagnosed and fourth leading cause of cancer death in men, with low survival rates for metastatic cancers. Androgen receptor (AR) is one of the most altered Oncogenes in castration-resistant prostate cancer (mCRPC). Suppression of AR signalling is one of the common strategies to treat prostate cancer. Androgen deprivation therapy (ADT) has been the backbone therapy for decades and demonstrated survival benefit when used alongside other therapies including Docetaxel, cabazitaxel or hormone based anti-androgen therapies such as Enzalutamide, abiraterone, darolutamide, and apalutamide. Unfortunately, amplification or mutation in AR gene along with its associated pathway such as alteration of PI3K pathway or upregulation of MYC oncogene drive mCRPC cell proliferation and confers resistance to existing therapies. To overcome such resistance mechanisms, targeted therapy towards Androgen receptor has emerged, where ligand conjugated small molecule inhibitors using proteolysis targeting chimera (PROTAC) strategy, could effectively downregulate the AR expression. Several PROTACs as ‘Androgen Receptor Degraders (ARD)’ are showing promising activity in early-stage clinical studies. Although a promising strategy, challenges exist for its development in future; given that finding the most appropriate protein-protein interaction is essential to find optimal ligand to successfully design PROTAC. Similarly, challenges to optimize safety and efficacy of PROTACs in the clinic, also remain to be addressed. Here we aim to provide comprehensive review, including patent landscape of the therapeutic benefits of using PROTACs and its future development prospect in context to metastatic prostate cancer.

Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Satish Katike, Adilakshmi Gandham. PROTACs as emergent treatment modality of metastatic prostate cancer. [R [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A037.
Abstract A040: In vivo imaging of ovarian and non-small cell lung cancer models hosted in the Sprague-Dawley Rag2 null Il2rgamma null SRG rat (OncoRat®)
Authors: Begemann Diane , Johnston Nicolas , O’Callaghan Marissa , Walton Grace , Steffey Valeriya , Noto Fallon
Published: January 2023

Human cancer xenografts are a vital tool for understanding tumor biology. While in vivo studies are traditionally done in immunocompromised mice, we have created the SRG OncoRat® that is an excellent host for human xenografts. In vivo luminescent imaging is routinely used in mouse models, and it is particularly useful for studying orthotopic xenografts or metastatic models. In this study, we validated the SRG rat as a model that can effectively be used for in vivo imaging of human cancers. For the current study, we assessed two tumor models. OV81.2-luc is a luciferase positive cell line that was generated from ascites collection from a grade IIIC serous ovarian carcinoma. Tumors were established by inoculating OV81.2-luc cells IP into female SRG rats and female NSG mice, then treated with vehicle or cisplatin for 28 days. Human non-small cell lung cancer line H358-luc is luciferase positive and metastasizes to lung when injected subcutaneously into the hind flank of SRG rats. Tumors were measured thrice weekly with calipers. For both studies, we performed weekly in vivo luciferase imaging using Spectral Instruments AMI-HT. Tumors established rapidly for both OV81.2-luc and H358-luc in both SRG rats and NSG mice, with luciferin positive signal starting one week post inoculation. In OV81.2-luc hosting animals, upon necropsy, tumors were found on multiple abdominal organs including the peritoneum, ovary, mesentery, intestines, kidneys, liver, and body cavity wall. Metastatic events outside the abdominal cavity were not evident in OV81.2-luc hosting animals. In H358-luc tumor bearing rats, a high metastatic tumor burden was found in the lungs. These data confirm that the SRG rat is an excellent host for studying human cancer when compared to commonly used immunodeficient mouse models. Data demonstrate that the SRG rat has a high utility for studies using both in vivo imaging, such as orthotopic tumor implantation, and studies on metastasis. As the most immunodeficient rat commercially available, the SRG rat retains the ability to establish human tumors while possessing size, physiology, and metabolism-based advantages when compared to mice.

Citation Format: Diane Begemann, Nicolas Johnston, Marissa O’Callaghan, Grace Walton, Valeriya Steffey, Fallon Noto. In vivo imaging of ovarian and non-small cell lung cancer models hosted in the Sprague-Dawley Rag2 null Il2rgamma null SRG rat (OncoRat®) [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A040.
Abstract B046: MLL1 regulates cytokine-driven cell migration and metastasis
Authors: Nair Praful R. , Danilova Ludmila , Gómez-de-Mariscal Estibaliz , Kim Dongjoo , Fan Rong , Muñoz-Barrutia Arrate , Fertig Elana , Wirtz Denis
Published: January 2023

Cell migration, particularly in three-dimensional (3D) environments, is a critical requirement for metastasis - the spread of cancer cells from a primary tumor to distant sites. Despite causing the vast majority of cancer-related deaths, targeting metastasis remains challenging clinically. Cancer cell migration can be triggered and maintained by elevated levels of cytokines, which are presumed to be predominantly secreted by immune cells in the tumor microenvironment. However, recent work has highlighted the importance and impact of cytokine production by cancer cells themselves. While the signaling cascades that regulate cell migration have been studied extensively, the epigenetic regulation of cell migration is still poorly understood. MLL1 is a histone methyltransferase, which along with its scaffold protein Menin, is integral to methylation at the histone 3 lysine 4 (H3K4) site. Here, we show that the MLL1-Menin interaction is essential for the migration of cancer cells and that the disruption of this interaction impairs cell migration and metastasis. MLL1 depletion reduces 3D cell migration in vitro and led to lesser metastatic burden and prolonged survival in vivo. Reduced lung metastatic burden was observed even after accounting for the difference in the growth rate of primary tumors. Mechanistically, MLL1-Menin interaction controls actin filament assembly via the IL-6/pSTAT3/Arp3 axis and acto-myosin contractility via the TGF-β1/Gli2/ROCK1/2/pMLC2 axis, which together regulate dynamic protrusion generation and 3D cell migration. MLL1-Menin inhibition also decreases cell proliferation by inhibiting mitosis and cell cycle-related pathways. MLL1 depletion decreases primary tumor growth, metastatic spread, and metastatic outgrowth in mouse models of triple-negative breast cancer (TNBC), thus improving survival. Combining an MLL1-Menin inhibitor with Paclitaxel, a standard TNBC chemotherapeutic, abrogated tumor growth and metastasis in a syngeneic TNBC mouse model. Overall, our studies show that MLL1 is an epigenetic regulator of 3D cancer cell migration, which exerts its effects by controlling the production of the key cytokines IL-6 and TGF-β1. Our in vivo studies demonstrate the potential of targeting the MLL1-Menin interaction in metastasis prevention and its potential to be combined with currently administered chemotherapeutics.

Citation Format: Praful R. Nair, Ludmila Danilova, Estibaliz Gómez-de-Mariscal, Dongjoo Kim, Rong Fan, Arrate Muñoz-Barrutia, Elana Fertig, Denis Wirtz. MLL1 regulates cytokine-driven cell migration and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B046.
Monitoring Blood Supply in Germany: A Regulatory Perspective
Authors: Fiedler Sarah Anna , Henseler Olaf , Hoffelner Marcus , Doll Manfred , Hutschenreuter Gabriele , Hoch Jochen , Weinauer Franz , Humpe Andreas , Funk Markus Benedikt , Hilger Anneliese
Published: January 2023

Background and Objectives: A sufficient supply of safe, high-quality blood components for transfusion is essential to the healthcare system in Germany. The requirements for the current reporting system are laid down in the German Transfusion Act. The present work elaborates on the advantages and limitations of the current reporting system and investigates the feasibility of a pilot project that collects specific data on blood supply based on weekly reports. Materials and Methods: Selected data on blood collection and supply from 2009 to 2021 derived from the §21 German Transfusion Act database were examined. In addition, a pilot study over a period of 12 months was conducted on a voluntary basis. The number of red blood cell (RBC) concentrates was documented and stock availability was calculated weekly. Results: From 2009 to 2021, the annual number of RBC concentrates decreased from 4.68 to 3.43 million, the per capita distribution decreased from 58 to 41 RBC concentrates per 1,000 inhabitants. These figures did not change significantly during the COVID-19 pandemic. The data of the 1-year pilot project represented 77% of the released RBC concentrates in Germany. Percentage share of O RhD positive RBC concentrates fluctuated between 35% and 22% and for O RhD negative concentrates between 17% and 5%. The availability of O RhD positive RBC concentrate stocks varied between 2.1 and 7.6 days. Conclusion: The data presented shows a decrease in annual RBC concentrate sales over an 11-year period and no further change over the past 2 years. A weekly monitoring of blood components detects acute problems in RBC provision and supply. Close monitoring seems helpful but should be combined with a nationwide supply strategy.
Exercise as Medicine Could Be a Chance for Early Detection and Prevention of Cardiotoxicity in Cancer Treatments: A Narrative Review
Authors: Zoth Nora , Tomanek Annika , Seuthe Katharina , Pfister Roman , Baumann Freerk Theeagnus
Published: January 2023

Background: For cancer patients, cardiovascular complications as a consequence of certain oncological therapies are the leading cause of death, apart from the cancer itself. Currently, there are no uniform guidelines for detecting subclinical cardiotoxicity. Hence, the identification of cardiotoxicity arises late in the course of myocardial dysfunction after cardiac damage has occurred already. Early detection, prevention, and treatment of these cardiotoxic effects remain a challenge; therefore, supportive strategies such as physical activity gain in importance. Summary: Exercise therapy, during and after cancer therapy, is considered to be safe, feasible, and effective. While animal models show protective effects, the evidence for the benefits of physical activity on future cardiovascular outcomes in human patients caused by certain cancer treatments is still limited. Consequently, targeted exercise recommendations such as frequency, intensity, time, or type are yet unclear, and certain guidelines, specifically preventing cardiotoxicity, are nonexistent. Low cardiorespiratory fitness is strongly associated with all-cause mortality as well as cardiac dysfunction. In this context, the role of cardiorespiratory fitness as an early predictor in the detection of cardiovascular dysfunction will be discussed. Key Message: Exercise therapy during cancer treatment could have the potential to aid in both the diagnosis and treatment of cardiovascular complications. This narrative review considers the current evidence on the impact of physical activity on cardiovascular outcomes in cancer patients and proposes, according to the present knowledge, a framework for cardioprotective exercise therapies.
Veterinary Naturopathy and Complementary Medicine: A Survey among Homepages of German Veterinary Practitioners
Authors: Stanossek Ines , Wehrend Axel
Published: January 2023

Background: The use and interest in veterinary naturopathy and complementary medicine are increasing and modes of treatment are diverse. To this point, only a few data on the German situation in small animal medicine exist. Material and Methods: An online research of 1,083 German veterinary homepages for contents of veterinary naturopathy and complementary medicine was performed in September and October 2017. “Veterinarian” and “Chamber of Veterinary Surgeons” were used as search items. Homepages of small animal medicine were included. They were surveyed for modes of complementary and naturopathic treatments and corresponding qualifications of the offering veterinarian. Data were collected and processed using Excel 2013 Version 15.0. Afterward, a descriptive data analysis was performed. Results: 60.7% (n = 657) of homepages showed contents of veterinary naturopathy and complementary medicine. The highest percentage was found in the Chamber of Veterinary Surgeons of Saarland (91.7%, n = 11 out of 12). Homeopathy was cited most frequently (58%, n = 381). Out of all homepages with relevant content, 31.4% (n = 206) gave information about user qualifications, with continuous education programs named most frequently (52.9%, n = 109). Conclusion: The given data illustrate the high number of German veterinary homepages with contents of veterinary naturopathy and complementary medicine, corresponding to actual data of a high usage in veterinary and human medicine. Therefore, further scientific research in this field seems reasonable. Modes of treatment and qualifications are highly diverse and despite of controversial public discussions, homeopathy was the most frequently cited treatment modality on German veterinary homepages.
Morfologia Original do Sítio Urbano de Cuiabá (MT)
Authors: Santos Rodrigo Lima dos , Rodrigues Cleide , Villela Fernando Nadal Junqueira , Cabral Ivaniza de Lourdes Lazzarotto
Published: January 2023

O estudo apresenta resultados da aplicação da cartografia geomorfológica retrospectiva visando a reconstituição da morfologia original do sítio urbano de Cuiabá (MT), correspondente ao estágio pré-urbano. Para essa reconstituição, o estudo combinou procedimentos tradicionais da pesquisa em geomorfologia e da antropogeomorfologia para a recuperação de informações geomorfológicas de áreas antropizadas. A pesquisa enfatiza o reconhecimento de sistemas hidromorfológicos do sítio urbano de Cuiabá e suas adjacências em fase anterior à intensa urbanização, portanto, em cenários de paisagem nos quais atributos morfológicos e morfométricos originais na escala de vertentes e de sistemas interfluviais predominavam. Os principais documentos utilizados nessa reconstituição englobam documentação histórica, relatos de expedições, de moradores, jornais, fotografias, toponímia, cartografia antiga e fotos aéreas. Além dessas fontes de informação, a pesquisa utilizou dados pedo-estratigráficos disponíveis em relatórios de obras de engenharia, observações de campo com descrições de afloramentos, sondagens com trado, trincheiras e análises de laboratório. Dentre os principais resultados, foi produzida a carta da morfologia original de Cuiabá, na escala 1:50:000. Sua análise permitiu identificar e associar morfologias de depressões interfluviais segundo sua representatividade regional, com provável comando de circulação hídrica interna evidenciado por níveis de exfiltração possivelmente correlacionados com descontinuidades litológicas e texturais. Ratificou-se também o potencial da cartografia geomorfológica retrospectiva para estudos morfodinâmicos e morfogenéticos, base da pesquisa geomorfológica para pesquisas aplicadas.
Atributos climáticos associados aos eventos de precipitação oculta no Parque Nacional de Aparados da Serra - RS/SC
Authors: Baratto Jakeline , Gobo João Paulo Assis , Alves Rogério Rozolen , Galvani Emerson , Wollmann Cássio Arthur
Published: January 2023

Este trabalho tem como objetivo estabelecer a relação entre a ocorrência de precipitação oculta e os atributos climáticos no Parque Nacional de Aparados da Serra. Para esta análise foram instalados um coletor de nevoeiro e uma Estação Meteorológica Automática no local de estudo, para a coleta das informações de precipitação oculta (PO) e dados meteorológicos. Os dados foram coletados do período de novembro de 2017 até dezembro de 2018. Os dados de PO foram organizados em totais horários e as variáveis meteorológicas em médias horárias. Como resultados observou-se que as variáveis meteorológicas não apresentaram influência estatisticamente relevante na ocorrência de PO. Porém, os gráficos de dispersão mostraram que existe uma semelhança nos valores das variáveis na coleta de água dos nevoeiros. Predominantemente, os dados de temperatura do ar e temperatura do ponto de orvalho, variando entre de 4,0ºC até 6,0ºC, 10,0ºC até 13,0ºC e 16,0ºC até 18,0ºC na coleta de PO. Para a umidade absoluta do ar, os maiores volumes foram coletados entre 6,0g/m³ até 8,0g/m³, 9,0g/m³ até 11,0g/m³ e 13,0g/m³ e 15,0g/m³. Entre 1,0m.s-1 e 3,0m.s-1 e 4,0m.s-1 até 6,0m.s-1 ocorreram os maiores volumes de coleta por evento de PO. Apesar de não existir correlações na ocorrência de PO, quanto às variáveis meteorológicas, observou-se uma semelhança nas variáveis quando ocorreram os maiores volumes e registros de PO.
Reflexões sobre a geografia do afeto: a excepcionalidade identitária em meio às distorções do espaço-tempo
Authors: Silva Leonardo Luiz Silveira da , Costa Alfredo
Published: January 2023

O debate acerca das teorias não-representacionais, que desde o final dos anos 1990 é muito presente na geografia anglófona, é incipiente na geografia brasileira. Resgatou consigo a discussão sobre o espaço relativo, alicerçando seu arcabouço no conceito de afeto, que é, por sua vez, diretamente ligado às associações heterogêneas entre atores humanos e actantes não-humanos dispostos em redes. Os deslocamentos dos atores pelo espaço auxiliam a dinamizar as múltiplas percepções do espaço, ao submeter o ente que desloca à experiência do movimento. As distorções espaciais provocadas pelas relações em redes são capazes de alongar ou dobrar o espaço, além de comprimir ou dilatar o tempo. Partindo do pressuposto de que o ser é indissociável ao espaço percebido, o artigo em questão, essencialmente epistemológico, defende a premissa de que as distorções relativas do espaço são distorções da própria identidade. Este processo rejeita uma relação clara de causa e consequência entre espaço e identidade, apontando para um processo dialético e retroalimentado, que ressoa o afeto das associações heterogêneas, bem como contribui para o afeto de outrem.
Acesso e acessibilidade aos serviços de estimulação precoce no Distrito Federal, 2015 – 2017: análise de uma série de casos de crianças com síndrome congênita por Zika e STORCH
Authors: Bezerra Amarílis Bahia , Gurgel Helen , Handschumacher Pascal , Araújo Wildo Navegantes de
Published: January 2023

No Brasil em 2015, foi constatada uma disseminação do vírus Zika, acompanhado do aumento de relatos de casos de recém-nascidos com microcefalia e outros distúrbios neurológicos causadas pelo vírus, levantando o debate sobre as dificuldades de acesso aos cuidados de crianças acometidas por infecções intrauterinas, denominadas Síndrome Congênita da Zika e STORCH. As repercussões na saúde infantil se espalharam por todas as regiões brasileiras, sendo as regiões Nordeste e Sudeste do Brasil as mais atingidas, desafiando-nos a compreender o acesso aos cuidados em saúde dessas crianças. O objetivo deste artigo é caracterizar o acesso e a mobilidade aos serviços de saúde e às atividades de estimulação precoce por crianças com Síndrome Congênita por Zika e STORCH, no Distrito Federal – Brasil. A metodologia consistiu no mapeamento dos casos de Síndrome Congênita por Zika e STORCH e das unidades de reabilitação e estimulação precoce, no período entre 2015 e 2017. Como resultado, verificou-se que as crianças com Síndrome Congênita, usuárias do serviço público de saúde, necessitam percorrer longas distâncias para ter acesso às unidades de reabilitação e estimulação precoce em unidades de saúde, enquanto para as unidades de educação, o deslocamento realizado é menor. No geral, nossos resultados evidenciam a dificuldade de execução de políticas de saúde para a estimulação precoce e o importante papel desempenhado pela educação nas atividades de educação precoce no Distrito Federal – Brasil.
Planejamento urbano e segregação socioespacial: estudo sobre os efeitos da expansão de condomínios fechados na produção do espaço urbano
Authors: Silva Bruno das Mercês , Martines Marcos Roberto , Burgos Rosalina
Published: January 2023

Nos últimos séculos, o advento da indústria impôs severas transformações ao espaço das cidades. Em resposta às mazelas decorrentes deste processo, mas também às demandas do capital, o planejamento urbano, sujeitando-se às mais variadas contradições, passa a ser crescentemente integrado aos processos de urbanização deflagrados. Nas cidades brasileiras, especialmente nas grandes e médias cidades, é comum que se observe uma estreita relação entre a produção do espaço urbano e as políticas de planejamento. Nesse contexto, os condomínios fechados emergem e se associam à expansão da malha urbana, produzindo variados e significativos efeitos no espaço geográfico. Esta pesquisa analisa as consequências do processo de expansão dos condomínios na malha urbana, com foco nos efeitos inerentes ao acesso às áreas verdes e espaços para o lazer. Para isso, à luz do esforço teórico, a pesquisa realizou um estudo comparativo de duas subáreas pertencentes ao mesmo setor censitário: Condomínio Bosque Ipanema, e o Bairro Jardim Botucatu, situados em Sorocaba/ SP. Utilizou-se da fotointerpretação, de análise estatística e de outros métodos associados para a produção e consequente análise dos dados. Os resultados apontaram para a existência de segregação socioespacial a partir das diferenças de estruturas observadas entre as subáreas (Condomínio Bosque Ipanema e Bairro Jardim Botucatu), segregação que se expressa, sobretudo, no acesso às áreas verdes e espaços para o lazer.
Variabilidade da Zona de Convergência do Atlântico Sul em relação a eventos ENOS de 2000 a 2021
Authors: Verdan Ian , Silva Maria Elisa Siqueira
Published: January 2023

A Zona de Convergência do Atlântico Sul, ZCAS, se estabelece sobre a faixa noroeste-sudeste da América do Sul, no verão, e contribui para grande parte da precipitação observada na região, sendo influenciada por padrões de teleconexão e variações da temperatura da superfície do oceano Pacífico. O objetivo deste estudo foi analisar a associação entre a ZCAS e o Índice Niño Oceânico, ONI, entre 2000 e 2021, com base nos dados da reanálise cinco do ECMWF, ERA-5. A identificação da ZCAS foi realizada com base nos dados diários de radiação de onda longa, água precipitável e circulação atmosférica. Os dados de ONI foram correlacionados à ocorrência mensal de ZCAS através dos coeficientes de correlação linear e de contingência. Os resultados apontam para a maior (menor) frequência de ZCAS na fase negativa (positiva) do ONI, indicando 42 eventos de ZCAS durante eventos de La Niña e 24 eventos de ZCAS durante períodos de El Niño. Embora o coeficiente de correlação linear calculado entre o número de ZCAS e ONI seja baixo para o período considerado (r = -0,20, p < 0,10), o coeficiente de contingência apresentou associação moderada, com valor igual a -0,46.
De Novo Postpartum Hypertension: Incidence and Risk Factors at a Safety-Net Hospital
Authors: Parker Samantha E. , Ajayi Ayodele , Yarrington Christina D.
Published: January 2023

Background:

Postpartum hypertension can be persistent, following a pregnancy complicated by hypertension, or new onset (de novo), following a normotensive pregnancy. The aim of this study is to estimate the incidence and identify risk factors for de novo postpartum hypertension (dn-PPHTN) among a diverse safety-net hospital population.

Methods:

We conducted a retrospective cohort study of 3925 deliveries from 2016 to 2018. All blood pressure (BP) measures during pregnancy through 12 months postpartum were extracted from medical records. Patients with chronic hypertension or hypertensive disorders of pregnancy were excluded. dn-PPHTN was defined as 2 separate BP readings with systolic BP ≥140 mm Hg and diastolic BP ≥90 mm Hg at least 48 hours after delivery. Severe dn-PPHTN was defined as systolic BP ≥160 and diastolic BP ≥110. We examined risk factors individually and in combination and timing of diagnosis.

Results:

Among the 2465 patients without a history of hypertension, 12.1% (n=298) developed dn-PPHTN; 17.1% of whom had severe dn-PPHTN (n=51). Compared to those without dn-PPHTN; cases were more likely to be ≥35 years, delivered via cesarean, or be current or former smokers. Patients with all of these characteristics had a 29% risk of developing dn-PPHTN, which was elevated among non-Hispanic Black patients (36%). Approximately 22% of cases were diagnosed after 6 weeks postpartum.

Conclusions:

More than 1 in 10 patients with normotensive pregnancies experience dn-PPHTN in the year after delivery. Opportunities to monitor and manage patients at the highest risk of dn-PPHTN throughout the entire year postpartum could mitigate cardiovascular related maternal morbidity.