bluuebunny/crossref_metadata_2025 huggingface dataset:
A Review of the Clinical Implications of Cachexia, Sarcopenia, and BMI in Patients with Peritoneal Carcinomatosis Receiving Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy
Authors: Freudenberger Devon C. , Vudatha Vignesh , Riner Andrea N. , Herremans Kelly M. , Fernandez Leopoldo J. , Trevino Jose G.
Published: June 2022

Peritoneal carcinomatosis (PC) is the dissemination of cancer throughout the peritoneal cavity. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the surgical treatment of choice in highly selected patients. The aim of this narrative review was to assess the impact of cachexia, sarcopenia, and body mass index (BMI) on patient outcomes for patients undergoing CRS and HIPEC for peritoneal carcinomatosis. A narrative review was performed and articles pertaining to cachexia, sarcopenia, BMI, peritoneal carcinomatosis, and CRS/HIPEC were reviewed and selected. In total, 3041 articles were screened and seven original studies met the inclusion criteria. In summary, obesity was found to not be a contraindication to surgery, but the impact of BMI was variable across the spectrum. Decreased skeletal muscle mass was found to be associated with poorer postoperative outcomes in three studies and with worse overall survival in two. With limited data, evaluating the impact of BMI, sarcopenia, and cachexia on patients with PC undergoing CRS and HIPEC was difficult as most studies included heterogeneous cancer patient populations; thus, postoperative outcomes and survival were inconsistent across studies. More research is needed to better understand its impact and to better generalize the results for each cancer subset treated with CRS and HIPEC across diverse patient populations.
Using a Clinicopathologic and Gene Expression (CP-GEP) Model to Identify Stage I–II Melanoma Patients at Risk of Disease Relapse
Authors: Mulder Evalyn E. A. P. , Johansson Iva , Grünhagen Dirk J. , Tempel Dennie , Rentroia-Pacheco Barbara , Dwarkasing Jvalini T. , Verver Daniëlle , Mooyaart Antien L. , van der Veldt Astrid A. M. , Wakkee Marlies , Nijsten Tamar E. C. , Verhoef Cornelis , Mattsson Jan , Ny Lars , Hollestein Loes M. , Olofsson Bagge Roger
Published: June 2022

Background: The current standard of care for patients without sentinel node (SN) metastasis (i.e., stage I–II melanoma) is watchful waiting, while >40% of patients with stage IB–IIC will eventually present with disease recurrence or die as a result of melanoma. With the prospect of adjuvant therapeutic options for patients with a negative SN, we assessed the performance of a clinicopathologic and gene expression (CP-GEP) model, a model originally developed to predict SN metastasis, to identify patients with stage I–II melanoma at risk of disease relapse. Methods: This study included patients with cutaneous melanoma ≥18 years of age with a negative SN between October 2006 and December 2017 at the Sahlgrenska University Hospital (Sweden) and Erasmus MC Cancer Institute (The Netherlands). According to the CP-GEP model, which can be applied to the primary melanoma tissue, the patients were stratified into high or low risk of recurrence. The primary aim was to assess the 5-year recurrence-free survival (RFS) of low- and high-risk CP-GEP. A secondary aim was to compare the CP-GEP model with the EORTC nomogram, a model based on clinicopathological variables only. Results: In total, 535 patients (stage I–II) were included. CP-GEP stratification among these patients resulted in a 5-year RFS of 92.9% (95% confidence interval (CI): 86.4–96.4) in CP-GEP low-risk patients (n = 122) versus 80.7% (95%CI: 76.3–84.3) in CP-GEP high-risk patients (n = 413; hazard ratio 2.93 (95%CI: 1.41–6.09), p < 0.004). According to the EORTC nomogram, 25% of the patients were classified as having a ‘low risk’ of recurrence (96.8% 5-year RFS (95%CI 91.6–98.8), n = 130), 49% as ‘intermediate risk’ (88.4% 5-year RFS (95%CI 83.6–91.8), n = 261), and 26% as ‘high risk’ (61.1% 5-year RFS (95%CI 51.9–69.1), n = 137). Conclusion: In these two independent European cohorts, the CP-GEP model was able to stratify patients with stage I–II melanoma into two groups differentiated by RFS.
Potential Therapeutics Targeting Upstream Regulators and Interactors of EHMT1/2
Authors: Ang Gareth , Gupta Amogh , Yap Shirlyn , Surana Uttam , Taneja Reshma
Published: June 2022

Euchromatin histone lysine methyltransferases (EHMTs) are epigenetic regulators responsible for silencing gene transcription by catalyzing H3K9 dimethylation. Dysregulation of EHMT1/2 has been reported in multiple cancers and is associated with poor clinical outcomes. Although substantial insights have been gleaned into the downstream targets and pathways regulated by EHMT1/2, few studies have uncovered mechanisms responsible for their dysregulated expression. Moreover, EHMT1/2 interacting partners, which can influence their function and, therefore, the expression of target genes, have not been extensively explored. As none of the currently available EHMT inhibitors have made it past clinical trials, understanding upstream regulators and EHMT protein complexes may provide unique insights into novel therapeutic avenues in EHMT-overexpressing cancers. Here, we review our current understanding of the regulators and interacting partners of EHMTs. We also discuss available therapeutic drugs that target the upstream regulators and binding partners of EHMTs and could potentially modulate EHMT function in cancer progression.
MCC Gene Silencing Is a CpG Island Methylator Phenotype-Associated Factor That Predisposes Colon Cancer Cells to Irinotecan and Olaparib
Authors: Jahan Zeenat , Benthani Fahad A. , Currey Nicola , Parker Hannah W. , Dahlstrom Jane E. , Caldon C. Elizabeth , Kohonen-Corish Maija R. J.
Published: June 2022

Chemotherapy is a mainstay of colorectal cancer treatment, and often involves a combination drug regime. CpG island methylator phenotype (CIMP)-positive tumors are potentially more responsive to the topoisomerase-inhibitor irinotecan. The mechanistic basis of the increased sensitivity of CIMP cancers to irinotecan is poorly understood. Mutated in Colorectal Cancer (MCC) is emerging as a multifunctional tumor suppressor gene in colorectal and liver cancers, and has been implicated in drug responsiveness. Here, we found that CIMP tumors undergo MCC loss almost exclusively via promoter hypermethylation rather than copy number variation or mutations. A subset of cancers display hypomethylation which is also associated with low MCC expression, particularly in rectal cancer, where CIMP is rare. MCC knockdown or deletion was found to sensitize cells to SN38 (the active metabolite of irinotecan) or the PARP-inhibitor Olaparib. A synergistic effect on cell death was evident when these drugs were used concurrently. The improved SN38/irinotecan efficacy was accompanied by the down-regulation of DNA repair genes. Thus, differential methylation of MCC is potentially a valuable biomarker to identify colorectal cancers suitable for irinotecan therapy, possibly in combination with PARP inhibitors.
Role of Artificial Intelligence in Radiogenomics for Cancers in the Era of Precision Medicine
Authors: Saxena Sanjay , Jena Biswajit , Gupta Neha , Das Suchismita , Sarmah Deepaneeta , Bhattacharya Pallab , Nath Tanmay , Paul Sudip , Fouda Mostafa M. , Kalra Manudeep , Saba Luca , Pareek Gyan , Suri Jasjit S.
Published: June 2022

Radiogenomics, a combination of “Radiomics” and “Genomics,” using Artificial Intelligence (AI) has recently emerged as the state-of-the-art science in precision medicine, especially in oncology care. Radiogenomics syndicates large-scale quantifiable data extracted from radiological medical images enveloped with personalized genomic phenotypes. It fabricates a prediction model through various AI methods to stratify the risk of patients, monitor therapeutic approaches, and assess clinical outcomes. It has recently shown tremendous achievements in prognosis, treatment planning, survival prediction, heterogeneity analysis, reoccurrence, and progression-free survival for human cancer study. Although AI has shown immense performance in oncology care in various clinical aspects, it has several challenges and limitations. The proposed review provides an overview of radiogenomics with the viewpoints on the role of AI in terms of its promises for computational as well as oncological aspects and offers achievements and opportunities in the era of precision medicine. The review also presents various recommendations to diminish these obstacles.
IFI35 Promotes Renal Cancer Progression by Inhibiting pSTAT1/pSTAT6-Dependent Autophagy
Authors: Chai Dafei , Shi Shang Yuchen , Sobhani Navid , Ding Jiage , Zhang Zichun , Jiang Nan , Wang Gang , Li Minle , Li Hailong , Zheng Junnian , Bai Jin
Published: June 2022

Interferon-induced protein 35 (IFI35), is currently acknowledged to govern the virus-related immune inflammatory responses. However, the biological significance and function of IFI35 in renal cell cancer (RCC) is still not well understood. Here, IFI35 expression and function were investigated in RCC tissues, renal cancer cells, and animal models. The results showed that IFI35 expression was significantly increased in 200 specimens of RCC patients. We found that higher IFI35 levels were significantly correlated with poor RCC prognosis. In human cell lines, the knockdown of IFI35 suppressed the malignant behavior of renal cancer cells. Similarly, the IFI35 knockdown resulted in significant inhibition of tumor progression in the subcutaneous or lung metastasis mouse model. Furthermore, the knockdown of IFI35 promoted the induction of autophagy by enhancing the autophagy-related gene expression (LC3-II, Beclin-1, and ATG-5). Additionally, blockade of STAT1/STAT6 phosphorylation (pSTAT1/pSTAT6) abrogated the induced autophagy by IFI35 knockdown in renal cancer cells. The autophagy inhibitor 3-MA also abolished the prevention of tumor growth by deleting IFI35 in renal cancer models. The above results suggest that the knockdown of IFI35 suppressed tumor progression of renal cancer by pSTAT1/pSTAT6-dependent autophagy. Our research revealed that IFI35 may serve as a potential diagnosis and therapeutic target for RCC.
Targeting Breast Cancer-Derived Stem Cells by Dietary Phytochemicals: A Strategy for Cancer Prevention and Treatment
Authors: Prajapati Kumari Sunita , Gupta Sanjay , Kumar Shashank
Published: June 2022

Breast cancer is heterogeneous disease with variable prognosis and therapeutic response. Approximately, 70% of diagnosed breast cancer represents the luminal A subtype. This subpopulation has a fair prognosis with a lower rate of relapse than the other clinical subtypes. Acquisition of stemness in luminal A subtype modifies the phenotype plasticity to accomplish increased aggressiveness and therapeutic resistance. Therefore, targeting luminal A-derived breast cancer stem cells (BCSCs) could be a promising strategy for its prevention and treatment. Extensive studies reveal that dietary phytochemicals have the potential to target BCSCs by modulating the molecular and signal transduction pathways. Dietary phytochemicals alone or in combination with standard therapeutic modalities exert higher efficacy in targeting BCSCs through changes in stemness, self-renewal properties and hypoxia-related factors. These combinations offer achieving higher radio- and chemo- sensitization through alteration in the key signaling pathways such as AMPK, STAT3, NF-ĸB, Hedgehog, PI3K/Akt/mTOR, Notch, GSK3β, and Wnt related to cancer stemness and drug resistance. In this review, we highlight the concept of targeting luminal A-derived BCSCs with dietary phytochemicals by summarizing the pathways and underlying mechanism(s) involved during therapeutic resistance.
An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment
Authors: Sharifi Majid , Cho William C. , Ansariesfahani Asal , Tarharoudi Rahil , Malekisarvar Hedyeh , Sari Soyar , Bloukh Samir Haj , Edis Zehra , Amin Mohamadreza , Gleghorn Jason P. , Hagen Timo L. M. ten , Falahati Mojtaba
Published: June 2022

The enhanced permeability and retention (EPR) effect in cancer treatment is one of the key mechanisms that enables drug accumulation at the tumor site. However, despite a plethora of virus/inorganic/organic-based nanocarriers designed to rely on the EPR effect to effectively target tumors, most have failed in the clinic. It seems that the non-compliance of research activities with clinical trials, goals unrelated to the EPR effect, and lack of awareness of the impact of solid tumor structure and interactions on the performance of drug nanocarriers have intensified this dissatisfaction. As such, the asymmetric growth and structural complexity of solid tumors, physicochemical properties of drug nanocarriers, EPR analytical combination tools, and EPR description goals should be considered to improve EPR-based cancer therapeutics. This review provides valuable insights into the limitations of the EPR effect in therapeutic efficacy and reports crucial perspectives on how the EPR effect can be modulated to improve the therapeutic effects of nanomedicine.
Genomic Aberrations in Circulating Tumor DNAs from Palbociclib-Treated Metastatic Breast Cancer Patients Reveal a Novel Resistance Mechanism
Authors: Abu-Khalaf Maysa , Wang Chun , Zhang Zhenchao , Luo Rui , Chong Weelic , Silver Daniel P. , Fellin Frederick , Jaslow Rebecca , Lopez AnaMaria , Cescon Terrence , Jiang Wei , Myers Ronald , Wei Qiang , Li Bingshan , Cristofanilli Massimo , Yang Hushan
Published: June 2022

Previously undescribed molecular mechanisms of resistance will emerge with the increased use of cyclin-dependent kinase 4/6 inhibitors in clinical settings. To identify genomic aberrations in circulating tumor DNA associated with treatment resistance in palbociclib-treated metastatic breast cancer (MBC) patients, we collected 35 pre- and post-treatment blood samples from 16 patients with estrogen receptor-positive (ER+) MBC, including 9 with inflammatory breast cancer (IBC). Circulating cell-free DNAs (cfDNAs) were isolated for sequencing using a targeted panel of 91 genes. Our data showed that FBXW7 and CDK6 were more frequently altered in IBC than in non-IBC, whereas conversely, PIK3CA was more frequently altered in non-IBC than in IBC. The cfDNA samples collected at follow-up harbored more mutations than baseline samples. By analyzing paired samples, we observed a higher percentage of patients with mutations in RB1, CCNE1, FBXW7, EZH2, and ARID1A, but a lower proportion of patients with mutated TSC2 at the post-treatment stage when they developed progression. Moreover, acquisition of CCNE1 mutations or loss of TSC2 mutations after treatment initiation conferred an unfavorable prognosis. These data provide insights into the relevance of novel genomic alterations in cfDNA to palbociclib resistance in MBC patients. Future large-scale prospective studies are warranted to confirm our findings.
Beyond Immunotherapy: Seizing the Momentum of Oncolytic Viruses in the Ideal Platform of Skin Cancers
Authors: Ziogas Dimitrios C. , Martinos Anastasios , Petsiou Dioni-Pinelopi , Anastasopoulou Amalia , Gogas Helen
Published: June 2022

Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the feasibility of this approach, skin cancers have become the ideal platform for intralesional infusions of many novel agents, including oncolytic viruses (OVs). Talimogene laherparepvec (T-VEC) was the first FDA-approved OV for the treatment of unresectable melanoma and this virus opened up further potential for the use of this class of agents, especially in combination with ICIs, in order to achieve deeper and longer immune-mediated responses. However, the recently announced phase III MASTERKEY-265 trial was not able to confirm that the addition of T-VEC to pembrolizumab treatment improves progression-free or overall survival over the use of pembrolizumab alone. Despite these results, numerous studies are currently active, evaluating T-VEC and several other OVs as monotherapies or in regimens with ICIs in different subtypes of skin cancer. This overview provides a comprehensive update on the evolution status of all available OVs in melanoma and non-melanoma skin cancers and summarizes the more interesting preclinical findings, the latest clinical evidence, and the future insights in relation to the expected selective incorporation of some of these OVs into oncological practice.
The Mycobiome: Cancer Pathogenesis, Diagnosis, and Therapy
Authors: Gamal Ahmed , Elshaer Mohammed , Alabdely Mayyadah , Kadry Ahmed , McCormick Thomas S. , Ghannoum Mahmoud
Published: June 2022

Cancer is among the leading causes of death globally. Despite advances in cancer research, a full understanding of the exact cause has not been established. Recent data have shown that the microbiome has an important relationship with cancer on various levels, including cancer pathogenesis, diagnosis and prognosis, and treatment. Since most studies have focused only on the role of bacteria in this process, in this article we review the role of fungi—another important group of the microbiome, the totality of which is referred to as the “mycobiome”—in the development of cancer and how it can impact responses to anticancer medications. Furthermore, we provide recent evidence that shows how the different microbial communities interact and affect each other at gastrointestinal and non-gastrointestinal sites, including the skin, thereby emphasizing the importance of investigating the microbiome beyond bacteria.
Clinical Exome Sequencing Revealed a De Novo FLNC Mutation in a Child with Restrictive Cardiomyopathy
Authors: Girolami Francesca , Passantino Silvia , Ballerini Adelaide , Gozzini Alessia , Porcedda Giulio , Olivotto Iacopo , Favilli Silvia
Published: June 2022

Restrictive cardiomyopathy (RCM) is a rare disease of the myocardium caused by mutations in several genes including TNNT2, DES, TNNI3, MYPN and FLNC. Individuals affected by RCM often develop heart failure at a young age, requiring early heart transplantation. A 7-year-old patient was referred for genetic testing following a diagnosis of restrictive cardiomyopathy. Clinical exome sequencing analysis identified a likely pathogenic mutation in the FLNC gene [(NM_001458.5 c.6527_6547dup p.(Arg2176_2182dup)]. Its clinical relevance was augmented by the fact that this variant was absent in the parents and was thus interpreted as de novo. Genetic testing is a powerful tool to clarify the diagnosis, guide intervention strategies and enable cascade testing in patients with pediatric-onset RCM.
A HCl-Mediated, Metal- and Oxidant-Free Photocatalytic Strategy for C3 Arylation of Quinoxalin(on)es with Arylhydrazine
Authors: Wang Kai , Xu Wenjing , Qi Haoran , Zhang Pengfei , Cao Xian-Ting , Wang Guannan
Published: June 2022

A novel and simple HCl-mediated, photocatalytic method for quinoxaline(on)es C3-H arylation with arylhydrazine under transition metal catalyst- and oxidant-free conditions is presented. Various quinoxaline(on)es underwent this transformation smoothly, demonstrating a broad substrate tolerance and providing the corresponding aryl products in moderate to excellent yields. Mechanistic studies indicated that a radical pathway may be involved in this transformation.
Architecture Evolution of Different Nanoparticles Types: Relationship between the Structure and Functional Properties of Catalysts for PEMFC
Authors: Belenov Sergey , Alekseenko Anastasia , Pavlets Angelina , Nevelskaya Alina , Danilenko Maria
Published: June 2022

This review considers the features of the catalysts with different nanoparticle structures architecture transformation under the various pre-treatment types. Based on the results of the publications analysis, it can be concluded that the chemical or electrochemical activation of bimetallic catalysts has a significant effect on their composition, microstructure, and catalytic activity in the oxygen reduction reaction. The stage of electrochemical activation is recommended for use as a mandatory catalyst pre-treatment to obtain highly active de-alloyed materials. The literature is studied, which covers possible variants of the structural modification under the influence of thermal treatment under different processing conditions. Additionally, based on the literature data analysis, recommendations are given for the thermal treatment of catalysts alloyed with various d-metals.
Neural Differentiation Potential of Mesenchymal Stem Cells Enhanced by Biocompatible Chitosan-Gold Nanocomposites
Authors: Hung Huey-Shan , Yang Yi-Chin , Chang Chih-Hsuan , Chang Kai-Bo , Shen Chiung-Chyi , Tang Chien-Lun , Liu Szu-Yuan , Lee Chung-Hsin , Yen Chun-Ming , Yang Meng-Yin
Published: June 2022

Chitosan (Chi) is a natural polymer that has been demonstrated to have potential as a promoter of neural regeneration. In this study, Chi was prepared with various amounts (25, 50, and 100 ppm) of gold (Au) nanoparticles for use in in vitro and in vivo assessments. Each as-prepared material was first characterized by UV-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), scanning electron microscopy (SEM), and Dynamic Light Scattering (DLS). Through the in vitro experiments, Chi combined with 50 ppm of Au nanoparticles demonstrated better biocompatibility. The platelet activation, monocyte conversion, and intracellular ROS generation was remarkably decreased by Chi–Au 50 pm treatment. Furthermore, Chi–Au 50 ppm could facilitate colony formation and strengthen matrix metalloproteinase (MMP) activation in mesenchymal stem cells (MSCs). The lower expression of CD44 in Chi–Au 50 ppm treatment demonstrated that the nanocomposites could enhance the MSCs undergoing differentiation. Chi–Au 50 ppm was discovered to significantly induce the expression of GFAP, β-Tubulin, and nestin protein in MSCs for neural differentiation, which was verified by real-time PCR analysis and immunostaining assays. Additionally, a rat model involving subcutaneous implantation was used to evaluate the superior anti-inflammatory and endothelialization abilities of a Chi–Au 50 ppm treatment. Capsule formation and collagen deposition were decreased. The CD86 expression (M1 macrophage polarization) and leukocyte filtration (CD45) were remarkably reduced as well. In summary, a Chi polymer combined with 50 ppm of Au nanoparticles was proven to enhance the neural differentiation of MSCs and showed potential as a biosafe nanomaterial for neural tissue engineering.
Myh9 Plays an Essential Role in the Survival and Maintenance of Hematopoietic Stem/Progenitor Cells
Authors: An Quanming , Dong Yong , Cao Yang , Pan Xu , Xue Yuan , Zhou Ya , Zhang Yonggang , Ma Feng
Published: June 2022

Myosin heavy chain 9 (MYH9) gene encodes a protein named non-muscle heavy chain IIA (NMHC IIA), interacting with actin and participating in various biological processes. Mutations in MYH9 cause an array of autosomal dominant disorders, known as MYH9-related diseases (MYH9-RD). However, the role of MYH9 in normal hematopoiesis remains largely unexplored. By using Mx1-cre Myh9 conditional knockout mice, we established an inducible system to precisely inactivate Myh9 function in hematopoietic cells in vivo. The results showed that deletion of Myh9 led to severe defects in hematopoiesis, characterized by pancytopenia, drastic decreases of hematopoietic stem/progenitor cells (HSPC), and bone marrow failure, causing early lethality in mice. The defect in hematopoiesis caused by Myh9 ablation is cell autonomous. In addition, Myh9 deletion impairs HSPC repopulation capacity and increases apoptosis. RNA sequencing results revealed significant alterations in the expression of genes related to HSC self-renewal and maintenance, while multiple signal pathways were also involved, including genes for HSC and myeloid cell development, intrinsic apoptosis, targets of mTOR signaling, and maturity of hematopoietic cells. Our present study suggests an essential role for Myh9 in the survival and maintenance of HSPC in normal hematopoiesis.
Axl Expression in Renal Mesangial Cells Is Regulated by Sp1, Ap1, MZF1, and Ep300, and the IL-6/miR-34a Pathway
Authors: Adams David E. , Zhen Yuxuan , Qi Xiaoyang , Shao Wen-Hai
Published: June 2022

Axl receptor tyrosine kinase expression in the kidney contributes to a variety of inflammatory renal disease by promoting glomerular proliferation. Axl expression in the kidney is negligible in healthy individuals but upregulated under inflammatory conditions. Little is known about Axl transcriptional regulation. We analyzed the 4.4 kb mouse Axl promoter region and found that many transcription factor (TF)-binding sites and regulatory elements are located within a 600 bp fragment proximal to the translation start site. Among four TFs (Sp1, Ap1, MZF1, and Ep300) identified, Sp1 was the most potent TF that promotes Axl expression. Luciferase assays confirmed the siRNA results and revealed additional mechanisms that regulate Axl expression, including sequences encoding a 5′-UTR mini-intron and potential G-quadruplex forming regions. Deletion of the Axl 5′-UTR mini-intron resulted in a 3.2-fold increases in luciferase activity over the full-length UTR (4.4 kb Axl construct). The addition of TMPyP4, a G-quadruplex stabilizer, resulted in a significantly decreased luciferase activity. Further analysis of the mouse Axl 3′-UTR revealed a miRNA-34a binding site, which inversely regulates Axl expression. The inhibitory role of miRNA-34a in Axl expression was demonstrated in mesangial cells using miRNA-34a mimicry and in primary kidney cells with IL-6 stimulated STAT3 activation. Taken together, Axl expression in mouse kidney is synergistically regulated by multiple factors, including TFs and secondary structures, such as mini-intron and G-quadruplex. A unique IL6/STAT3/miRNA-34a pathway was revealed to be critical in inflammatory renal Axl expression.
Targeting Acid Ceramidase Inhibits Glioblastoma Cell Migration through Decreased AKT Signaling
Authors: Hawkins Cyntanna C. , Jones Amber B. , Gordon Emily R. , Williford Sarah E. , Harsh Yuvika , Ziebro Julia K. , Landis Catherine J. , Gc Sajina , Crossman David K. , Cooper Sara J. , Ramanadham Sasanka , Doan Ninh , Hjelmeland Anita B.
Published: June 2022

Glioblastoma (GBM) remains one of the most aggressive cancers, partially due to its ability to migrate into the surrounding brain. The sphingolipid balance, or the balance between ceramides and sphingosine-1-phosphate, contributes to the ability of GBM cells to migrate or invade. Of the ceramidases which hydrolyze ceramides, acid ceramidase (ASAH1) is highly expressed in GBM samples compared to non-tumor brain. ASAH1 expression also correlates with genes associated with migration and focal adhesion. To understand the role of ASAH1 in GBM migration, we utilized shRNA knockdown and observed decreased migration that did not depend upon changes in growth. Next, we inhibited ASAH1 using carmofur, a clinically utilized small molecule inhibitor. Inhibition of ASAH1 by carmofur blocks in vitro migration of U251 (GBM cell line) and GBM cells derived from patient-derived xenografts (PDXs). RNA-sequencing suggested roles for carmofur in MAPK and AKT signaling. We found that carmofur treatment decreases phosphorylation of AKT, but not of MAPK. The decrease in AKT phosphorylation was confirmed by shRNA knockdown of ASAH1. Our findings substantiate ASAH1 inhibition using carmofur as a potential clinically relevant treatment to advance GBM therapeutics, particularly due to its impact on migration.
The Impact of General Anesthesia on Redox Stability and Epigenetic Inflammation Pathways: Crosstalk on Perioperative Antioxidant Therapy
Authors: Ritiu Stelian Adrian , Rogobete Alexandru Florin , Sandesc Dorel , Bedreag Ovidiu Horea , Papurica Marius , Popovici Sonia Elena , Toma Daiana , Ivascu Robert Iulian , Velovan Raluca , Garofil Dragos Nicolae , Corneci Dan , Bratu Lavinia Melania , Pahontu Elena Mihaela , Pistol Adriana
Published: June 2022

Worldwide, the prevalence of surgery under general anesthesia has significantly increased, both because of modern anesthetic and pain-control techniques and because of better diagnosis and the increased complexity of surgical techniques. Apart from developing new concepts in the surgical field, researchers and clinicians are now working on minimizing the impact of surgical trauma and offering minimal invasive procedures due to the recent discoveries in the field of cellular and molecular mechanisms that have revealed a systemic inflammatory and pro-oxidative impact not only in the perioperative period but also in the long term, contributing to more difficult recovery, increased morbidity and mortality, and a negative financial impact. Detailed molecular and cellular analysis has shown an overproduction of inflammatory and pro-oxidative species, responsible for augmenting the systemic inflammatory status and making postoperative recovery more difficult. Moreover, there are a series of changes in certain epigenetic structures, the most important being the microRNAs. This review describes the most important molecular and cellular mechanisms that impact the surgical patient undergoing general anesthesia, and it presents a series of antioxidant therapies that can reduce systemic inflammation.
Immunogenicity of Novel AAV Capsids for Retinal Gene Therapy
Authors: Gehrke Miranda , Diedrichs-Möhring Maria , Bogedein Jacqueline , Büning Hildegard , Michalakis Stylianos , Wildner Gerhild
Published: June 2022

Objectives: AAV vectors are widely used in gene therapy, but the prevalence of neutralizing antibodies raised against AAV serotypes in the course of a natural infection, as well as innate and adaptive immune responses induced upon vector administration, is still considered an important limitation. In ocular gene therapy, vectors applied subretinally bear the risk of retinal detachment or vascular leakage. Therefore, new AAV vectors that are suitable for intravitreal administration for photoreceptor transduction were developed. Methods: Here, we compared human immune responses from donors with suspected previous AAV2 infections to the new vectors AAV2.GL and AAV2.NN—two capsid peptide display variants with an enhanced tropism for photoreceptors—with the parental serotype AAV2 (AAV2 WT). We investigated total and neutralizing antibodies, adaptive and innate cellular immunogenicity determined by immunofluorescence staining and flow cytometry, and cytokine secretion analyzed with multiplex beads. Results: While we did not observe obvious differences in overall antibody binding, variants—particularly AAV2.GL—were less sensitive to neutralizing antibodies than the AAV2 WT. The novel variants did not differ from AAV2 WT in cellular immune responses and cytokine production in vitro. Conclusion: Due to their enhanced retinal tropism, which allows for dose reduction, the new vector variants are likely to be less immunogenic for gene therapy than the parental AAV2 vector.
Neutrophils Actively Contribute to Obesity-Associated Inflammation and Pathological Complications
Authors: Uribe-Querol Eileen , Rosales Carlos
Published: June 2022

Obesity is characterized by an increase in body weight associated with an exaggerated enlargement of the adipose tissue. Obesity has serious negative effects because it is associated with multiple pathological complications such as type 2 diabetes mellitus, cardiovascular diseases, cancer, and COVID-19. Nowadays, 39% of the world population is obese or overweight, making obesity the 21st century epidemic. Obesity is also characterized by a mild, chronic, systemic inflammation. Accumulation of fat in adipose tissue causes stress and malfunction of adipocytes, which then initiate inflammation. Next, adipose tissue is infiltrated by cells of the innate immune system. Recently, it has become evident that neutrophils, the most abundant leukocytes in blood, are the first immune cells infiltrating the adipose tissue. Neutrophils then get activated and release inflammatory factors that recruit macrophages and other immune cells. These immune cells, in turn, perpetuate the inflammation state by producing cytokines and chemokines that can reach other parts of the body, creating a systemic inflammatory condition. In this review, we described the recent findings on the role of neutrophils during obesity and the initiation of inflammation. In addition, we discuss the involvement of neutrophils in the generation of obesity-related complications using diabetes as a prime example.
Lung Inflammation Is Associated with Preeclampsia Development in the Rat
Authors: Curtis Katrina , Clarke Derek , Hanegan Makayla , Stapley Brendan , Wendt Ryan , Beckett Nathan , Litchfield Cade , Campbell Kennedy , Reynolds Paul , Arroyo Juan
Published: June 2022

Preeclampsia (PE) is an obstetric complication associated with significant health implications for the fetus and mother. Studies have shown a correlation between lung disease development and PE. Gas6 protein is expressed in the lung and placenta, and binds to the AXL Tyrosine kinase receptor. Recently, our laboratory utilized Gas6 to induce preeclamptic-like conditions in rats. Our objective was to determine the role of Gas6/AXL signaling in the maternal lung during PE development. Briefly, pregnant rats were divided into control, Gas6, or Gas6 + R428 (an AXL inhibitor). Immunofluorescence was performed to determine AXL expression. Bronchoalveolar lavage fluid (BALF) was procured for the assessment of inflammatory cell secretion. Western blot was performed to detect signaling molecules and ELISA determined inflammatory cytokines. We observed increased proteinuria and increased blood pressure in Gas6-treated animals. AXL was increased in the lungs of the treated animals and BALF fluid revealed elevated total protein abundance in Gas6 animals. Extracellular-signal regulated kinase (ERK) and protein kinase B (AKT) signaling in the lung appeared to be mediated by Gas6 as well as the secretion of inflammatory cytokines. We conclude that Gas6 signaling is capable of inducing PE and that this is associated with increased lung inflammation.
Aquaporin-6 May Increase the Resistance to Oxidative Stress of Malignant Pleural Mesothelioma Cells
Authors: Pellavio Giorgia , Martinotti Simona , Patrone Mauro , Ranzato Elia , Laforenza Umberto
Published: June 2022

Malignant pleural mesothelioma (MPM) is an aggressive cancer of the pleural surface and is associated with previous asbestos exposure. The chemotherapy drug is one of the main treatments, but the median survival ranges from 8 to 14 months from diagnosis. The redox homeostasis of tumor cells should be carefully considered since elevated levels of ROS favor cancer cell progression (proliferation and migration), while a further elevation leads to ferroptosis. This study aims to analyze the functioning/role of aquaporins (AQPs) as a hydrogen peroxide (H2O2) channel in epithelial and biphasic MPM cell lines, as well as their possible involvement in chemotherapy drug resistance. Results show that AQP-3, -5, -6, -9, and -11 were expressed at mRNA and protein levels. AQP-6 was localized in the plasma membrane and intracellular structures. Compared to normal mesothelial cells, the water permeability of mesothelioma cells is not reduced by exogenous oxidative stress, but it is considerably increased by heat stress, making these cells resistant to ferroptosis. Functional experiments performed in mesothelioma cells silenced for aquaporin-6 revealed that it is responsible, at least in part, for the increase in H2O2 efflux caused by heat stress. Moreover, mesothelioma cells knocked down for AQP-6 showed a reduced proliferation compared to mock cells. Current findings suggest the major role of AQP-6 in providing mesothelioma cells with the ability to resist oxidative stress that underlies their resistance to chemotherapy drugs.
A Plankton Detection Method Based on Neural Networks and Digital Holographic Imaging
Authors: Lang Kaiqi , Cai Hui , Wang Xiaoping
Published: June 2022

Detecting marine plankton by means of digital holographic microscopy (DHM) has been successfully deployed in recent decades; however, in most previous studies, the identification of the position, shape, and size of plankton has been neglected, which may negate some of the advantages of DHM. Therefore, the procedure of image fusion has been added between the reconstruction of initial holograms and the final identification, which could help present all the images of plankton clearly in a volume of seawater. A new image fusion method called digital holographic microscopy-fully convolutional networks (DHM-FCN) is proposed, which is based on the improved fully convolutional networks (FCN). The DHM-FCN model runs 20 times faster than traditional image fusion methods and suppresses the noise in the holograms. All plankton in a 2 mm thick water body could be clearly represented in the fusion image. The edges of the plankton in the DHM-FCN fusion image are continuous and clear without speckle noise inside. The neural network model, YOLOv4, for plankton identification and localization, was established. A mean average precision (mAP) of 97.69% was obtained for five species, Alexandrium tamarense, Chattonella marina, Mesodinium rubrum, Scrippsiella trochoidea, and Prorocentrum lima. The results of this study could provide a fast image fusion method and a visual method to detect organisms in water.
Short-Term Outcomes of the Boston Brace 3D Program Based on SRS and SOSORT Criteria: A Retrospective Study
Authors: Wynne James H. , Houle Lauren R.
Published: June 2022

Background: Adolescent idiopathic scoliosis (AIS) is characterized by a lateral curvature of the spine with a Cobb angle greater than 10 degrees, accompanied by rotation of the vertebral body. Bracing has been shown to be effective in halting the progression of at-risk curves, and, in some cases, even improving the Cobb angle by 6° or more. The Boston Brace 3D is part of the Boston Orthotics and Prosthetics standardized scoliosis program. The orthosis is custom-fabricated from scans, computer-aided design (CAD), and computer-aided manufactured (CAM) thoracolumbosacral orthosis used in the non-operative management of AIS. Aim: To evaluate the outcomes of a scoliosis program utilizing the Boston Brace 3D orthosis for patients with AIS, based on SRS and SOSORT criteria. Design: Retrospective study. Methods: An electronic medical records search was conducted to identify first-time brace wearers fitted between 1 January 2018, and 30 June 2019, at Boston Orthotics and Prosthetics Boston area clinics that met the SRS/SOSORT research guidelines. The initial out-of-brace, in-brace, and last follow-up X-rays (taken at least 12 months after fitting) were compared. Results: 84% of patients presenting with a single curve and 69% of patients with a double curve saw their curves improve (reduced 6° or more) or remain unchanged (±5°). Thirty-one patients started with a single curve between 25° and 30°, and thirty-two presented at 30° or below. Fifty-nine patients started with a double curve between 25° and 30°, and 59 patients presented at 30° or below. In general, the patients who wore their brace for more hours per day saw improved results. Conclusion: The Boston Brace 3D program is effective in controlling (and in some cases improving) curve progression in the non-operative management of adolescent idiopathic scoliosis. The approach is a repeatable system, as shown in this cohort of thirteen clinicians across six area clinics following the Boston Brace 3D clinical guidelines.
A Mixed Method Study: Defining the Core Learning Needs of Nurses Delivering Care to Children and Young People with Rheumatic Disease to Inform Paediatric Musculoskeletal Matters, a Free Online Educational Resource
Authors: Smith Nicola , English Christine , Davies Barbara , Wyllie Ruth , Foster Helen E. , Rapley Tim
Published: June 2022

Children and young people with rheumatic diseases and their families are often supported by nurses who may not have had specialist training in paediatric rheumatology. The purpose of our study was to establish the core learning needs of all nurses who may encounter these children and young people in their clinical practice and use this information to inform the content and format of Paediatric Musculoskeletal Matters Nursing (PMM-Nursing) Engagement with nurses working in different roles and with various levels of experience in musculoskeletal medicine informed these learning needs and PMM-Nursing content. Mixed methods ascertained learning needs under the following themes: (1) Need for increased awareness about rheumatic disease; (2) Impact of experience and nursing role; (3) Need for increased knowledge about rheumatic disease and management. In addition, our methods informed design components for an impactful learning and information resource. Representatives from stakeholder nursing groups, social sciences, and web development used this information to create a suitable framework for PMM-Nursing. The content of PMM-Nursing is now live and freely available.
Elastic Stable Intramedullary Nailing for Treatment of Pediatric Tibial Fractures: A 20-Year Single Center Experience of 132 Cases
Authors: Pogorelić Zenon , Vegan Viktor , Jukić Miro , Llorente Muñoz Carlos Martin , Furlan Dubravko
Published: June 2022

Objective: The aim of this study was to analyze the outcomes and complications in children treated with elastic stable intramedullary nailing (ESIN) for tibial fractures. Methods: The study included 132 patients (92 males) with a median age of 11 years (IQR 10, 15) treated with ESIN for displaced tibial shaft fractures or dia-metaphyseal distal tibial fractures from March 2002 to March 2022. The median follow-up was 118.5 months (IQR 74.5, 170). The primary outcome was success rate, while secondary outcomes were the time of bone healing, length of hospital stay, and associated injuries. Demographic data, type and nature of fracture, indication for surgery, healing time, operative time, complications of treatment, and time to implant removal were recorded. Results: Complete radiographic healing was achieved at a median of 7 weeks (IQR 6, 9). Most of the patients (n = 111; 84.1%) had fractures localized in the shaft of the tibia. The most common injuries were acquired by road traffic accidents (n = 42) and by a fall in the same level (n = 29), followed by injuries from sport activities (n = 21) or motorbike accidents (n = 18). Associated injuries were reported in 37 (28%) children. Fractures were closed in the majority of the children (n = 100; 76%), while 32 (24%) children presented with an open fracture. Children with open fractures were significantly older than children with closed fractures (13.5 years (IQR 10, 15) vs. 11 years (IQR 8.5, 14.5); p = 0.031). Furthermore, children with open fractures had a significantly longer hospital stay (7 days (IQR 5, 9) vs. 3 days (IQR 3, 6); p = 0.001), a higher rate of associated injuries (n = 14 (43.7%) vs. n = 23 (23%); p = 0.022), and a higher rate of postoperative complications (n = 7 (21.9%) vs. n = 8 (8%); p = 0.031). No intraoperative complications were recorded. A total of 15 (11.4%) postoperative complications were recorded. Most complications (60%) were minor complications, mostly related to the wound at the nail insertion site and were managed conservatively. A total of six (4.5%) patients required reoperation due to angulation of the fragments (n = 5) or refracture (n = 1). Conclusion: ESIN is a minimally invasive bone surgery technique and is a highly effective treatment for pediatric tibial unstable fractures with a low rate of complications. Based on the given results, surgical stabilization of the tibial fractures using titanium intramedullary nailing can be safely performed without casting with early physiotherapy.
Fibrothecoma in a Virgo Intacta Adolescent with Elevated Levels of CA 125 and B-hCG: A Case Report
Authors: Raičević Saša , Radoman Kristina , Radović Saša , Vučković Ljiljana , Vukmirović Filip
Published: June 2022

Ovarian fibromas are benign tumors that consist of spindle cells in bundles or storiformly arranged with collagen fibers in the stroma. Thecomas resemble theca interna ovarian cells, and there is lipid material in their cytoplasm. There is an overlap in histological and immunohistochemical characteristics of these two benign tumors, and the term “fibrothecoma” was coined to describe such cases. Their incidence is extremely rare in adolescents. The subject of our study is a 15-year-old, unmarried, virgo intacta patient who was referred to us due to profuse vaginal bleeding and the loss of consciousness. A right ovary ultrasound examination exposed the formation of a hyperechoic tumor with a diameter of 41.2 mm × 29.5 mm. Findings of cancer antigen 125 (CA 125) in the amounts of 621.1 U/mL and 142.87 mIU/mL of the B-human chorionic gonadotropin (B-hCG) serum were determined. After preoperative preparation, we operated on the patient to remove a tumor with a diameter of 37 mm × 30 mm × 22 mm, smooth outer surface, solid cross-section, and yellowish white color. The diagnosis of fibrothecoma was made based on pathohistological examination. An unusual finding of fibrothecoma in a virgo intacta adolescent with profuse vaginal bleeding and increased levels of CA 125 and B-hCG may serve as a basis for broader thinking about the pathology of juvenile bleeding.
Long-Term Outcomes of Congenital Diaphragmatic Hernia: Report of a Multicenter Study in Japan
Authors: Yamoto Masaya , Nagata Kouji , Terui Keita , Hayakawa Masahiro , Okuyama Hiroomi , Amari Shoichiro , Yokoi Akiko , Masumoto Kouji , Okazaki Tadaharu , Inamura Noboru , Toyoshima Katsuaki , Koike Yuhki , Yazaki Yuta , Furukawa Taizo , Usui Noriaki
Published: June 2022

Background: Treatment modalities for neonates with congenital diaphragmatic hernia (CDH) have greatly improved in recent years, with a concomitant increase in survival. However, long-term outcomes restrict the identification of optimal care pathways for CDH survivors in adolescence and adulthood. Therefore, we evaluated the long-term outcomes within the Japanese CDH Study Group (JCDHSG). Methods: Participants were born with CDH between 2006 and 2018 according to the JCDHSG. Participants were enrolled in the database at 1.5, 3, 6, and 12 years old. Follow-up items included long-term complications, operations for long-term complication, and home medical care. Results: A total of 747 patients were included in this study, with 626 survivors (83.8%) and 121 non-survivors (16.2%). At 1.5, 3, 6, and 12 years old, 45.4%, 36.5%, 34.8%, and 43.6% developed complications, and 20.1%, 14.7%, 11.5%, and 5.1% of participants required home care, respectively. Recurrence, pneumonia, pneumothorax, gastroesophageal reflux disease, and intestinal obstruction decreased with age, and thoracic deformity increased with age. Conclusions: As CDH survival rates improve, there is a need for continued research and fine-tuning of long-term care to optimize appropriate surveillance and long-term follow-up.