bluuebunny/crossref_metadata_2025 huggingface dataset:
Tetrahydrobiopterin Administration Augments Exercise-Induced Hyperemia and Endothelial Function in Patients With Systemic Sclerosis
Authors: Machin Daniel R. , Clifton Heather L. , Wray D. Walter , Frech Tracy M. , Donato Anthony J.
Published: January 2022

Systemic sclerosis (SSc) is a rare, auto-immune disease with variably progressive fibrosis of the skin and internal organs, as well as vascular dysfunction. Recently, we demonstrated a decrement in exercising skeletal muscle blood flow and endothelium-dependent vasodilation in SSc, but the mechanisms responsible for these impairments have not been investigated. Thus, we sought to determine if acute administration of tetrahydrobiopterin (BH4), an essential cofactor for endothelial nitric oxide synthase (eNOS), would improve hyperemia and brachial artery vasodilation during progressive handgrip exercise in SSc. Thirteen patients with SSc (63 ± 11 years) participated in this placebo-controlled, randomized, double-blind, crossover study. Tetrahydrobiopterin (10 mg/kg) administration resulted in a ~4-fold increase in circulating BH4 concentrations (P < 0.05). Cardiovascular variables at rest were unaffected by BH4 (P > 0.05). During handgrip exercise, BH4 administration increased brachial artery blood flow (placebo: 200 ± 87; BH4: 261 ± 115 ml/min; P < 0.05) and vascular conductance (placebo: 2.0 ± 0.8; BH4: 2.5 ± 1.0 ml/min/mmHg; P < 0.05), indicating augmented resistance artery vasodilation. Tetrahydrobiopterin administration also increased brachial artery vasodilation in response to exercise (placebo: 12 ± 6; BH4: 17 ± 7%; P < 0.05), resulting in a significant upward shift in the slope relationship between Δ brachial artery vasodilation and Δ shear rate (placebo: 0.030 ± 0.007; BH4: 0.047 ± 0.007; P < 0.05) that indicates augmented sensitivity of the brachial artery to vasodilate to the sustained elevations in shear rate during handgrip exercise. These results demonstrate the efficacy of acute BH4 administration to improve both resistance and conduit vessel endothelial function in SSc, suggesting that eNOS recoupling may be an effective strategy for improving vasodilatory capacity in this patient group.
Mini Review: The Forensic Value of Heat Shock Proteins
Authors: Prangenberg Julian , Doberentz Elke , Mawick Anthea , Madea Burkhard
Published: January 2022

Forensic pathologists are routinely confronted with unclear causes of death or related findings. In some instances, difficulties arise in relation to questions posed by criminal investigators or prosecutors. Such scenarios may include questions about wound vitality or cause of death where typical or landmark findings are difficult to ascertain. In addition to the usual examinations required to clarify unclear causes of death or address specific questions, immunohistochemistry and genetic analyses have become increasingly important techniques in this area since their establishment last century. Since then, many studies have determined the usefulness and significance of immunohistochemical and genetic investigations on cellular structures and proteins. For example, these proteins include heat shock proteins (Hsp), which were first described in 1962 and are so called based on their molecular weight. They predominantly act as molecular chaperones with cytoprotective functions that support cell survival under (sub) lethal conditions. They are expressed in specific cellular compartments and have many divergent functions. Central family members include, Hsp 27, 60, and 70. This mini review investigates recent research on the Hsp family, their application range, respective forensic importance, and current limitations and provides an outlook on possible applications within forensic science.
Hemodynamics and Metabolic Parameters in Normothermic Kidney Preservation Are Linked With Donor Factors, Perfusate Cells, and Cytokines
Authors: Weissenbacher Annemarie , Stone John P. , Lo Faro Maria Letizia , Hunter James P. , Ploeg Rutger J. , Coussios Constantin C. , Fildes James E. , Friend Peter J.
Published: January 2022

Kidney transplantation is the best renal-replacement option for most patients with end-stage renal disease. Normothermic machine preservation (NMP) of the kidney has been studied extensively during the last two decades and implemented in clinical trials. Biomarker research led to success in identifying molecules with diagnostic, predictive and therapeutic properties in chronic kidney disease. However, perfusate biomarkers and potential predictive mechanisms in NMP have not been identified yet. Twelve discarded human kidneys (n = 7 DBD, n = 5 DCD) underwent NMP for up to 24 h. Eight were perfused applying urine recirculation (URC), four with replacement of urine (UR) using Ringer's lactate. The aim of our study was to investigate biomarkers (NGAL, KIM-1, and L-FABP), cells and cytokines in the perfusate in context with donor characteristics, perfusate hemodynamics and metabolic parameters. Cold ischemia time did not correlate with any of the markers. Perfusates of DBD kidneys had a significantly lower number of leukocytes after 6 h of NMP compared to DCD. Arterial flow, pH, NGAL and L-FABP correlated with donor creatinine and eGFR. Arterial flow was higher in kidneys with lower perfusate lactate. Perfusate TNF-α was higher in kidneys with lower arterial flow. The cytokines IL-1β and GM-CSF decreased during 6 h of NMP. Kidneys with more urine output had lower perfusate KIM-1 levels. Median and 6-h values of lactate, arterial flow, pH, NGAL, KIM-1, and L-FABP correlated with each other indicating a 6-h period being applicable for kidney viability assessment. The study results demonstrate a comparable cytokine and cell profile in perfusates with URC and UR. In conclusion, clinically available perfusate and hemodynamic parameters correlate well with donor characteristics and measured biomarkers in a discarded human NMP model.
Emerging Progress in Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum: Challenges and Opportunities
Authors: Liu Chuan , Zhao Guo , Qiao Danni , Wang Lintao , He Yeling , Zhao Mingge , Fan Yuanyuan , Jiang Enshe
Published: January 2022

Nausea and vomiting of pregnancy (NVP) is a common condition that affects up to 70% of pregnant women. Hyperemesis gravidarum (HG) is considered the serious form of NVP, which is reported in 0.3–10.8% of pregnant women. NVP has a relatively benign course, but HG can be linked with some poor maternal, fetal, and offspring outcomes. The exact causes of NVP and HG are unknown, but various factors have been hypothesized to be associated with pathogenesis. With the advance of precision medicine and molecular biology, some genetic factors such as growth/differentiation factor 15 (GDF15) have become therapeutic targets. In our review, we summarize the historical hypotheses of the pathogenesis of NVP and HG including hormonal factors, Helicobacter pylori, gastrointestinal dysmotility, placenta-related factors, psychosocial factors, and new factors identified by genetics. We also highlight some approaches to the management of NVP and HG, including pharmacological treatment, complementary treatment, and some supporting treatments. Looking to the future, progress in understanding NVP and HG may reduce the adverse outcomes and improve the maternal quality of life during pregnancy.
Hepatic Unsaturated Fatty Acids Are Linked to Lower Degree of Fibrosis in Non-alcoholic Fatty Liver Disease
Authors: Fridén Michael , Rosqvist Fredrik , Ahlström Håkan , Niessen Heiko G. , Schultheis Christian , Hockings Paul , Hulthe Johannes , Gummesson Anders , Wanders Alkwin , Rorsman Fredrik , Risérus Ulf , Vessby Johan
Published: January 2022

Background: The hepatic lipidome of patients with early stages of non-alcoholic fatty liver disease (NAFLD) has been fairly well-explored. However, studies on more progressive forms of NAFLD, i.e., liver fibrosis, are limited.

Materials and methods: Liver fatty acids were determined in cholesteryl esters (CE), phospholipids (PL), and triacylglycerols (TAG) by gas chromatography. Cross-sectional associations between fatty acids and biopsy-proven NAFLD fibrosis (n = 60) were assessed using multivariable logistic regression models. Stages of fibrosis were dichotomized into none-mild (F0–1) or significant fibrosis (F2–4). Models were adjusted for body-mass index (BMI), age and patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409) (I148M) genotype. A secondary analysis examined whether associations from the primary analysis could be confirmed in the corresponding plasma lipid fractions.

Results: PL behenic acid (22:0) was directly associated [OR (95% CI): 1.86 (1.00, 3.45)] whereas PL docosahexaenoic acid (22:6n-3) [OR (95% CI): 0.45 (0.23, 0.89)], TAG oleic acid (18:1n-9) [OR (95% CI): 0.52 (0.28, 0.95)] and 18:1n-9 and vaccenic acid (18:1n-7) (18:1) [OR (95% CI): 0.52 (0.28, 0.96)] were inversely associated with liver fibrosis. In plasma, TAG 18:1n-9 [OR (95% CI): 0.55 (0.31, 0.99)], TAG 18:1 [OR (95% CI): 0.54 (0.30, 0.97)] and PL 22:0 [OR (95% CI): 0.46 (0.25, 0.86)] were inversely associated with liver fibrosis.

Conclusion: Higher TAG 18:1n-9 levels were linked to lower fibrosis in both liver and plasma, possibly reflecting an altered fatty acid metabolism. Whether PL 22:6n-3 has a protective role, together with a potentially adverse effect of hepatic 22:0, on liver fibrosis warrants large-scale studies.
Genetic Diversity of Listeria monocytogenes Isolated From Three Commercial Tree Fruit Packinghouses and Evidence of Persistent and Transient Contamination
Authors: Chen Yi , Simonetti Tobin , Peter Kari , Jin Qing , Brown Eric , LaBorde Luke F. , Macarisin Dumitru
Published: January 2022

Whole genome analysis was performed on 501 isolates obtained from a previous survey which recovered 139 positive environmental sponge samples (i.e., up to 4 isolates per sample) from a total of 719 samples collected at 40 standardized sites in 3 commercial apple packinghouse facilities (i.e., P1, P2, and P3) over 3 successive seasons in a single production year. After excluding duplicated isolates, the data from 156 isolates revealed the clonal diversity of L. monocytogenes and allowed the detection of transient contamination, persistent contamination, and cross-area transmission events. Facility P2 with the poorest sanitary conditions had the least diversity (Shannon’s index of 0.38). P2 contained a Clonal Complex (CC) 554, serogroup IVb-v1 strain that persisted throughout the year and spread across the entire facility, a singleton Sequence Type (ST) 1003, lineage III strain that persisted through two seasons and spread across two areas of the facility, and 3 other clones from transient contaminations. P1 and P3, facilities with better sanitary conditions, had much higher diversity (i.e., 15 clones with a Shannon’s index of 2.49 and 10 clones with a Shannon’s index of 2.10, respectively) that were the result of transient contamination. Facilities P1 and P3 had the highest incidence (43.1%) of lineage III isolates, followed by lineage I (31.3%) and lineage II (25.5%) isolates. Only 1 isolate in the three facilities contained a premature stop codon in virulence gene inlA. Fourteen samples yielded 2–3 clones per sample, demonstrating the importance of choosing appropriate methodologies and selecting a sufficient number of isolates per sample for studying L. monocytogenes diversity. Only 1 isolate, belonging to CC5 and from facility P3, contained a known plasmid, and this was also the only isolate containing benzalkonium chloride tolerance genes. The persistent CC554 strain did not exhibit stronger sanitizer resistance than other isolates and did not contain any confirmed molecular determinants of L. monocytogenes stress resistance that were differentially present in other isolates, such as genes involved in sanitizer tolerance, heavy metal resistance, biofilm-forming, stress survival islet 1 (SSI-1), stress survival islet 2 (SSI-2) or Listeria genomic island (LGI2).
Helminth Glycans at the Host-Parasite Interface and Their Potential for Developing Novel Therapeutics
Authors: Bunte Myrna J. M. , Schots Arjen , Kammenga Jan E. , Wilbers Ruud H. P.
Published: January 2022

Helminths are parasitic worms that have successfully co-evolved with their host immune system to sustain long-term infections. Their successful parasitism is mainly facilitated by modulation of the host immune systemviathe release of excretory-secretory (ES) products covered with glycan motifs such as Lewis X, fucosylated LDN, phosphorylcholine and tyvelose. Evidence is accumulating that these glycans play key roles in different aspects of helminth infection including interactions with immune cells for recognition and evasion of host defences. Moreover, antigenic properties of glycans can be exploited for improving the efficacy of anti-helminthic vaccines. Here, we illustrate that glycans have the potential to open new avenues for the development of novel biopharmaceuticals and effective vaccines based on helminth glycoproteins.
Epstein-Barr Virus and Neurological Diseases
Authors: Zhang Nan , Zuo Yuxin , Jiang Liping , Peng Yu , Huang Xu , Zuo Lielian
Published: January 2022

Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a double-stranded DNA virus that is ubiquitous in 90–95% of the population as a gamma herpesvirus. It exists in two main states, latent infection and lytic replication, each encoding viral proteins with different functions. Human B-lymphocytes and epithelial cells are EBV-susceptible host cells. EBV latently infects B cells and nasopharyngeal epithelial cells throughout life in most immunologically active individuals. EBV-infected cells, free viruses, their gene products, and abnormally elevated EBV titers are observed in the cerebrospinal fluid. Studies have shown that EBV can infect neurons directly or indirectly via infected B-lymphocytes, induce neuroinflammation and demyelination, promote the proliferation, degeneration, and necrosis of glial cells, promote proliferative disorders of B- and T-lymphocytes, and contribute to the occurrence and development of nervous system diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, acute cerebellar ataxia, meningitis, acute disseminated encephalomyelitis, and brain tumors. However, the specific underlying molecular mechanisms are unclear. In this paper, we review the mechanisms underlying the role of EBV in the development of central nervous system diseases, which could bebeneficial in providing new research ideas and potential clinical therapeutic targets for neurological diseases.
Within and Beyond the Nucleotide Addition Cycle of Viral RNA-dependent RNA Polymerases
Authors: Gong Peng
Published: January 2022

Nucleotide addition cycle (NAC) is a fundamental process utilized by nucleic acid polymerases when carrying out nucleic acid biosynthesis. An induced-fit mechanism is usually taken by these polymerases upon NTP/dNTP substrate binding, leading to active site closure and formation of a phosphodiester bond. In viral RNA-dependent RNA polymerases, the post-chemistry translocation is stringently controlled by a structurally conserved motif, resulting in asymmetric movement of the template-product duplex. This perspective focuses on viral RdRP NAC and related mechanisms that have not been structurally clarified to date. Firstly, RdRP movement along the template strand in the absence of catalytic events may be relevant to catalytic complex dissociation or proofreading. Secondly, pyrophosphate or non-cognate NTP-mediated cleavage of the product strand 3′-nucleotide can also play a role in reactivating paused or arrested catalytic complexes. Furthermore, non-cognate NTP substrates, including NTP analog inhibitors, can not only alter NAC when being misincorporated, but also impact on subsequent NACs. Complications and challenges related to these topics are also discussed.
Positron Emission Tomography in Animal Models of Tauopathies
Authors: Cao Lei , Kong Yanyan , Ji Bin , Ren Yutong , Guan Yihui , Ni Ruiqing
Published: January 2022

The microtubule-associated protein tau (MAPT) plays an important role in Alzheimer’s disease and primary tauopathy diseases. The abnormal accumulation of tau contributes to the development of neurotoxicity, inflammation, neurodegeneration, and cognitive deficits in tauopathy diseases. Tau synergically interacts with amyloid-beta in Alzheimer’s disease leading to detrimental consequence. Thus, tau has been an important target for therapeutics development for Alzheimer’s disease and primary tauopathy diseases. Tauopathy animal models recapitulating the tauopathy such as transgenic, knock-in mouse and rat models have been developed and greatly facilitated the understanding of disease mechanisms. The advance in PET and imaging tracers have enabled non-invasive detection of the accumulation and spread of tau, the associated microglia activation, metabolic, and neurotransmitter receptor alterations in disease animal models. In vivo microPET studies on mouse or rat models of tauopathy have provided significant insights into the phenotypes and time course of pathophysiology of these models and allowed the monitoring of treatment targeting at tau. In this study, we discuss the utilities of PET and recently developed tracers for evaluating the pathophysiology in tauopathy animal models. We point out the outstanding challenges and propose future outlook in visualizing tau-related pathophysiological changes in brain of tauopathy disease animal models.
Age-Related Decrease in Default-Mode Network Functional Connectivity Is Accelerated in Patients With Major Depressive Disorder
Authors: Tang Shixiong , Wu Zhipeng , Cao Hengyi , Chen Xudong , Wu Guowei , Tan Wenjian , Liu Dayi , Yang Jie , Long Yicheng , Liu Zhening
Published: January 2022

Major depressive disorder (MDD) is a common psychiatric disorder which is associated with an accelerated biological aging. However, little is known whether such process would be reflected by a more rapid aging of the brain function. In this study, we tested the hypothesis that MDD would be characterized by accelerated aging of the brain’s default-mode network (DMN) functions. Resting-state functional magnetic resonance imaging data of 971 MDD patients and 902 healthy controls (HCs) was analyzed, which was drawn from a publicly accessible, multicenter dataset in China. Strength of functional connectivity (FC) and temporal variability of dynamic functional connectivity (dFC) within the DMN were calculated. Age-related effects on FC/dFC were estimated by linear regression models with age, diagnosis, and diagnosis-by-age interaction as variables of interest, controlling for sex, education, site, and head motion effects. The regression models revealed (1) a significant main effect of age in the predictions of both FC strength and dFC variability; and (2) a significant main effect of diagnosis and a significant diagnosis-by-age interaction in the prediction of FC strength, which was driven by stronger negative correlation between age and FC strength in MDD patients. Our results suggest that (1) both healthy participants and MDD patients experience decrease in DMN FC strength and increase in DMN dFC variability along age; and (2) age-related decrease in DMN FC strength may occur at a faster rate in MDD patients than in HCs. However, further longitudinal studies are still needed to understand the causation between MDD and accelerated aging of brain.
Transcriptome Analyses Reveal Systematic Molecular Pathology After Optic Nerve Crush
Authors: Pan Yuan-Bo , Sun Yiyu , Li Hong-Jiang , Zhou Lai-Yang , Zhang Jianmin , Feng Dong-Fu
Published: January 2022

The function of glial cells in axonal regeneration after injury has been the subject of controversy in recent years. Thus, deeper insight into glial cells is urgently needed. Many studies on glial cells have elucidated the mechanisms of a certain gene or cell type in axon regeneration. However, studies that manipulate a single variable may overlook other changes. Here, we performed a series of comprehensive transcriptome analyses of the optic nerve head over a period of 90 days after optic nerve crush (ONC), showing systematic molecular changes in the optic nerve head (ONH). Furthermore, using weighted gene coexpression network analysis (WGCNA), we established gene module programs corresponding to various pathological events at different times post-ONC and found hub genes that may be potential therapeutic targets. In addition, we analyzed the changes in different glial cells based on their subtype markers. We revealed that the transition trend of different glial cells depended on the time course, which provides clues for modulating glial function in further research.
Comparison of Two-Dimensional- and Three-Dimensional-Based U-Net Architectures for Brain Tissue Classification in One-Dimensional Brain CT
Authors: Srikrishna Meera , Heckemann Rolf A. , Pereira Joana B. , Volpe Giovanni , Zettergren Anna , Kern Silke , Westman Eric , Skoog Ingmar , Schöll Michael
Published: January 2022

Brain tissue segmentation plays a crucial role in feature extraction, volumetric quantification, and morphometric analysis of brain scans. For the assessment of brain structure and integrity, CT is a non-invasive, cheaper, faster, and more widely available modality than MRI. However, the clinical application of CT is mostly limited to the visual assessment of brain integrity and exclusion of copathologies. We have previously developed two-dimensional (2D) deep learning-based segmentation networks that successfully classified brain tissue in head CT. Recently, deep learning-based MRI segmentation models successfully use patch-based three-dimensional (3D) segmentation networks. In this study, we aimed to develop patch-based 3D segmentation networks for CT brain tissue classification. Furthermore, we aimed to compare the performance of 2D- and 3D-based segmentation networks to perform brain tissue classification in anisotropic CT scans. For this purpose, we developed 2D and 3D U-Net-based deep learning models that were trained and validated on MR-derived segmentations from scans of 744 participants of the Gothenburg H70 Cohort with both CT and T1-weighted MRI scans acquired timely close to each other. Segmentation performance of both 2D and 3D models was evaluated on 234 unseen datasets using measures of distance, spatial similarity, and tissue volume. Single-task slice-wise processed 2D U-Nets performed better than multitask patch-based 3D U-Nets in CT brain tissue classification. These findings provide support to the use of 2D U-Nets to segment brain tissue in one-dimensional (1D) CT. This could increase the application of CT to detect brain abnormalities in clinical settings.
Effects of Cage Position and Light Transmission on Home Cage Activity and Circadian Entrainment in Mice
Authors: Steel Laura C. E. , Tir Selma , Tam Shu K. E. , Bussell James N. , Spitschan Manuel , Foster Russell G. , Peirson Stuart N.
Published: January 2022

Light is known to exert powerful effects on behavior and physiology, including upon the amount and distribution of activity across the day/night cycle. Here we use home cage activity monitoring to measure the effect of differences in home cage light spectrum and intensity on key circadian activity parameters in mice. Due to the relative positioning of any individually ventilated cage (IVC) with regard to the animal facility lighting, notable differences in light intensity occur across the IVC rack. Although all mice were found to be entrained, significant differences in the timing of activity onset and differences in activity levels were found between mice housed in standard versus red filtering cages. Furthermore, by calculating the effective irradiance based upon the known mouse photopigments, a significant relationship between light intensity and key circadian parameters are shown. Perhaps unsurprisingly given the important role of the circadian photopigment melanopsin in circadian entrainment, melanopic illuminance is shown to correlate more strongly with key circadian activity parameters than photopic lux. Collectively, our results suggest that differences in light intensity may reflect an uncharacterized source of variation in laboratory rodent research, with potential consequences for reproducibility. Room design and layout vary within and between facilities, and caging design and lighting location relative to cage position can be highly variable. We suggest that cage position should be factored into experimental design, and wherever possible, experimental lighting conditions should be characterized as a way of accounting for this source of variation.
Association of Acute Postoperative Pain and Cigarette Smoking With Cerebrospinal Fluid Levels of Beta-Endorphin and Substance P
Authors: Wang Fan , Li Hui , Mu Qingshuang , Shan Ligang , Kang Yimin , Yang Shizhuo , Chang Hui-Chih , Su Kuan-Pin , Liu Yanlong
Published: January 2022

Objectives: Cigarette smoking is associated with postoperative pain perception, which might be mediated by beta-endorphin and substance P. These effects on postoperative pain perception have never been investigated in human cerebrospinal fluid (CSF), which reflects biochemical alterations in the brain. Therefore, we investigated the associations among cigarette smoking, postoperative pain, and levels of beta-endorphin and substance P in human CSF.

Methods: We recruited 160 Chinese men (80 active smokers and 80 nonsmokers) who underwent lumbar puncture before anterior cruciate ligament reconstruction, and 5-ml CSF samples were collected. Pain visual analog scale (VAS) scores, post-anesthetic recovery duration (PARD), and smoking variables were obtained. CSF levels of beta-endorphin and substance P were measured.

Results: Compared to non-smokers, active smokers had significantly higher pain VAS (2.40 ± 0.67 vs. 1.70 ± 0.86,p< 0.001) and PARD scores (9.13 ± 2.11 vs. 7.27 ± 1.35,p= 0.001), lower CSF beta-endorphin (33.76 ± 1.77 vs. 35.66 ± 2.20,p= 0.001) and higher CSF substance P (2,124.46 ± 217.34 vs. 1,817.65 ± 302.14,p< 0.001) levels. Pain VAS scores correlated with PARD in active smokers (r= 0.443,p= 0.001).

Conclusions: Cigarette smoking is associated with increased postoperative pain intensity, shown by delayed pain perception, higher pain VAS scores, and lower beta-endorphin and higher substance P levels in the CSF of active smokers. The more extended postoperative pain perception is delayed, the more pain intensity increases.
A Novel in vitro Model Delineating Hair Cell Regeneration and Neural Reinnervation in Adult Mouse Cochlea
Authors: Li Wenyan , Quan Yizhou , Huang Mingqian , Wei Wei , Shu Yilai , Li Huawei , Chen Zheng-Yi
Published: January 2022

The study of an adult mammalian auditory system, such as regeneration, has been hampered by the lack of an in vitro system in which hypotheses can be tested efficiently. This is primarily due to the fact that the adult inner ear is encased in the toughest bone of the body, whereas its removal leads to the death of the sensory epithelium in culture. We hypothesized that we could take advantage of the integral cochlear structure to maintain the overall inner ear architecture and improve sensory epithelium survival in culture. We showed that by culturing adult mouse cochlea with the (surrounding) bone intact, the supporting cells (SCs) survived and almost all hair cells (HCs) degenerated. To evaluate the utility of the explant culture system, we demonstrated that the overexpression of Atoh1, an HC fate-determining factor, is sufficient to induce transdifferentiation of adult SCs to HC-like cells (HCLCs). Transdifferentiation-derived HCLCs resemble developmentally young HCs and are able to attract adult ganglion neurites. Furthermore, using a damage model, we showed that degenerated adult ganglions respond to regenerated HCLCs by directional neurite outgrowth that leads to HCLC-neuron contacts, strongly supporting the intrinsic properties of the HCLCs in establishing HCLC-neuron connections. The adult whole cochlear explant culture is suitable for diverse studies of the adult inner ear including regeneration, HC-neuron pathways, and inner ear drug screening.
The Active Components of Sunflower (Helianthus annuus L.) Calathide and the Effects on Urate Nephropathy Based on COX-2/PGE2 Signaling Pathway and the Urate Transporter URAT1, ABCG2, and GLUT9
Authors: Dai Huining , Lv Shuai , Qiao Zi'an , Wang Kaiyu , Zhou Xipeng , Bao Chunyang , Zhang Shitao , Fu Xueqi , Li Wannan
Published: January 2022

The sunflower (Helianthus annuus L.) calathide is gradually used as an alternative treatment for hyperuricemia; nevertheless, evidence regarding its main components and therapeutic capacity for urate nephropathy is lacking. Identification of sunflower calathide aqueous extract (SCE) was rapidly done by UPLC-ESI-Q-Orbitrap, and 32 water-soluble compounds with a comprehensive score >80 were discovered. Besides, yeast extract was administrated to induce high UA levels and hyperuricemic renal injury. We found that SCE treatment not only decreased UA levels to a comparable degree as allopurinol and benzbromarone, but also reduced the BUN levels and participated in kidney injury repair induced by uric acid. Moreover, it regulated the expression of URAT1 and ABCG2, especially inhibiting the GLUT9 in the normal kidney. Results were multifacetedly evaluated with a view to suggesting a possible mechanism of action as compared with those of allopurinol and benzbromarone by western blotting, H&E staining, and immunohistochemistry. However, the H&E staining showed histological changes in model, benzbromarone, and allopurinol groups rather than SCE treatments, and at the same time, the uric acid was identified as a cause of renal damage. The antiinflammatory effects and the regulations of COX-2/PGE2 signaling pathway were revealed on the LPS-induced RAW264.7 cells, indicating that the SCE not only increased cellular proliferation but also downregulated the COX-2, PGE2, NO, and IFN-γ cytokines in the RAW264.7 cells. To conclude, the SCE acts on urate transporters and contributes to prevent urate nephropathy via alleviating inflammatory process involving COX-2/PGE2 signaling pathway. It is available to develop SCE as food supplemental applications for hyperuricemia and nephritic inflammation.
Bifidobacterium animalis subsp. lactis BB-12 Has Effect Against Obesity by Regulating Gut Microbiota in Two Phases in Human Microbiota-Associated Rats
Authors: Mao Kemin , Gao Jie , Wang Xianghong , Li Xiyu , Geng Shuo , Zhang Tuo , Sadiq Faizan Ahmed , Sang Yaxin
Published: January 2022

Bifidobacterium animalis subsp. lactis BB-12 (BB-12) is an extensively studied probiotics species, which has been reported to improve the human gut microbiota. This study aimed to confirm the effects of BB-12 on high-fat diet (HFD)-induced gut microbiota disorders. The probiotic BB-12 was consumed by human microbiota-associated rats and changes in gut microbiota were compared using next generation sequencing of the fecal samples collected from the normal chow group, the HFD group, and the BB-12-supplemented group. The enterotypes switched from Prevotella dominant to Akkermansia dominant as a result of switching diet from normal chow to HFD. BB-12 conferred protection on the gut microbiota composition of the rats by increasing the abundance of Prevotella and decreasing the abundance of Clostridium, Blautia, and Bacteroides in 0–3 weeks. In addition, Prevotella-dominant enterotype was maintained, which provides improve obesity effects. A decrease in body weight and the Firmicutes/Bacteroidetes ratio were also observed at week 3. While in 4–8 weeks, the enrichment of short-chain fatty acids-producing bacteria such as Eubacterium and Parabacteroides and probiotics such as Bifidobacterium was observed. The results revealed that BB-12 against obesity by regulating gut microbiota in two phases. After a short-term intervention, BB-12 supplementation suppressed the transition from the healthy to obesity state by protecting Prevotella-dominant enterotype, whereas after a long-term intervention, BB-12 ameliorates obesity by enriching beneficial bacteria in the gut.
Immune-Related lncRNA Pairs as Prognostic Signature and Immune-Landscape Predictor in Lung Adenocarcinoma
Authors: Yin Zhengrong , Zhou Mei , Liao Tingting , Xu Juanjuan , Fan Jinshuo , Deng Jingjing , Jin Yang
Published: January 2022

Background

Suppressive tumor microenvironment is closely related to the progression and poor prognosis of lung adenocarcinoma (LUAD). Novel individual and universal immune-related biomarkers to predict the prognosis and immune landscape of LUAD patients are urgently needed. Two-gene pairing patterns could integrate and utilize various gene expression data.

Methods

The RNA-seq and relevant clinicopathological data of the LUAD project from the TCGA and well-known immune-related genes list from the ImmPort database were obtained. Co-expression analysis followed by an analysis of variance was performed to identify differentially expressed immune-related lncRNA (irlncRNA) (DEirlncRNA) between tumor and normal tissues. Two arbitrary DEirlncRNAs (DEirlncRNAs pair) in a tumor sample underwent pairwise comparison to generate a score (0 or 1). Next, Univariate analysis, Lasso regression and Multivariate analysis were used to screen survival-related DEirlncRNAs pairs and construct a prognostic model. The Acak information standard (AIC) values of the receiver operating characteristic (ROC) curve for 3 years are calculated to determine the cut-off point for high- or low-risk score. Finally, we evaluated the relationship between the risk score and overall survival, clinicopathological features, immune landscape, and chemotherapy efficacy.

Results

Data of 54 normal and 497 tumor samples of LUAD were enrolled. After a strict screening process, 15 survival-independent-related DEirlncRNA pairs were integrated to construct a prognostic model. The AUC value of the 3-year ROC curve was 0.828. Kaplan–Meier analysis showed that patients with low risk lived longer than patients with high risk (p <0.001). Univariate and Multivariate Cox analysis suggested that the risk score was an independent factor of survival. The risk score was negatively associated with most tumor-infiltrating immune cells, immune score, and microenvironment scores. The low-risk group was correlated with increased expression of ICOS. The high-risk group had a connection with lower half inhibitory centration (IC50) of most chemotherapy drugs (e.g., etoposide, paclitaxel, vinorelbine, gemcitabine, and docetaxel) and targeted medicine—erlotinib, but with higher IC50 of methotrexate.

Conclusion

The established irlncRNA pairs-based model is a promising prognostic signature for LUAD patients. Furthermore, the prognostic signature has great potential in the evaluation of tumor immune landscape and guiding individualized treatment regimens.
A Combined-Radiomics Approach of CT Images to Predict Response to Anti-PD-1 Immunotherapy in NSCLC: A Retrospective Multicenter Study
Authors: Wu Minghao , Zhang Yanyan , Zhang Jianing , Zhang Yuwei , Wang Yina , Chen Feng , Luo Yahong , He Shuai , Liu Yulin , Yang Qian , Li Yanying , Wei Hong , Zhang Hong , Lu Nian , Wang Sicong , Guo Yan , Ye Zhaoxiang , Liu Ying
Published: January 2022

Objective

Based on non-contrast-enhanced (NCE)/contrast-enhanced (CE) computed tomography (CT) images, we try to identify a combined-radiomics model and evaluate its predictive capacity regarding response to anti-PD1 immunotherapy of patients with non-small-cell lung cancer (NSCLC).

Methods

131 patients with NSCLC undergoing anti-PD1 immunotherapy were retrospectively enrolled from 7 institutions. Using largest lesion (LL) and target lesions (TL) approaches, we performed a radiomics analysis based on pretreatment NCE-CT (NCE-radiomics) and CE-CT images (CE-radiomics), respectively. Meanwhile, a combined-radiomics model based on NCE-CT and CE-CT images was constructed. Finally, we developed their corresponding nomograms incorporating clinical factors. ROC was used to evaluate models’ predictive performance in the training and testing set, and a DeLong test was employed to compare the differences between different models.

Results

For TL approach, both NCE-radiomics and CE-radiomics performed poorly in predicting response to immunotherapy. For LL approach, NCE-radiomics nomograms and CE-radiomics nomograms incorporating with clinical factor of distant metastasis all showed satisfactory results, reflected by the AUCs in the training (AUC=0.84, 95% CI: 0.75-0.92; AUC=0.77, 95% CI: 0.67-0.87) and test sets (AUC=0.78, 95% CI: 0.64-0.92, AUC=0.73, 95% CI: 0.57-0.88), respectively. Compared with the NCE-radiomics nomograms, the combined-radiomics nomogram showed incremental predictive capacity in the training set (AUC=0.85, 95% CI: 0.77-0.92) and test set (AUC=0.81, 95% CI: 0.67-0.94), respectively, but no statistical difference (P=0.86, P=0.79).

Conclusion

Compared with radiomics based on single NCE or CE-CT images, the combined-radiomics model has potential advantages to identify patients with NSCLC most likely to benefit from immunotherapy, and may effectively improve more precise and individualized decision support.
LINC00883 Promotes Drug Resistance of Glioma Through a microRNA-136/NEK1-Dependent Mechanism
Authors: Li Yongzhe , Gao Xin
Published: January 2022

Objective

Accumulating evidence has highlighted the roles of long noncoding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) of microRNAs (miRNAs) through their binding sites in the progression of glioma. Hereby, we aim to explore the role of LINC00883 as a regulator of miR-136 and its target, NIMA-related kinase 1 (NEK1), thus, its involvement in the drug resistance of glioma cells.

Methods and Results

Mechanistic investigations by dual-luciferase reporter, RNA pull-down, and RNA-binding protein immunoprecipitation (RIP) assays indicated that LINC00883 bound to miR-136, thereby blocking miR-136-induced downregulation of NEK1. Through gain-of-function experiments in U251 cells that presented a high drug resistance, we found that ectopic expression of LINC00883 resulted in increased MRP (encoding multidrug resistance-associated protein), limited cell apoptosis, and increased proliferation. Expectedly, depleting LINC00883 yielded tumor-suppressive and anti-chemoresistance effects on U251 cells by increasing miR-136 and inhibiting NEK1. Next, drug-resistant glioma cell line SOWZ1, drug-sensitive glioma cell line SOWZ2, and drug-resistant glioma cell line SOWZ2-BCNU (SOWZ2 cultured in BCNU) were applied to validate the roles of LINC00883 in the regulation of multidrug resistance. LINC00883 knockdown suppressed the viability of SWOZ1, SWOZ2, and SWOZ2-BCNU cells.

Conclusion

In conclusion, LINC00883 knockdown reduces drug resistance in glioma. Hence, our study provides a future strategy to prevent drug resistance-induced therapeutic failure in glioma.
Intraoperative Magnetic Resonance Imaging Assisted Endoscopic Endonasal Resection of Clival Chordomas
Authors: Gulsuna Beste , Karaaslan Burak , Kaymaz Memduh , Emmez Hakan , Cindil Emetullah , Sahin Muammer Melih , Celtikci Emrah
Published: January 2022

Background

Cranial base chordomas are typically indolent and usually appear as encapsulated tumors. They slowly grow by infiltrating the bone, along with the lines of least resistance. Due to its relationship with important neurovascular structures, skull base chordoma surgery is challenging.

Objective

The usefulness of intraoperative magnetic resonance imaging (IO-MRI) in achieving the goal of surgery, is evaluated in this study.

Methods

Between March 2018 and March 2020, 42 patients were operated on for resection of skull base chordomas in our institution. All of them were operated on under IO-MRI. Patients were analyzed retrospectively for identifying common residue locations, complications and early post-operative outcomes.

Results

In 22 patients (52,4%) gross total resection was achieved according to the final IO-MRI. In 20 patients (47,6%) complete tumor removal was not possible because of extension to the petrous bone (8 patients), pontocerebellar angle (6 patients), prepontine cistern (4 patients), temporobasal (1 patient), cervical axis (1 patient). In 13 patients, the surgery was continued after the first IO-MRI control was performed, which showed a resectable residual tumor. 7 of these patients achieved total resection according to the second IO-MRI, in the other 6 patients all efforts were made to ensure maximal resection of the tumor as much as possible without morbidity. Repeated IO-MRI helped achieve gross total resection in 7 patients (53.8%).

Conclusions

Our study proves that the use of IO-MRI is a safe method that provides the opportunity to show the degree of resection in skull base chordomas and to evaluate the volume and location of the residual tumor intraoperatively. Hence IO-MRI can improve the life expectancy of patients because it provides an opportunity for both gross total resection and maximal safe resection in cases where total resection is not possible.
CARving the Path to Allogeneic CAR T Cell Therapy in Acute Myeloid Leukemia
Authors: Pasvolsky Oren , Daher May , Alatrash Gheath , Marin David , Daver Naval , Ravandi Farhad , Rezvani Katy , Shpall Elizabeth , Kebriaei Partow
Published: January 2022

Despite advances in the understanding of the genetic landscape of acute myeloid leukemia (AML) and the addition of targeted biological and epigenetic therapies to the available armamentarium, achieving long-term disease-free survival remains an unmet need. Building on growing knowledge of the interactions between leukemic cells and their bone marrow microenvironment, strategies to battle AML by immunotherapy are under investigation. In the current review we describe the advances in immunotherapy for AML, with a focus on chimeric antigen receptor (CAR) T cell therapy. CARs constitute powerful immunologic modalities, with proven clinical success in B-Cell malignancies. We discuss the challenges and possible solutions for CAR T cell therapy development in AML, and examine the path currently being paved by preclinical and clinical efforts, from autologous to allogeneic products.
WHO Grade Loses Its Prognostic Value in Molecularly Defined Diffuse Lower-Grade Gliomas
Authors: Carstam Louise , Corell Alba , Smits Anja , Dénes Anna , Barchéus Hanna , Modin Klara , Sjögren Helene , Ferreyra Vega Sandra , Bontell Thomas Olsson , Carén Helena , Jakola Asgeir Store
Published: January 2022

Background

While molecular insights to diffuse lower-grade glioma (dLGG) have improved the basis for prognostication, most established clinical prognostic factors come from the pre-molecular era. For instance, WHO grade as a predictor for survival in dLGG with isocitrate dehydrogenase (IDH) mutation has recently been questioned. We studied the prognostic role of WHO grade in molecularly defined subgroups and evaluated earlier used prognostic factors in the current molecular setting.

Material and Methods

A total of 253 adults with morphological dLGG, consecutively included between 2007 and 2018, were assessed. IDH mutations, codeletion of chromosomal arms 1p/19q, and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions were analyzed.

Results

There was no survival benefit for patients with WHO grade 2 over grade 3 IDH-mut dLGG after exclusion of tumors with known CDKN2A/B homozygous deletion (n=157) (log-rank p=0.97). This was true also after stratification for oncological postoperative treatment and when astrocytomas and oligodendrogliomas were analyzed separately. In IDH-mut astrocytomas, residual tumor volume after surgery was an independent prognostic factor for survival (HR 1.02; 95% CI 1.01–1.03; p=0.003), but not in oligodendrogliomas (HR 1.02; 95% CI 1.00–1.03; p=0.15). Preoperative tumor size was an independent predictor in both astrocytomas (HR 1.03; 95% CI 1.00–1.05; p=0.02) and oligodendrogliomas (HR 1.05; 95% CI 1.01–1.09; p=0.01). Age was not a significant prognostic factor in multivariable analyses (astrocytomas p=0.64, oligodendrogliomas p=0.08).

Conclusion

Our findings suggest that WHO grade is not a robust prognostic factor in molecularly well-defined dLGG. Preoperative tumor size remained a prognostic factor in both IDH-mut astrocytomas and oligodendrogliomas in our cohort, whereas residual tumor volume predicted prognosis in IDH-mut astrocytomas only. The age cutoffs for determining high risk in patients with IDH-mut dLGG from the pre-molecular era are not supported by our results.
Prognosis of Upfront Surgery for Pancreatic Cancer: A Systematic Review and Meta-Analysis of Prospective Studies
Authors: Pecorelli Nicolò , Licinio Alice W. , Guarneri Giovanni , Aleotti Francesca , Crippa Stefano , Reni Michele , Falconi Massimo , Balzano Gianpaolo
Published: January 2022

Background

The rate of patients with pancreatic ductal adenocarcinoma (PDAC) receiving neoadjuvant chemotherapy is increasing, but upfront resection is still offered to most patients with resectable or borderline resectable disease. Encouraging data reported in adjuvant chemotherapy trials prompts surgeons towards upfront surgery, but such trials are subject to a significant selection bias. This systematic review aims to summarize available high-quality evidence regarding survival of patients treated with upfront surgery for PDAC.

Methods

Pubmed, Cochrane, and Web of Science Databases were interrogated for prospective studies published between 2000 and 2021 that included at least a cohort of patients treated with upfront surgery for resectable or borderline resectable PDAC. The Cochrane Collaboration’s risk-of-bias tool for randomized trials (RoB-2) was used to assess risk of bias in all randomized studies. Patient weighted median overall survival (OS) and disease-free survival (DFS) were calculated.

Results

Overall, 8,341 abstracts were screened, 17 reports were reviewed in full text, and finally 5 articles and 1 conference abstract underwent data extraction. Included studies were published between 2014 and 2021. All studies were RCTs comparing different neoadjuvant treatment strategies to upfront surgery. Three studies included only resectable PDAC patients, two studies recruited patients with resectable and borderline resectable disease, and one study selected only borderline resectable patients. A total of 439 patients were included in the upfront resection cohorts of the 6 studies, ranging between 20 to 180 patients per study. The weighted median OS after upfront surgery was 18.8 (95% CI 12.4 – 20.6) months. Median DFS was 9 (95% CI 1.6 – 12.5) months. Resection rate was 74.5% (range 65-90%). Adjuvant treatment was initiated in 68% (range 43-77%) of resected patients.

Conclusions

High-quality data for PDAC patients undergoing upfront surgery is scarce. Meta-analysis from the included studies showed a significantly shorter OS and DFS compared to recently published studies focusing on adjuvant combination chemotherapy, suggesting that the latter may overestimate survival due to the exclusion of most patients scheduled for upfront surgery.