bluuebunny/crossref_metadata_2025 huggingface dataset:
Ovarian cancer subtypes based on the regulatory genes of RNA modifications: Novel prediction model of prognosis
Authors: Zheng Peixian , Li Na , Zhan Xianquan
Published: December 2022

Background

Ovarian cancer (OC) is a female reproductive system tumor. RNA modifications play key roles in gene expression regulation. The growing evidence demonstrates that RNA methylation is critical for various biological functions, and that its dysregulation is related to the progression of cancer in human.

Method

OC samples were classified into different subtypes (Clusters 1 and 2) based on various RNA-modification regulatory genes (RRGs) in the process of RNA modifications (m1A, m6A, m6Am, m5C, m7G, ac4C, m3C, and Ψ) by nonnegative matrix factorization method (NMF). Based on differently expressed RRGs (DERRGs) between clusters, a pathologically specific RNA-modification regulatory gene signature was constructed with Lasso regression. Kaplan-Meier analysis and receiver operating characteristic (ROC) curves were used to evaluate the prognostic ability of the identified model. The correlations of clinicopathological features, immune subtypes, immune scores, immune cells, and tumor mutation burden (TMB) were also estimated between different NMF clusters and riskscore groups.

Results

In this study, 59 RRGs in the process of RNA modifications (m1A, m6A, m6Am, m5C, m7G, ac4C, m3C, and Ψ) were obtained from TCGA database. These RRGs were interactional, and sample clusters based on these regulators were significantly correlated with survival rate, clinical characteristics (involving survival status and pathologic stage), drug sensibility, and immune microenvironment. Furthermore, Lasso regression based on these 21 DERRGs between clusters 1 and 2 constructed a four-DERRG signature (ALYREF, ZC3H13, WTAP, and METTL1). Based on this signature, 307 OC patients were classified into high- and low-risk groups based on median value of riskscores from lasso regression. This identified signature was significantly associated with overall survival, radiation therapy, age, clinical stage, cancer status, and immune cells (involving CD4+ memory resting T cells, plasma cells, and Macrophages M1) of ovarian cancer patients. Further, GSEA revealed that multiple biological behaviors were significantly enriched in different groups.

Conclusions

OC patients were classified into two subtypes per these RRGs. This study identified four-DERRG signature (ALYREF, ZC3H13, WTAP, and METTL1) in OC, which was an independent prognostic model for patient stratification, prognostic evaluation, and prediction of response to immunotherapy in ovarian cancer by classifying OC patients into high- and low-risk groups.
Drivers of population divergence and genetic variation in Elymus breviaristatus (Keng) Keng f. (Poaceae: Triticeae), an endemic perennial herb of the Qinghai-Tibet plateau
Authors: Li Jin , Ma Saier , Jiang Keke , Zhang Changbing , Liu Wenhui , Chen Shiyong
Published: December 2022

Elymus breviaristatus, a rare grass species with excellent resistance and ecological importance, is narrowly distributed on the Qinghai-Tibet plateau. Populations of E. breviaristatus are declining due to habitat fragmentation, and thus far, characteristics of genetic differentiation and adaptive responses to climate change remain poorly understood in this species. Here, we explored the genetic structure of 18 natural populations (269 individuals) in the transition zone between Tibet and the Hengduan Mountains using 15 expressed sequence tag (EST)-SSR primer pairs and identified possible barriers to gene flow that might have caused genetic discontinuities. Additional analyses were performed to identify the environmental factors affecting genetic diversity and to test whether the patterns of genetic variation among populations were more consistent with the isolation by distance (IBD) or isolation by environment (IBE) model. Multiple measures of genetic diversity revealed that intra-population genetic variation was low, while inter-population genetic variation was high. Clustering, structure, and principal coordinate analyses identified three genetic groups: (a) Eastern Qamdo, (b) Nagqu and Western Qamdo, and (c) Lhasa and Nyingchi. A clear physical barrier to gene flow was formed by the Yarlung Zangbo Grand Canyon and the Tanggula Mountains. We found that both IBD and IBE contributed to the observed patterns of genetic variation, and the IBE model played a leading role. In addition, precipitation-related variables, soil phosphorus content and soil K:P ratio significantly affected population genetic variation. Overall, our results emphasized the genetic fragility of E. breviaristatus populations and showed that this species requires attention, as future climate changes and human activities may further threaten its survival. In addition, the genetic differences among E. breviaristatus populations should be considered when formulating conservation measures for E. breviaristatus populations in the study area.
The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?
Authors: Jiang Aimin , Liu Na , Wang Jingjing , Zheng Xiaoqiang , Ren Mengdi , Zhang Wei , Yao Yu
Published: December 2022

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with a bleak prognosis. Mounting evidence suggests that IPF shares bio-molecular similarities with lung cancer. Given the deep understanding of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in cancer immunity and the successful application of immune checkpoint inhibitors (ICIs) in lung cancer, recent studies have noticed the role of the PD-1/PD-L1 axis in IPF. However, the conclusions are ambiguous, and the latent mechanisms remain unclear. In this review, we will summarize the role of the PD-1/PD-L1 axis in IPF based on current murine models and clinical studies. We found that the PD-1/PD-L1 pathway plays a more predominant profibrotic role than its immunomodulatory role in IPF by interacting with multiple cell types and pathways. Most preclinical studies also indicated that blockade of the PD-1/PD-L1 pathway could attenuate the severity of pulmonary fibrosis in mice models. This review will bring significant insights into understanding the role of the PD-1/PD-L1 pathway in IPF and identifying new therapeutic targets.
Immunological hyporesponsiveness in tuberculosis: The role of mycobacterial glycolipids
Authors: Correia-Neves Margarida , Nigou Jérôme , Mousavian Zaynab , Sundling Christopher , Källenius Gunilla
Published: December 2022

Glycolipids constitute a major part of the cell envelope ofMycobacterium tuberculosis(Mtb). They are potent immunomodulatory molecules recognized by several immune receptors like pattern recognition receptors such as TLR2, DC-SIGN and Dectin-2 on antigen-presenting cells and by T cell receptors on T lymphocytes. The Mtb glycolipids lipoarabinomannan (LAM) and its biosynthetic relatives, phosphatidylinositol mannosides (PIMs) and lipomannan (LM), as well as other Mtb glycolipids, such as phenolic glycolipids and sulfoglycolipids have the ability to modulate the immune response, stimulating or inhibiting a pro-inflammatory response. We explore here the downmodulating effect of Mtb glycolipids. A great proportion of the studies usedin vitroapproaches althoughin vivoinfection with Mtb might also lead to a dampening of myeloid cell and T cell responses to Mtb glycolipids. This dampened response has been exploredex vivowith immune cells from peripheral blood from Mtb-infected individuals and in mouse models of infection. In addition to the dampening of the immune response caused by Mtb glycolipids, we discuss the hyporesponse to Mtb glycolipids caused by prolonged Mtb infection and/or exposure to Mtb antigens. Hyporesponse to LAM has been observed in myeloid cells from individuals with active and latent tuberculosis (TB). For some myeloid subsets, this effect is stronger in latent versus active TB. Since the immune response in individuals with latent TB represents a more protective profile compared to the one in patients with active TB, this suggests that downmodulation of myeloid cell functions by Mtb glycolipids may be beneficial for the host and protect against active TB disease. The mechanisms of this downmodulation, including tolerance through epigenetic modifications, are only partly explored.
NAFLD and HBV interplay - related mechanisms underlying liver disease progression
Authors: Tourkochristou Evanthia , Assimakopoulos Stelios F. , Thomopoulos Konstantinos , Marangos Markos , Triantos Christos
Published: December 2022

Non-alcoholic fatty liver disease (NAFLD) and Hepatitis B virus infection (HBV) constitute common chronic liver diseases with worldwide distribution. NAFLD burden is expected to grow in the coming decade, especially in western countries, considering the increased incidence of diabetes and obesity. Despite the organized HBV vaccinations and use of anti-viral therapies globally, HBV infection remains endemic and challenging public health issue. As both NAFLD and HBV have been associated with the development of progressive fibrosis, cirrhosis and hepatocellular carcinoma (HCC), the co-occurrence of both diseases has gained great research and clinical interest. The causative relationship between NAFLD and HBV infection has not been elucidated so far. Dysregulated fatty acid metabolism and lipotoxicity in NAFLD disease seems to initiate activation of signaling pathways that enhance pro-inflammatory responses and disrupt hepatocyte cell homeostasis, promoting progression of NAFLD disease to NASH, fibrosis and HCC and can affect HBV replication and immune encountering of HBV virus, which may further have impact on liver disease progression. Chronic HBV infection is suggested to have an influence on metabolic changes, which could lead to NAFLD development and the HBV-induced inflammatory responses and molecular pathways may constitute an aggravating factor in hepatic steatosis development. The observed altered immune homeostasis in both HBV infection and NAFLD could be associated with progression to HCC development. Elucidation of the possible mechanisms beyond HBV chronic infection and NAFLD diseases, which could lead to advanced liver disease or increase the risk for severe complications, in the case of HBV-NAFLD co-existence is of high clinical significance in the context of designing effective therapeutic targets.
Confocal Raman microscopy for assessing effects of preservation methods on symbiotic deep-sea mussel gills
Authors: He Wanying , Wang Minxiao , Li Mengna , Zhong Zhaoshan , Chen Hao , Xi Shichuan , Luan Zhendong , Li Chaolun , Zhang Xin
Published: December 2022

Confocal Raman microscopy (CRM) is a powerful tool for biological research, which can provide information regarding the composition and distribution of biomolecules in an in situ, label-free, non-destructive manner and with high spatial resolution. Sample preservation is often an unavoidable step, especially for symbiotic deep-sea samples. Moreover, protocols for the preservation of samples for CRM have not been established and specific effects of different preservation methods on biomolecules have not been studied for relevant samples. In this study, we used deep-sea mussel Gigantidas platifrons, an ideal model in the study of deep-sea symbiosis and investigated the effect of four common preservation methods on the results of CRM imaging and signals. The methods included snap-freeze (SF), SF followed by rapid fixation in methanol (SF-MeOH), 2.5% glutaraldehyde and 2% paraformaldehyde fixation (SF-GP), and 4% paraformaldehyde and alcohol fixation (PS-PA). The results of this study indicate that SF was the most effective method for the comprehensive analysis of the biomolecular composition although the sectioning success rate was relatively low. Moreover, SF-MeOH was found to be effective when SF is not sufficient in obtaining good morphology in sections, or when the effect of chemical bonding on the composition of biomolecules upon SF-MeOH can be neglected. Finally, SF-GP and PS-PA were found to be the most effective methods considering the overall morphological observation. However, they were less suitable for metabolic studies. We believe our results can provide guidance for further studies of Raman on symbiotic deep-sea biological samples. It is of great importance for the wide application of Raman technique.
Metformin Use Was Associated With Reduced Risk of Incidental Sjögren's Syndrome in Patients With Type 2 Diabetes: A Population-Based Cohort Study
Authors: Wang Cheng-You , Lai Jung-Nien , Liu Chin-Hsiu , Hu Kai-Chieh , Sheu Kai-Lun , Wei James Cheng-Chung
Published: December 2022

Purpose:Previous studies have shown that metformin exhibits an anti-inflammatory effect and may decrease the risk of incidental diabetes. But the effect of metformin on incidental Sjögren's syndrome is unknown. The aim of the study was to examine the association between metformin exposure and Sjögren's syndrome in diabetic patients.

Methods:The dataset in this retrospective cohort study was obtained from the National Health Insurance Research Database (2000–2013) in Taiwan. In total, 15,098 type 2 diabetic patients under metformin treatment and an equivalent number without metformin treatment matched for comparison were included. The primary endpoint was the incidence of Sjogren's syndrome. Univariate and multivariate Cox proportional hazards models were used for data analysis. A subgroup analysis and sensitivity test were also performed.

Results:The incidence rate of Sjögren's syndrome in non-metformin controls was 40.83 per 100,000 person-years and 16.82 per 100,000 person-years in metformin users. The adjusted hazard ratio (aHR) in diabetic patients under metformin treatment was 0.46 (95% CI, 0.23 to 0.92). In subgroup analysis, men had a lower risk of developing Sjögren's syndrome than women [aHR = 0.15, 95% CI = (0.05, 0.41)]. After prescribing metformin to type 2 diabetic patients aged 60 years or more, those patients had a lower risk of developing Sjögren's syndrome [aHR = 0.34, 95% CI = (0.12, 0.96)].

Conclusion:In this large population-based cohort study, metformin exposure was associated with a reduced risk of developing Sjögren's syndrome in type 2 diabetic patients.
The effects of intravenous tramadol vs. intravenous ketamine in the prevention of shivering during spinal anesthesia: A meta-analysis of randomized controlled trials
Authors: Fenta Efrem , Kibret Simegnew , Hunie Metages , Tamire Tadese , Fentie Yewlsew , Seid Shimelis , Teshome Diriba
Published: December 2022

Background

Shivering is a common complication after subarachnoid administration of local anesthetics. Intravenous ketamine and tramadol are widely available anti-shivering drugs, especially in developing settings. This meta-analysis aimed to compare the effects of intravenous ketamine vs. tramadol for post-spinal anesthesia shivering.

Materials and methods

PubMed/MEDLINE, Web of Science, Cochrane Library, Embase, and Google Scholar databases were used to search for relevant articles for this study. Mean difference (MD) with 95% confidence interval (CI) was used to analyze continuous outcomes, and risk ratio (RR) with 95% CI to analyze categorical results. The heterogeneity of the included studies was assessed using the I2 test. We utilized Review Manager 5.4.1 to perform statistical analysis.

Results

Thirteen studies involving 1,532 patients were included in this meta-analysis. Ketamine had comparable effects in preventing post-spinal anesthetics shivering [RR = 1.06; 95% CI (0.94, 1.20), P = 0.33, I2 = 77], and onset of shivering [MD = −0.10; 95%CI (– 2.68, 2.48), P = 0.94, I2 = 0%], lower incidences of nausea and vomiting [RR = 0.51; 95%CI (0.26, 0.99), P = 0.05, I2 = 67%], and lower incidences of bradycardia [RR = 0.16; 95%CI (0.05, 0.47), P = 0.001, I2 = 33%], higher incidence of hallucinations [RR = 12; 95%CI (1.58, 91.40), P = 0.02, I2 = 0%], and comparable effects regarding the incidences of hypotension [RR = 0.60; 95%CI (0.30, 1.21), P = 0.15, I2 = 54%] as compared to tramadol.

Conclusions

Intravenous ketamine and tramadol are comparable in the prevention of post-spinal anesthetic shivering. Ketamine had a better outcome with less occurrences of nausea, vomiting, and bradycardia. However, ketamine was associated with higher incidences of hallucinations than tramadol.
A case of VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) with decreased oxidative stress levels after oral prednisone and tocilizumab treatment
Authors: Tozaki Nagie , Tawada Chisato , Niwa Hirofumi , Mizutani Yoko , Shu En , Kawase Aki , Miwa Yuki , Ohnishi Hidenori , Sasai Hideo , Miyako Keisuke , Hosokawa Junichi , Kato Ayaka , Kobayashi Kazuhiro , Miyazaki Tatsuhiko , Shirakami Yohei , Shimizu Masahito , Iwata Hiroaki
Published: December 2022

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has recently been described as an autoinflammatory disease associated with severe adult-onset inflammatory manifestations. The various clinical manifestations include recurrent high-grade fever, neutrophilic dermatoses, cutaneous vasculitis, chondritis of the ear and nose, pulmonary infiltrates, cytopenia, uveitis, gastrointestinal pain or inflammation, aortitis, hepatosplenomegaly, and hematological disorders. VEXAS syndrome is caused by somatic mutations of the ubiquitin-like modifier activating enzyme 1 (UBA1) gene in myeloid-lineage cells. It is characterized by vacuolated myeloid and erythroid progenitor cells seen by bone marrow biopsy. We report the case of a 64-year-old Japanese man with VEXAS syndrome. At age 63, he was referred to us with a recurrent erythema on the hands associated with a general fever of 38–40°C that had persisted for 4 or 5 days and had recurred about once a month for a year. The skin rash appeared 2 or 3 days after the onset of each fever episode. Computed tomography (CT) of the chest revealed bilateral hilar lymphadenopathy (BHL), and the mediastinal lymph nodes were swollen. Sarcoidosis was suspected but was ruled out by several tests. Laboratory examinations showed elevated inflammatory markers. Bone marrow examination showed the vacuolization of myeloid precursor cells. A skin biopsy revealed dense dermal, predominantly perivascular, infiltrates. These consisted of mature neutrophils admixed with myeloperoxidase-positive CD163-positive myeloid cells, lymphoid cells and eosinophils. Sequencing analysis identified the somatic UBA1 variant c.122T > C, which results in p.Met41Thr. Treatment with oral prednisone (15 mg/day) and monthly intravenous tocilizumab injections (400 mg) completely resolved the symptoms. Neutrophils are a major source of reactive oxygen species, and the present case demonstrated numerous neutrophilic infiltrates. We hypothesize that the patient might have had elevated derivatives of reactive oxygen metabolites (d-ROMs). d-ROM quantification is a simple method for detecting hydroperoxide levels, and clinical trials have proven it useful for evaluating oxidative stress. In this study, we measured serum d-ROM before and after oral prednisone and tocilizumab treatment. The levels decreased significantly during treatment.
Fertilization drives distinct biotic and abiotic factors in regulating functional groups of protists in a 5-year fertilization system
Authors: Zhang Siyu , Zhang Haifang , Liu Hongmei , Wang Hui , Xiu Weiming , Li Gang , Zhang Guilong , Zhou Zhongkai , Jiang Na , Zhang Hao , Zhao Jianning , Yang Dianlin
Published: December 2022

Introduction

Protists play an important role in nutrient cycling, microbiome stability and soil fertility maintenance. However, the driving force of protistan functional groups remains poorly understood in agricultural ecosystems.

Methods

We investigated the impacts of fertilization regimes on the diversity, composition and functional groups of protists and further disentangled the effects of multiple factors shaping the community composition of functional groups in a 5-year fertilization regime (CK, no fertilization; M, organic fertilization; MNPK, combined inorganic and organic fertilization; NPK, inorganic fertilization).

Results

Fertilization significantly changed the community composition of protists rather than diversity. The MNPK treatment significantly increased the relative abundance of phototrophs and decreased that of the parasites and consumers. Partial least squares path modeling indicated that fertilization indirectly regulated protistan consumers via changes in the P content, which affected the composition of consumers mainly by regulating fungal community composition. Soil moisture (SM) and available phosphorus (AP) were identified as the top predictors for the composition of parasites, and the composition of phototrophs was mainly affected by SM, indicating that parasites and phototrophs were more sensitive to abiotic factors in the fertilization system.

Discussion

Taken together, our findings highlight that fertilization significantly affects the composition of functional groups of protists and their biotic or abiotic regulatory processes, which have implications for the potential changes in their ecosystem functions for soil management systems.
Copper regulation of immune response and potential implications for treating orthopedic disorders
Authors: Liu Yamei , Zhu Junlang , Xu Liangliang , Wang Bin , Lin Weiping , Luo Yiwen
Published: December 2022

Copper is an indispensable trace metal element in human body, and copper deficiency is rare in clinic. However, diseases associated with serum copper deficiency, such as leukopenia, neutropenia, arthritis, osteoporosis, and bone defects, are well known. Copper ions can also achieve the effect of fighting pathogenic bacteria through the “contact killing” characteristic. Copper ion is also an important cofactor of bone matrix synthase, plays an important role in the pathophysiology of orthopedic diseases. The present review highlights the biological functions of copper in immunity, bone diseases and stem cells, as well as potential drug development targeting copper status for diagnostics and therapeutics of copper-associated bone diseases.
Deep learning based CT images automatic analysis model for active/non-active pulmonary tuberculosis differential diagnosis
Authors: Nijiati Mayidili , Zhou Renbing , Damaola Miriguli , Hu Chuling , Li Li , Qian Baoxin , Abulizi Abudukeyoumujiang , Kaisaier Aihemaitijiang , Cai Chao , Li Hongjun , Zou Xiaoguang
Published: December 2022

Active pulmonary tuberculosis (ATB), which is more infectious and has a higher mortality rate compared with non-active pulmonary tuberculosis (non-ATB), needs to be diagnosed accurately and timely to prevent the tuberculosis from spreading and causing deaths. However, traditional differential diagnosis methods of active pulmonary tuberculosis involve bacteriological testing, sputum culturing and radiological images reading, which is time consuming and labour intensive. Therefore, an artificial intelligence model for ATB differential diagnosis would offer great assistance in clinical practice. In this study, computer tomography (CT) scans images and corresponding clinical information of 1160 ATB patients and 1131 patients with non-ATB were collected and divided into training, validation, and testing sets. A 3-dimension (3D) Nested UNet model was utilized to delineate lung field regions in the CT images, and three different pre-trained deep learning models including 3D VGG-16, 3D EfficientNet and 3D ResNet-50 were used for classification and differential diagnosis task. We also collected an external testing set with 100 ATB cases and 100 Non-ATB cases for further validation of the model. In the internal and external testing set, the 3D ResNet-50 model outperformed other models, reaching an AUC of 0.961 and 0.946, respectively. The 3D ResNet-50 model reached even higher levels of diagnostic accuracy than experienced radiologists, while the CT images reading and diagnosing speed was 10 times faster than human experts. The model was also capable of visualizing clinician interpretable lung lesion regions important for differential diagnosis, making it a powerful tool assisting ATB diagnosis. In conclusion, we developed an auxiliary tool to differentiate active and non-active pulmonary tuberculosis, which would have broad prospects in the bedside.
Selective vulnerability of the intermediate retinal capillary plexus precedes retinal ganglion cell loss in ocular hypertension
Authors: Pitale Priyamvada M. , Shen Guofu , Sigireddi Rohini R. , Polo-Prieto Maria , Park Yong H. , Gibson Solomon E. , Westenskow Peter D. , Channa Roomasa , Frankfort Benjamin J.
Published: December 2022

Introduction: Glaucoma, a disease of retinal ganglion cell (RGC) injury and potentially devastating vision loss, is associated with both ocular hypertension (OHT) and reduced ocular blood flow. However, the relationship between OHT and retinal capillary architecture is not well understood. In this project, we studied microvasculature damage in mice exposed to mild levels of induced OHT.

Methods: Mild OHT was induced with the microbead model for 2 weeks. At this time point, some retinas were immunostained with CD31 (endothelium), Collagen IV (basement membrane), and RBPMS (RGCs) for z-stack confocal microscopy. We processed these confocal images to distinguish the three retinal capillary plexi (superficial, intermediate, and deep). We manually counted RGC density, analyzed vascular complexity, and identified topographical and spatial vascular features of the retinal capillaries using a combination of novel manual and automated workflows. Other retinas were dissociated and immunopanned to isolate RGCs and amacrine cells (ACs) for hypoxia gene array analysis.

Results: RGC counts were normal but there was decreased overall retinal capillary complexity. This reduced complexity could be explained by abnormalities in the intermediate retinal capillary plexus (IRCP) that spared the other plexi. Capillary junction density, vessel length, and vascular area were all significantly reduced, and the number of acellular capillaries was dramatically increased. ACs, which share a neurovascular unit (NVU) with the IRCP, displayed a marked increase in the relative expression of many hypoxia-related genes compared to RGCs from the same preparations.

Discussion: We have discovered a rapidly occurring, IRCP-specific, OHT-induced vascular phenotype that precedes RGC loss. AC/IRCP NVU dysfunction may be a mechanistic link for early vascular remodeling in glaucoma.
The efficacy of neuro-optometric visual rehabilitation therapy in patients with visual snow syndrome
Authors: Tsang Terry , Shidlofsky Charles , Mora Vanessa
Published: December 2022

Objective

This study intends to evaluate the feasibility of Neuro-Optometric Rehabilitation Therapy (NORT) to treat Visual Snow Syndrome (VSS). This pilot study utilized the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) to assess quality of life (QOL) before and after treatment.

Methods

Twenty-one participants were recruited as successive intake patients diagnosed with VSS at the clinics of Dr. Terry Tsang Optometry, Inc and Neuro-Vision Associates of North Texas. Participants completed the NEI Visual Function Questionnaire 25-2000 edition and performed NORT, conducted by a neuro-optometrist or a qualified vision therapist. The NEI-VFQ-25 was administered before, at 6 weeks, and at 12 weeks of NORT to evaluate the effects of treatment on patient QOL.

Results

The participants demonstrated an improvement in QOL composite and subscale scores after 6 and 12 weeks of NORT treatment. The NEI-VFQ-25 composite scores from the pre-test (M = 68, SD = 18) and at 6 weeks of treatment (M = 75, SD = 17) indicate an improvement in QOL [t (20) = 4.0, p = 0.0007]. The NEI-VFQ-25 composite scores from pretest to 12 weeks of treatment showed further improvements. This trend of improvement on NEI-VFQ-25 composite scores continued into the 12th week (M = 77, SD = 17) of treatment [t (20) = 4.5, p = 0.0002]. The subscales of general vision, distance activities, near activities, social functioning, mental health, role difficulties and dependency also showed improvement.

Conclusion

Our results suggest that patients with VSS experience improvement in QOL in as little as 6 weeks, with further improvement by 12 weeks of NORT. This suggests NORT is an effective treatment option for managing the condition and improving QOL in patients with VSS, although a reduction in specific symptoms has yet to be demonstrated. This study provides justification that NORT warrants further investigation on VSS symptom reduction.
Advances in the study of axon–associated vesicles
Authors: Liu Yanling , Shuai Ke , Sun Yiyan , Zhu Li , Wu Xiao-Mei
Published: December 2022

The central nervous system is the most important and difficult to study system in the human body and is known for its complex functions, components, and mechanisms. Neurons are the basic cellular units realizing neural functions. In neurons, vesicles are one of the critical pathways for intracellular material transport, linking information exchanges inside and outside cells. The axon is a vital part of neuron since electrical and molecular signals must be conducted through axons. Here, we describe and explore the formation, trafficking, and sorting of cellular vesicles within axons, as well as related-diseases and practical implications. Furthermore, with deepening of understanding and the development of new approaches, accumulating evidence proves that besides signal transmission between synapses, the material exchange and vesicular transmission between axons and extracellular environment are involved in physiological processes, and consequently to neural pathology. Recent studies have also paid attention to axonal vesicles and their physiological roles and pathological effects on axons themselves. Therefore, this review mainly focuses on these two key nodes to explain the role of intracellular vesicles and extracellular vesicles migrated from cells on axons and neurons, providing innovative strategy for future researches.
The novel subclusters based on cancer-associated fibroblast for pancreatic adenocarcinoma
Authors: Zhao Guojie , Wang Changjing , Jiao Jian , Zhang Wei , Yang Hongwei
Published: December 2022

Introduction

Pancreatic adenocarcinoma (PAAD) is a fatal disease characterized by promoting connective tissue proliferation in the stroma. Activated cancer-associated fibroblasts (CAFs) play a key role in fibrogenesis in PAAD. CAF-based tumor typing of PAAD has not been explored.

Methods

We extracted single-cell sequence transcriptomic data from GSE154778 and CRA001160 datasets from Gene Expression Omnibus or Tumor Immune Single-cell Hub to collect CAFs in PAAD. On the basis of Seurat packages and new algorithms in machine learning, CAF-related subtypes and their top genes for PAAD were analyzed and visualized. We used CellChat package to perform cell–cell communication analysis. In addition, we carried out functional enrichment analysis based on clusterProfiler package. Finally, we explored the prognostic and immunotherapeutic value of these CAF-related subtypes for PAAD.

Results

CAFs were divided into five new subclusters (CAF-C0, CAF-C1, CAF-C2, CAF-C3, and CAF-C4) based on their marker genes. The five CAF subclusters exhibited distinct signaling patterns, immune status, metabolism features, and enrichment pathways and validated in the pan-cancer datasets. In addition, we found that both CAF-C2 and CAF-C4 subgroups were negatively correlated with prognosis. With their top genes of each subclusters, the sub-CAF2 had significantly relations to immunotherapy response in the patients with pan-cancer and immunotherapy.

Discussion

We explored the heterogeneity of five subclusters based on CAF in signaling patterns, immune status, metabolism features, enrichment pathways, and prognosis for PAAD.
Isolation and characterization of head and neck cancer-derived peritumoral and cancer-associated fibroblasts
Authors: Zhou Jiefu , Schwenk-Zieger Sabina , Kranz Gisela , Walz Christoph , Klauschen Frederik , Dhawan Sharduli , Canis Martin , Gires Olivier , Haubner Frank , Baumeister Philipp , Kohlbauer Vera
Published: December 2022

Introduction

Head and neck squamous cell carcinomas (HNSCC) are characterized by strong cellular and molecular heterogeneity and treatment resistance entailing poor survival. Besides cell-intrinsic properties, carcinoma cells receive important cues from non-malignant cells within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a major component of the TME that impact on the molecular make-up of malignant cells and have a decisive function in tumor progression. However, the potential functionality of fibroblasts within tumor-adjacent, macroscopically normal tissue remains poorly explored.

Methods

Here, we isolated primary peritumoral fibroblasts (PtFs) from macroscopically normal tissue in vicinity of primary human papillomavirus-negative and -positive oropharyngeal HNSCC and compared their phenotype and functionality with matched CAFs (n = 5 pairs) and with human oral fibroblasts (hOFs).

Results

Expression patterns of CD90, CD73, CD105, smooth muscle actin, Vimentin, and S100A4 were comparable in PtFs, CAFs, and hOFs. Cell proliferation and doubling times of CAFs and PtFs were heterogeneous across patients (n =2 PtF>CAF; n = 1 CAF>PtF; n = 2 CAF=PtF) and reflected inferior growth than hOFs. Furthermore, PtFs displayed an reduced heterogeneity in cell size compared to matched CAFs, which were characterized by the presence of single large cells. Overall, conditioned supernatants from CAFs had more frequently growth-promoting effects on a panel of carcinoma cell lines of the upper aerodigestive tract carcinoma cell lines (Cal27, Cal33, FaDu, and Kyse30), whereas significant differences in migration-inducing effects demonstrated a higher potential of PtFs. Except for Kyse30, CAFs were significantly superior to hOFs in promoting proliferation, while PtFs induced stronger migration than hOFs in all carcinoma lines tested. Analysis of soluble factors demonstrated significantly increased VEGF-A production in CAFs (except in pat.8), and significantly increased PDGF-BB production in PtFs of two patients. Tube formation assays confirmed a significantly enhanced angiogenic potential of conditioned supernatants from CAFs compared to hOFs on human umbilical vascular endothelial cells (HUVECs) in vitro.

Discussion

Hence, matched CAFs and PtFs present in HNSCC patients are heterogeneous in their proliferation-, migration-, and angiogenesis-promoting capacity. Despite this heterogeneity, CAFs induced stronger carcinoma cell proliferation and HUVEC tube formation overall, whereas PtFs promoted migration of tumor cells more strongly.
Design of new drugs for medullary thyroid carcinoma
Authors: Li Yanqing , Luo Ziyu , Wang Xinxing , Zhang Songtao , Hei Hu , Qin Jianwu
Published: December 2022

Medullary thyroid carcinoma (MTC) is one of the common malignant endocrine tumors, which seriously affects human health. Although surgical resection offers a potentially curative therapeutic option to some MTC patients, most patients do not benefit from it due to the difficulty to access the tumors and tumor metastasis. The survival rate of MTC patients has improved with the recent advances in the research, which has improved our understanding of the molecular mechanism underlying MTC and enabled the development and approval of novel targeted drugs. In this article, we reviewed the molecular mechanisms related to MTC progression and the principle for the design of molecular targeted drugs, and proposed some future directions for prospective studies exploring targeted drugs for MTC.
Kidney injury molecule type-1, interleukin-18, and insulin-like growth factor binding protein 7 levels in urine to predict acute kidney injury in pediatric sepsis
Authors: Ganda Idham Jaya , Kasri Yusriwanti , Susanti Maya , Hamzah Fitrayani , Rauf Syarifuddin , Albar Husein , Aras Jusli , Fikri Bahrul , Lawang Sitti Aizah , Daud Dasril , Laompo Amiruddin , Massi Muhammad Nasrum
Published: December 2022

Background

This study aimed to observe the role of urinary kidney injury molecule (KIM-1), interleukin (IL-18), and insulin-like growth factor-binding protein 7 (IGFBP-7) levels in predicting acute kidney injury (AKI) in children with sepsis.

Material and Methods

This prospective cohort observational study was conducted at Dr. RSUP. Wahidin Sudirohusodo, Makassar, South Sulawesi, from January to December 2021. Inclusion criteria were septic patients treated in the pediatric intensive care unit (PICU) aged 1 month to 18 years with normal serum creatinine or normal urine output (>5 ml/kg/body weight (BW)/h in 6–12 h). Patients with a history of kidney disease, prior urinary tract infection, or history of using nephrotoxic drugs were excluded.

Results

There was a significant difference in urinary KIM-1, IL-18, and IGFBP-7 levels between septic patients with and without AKI. The cut-off point for urinary KIM-1 level in sepsis with and without AKI was 1.666 ng/ml, with sensitivity of 82.5%, specificity of 82.2%, and a relative risk (RR) [95% confidence interval (CI)] of 6.866 (95% CI, 3.329–14.165). The cut-off point for urinary IL-18 levels was 3.868 ng/ml, with sensitivity of 92.50%, specificity of 91.78%, and RR of 20.078 (95%CI, 6.593–61.142). The cut-off point for urinary IGFBP-7 levels was ≥0.906 ng/ml with a sensitivity of 75.00%, specificity of 75.34%, and RR of 4.063 (95% CI, 2.206–7.483).

Conclusion

Urinary KIM-1, IL-8, and IGFBP-7 levels could be used to predict AKI in septic patients. Urinary IL-8 has a higher sensitivity and specificity as a predictor of AKI in patients with sepsis.
Factors related to employment in childhood cancer survivors in Japan: A preliminary study
Authors: Kobayashi Kyoko , Ishida Yasushi , Gunji Michiyo , Nagase Kyoko , Yoshimoto-Suzuki Yuri , Hosoya Yosuke , Hasegawa Daisuke , Manabe Atsushi , Ohde Sachiko , Ozawa Miwa
Published: December 2022

Purpose

Previous research has revealed vocational and academic difficulties in childhood cancer survivors, and explored impact of survivors' medical history and physical function on vocational and academic status. However, we often encounter survivors with similar diagnoses and late effects but different academic or employment statuses. This raises the question of what affects academic attainment and employment other than treatment or late effects. This study aimed to explore factors associated with childhood cancer survivors' employment status and academic achievement.

Methods

Comprehensive health check-up and questionnaire survey were conducted for 69 survivors who were over the age of 18 and participated in St. Luke's Lifetime cohort study. We obtained survivors' biological function using comprehensive health check-up, neurocognitive states, quality of life, transition readiness, and family function. We conducted univariate analysis (Mann–Whitney U tests or chi-square tests) to compare the differences between the regular workers/students and non-regular workers/unemployed groups. The variables with p-values <0.1 were used as independent variables multivariate logistic regression to explore predictors of employment status and academic attainment.

Results

Result of the univariate analysis, intelligence quotient, SF-8 PCS, transition readiness, family function were used for multivariate logistic regression as independent variables. The stepwise likelihood method was conducted; intelligence quotient (odds ratio [OR] = 1.100; 95% confidence interval [CI] 1.015–1.193; p = 0.021), transition readiness (OR = 0.612; 95% CI 0.396–0.974; p = 0.038), and family function (OR = 2.337; 95% CI 1.175–4.645; p = 0.015) were found to be associated with survivors' regular workers/students in the final regression model.

Conclusion

Long-term follow-up of pediatric cancer survivors requires the provision of total care, which supports physical, psychological, and social functions to improve health, readiness for transition to self-management, and family functioning.
Decreased xCT activity in patients associated with Helicobacter pylori infection
Authors: Wang Ling , Li Wen-Qun , Liu Fen , Li Yuan-Jian , Du Jie
Published: December 2022

Objective: In animals, Helicobacter pylori (Hp)-induced gastric injury is accompanied by a decrease in the activity of the cysteine/glutamate transporter (xCT), which regulates extracellular glutamate levels. However, the impact of xCT activity in patients with Hp infection remains unclear. This study aims to investigate variations of xCT activity in the gastric mucosa of patients with Hp infection and to provide a clinical basis for identifying targets related to Hp infection.

Methods: Our study included a total of 67 patients with gastritis, which consisted of 44 Hp-negative and 23 Hp-positive peptic ulcer cases. The inclusion criteria used to select patients were as follows: gastric histology was determined with a gastroscope, antral biopsies were taken for urease tests, and pathology and culture were performed for analysis of Hp-colonization. The clinical characteristics of the patients were obtained, the expressions of microRNAs and xCT protein were detected using immune histochemical analysis, and the concentration of glutamate in their gastric secretion was determined.

Results: The findings revealed that xCT expression was significantly lower in Hp-positive patients as compared to Hp-negative individuals, which was accompanied by a decrease in glutamate concentration in gastric juice. We also discovered a high expression of microRNAs that have been shown to negatively regulate xCT expression, in Hp-positive patients.

Conclusion: Reduced xCT activity in patients may play an important role in gastric ulcers caused by Hp infection. Our findings suggest that the microRNA/xCT pathway could be a potential treatment target for Hp-infection-related ulcers.
Curcumae Rhizoma - combined with Sparganii Rhizoma in the treatment of liver cancer: Chemical analysis using UPLC-LTQ-Orbitrap MSn, network analysis, and experimental assessment
Authors: Wei Jing , Wang Xiaoping , Dong Ying , Zhong Xiangjian , Ren Xueyang , Song Ruolan , Ma Jiamu , Yu Axiang , Fan Qiqi , Yao Jianling , Shan Dongjie , Lv Fang , Zheng Yuan , Deng Qingyue , Li Xianxian , He Yingyu , Fan Shusheng , Zhao Chongjun , Wang Xiuhuan , Yuan Ruijuan , She Gaimei
Published: December 2022

Objective:Curcumae Rhizoma–Sparganii Rhizoma (CR-SR) is a traditional botanical drug pair that can promote blood circulation, remove blood stasis, and treat tumors in clinics. The aim of the present study was to investigate the therapeutic material basis and potential mechanisms of CR-SR, CR, and SR for the treatment of liver cancer.

Method: The chemical profile analyses of CR-SR, CR, and SR were performed by molecular networking and UPLC-LTQ-Orbitrap MSn. The anti-liver cancer activities of CR-SR, CR, and SR were assessed by using a zebrafish xenograft model in vivo for the first time and detected by the HepG2 cell model in vitro. Combining the network analysis and molecular docking, real-time quantitative polymerase chain reaction (RT-qPCR) experiments were undertaken to further explore the mechanisms of CR-SR, CR, and SR for the treatment of liver cancer.

Results: In total, 65 components were identified in CR-SR, CR, and SR. Based on the clusters of molecular networking, a total of 12 novel diarylheptanoids were identified from CR-SR and CR. By combining our results with information from the literature, 32 sesquiterpenoids and 21 cyclic dipeptides were identified from CR-SR, CR, and SR. The anti-liver cancer activities were observed in both the drug pair and the single botanical drugs in vitro and in vivo, and the order of activity was CR-SR > CR > SR. They could downregulate the expression of proto-oncogene tyrosine-protein kinase Src (SRC), epidermal growth factor receptor (EGFR), estrogen receptor-α (ESR1), prostaglandin endoperoxide synthase 2 (PTGS2), and amyloid precursor protein (APP).

Conclusion: Taken together, the present study provided an experimental basis for the therapeutic material basis and potential molecular mechanisms of CR-SR, CR, and SR. This study provided a novel insight for objective clinical treatment of liver cancer.
Sources of inter-individual variability leading to significant changes in anti-PD-1 and anti-PD-L1 efficacy identified in mouse tumor models using a QSP framework
Authors: Leete Jessica C. , Zager Michael G. , Musante Cynthia J. , Shtylla Blerta , Qiao Wenlian
Published: December 2022

While anti-PD-1 and anti-PD-L1 [anti-PD-(L)1] monotherapies are effective treatments for many types of cancer, high variability in patient responses is observed in clinical trials. Understanding the sources of response variability can help prospectively identify potential responsive patient populations. Preclinical data may offer insights to this point and, in combination with modeling, may be predictive of sources of variability and their impact on efficacy. Herein, a quantitative systems pharmacology (QSP) model of anti-PD-(L)1 was developed to account for the known pharmacokinetic properties of anti-PD-(L)1 antibodies, their impact on CD8+ T cell activation and influx into the tumor microenvironment, and subsequent anti-tumor effects in CT26 tumor syngeneic mouse model. The QSP model was sufficient to describe the variability inherent in the anti-tumor responses post anti-PD-(L)1 treatments. Local sensitivity analysis identified tumor cell proliferation rate, PD-1 expression on CD8+ T cells, PD-L1 expression on tumor cells, and the binding affinity of PD-1:PD-L1 as strong influencers of tumor growth. It also suggested that treatment-mediated tumor growth inhibition is sensitive to T cell properties including the CD8+ T cell proliferation half-life, CD8+ T cell half-life, cytotoxic T-lymphocyte (CTL)-mediated tumor cell killing rate, and maximum rate of CD8+ T cell influx into the tumor microenvironment. Each of these parameters alone could not predict anti-PD-(L)1 treatment response but they could shift an individual mouse’s treatment response when perturbed. The presented preclinical QSP modeling framework provides a path to incorporate potential sources of response variability in human translation modeling of anti-PD-(L)1.
Short-term effect of sacubitril/valsartan on endothelial dysfunction and arterial stiffness in patients with chronic heart failure
Authors: Cassano Velia , Armentaro Giuseppe , Magurno Marcello , Aiello Vincenzo , Borrello Francesco , Miceli Sofia , Maio Raffaele , Perticone Maria , Marra Alberto M. , Cittadini Antonio , Hribal Marta L. , Andreozzi Francesco , Sesti Giorgio , Sciacqua Angela
Published: December 2022

Heart failure (HF) is associated to endothelial dysfunction that promotes the increase of arterial stiffness thus augmenting myocardial damage. Sacubitril/Valsartan is used in the treatment of HF reduced ejection fraction (HFrEF) and has been proven effective in reducing cardiovascular disease (CVD) progression and all-cause mortality. The aim of this study was to evaluate the effect of Sacubitril/Valsartan on endothelial dysfunction, arterial stiffness, oxidative stress levels and platelets activation in patients with HFrEF, at baseline and after 6 months of treatment. We enrolled 100 Caucasian patients. Endothelial function was evaluated by the reactive hyperemia index (RHI) and arterial stiffness (AS) by the measurement of carotid-femoral pulse wave velocity (PWV), augmentation pressure (AP) and augmentation index (AI). At baseline, among enrolled outpatients, 43% showed a NYHA class II and 57% a NYHA class III. At 6 months, there was a significant improvement of several hemodynamic, clinical and metabolic parameters with a significant reduction in oxidative stress indices such as 8-isoprostane (p < 0.0001) and Nox-2 (p < 0.0001), platelets activity biomarkers such as sP-selectin (p < 0.0001) and Glycoprotein-VI (p < 0.0001), and inflammatory indices. Moreover, we observed a significant improvement in arterial stiffness parameters and in endothelial function indices. Our study demonstrated that 6 months treatment with Sacubitril/Valsartan, in patients with HFrEF, improves endothelial dysfunction and arterial stiffness, by reducing oxidative stress, platelet activation and inflammation circulating biomarkers, without adverse effects.