bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Standardized Analysis of Tertiary Lymphoid Structures in Human Melanoma: Disease Progression- and Tumor Site-Associated Changes With Germinal Center Alteration
Authors: Werner Franziska , Wagner Christine , Simon Martin , Glatz Katharina , Mertz Kirsten D. , Läubli Heinz , Griss Johannes , Wagner Stephan N. 
Published: June 2021

There is increasing evidence that tertiary lymphoid structures (TLS) control not only local adaptive B cell responses at melanoma tumor sites but also the cellular composition and function of other immune cells. In human melanoma, however, a comprehensive analysis of TLS phenotypes, density and spatial distribution at different disease stages is lacking. Here we used 7-color multiplex immunostaining of whole tissue sections from 103 human melanoma samples to characterize TLS phenotypes along the expression of established TLS-defining molecular and cellular components. TLS density and spatial distribution were determined by referring TLS counts to the tissue area within defined intra- and extratumoral perimeters around the invasive tumor front. We show that only a subgroup of primary human melanomas contains TLS. These TLS rarely formed germinal centers and mostly located intratumorally within 1 mm distance to the invasive tumor front. In contrast, melanoma metastases had a significantly increased density of secondary follicular TLS. They appeared preferentially in stromal areas within an extratumoral 1 mm distance to the invasive tumor front and their density varied over time and site of metastasis. Interestingly, secondary follicular TLS in melanoma often lacked BCL6+ lymphatic cells and canonical germinal center polarity with the formation of dark and light zone areas. Our work provides an integrated qualitative, quantitative and spatial analysis of TLS in human melanoma and shows disease progression- and site-associated changes in TLS phenotypes, density and spatial distribution. The frequent absence of canonical germinal center polarity in melanoma TLS highlights the induction of TLS maturation as a potential additive to future immunotherapy studies. Given the variable evaluation strategies used in previous TLS studies of human tumors, an important asset of this study is the standardized quantitative evaluation approach that provides a high degree of reproducibility.
The Role of Growth Hormone in Depression: A Human Model
Authors: Algahtany Mubarak , Sharma Shubham , Fahoum Khalid , Jing Rowan , Zhang Stanley , Kovacs Kalman , Rotondo Fabio , Lee John , Vanek Irene , Cusimano Michael D. 
Published: June 2021

BackgroundAlthough the relationship between acromegaly and depression has been ascribed to the effects of chronic disease, the role of growth hormone (GH), and insulin like growth factor-1 (IGF-1) is not clear.ObjectiveTo determine whether related hormones levels in acromegalics are correlated with depressive symptoms and whether these symptoms are ameliorated following surgery.Materials and MethodsA prospective cohort study was conducted on patients diagnosed with acromegaly (n = 15) or non-functioning pituitary adenomas (NFPA; n = 20, as controls) and undergoing first-time surgery, who completed the Center for Epidemiological Studies Depression (CES-D) questionnaire both pre-surgery and post-surgery. The primary outcome was the patient’s severity of depression symptomatology using the CES-D score; GH, IGF-1 levels, and tumor characteristics were also measured.ResultsHormone levels (GH and IGF-1) and depression scores in acromegaly patients showed significant reductions following surgery (p &lt; 0.05). The average change in CES-D score was 5.73 ± 2.58 (mean ± SE). A moderate correlation was found between GH levels and CES-D scores (r = 0.52, p &lt; 0.01). The depressed affect subscale accounted for the most improvement in CES-D scores postoperatively and correlated most highly with GH levels. We did not find similar declines in the matched cohort of NFPA patients.Conclusion and RelevanceSurgical resection of the pituitary tumor in acromegaly patients leads to reduction in GH levels that is correlated with reduction in CES-D scores. The results suggest a role for GH in depression and provide a stronger foundation on which to build the hypothesis that GH impacts affect. The study also suggests that hormones should be factored into the matrix that entails the neuro-biological underpinnings of depressive disorders. Future work could explore the mechanisms involved, further brain and neuropeptide interactions, and, novel potential therapeutic targets in depressive and other mental health disorders.
Enhanced Drug Delivery to Solid Tumors via Drug-Loaded Nanocarriers: An Image-Based Computational Framework
Authors: Moradi Kashkooli Farshad , Soltani M. , Momeni Mohammad Masoud , Rahmim Arman 
Published: June 2021

ObjectiveNano-sized drug delivery systems (NSDDSs) offer a promising therapeutic technology with sufficient biocompatibility, stability, and drug-loading rates towards efficient drug delivery to solid tumors. We aim to apply a multi-scale computational model for evaluating drug delivery to predict treatment efficacy.MethodologyThree strategies for drug delivery, namely conventional chemotherapy (one-stage), as well as chemotherapy through two- and three-stage NSDDSs, were simulated and compared. A geometric model of the tumor and the capillary network was obtained by processing a real image. Subsequently, equations related to intravascular and interstitial flows as well as drug transport in tissue were solved by considering real conditions as well as details such as drug binding to cells and cellular uptake. Finally, the role of periodic treatments was investigated considering tumor recurrence between treatments. The impact of different parameters, nanoparticle (NP) size, binding affinity of drug, and the kinetics of release rate, were additionally investigated to determine their therapeutic efficacy.ResultsUsing NPs considerably increases the fraction of killed cells (FKCs) inside the tumor compared to conventional chemotherapy. Tumoral FKCs for two-stage DDS with smaller NP size (20nm) is higher than that of larger NPs (100nm), in all investigate release rates. Slower and continuous release of the chemotherapeutic agents from NPs have better treatment outcomes in comparison with faster release rate. In three-stage DDS, for intermediate and higher binding affinities, it is desirable for the secondary particle to be released at a faster rate, and the drug with slower rate. In lower binding affinities, high release rates have better performance. Results also demonstrate that after 5 treatments with three-stage DDS, 99.6% of tumor cells (TCs) are killed, while two-stage DDS and conventional chemotherapy kill 95.6% and 88.5% of tumor cells in the same period, respectively.ConclusionThe presented framework has the potential to enable decision making for new drugs via computational modeling of treatment responses and has the potential to aid oncologists with personalized treatment plans towards more optimal treatment outcomes.
In Vivo Safety of Tumor Treating Fields (TTFields) Applied to the Torso
Authors: Blatt Roni , Davidi Shiri , Munster Mijal , Shteingauz Anna , Cahal Shay , Zeidan Adel , Marciano Tal , Bomzon Zeev , Haber Adi , Giladi Moshe , Weinberg Uri , Kinzel Adrian , Palti Yoram 
Published: June 2021

BackgroundTumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional, anti-mitotic treatment modality that targets rapidly dividing cancerous cells, utilizing low intensity, alternating electric fields at cancer-cell-type specific frequencies. TTFields therapy is approved for the treatment of newly diagnosed and recurrent glioblastoma (GBM) in the US, Europe, Israel, Japan, and China. The favorable safety profile of TTFields in patients with GBM is partially attributed to the low rate of mitotic events in normal, quiescent brain cells. However, specific safety evaluations are warranted at locations with known high rates of cellular proliferation, such as the torso, which is a primary site of several of the most aggressive malignant tumors.MethodsThe safety of delivering TTFields to the torso of healthy rats at 150 or 200 kHz, which were previously identified as optimal frequencies for treating multiple torso cancers, was investigated. Throughout 2 weeks of TTFields application, animals underwent daily clinical examinations, and at treatment cessation blood samples and internal organs were examined. Computer simulations were performed to verify that the targeted internal organs of the torso were receiving TTFields at therapeutic intensities (≥ 1 V/cm root mean square, RMS).ResultsNo treatment-related mortality was observed. Furthermore, no significant differences were observed between the TTFields-treated and control animals for all examined safety parameters: activity level, food and water intake, stools, motor neurological status, respiration, weight, complete blood count, blood biochemistry, and pathological findings of internal organs. TTFields intensities of 1 to 2.5 V/cm RMS were confirmed for internal organs within the target region.ConclusionsThis research demonstrates the safety of therapeutic level TTFields at frequencies of 150 and 200 kHz when applied as monotherapy to the torso of healthy rats.
Prebiotic Mannan Oligosaccharide Pretreatment Improves Mice Survival Against Lethal Effects of Gamma Radiation by Protecting GI Tract and Hematopoietic Systems
Authors: Sanguri Sweta , Gupta Damodar 
Published: June 2021

Total body irradiation (TBI) results in critical injuries in a dose dependent manner that primarily damages highly proliferating tissues including hematopoietic stem cells (HSCs) and intestinal crypt stem cells etc. This may result in hematopoietic syndrome leading to bone marrow failure and gastrointestinal syndrome leading to chronic intestinal functional alterations. Death results from the gastrointestinal syndrome due to sepsis, bleeding, dehydration, and multi-system organ failure. We demonstrate that the prebiotic mannan oligosaccharide (MOS) pretreatment substantially prolongs survival in both male and female mice when administered 2 h prior to radiation either through oral or intraperitoneal route. The radioprotective efficacy of MOS was found to be age dependent and improves survival even in aged mice (12–13 months old). MOS pretreatment effectively abrogates radiation-induced hematopoietic injury and accelerates recovery of lymphocytes and WBCs and alleviates depletion of circulatory blood cells. Results also illustrate that MOS pretreatment abolishes crypt cell death and denudation of villi in comparison to the respective irradiated animals and ameliorates the overall radiation-induced damage to the GI system. MOS pretreatment facilitates intestinal recovery leading to enhanced animal survival demonstrating its protection efficacy against TBI induced mortality. Moreover, MOS pretreated animals show signs of accelerated recovery in terms of severity of radiation sickness symptoms including weight loss and completely abolish TBI associated mortality.
A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells
Authors: De Grandis Rone A. , Oliveira Katia M. , Guedes Adriana P. M. , dos Santos Patrick W. S. , Aissa Alexandre F. , Batista Alzir A. , Pavan Fernando R. 
Published: June 2021

Lapachol is a well-studied natural product that has been receiving great interest due to its anticancer properties that target oxidative stress. In the present work, two novel lapachol-containing ruthenium(II) complexes [Ru(Lap)(dppm)(bipy)]PF6 (1) and [Ru(Lap)(dppm)(phen)]PF6 (2) [Lap = lapachol, dppm = 1,1′-bis(diphosphino)methane, bipy = 2,2′-bipyridine, phen = 1,10-phenantroline] were synthesized, fully characterized, and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures, as well as in a 3D model of multicellular spheroids formed from DU-145 human prostate adenocarcinoma cells. Furthermore, the complex (2) suppressed the colony formation, induced G2/M-phase arrest, and downregulated Aurora-B. The mechanism studies suggest that complex (2) stimulate the overproduction of reactive oxygen species (ROS) and triggers caspase-dependent apoptosis as a result of changes in expression of several genes related to cell proliferation and caspase-3 and -9 activation. Interestingly, we found that N-acetyl-L-cysteine, a ROS scavenger, suppressed the generation of intracellular ROS induced by complex (2), and decreased its cytotoxicity, indicating that ROS-mediated DNA damage leads the DU-145 cells into apoptosis. Overall, we highlighted that coordination of lapachol to phosphinic ruthenium(II) compounds considerably improves the antiproliferative activities of resulting complexes granting attractive selectivity to human prostate adenocarcinoma cells. The DNA damage response to ROS seems to be involved in the induction of caspase-mediated cell death that plays an important role in the complexes' cytotoxicity. Upon further investigations, this novel class of lapachol-containing ruthenium(II) complexes might indicate promising chemotherapeutic agents for prostate cancer therapy.
Clinical Relevance of PD-L1 Expression and CD8+ T Cells’ Infiltration in Patients With Lung Invasive Mucinous Adenocarcinoma
Authors: Xu Xiaoling , Li Na , Wang Ding , Chen Wei , Fan Yun 
Published: June 2021

BackgroundInvasive mucinous adenocarcinoma (IMA) of the lung is a rare and distinct subtype of adenocarcinoma. At present, people have no idea whether IMA patients can benefit from immunotherapy and target therapy; thus there is an urgent need to clarify the immune microenvironment and genetic characteristics of this cohort.MethodsA total of 31 IMA patients matched with 27 non-mucinous adenocarcinoma (non-IMA) patients were enrolled in this study, and clinical data was collected. The expression of PD-L1, CD8+ tumor-infiltrating lymphocytes (TILs) and ALK was determined by immunohistochemistry. Polymerase Chain Reaction was used to determine the mutations of EGFR. The Chi-square test, Kaplan–Meier method and Cox proportional hazard regression model were used to explore the correlations between these clinicopathological variables, survival and identify risk factors.ResultsOf the patients with IMA 9.7% (3/31) revealed positive PD-L1 expression and 35.5% (11/31) showed CD8+ TIL infiltration, which were markedly lower than that of non-IMA group [PD-L1: 48.1% (13/27); CD8: 81.5% (22/27)]. Moreover, five (16.1%) patients in IMA group and 10 (37.0%) patients in non-IMA group had EGFR mutations, and nine (29.0%) patients in IMA group and zero (0.0%) patient in non-IMA group had ALK rearrangements. Additionally, we observed that IMA patients with CD8+ TIL infiltration had a worse prognosis than CD8-negative group (P = 0.024). Multivariate analyses showed that CD8 was an independent prognostic factor for patient’s survival (HR = 5.60, 95% CI: 1.35–23.22, P = 0.017).ConclusionPatients with IMA have down-regulated expression of PD-L1 and less CD8+ TIL infiltration in tumor microenvironment. Besides, a lower frequency of EGFR mutations was detected in patients with IMA than non-IMA patients while a higher rate of ALK rearrangements was found. Our results provide important reference for therapy of lung IMA.
An Intrasheath Separation Technique for Nerve-Sparing High Ligation of the Inferior Mesenteric Artery in Colorectal Cancer Surgery
Authors: Zheng Zhifang , Wang Xiaojie , Huang Ying , Lu Xingrong , Zhao Xiaozhen , Chi Pan 
Published: June 2021

PurposeTo investigate the relationship between the left trunk of the inferior mesenteric plexus (IMP) and the vascular sheath of the inferior mesenteric artery (IMA) and to explore anatomical evidence for autonomic nerve preservation during high ligation of the IMA in colorectal cancer surgery.MethodsWe evaluated the relationship in 23 consecutive cases of laparoscopic or robotic colorectal surgery with high ligation of the IMA at our institute. Anatomical dissection was performed on 5 formalin-fixed abdominal specimens. A novel anatomical evidence-based operative technique was proposed.ResultsAnatomical observation showed that the left trunk of the IMP was closely connected with the IMA and was involved in the composition of the vascular sheath. Based on anatomical evidence, we present a novel operative technique for nerve-sparing high ligation of the IMA that was successfully performed in 45 colorectal cancer surgeries with no intraoperative complications and satisfactory postoperative urogenital functional outcomes.ConclusionThe left trunk of the IMP is involved in the composition of the IMA vascular sheath. This novel anatomical evidence-based operative technique for nerve-sparing high ligation of the IMA is technically safe and feasible.
The Use of Chinese Yang/Qi-Invigorating Tonic Botanical Drugs/Herbal Formulations in Ameliorating Chronic Kidney Disease by Enhancing Mitochondrial Function
Authors: Tian Jiayi , Huang Yuqi , Wu Tong , Huang Hsien-Da , Ko Kam Ming , Zhu Bao Ting , Chen Jihang 
Published: June 2021

Background: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality. Mitochondrial dysfunction has been implicated as a key factor in the development of CKD. According to traditional Chinese medicine (TCM) theory, many Chinese Yang/Qi-invigorating botanical drugs/herbal formulations have been shown to produce promising outcomes in the clinical management of CKD. Experimental studies have indicated that the health-promoting action of Yang/Qi invigoration in TCM is related to the up-regulation of mitochondrial energy generation and antioxidant status.Objective: In this review, we aim to test whether Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations can provide medical benefits in CKD and its complications. And we also explore the possible involvement of mitochondrial-associated signaling pathway underlying the beneficial effects of Yang/Qi invigoration in TCM.Methods: A systematic search of “PubMed”, “China National Knowledge Infrastructure (CNKI)” and “Google Scholar” was carried out to collect all the available articles in English or Chinese related to Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations and their effects on mitochondrial function and chronic kidney disease.Result and Discussion: The relationship between the progression of CKD and mitochondrial function is discussed. The effects of Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations and their active ingredients, including phytosterols/triterpenes, flavonoids, and dibenzocyclooctadiene lignans, on CKD and related alterations in mitochondrial signaling pathways are also presented in this review. In the future, exploration of the possible beneficial effects and clinical studies of more Yang- and Qi-invigorating botanical drugs/herbal formulations in the prevention and/or/treatment of CKD and the molecular mechanisms relating to the enhancement of mitochondrial functions warrants further investigation.Conclusion: Given the critical role of mitochondrial function in safeguarding renal functional integrity, the enhancement of mitochondrial energy metabolism and antioxidant status in kidney tissue is likely involved in renal protection. Future studies on the biochemical and chemical basis underlying the effects of Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations from a mitochondrial perspective will hopefully provide novel insights into the rational development of new drugs for the prevention and/or treatment of CKD.
Nephroprotective Effects of Tetramethylpyrazine Nitrone TBN in Diabetic Kidney Disease
Authors: Jing Mei , Cen Yun , Gao Fangfang , Wang Ting , Jiang Jinxin , Jian Qianqian , Wu Liangmiao , Guo Baojian , Luo Fangcheng , Zhang Gaoxiao , Wang Ying , Xu Lipeng , Zhang Zaijun , Sun Yewei , Wang Yuqiang 
Published: June 2021

Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, but therapeutic options for nephroprotection are limited. Oxidative stress plays a key role in the pathogenesis of DKD. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a novel nitrone derivative of tetramethylpyrazine with potent free radical-scavenging activity, exerted multifunctional neuroprotection in neurological diseases. However, the effect of TBN on DKD and its underlying mechanisms of action are not yet clear. Herein, we performed streptozotocin-induced rat models of DKD and found that TBN administrated orally twice daily for 6 weeks significantly lowered urinary albumin, N-acetyl-β-D-glycosaminidase, cystatin C, malonaldehyde, and 8-hydroxy-2′-deoxyguanosine levels. TBN also ameliorated renal histopathological changes. More importantly, in a nonhuman primate model of spontaneous stage III DKD, TBN increased the estimated glomerular filtration rate, decreased serum 3-nitrotyrosine, malonaldehyde and 8-hydroxy-2′-deoxyguanosine levels, and improved metabolic abnormalities. In HK-2 cells, TBN increased glycolytic and mitochondrial functions. The protective mechanism of TBN might involve the activation of AMPK/PGC-1α-mediated downstream signaling pathways, thereby improving mitochondrial function and reducing oxidative stress in the kidneys of DKD rodent models. These results support the clinical development of TBN for the treatment of DKD.
SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis
Authors: Lin Hui , Guan Le , Meng Liping , Uzui Hiroyasu , Guo Hangyuan 
Published: June 2021

Background: Cardiac fibroblast (CF) activation is a hallmark feature of cardiac fibrosis in diabetic cardiomyopathy (DCM). Inhibition of the sodium-dependent glucose transporter 1 (SGLT1) attenuates cardiomyocyte apoptosis and delays the development of DCM. However, the role of SGLT1 in CF activation remains unclear.Methods: A rat model of DCM was established and treated with si‐SGLT1 to examine cardiac fibrosis. In addition, in vitro experiments were conducted to verify the regulatory role of SGLT1 in proliferation and collagen secretion in high-glucose– (HG–) treated CFs.Results: SGLT1 was found to be upregulated in diabetic cardiac tissues and HG-induced CFs. HG stimulation resulted in increased proliferation and migration, increased the expression of transforming growth factor-β1 and collagen I and collagen III, and increased phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) 1/2. These trends in HG-treated CFs were significantly reversed by si-SGLT1. Moreover, the overexpression of SGLT1 promoted CF proliferation and collagen synthesis and increased phosphorylation of p38 mitogen-activated protein kinase and ERK1/2. SGLT1 silencing significantly alleviated cardiac fibrosis, but had no effect on cardiac hypertrophy in diabetic hearts.Conclusion: These findings provide new information on the role of SGLT1 in CF activation, suggesting a novel therapeutic strategy for the treatment of DCM fibrosis.