bluuebunny/crossref_metadata_2025 huggingface dataset:
Lessons learned from immunological characterization of nanomaterials at the Nanotechnology Characterization Laboratory
Authors: Dobrovolskaia Marina A.
Published: October 2022

Nanotechnology carriers have become common in pharmaceutical products because of their benefits to drug delivery, including reduced toxicities and improved efficacy of active pharmaceutical ingredients due to targeted delivery, prolonged circulation time, and controlled payload release. While available examples of reduced drug toxicity through formulation using a nanocarrier are encouraging, current data also demonstrate that nanoparticles may change a drug’s biodistribution and alter its toxicity profile. Moreover, individual components of nanoparticles and excipients commonly used in formulations are often not immunologically inert and contribute to the overall immune responses to nanotechnology-formulated products. Said immune responses may be beneficial or adverse depending on the indication, dose, dose regimen, and route of administration. Therefore, comprehensive toxicology studies are of paramount importance even when previously known drugs, components, and excipients are used in nanoformulations. Recent data also suggest that, despite decades of research directed at hiding nanocarriers from the immune recognition, the immune system’s inherent property of clearing particulate materials can be leveraged to improve the therapeutic efficacy of drugs formulated using nanoparticles. Herein, I review current knowledge about nanoparticles’ interaction with the immune system and how these interactions contribute to nanotechnology-formulated drug products’ safety and efficacy through the lens of over a decade of nanoparticle characterization at the Nanotechnology Characterization Laboratory.
Identifying enhancer-driven subtype-specific prognostic markers in breast cancer based on multi-omics data
Authors: Zhao Hongying , Zhang Siwen , Yin Xiangzhe , Zhang Caiyu , Wang Lixia , Liu Kailai , Xu Haotian , Liu Wangyang , Bo Lin , Lin Shihua , Feng Ke , Lin Lin , Fei Meiting , Ning Shangwei , Wang Li
Published: October 2022

Breast cancer is a cancer of high complexity and heterogeneity, with differences in prognosis and survival among patients of different subtypes. Copy number variations (CNVs) within enhancers are crucial drivers of tumorigenesis by influencing expression of their targets. In this study, we performed an integrative approach to identify CNA-driven enhancers and their effect on expression of target genes in four breast cancer subtypes by integrating expression data, copy number data and H3K27ac data. We identified 672, 555, 531, 361 CNA-driven enhancer-gene pairs and 280, 189, 113 and 98 CNA-driven enhancer-lncRNA pairs in the Basal-like, Her2, LumA and LumB subtypes, respectively. We then reconstructed a CNV-driven enhancer-lncRNA-mRNA regulatory network in each subtype. Functional analysis showed CNA-driven enhancers play an important role in the progression of breast cancer subtypes by influencing P53 signaling pathway, PPAR signaling pathway, systemic lupus erythematosus and MAPK signaling pathway in the Basal-like, Her2, LumA and LumB subtypes, respectively. We characterized the potentially prognostic value of target genes of CNV-driven enhancer and lncRNA-mRNA pairs in the subtype-specific network. We identified MUM1 and AC016876.1 as prognostic biomarkers in LumA and Basal-like subtypes, respectively. Higher expression of MUM1 with an amplified enhancer exhibited poorer prognosis in LumA patients. Lower expression of AC016876.1 with a deleted enhancer exhibited poorer survival outcomes of Basal-like patients. We also identified enhancer-related lncRNA-mRNA pairs as prognostic biomarkers, including AC012313.2-MUM1 in the LumA, AC026471.4-PLK5 in the LumB, AC027307.2-OAZ1 in the Basal-like and AC022431.1-HCN2 in the Her2 subtypes. Finally, our results highlighted target genes of CNA-driven enhancers and enhancer-related lncRNA-mRNA pairs could act as prognostic markers and potential therapeutic targets in breast cancer subtypes.
Metabolomic and transcriptomic analyses reveal response mechanisms of juvenile flounder (Paralichthys olivaceus) to sublethal methylmercury
Authors: Ren Zhonghua , Ning Junhao , Cao Liang , Liu Jinhu , Zhan Junfei , Wang Zhikang , Yu Junbao , Yang Jisong , Lv Zhenbo
Published: October 2022

Although methylmercury (MeHg) has been recognized as a typical heavy metal posing huge damages to various life processes of fish, the response mechanisms of marine fish at early life stages (ELSs) to MeHg is still poorly understood. In this study, non-targeted liquid chromatography-mass spectrometry (LC-MS) based metabolomic and transcriptomic approaches were used to explore response mechanisms of juvenile flounder (Paralichthys olivaceus) to long-term sublethal MeHg exposure (0 and 1.0 μg L-1; 30 d). After exposure, growth parameters of flounder were significantly decreased. Metabolomic and transcriptomic analyses of liver tissue showed obvious difference about biological pathways and identified biomarkers (around 2502 genes and 16 secondary metabolites). Those significantly differentially expressed genes (DEGs) and their enriched pathways were mainly related to immune response, oxidative stress, lipids metabolism, glycometabolism, amino acid and nucleotide metabolism and regulation of protein processes, while those identified secondary metabolites were mainly enriched in tryptophan metabolism, biosynthesis of unsaturated fatty acids, linoleic acid metabolism and glutathione metabolism. Additionally, multi-omic method was used to explore response mechanisms of key pathways under MeHg stress. In this regard, only 57 DEGs and 6 secondary metabolites were significantly enriched in 7 pathways to constitute an integrated regulatory network, including glutathione metabolism, thyroid hormone synthesis, linoleic acid metabolism, biosynthesis of unsaturated fatty acids, tryptophan metabolism pathway, serotonergic synapse and African trypanosomiasis. Above all, we could speculate that antioxidative function, lipids metabolism, nervous system and amino acid metabolism were the more sensitive targets in response to MeHg stress, which were conductive to deeply understand the response mechanisms of fish at ELSs under MeHg exposure. Those identified biomarkers could also be widely used for toxicological studies of pollutants and ecological risks monitoring.
Pathological findings in stranded harbor porpoises (Phocoena phocoena) with special focus on anthropogenic causes
Authors: IJsseldijk Lonneke L. , Leopold Mardik F. , Begeman Lineke , Kik Marja J. L. , Wiersma Lidewij , Morell Maria , Bravo Rebolledo Elisa L. , Jauniaux Thierry , Heesterbeek Hans , Gröne Andrea
Published: October 2022

Humans impact natural systems at an unprecedented rate. The North Sea is one of the regions in the world with the highest levels of anthropogenic activity. Here, the harbor porpoise (Phocoena phocoena) is an abundant species and is often regarded as an ecosystem sentinel. A post-mortem surveillance program was established in the Netherlands aimed at increasing knowledge of the effects of human activities on harbor porpoises. In this study, we describe the pathological findings related to anthropogenic and natural causes of death categories in 612 harbor porpoises that stranded between 2008 and 2019, and assess their relations to age, sex, season, and location. The largest anthropogenic category was bycatch (17%), with mainly juveniles affected and peak periods in March and September–October. Other, infrequently diagnosed anthropogenic causes of death were trauma (4%), largely most likely due to ship collisions, and marine debris ingestion and entanglement (0.3%). The risk of dying from anthropogenic causes was highest for juveniles. Lesions compatible with noise-induced hearing loss were investigated in carcasses which were fresh enough to do so (n = 50), with lesions apparent in two porpoises. Non-direct human-induced threats included infectious diseases, which were by far the largest cause of death category (32%), and affected mainly adults. Also, gray seal (Halichoerus grypus) attacks were a frequently assigned cause of death category (24%). There were more acute predation cases in the earlier study years, while porpoises with lesions that suggested escape from gray seal attacks were diagnosed more recently, which could suggest that porpoises adapted to this threat. Our study contributes to understanding porpoise health in response to persisting, new, emerging, and cumulative threats. Building up such knowledge is crucial for conservation management of this protected species.
Co-delivery of sorafenib and metformin from amphiphilic polypeptide-based micelles for colon cancer treatment
Authors: Zhang Xiaohui , Cao Lanqing , Xu Guangmeng , He Hongyu , Zhao Hongyu , Liu Tongjun
Published: October 2022

Colorectal cancer (CRC) is a common clinical disease with a poor prognosis and a high recurrence rate. Chemotherapy is important to inhibit the post-surgical recurrence of CRC patients. But many limitations restrict the further application of chemotherapy. In this study, sorafenib (Sor) and metformin (Met) co-loaded poly(ethylene glycol)-block-poly(L-glutamic acid-co-L-phenylalanine) [mPEG-b-P(Glu-co-Phe)] micelles were developed. The characterizations, drug release, in vivo biodistribution, and pharmacokinetics of the micelles were analyzed. The treatment efficacy of the dual-drug loaded micelles was evaluated in a subcutaneous colon cancer mice model. Sor is a common molecular target agent that can inhibit the mitogen-activated protein kinase (MAPK) pathway to treat solid tumors. Met can also regulate the MAPK pathway and inhibit the expression of the phosphorylated extracellular signal-regulated kinase (p-ERK). Moreover, both Sor and Met play important roles in cell cycle arrest. The integration of these two drugs aims to achieve synergistic effects against colon cancer. The micelles can be targeted to cancer cells and possess longer blood circulation time. The two agents can be released rapidly in the tumor sites. The in vivo study showed that the micelles can prevent tumor progression by inhibiting the expressions of p-ERK and cyclin D1. This study indicated that the Sor/Met-loaded micelles are suitable for CRC treatment.
Development and validation of Chronic Kidney Disease Knowledge, Attitude, and Practices (CKD-KAP) questionnaire
Authors: Tariq Muhammad Haseeb , Sulaiman Syed Azhar Syed , Farrukh Muhammad Junaid , Goh Khang Wen , Ming Long Chiau
Published: October 2022

Background

Chronic Kidney Disease (CKD) is a complex condition leading to loss of kidney function. The objective of this study was to develop and validate a Knowledge, Attitude, and Practice questionnaire on CKD (CKD-KAP) among practicing physicians in Pakistan since no validated tool was available for the said purpose.

Methods

The study consisted of four phases with phase-I focusing on literature review, phase II was the actual questionnaire development phase, face and content validity was determined in phase III, and finally pilot testing was performed in phase IV to determine validity and reliability. The development phase encompassed a thorough review of literature, focus-group discussion, expert review, and evaluation. The validation phase consisted of content validity, face validity, construct validity, convergent validity, and reliability. The pilot testing was performed by studying the KAP of 100 practicing physicians in tertiary care hospitals in Pakistan. The knowledge section of the validation phase utilized Item Response Theory (IRT) analysis. The attitude and practices sections utilized Exploratory Factor Analysis (EFA) theory. The reliability analysis utilized Cronbach’s alpha and correlations.

Results

The CKD-KAP questionnaire had three main sections: knowledge, attitude, and practice. During the validation, IRT analysis was performed on knowledge, which focused on the measure of the coefficient of discrimination and difficulty of the items; 40 out of 41 knowledge items have both discrimination and difficulty coefficients within an acceptable range. The EFA model was also fitted in the attitude and practices section, and scree plot and Eigenvalues suggested three and four dimensions within the attitude and practices section. The factor loading of all items was found to be acceptable except for one item in attitude which was deleted. The convergent validity demonstrated a significant association between all three sections except knowledge and practices. The reliability (internal consistency) analysis demonstrated Cronbach’s alpha values above 0.7 and significant inter-item correlation. The final model of CKD-KAP had 40 knowledge, 13 attitude, and 10 practice items with a combination of both positive as well as negative questions and statements.

Conclusions

The CKD-KAP was found to be psychometrically valid and reliable, hence can be used to determine the knowledge, attitude, and practices of physicians toward chronic kidney disease.
Diarrhea with deficiency kidney-yang syndrome caused by adenine combined with Folium senna was associated with gut mucosal microbiota
Authors: Zhu Jiayuan , Li Xiaoya , Deng Na , Peng Xinxin , Tan Zhoujin
Published: October 2022

The present study aims to study and analyze the characteristics of gut mucosal microbiota in diarrhea mice with deficiency kidney-yang syndrome. Ten male mice were randomly divided into the control group and the model group. Diarrhea mice model with deficiency kidney-yang syndrome was established by adenine combined with Folium sennae. The kidney structure was observed by hematoxylin-eosin (HE) staining. Serum Na+-K+-ATP-ase and Ca2+-Mg2+-ATP-ase were detected by enzyme-linked immunosorbent assay (ELISA). The characteristics of gut mucosal microbiota were analyzed by performing third-generation high-throughput sequencing. The results showed that the model mice exhibit obvious structural damage to the kidney. Serum Na+-K+-ATP-ase and Ca2+-Mg2+-ATP-ase levels showed a decreased trend in the model group. The diversity and community structure of the gut mucosal microbiota improved in the model group. Dominant bacteria like Candidatus Arthromitus, Muribaculum, and Lactobacillus reuteri varied significantly at different taxonomic levels. The characteristic bacteria like Bacteroides, Erysipelatoclostridium, Anaerotignum, Akkermansia muciniphila, Clostridium cocleatum, Bacteroides vulgatus, and Bacteroides sartorii were enriched in the model group. A correlation analysis described that Erysipelatoclostridium was positively correlated with Na+-K+-ATP-ase and Ca2+-Mg2+-ATP-ase levels, while Anaerotignum exhibited an opposite trend. Together, adenine combined with Folium sennae damaged the structure of the kidney, affected energy metabolism, and caused disorders of gut mucosal microbiota in mice. Bacteroides, Erysipelatoclostridium, and Anaerotignum showed significant inhibition or promotion effects on energy metabolism. Besides, Akkermansia muciniphila, Clostridium cocleatum, Bacteroides vulgatus, and Bacteroides sartorii might be the characteristic species of gut mucosal microbiota responsible for causing diarrhea with deficiency kidney-yang syndrome.
Milder symptoms and shorter course in patients with re-positive COVID-19: A cohort of 180 patients from Northeast China
Authors: Li Hongyan , Zhu Mingqin , Zhang Peng , Yan Xingjian , Niu Junqi , Wang Zhenyu , Cao Jie
Published: October 2022

China experienced another widespread Coronavirus disease 2019 (COVID-19) outbreak recently caused by the Omicron variant, which is less severe but far more contagious than the other COVID-19 variants, leading local governments to focus efforts on eliminating the spread of the disease. Previous studies showed that after “recovering” from the virus, some patients could re-test positive for COVID-19 with nucleic acid tests, challenging the control of disease spread. In this study, we aimed to analyze the clinical and laboratory characteristics of re-positive COVID-19 patients in Northeast China. We retrospectively analyzed data from confirmed reverse transcription polymerase chain reaction (RT-PCR) re-positive COVID-19 patients who were admitted to the First Hospital of Jilin University, Jilin Province, China, from March to June 2022. Detailed clinical symptoms, medical history, anti-Corona Virus (CoV) IgG and IgM levels, and CoV nucleic acid cycle threshold (Ct) values during the re-positive period were collected and analyzed. A total of 180 patients were included in this study, including 62 asymptomatic cases and 118 mild cases. The cohort included 113 men and 67 women, with an average age of 45.73 years. The median time between recovery from the virus and re-positivity was 13 days. Our results showed that the proportion of re-positive patients with symptoms was lower, and the nucleic acid test-positive duration was shorter during the re-positive period. Furthermore, in patients with underlying disease, the proportion of patients with symptoms was higher, anti-CoV IgG levels were lower, and the total disease duration was longer. In conclusion, during the re-positive period, the symptoms were milder, and the CoV nucleic acid test-positive course was shorter. The concomitant underlying disease is an important factor associated with clinical symptoms, and the overall course of COVID-19 re-positive patients may be associated with lower anti-CoV IgG levels. Large-scale and multicenter studies are recommended to better understand the pathophysiology of recurrence in patients with COVID-19.
Safety switch optimization enhances antibody-mediated elimination of CAR T cells
Authors: Shabaneh Tamer B. , Moffett Howell F. , Stull Sylvia M. , Derezes Thomas , Tait Leah J. , Park Spencer , Riddell Stan R. , Lajoie Marc J.
Published: October 2022

Activation of a conditional safety switch has the potential to reverse serious toxicities arising from the administration of engineered cellular therapies, including chimeric antigen receptor (CAR) T cells. The functionally inert, non-immunogenic cell surface marker derived from human epidermal growth factor receptor (EGFRt) is a promising safety switch that has been used in multiple clinical constructs and can be targeted by cetuximab, a clinically available monoclonal antibody. However, this approach requires high and persistent cell surface expression of EGFRt to ensure that antibody-mediated depletion of engineered cells is rapid and complete. Here we show that incorporating a short juxtamembrane sequence into the EGFRt polypeptide enhances its expression on the surface of T cells and their susceptibility to antibody-dependent cellular cytotoxicity (ADCC). Incorporating this optimized variant (EGFRopt) into bicistronic and tricistronic CAR designs results in more rapid in vivo elimination of CAR T cells and robust termination of their effector activity compared to EGFRt. These studies establish EGFRopt as a superior safety switch for the development of next-generation cell-based therapeutics.
Soluble guanylyl cyclase: Molecular basis for ligand selectivity and action in vitro and in vivo
Authors: Wu Gang , Sharina Iraida , Martin Emil
Published: October 2022

Nitric oxide (NO), carbon monoxide (CO), oxygen (O2), hydrogen sulfide (H2S) are gaseous molecules that play important roles in the physiology and pathophysiology of eukaryotes. Tissue concentrations of these physiologically relevant gases vary remarkable from nM range for NO to high μM range of O2. Various hemoproteins play a significant role in sensing and transducing cellular signals encoded by gaseous molecules or in transporting them. Soluble guanylyl cyclase (sGC) is a hemoprotein that plays vital roles in a wide range of physiological functions and combines the functions of gaseous sensor and signal transducer. sGC uniquely evolved to sense low non-toxic levels of NO and respond to elevated NO levels by increasing its catalytic ability to generate the secondary signaling messenger cyclic guanosine monophosphate (cGMP). This review discusses sGC’s gaseous ligand selectivity and the molecular basis for sGC function as high-affinity and selectivity NO receptor. The effects of other gaseous molecules and small molecules of cellular origin on sGC’s function are also discussed.
Clinical tooth segmentation based on local enhancement
Authors: Wu Jipeng , Zhang Ming , Yang Delong , Wei Feng , Xiao Naian , Shi Lei , Liu Huifeng , Shang Peng
Published: October 2022

The tooth arrangements of human beings are challenging to accurately observe when relying on dentists’ naked eyes, especially for dental caries in children, which is difficult to detect. Cone-beam computer tomography (CBCT) is used as an auxiliary method to measure patients’ teeth, including children. However, subjective and irreproducible manual measurements are required during this process, which wastes much time and energy for the dentists. Therefore, a fast and accurate tooth segmentation algorithm that can replace repeated calculations and annotations in manual segmentation has tremendous clinical significance. This study proposes a local contextual enhancement model for clinical dental CBCT images. The local enhancement model, which is more suitable for dental CBCT images, is proposed based on the analysis of the existing contextual models. Then, the local enhancement model is fused into an encoder–decoder framework for dental CBCT images. At last, extensive experiments are conducted to validate our method.
Application of lymphoplasmapheresis in the treatment of severe myasthenia gravis
Authors: Duan Weiwei , Zhou Hao , Dong Xiaohua , Li Bijuan , Li Yi , Cai Haobing , Zhou Qian , Ouyang Song , Yin Weifan , Yang Huan
Published: October 2022

Background

Lymphoplasmapheresis (LPE) is a treatment that combines traditional plasma exchange and lymphocyte removal technique. It has been applied to treat a variety of autoimmune diseases, but its application value in the treatment of severe myasthenia gravis (MG) is not yet clear. Therefore, the aim of this study was to investigate the efficacy and safety of LPE in severe MG.

Methods

Clinical data of 123 severe patients with MG (Myasthenia Gravis Foundation of America Clinical Classification, Class IV) who received LPE treatment were included in a retrospective analysis. Efficacy was evaluated by the change of Quantitative Myasthenia Gravis score (QMGS) before and after treatment. Univariate and multivariate logistic regression analysis was used to explore clinical factors affecting efficacy.

Results

A total of 220 replacements were performed in 123 patients, with an average of 1.79 replacements per patient. The overall safety of LPE was good, and no serious adverse reactions occurred. After treatment, the mean QMGS of patients decreased significantly, from 23.40 ± 4.25 points before treatment to 17.93 ± 5.61 points after treatment, a decrease of 5.47 ± 4.16 points. 75.6% of patients experienced remission of clinical symptoms. During a 2-month follow-up of 64 patients, a progressive improvement in QMGS was found. Each muscle group involved in MG responded well to LPE treatment. In addition, LPE significantly reduced the levels of AChR-Ab and inflammatory cytokines in patients. Age ≥ 50 years and co-infection were unfavorable factors affecting the efficacy.

Conclusions

In this study cohort, LPE is safe for the treatment of severe MG and achieves good treatment outcome with fewer replacements. In patients with MG, the avoidance and timely control of infection are necessary. Our study provides a potential new treatment option for severe MG.
Characterization of the blood oxygen level dependent hemodynamic response function in human subcortical regions with high spatiotemporal resolution
Authors: Kim Jung Hwan , Taylor Amanda J. , Himmelbach Marc , Hagberg Gisela E. , Scheffler Klaus , Ress David
Published: October 2022

Subcortical brain regions are absolutely essential for normal human function. These phylogenetically early brain regions play critical roles in human behaviors such as the orientation of attention, arousal, and the modulation of sensory signals to cerebral cortex. Despite the critical health importance of subcortical brain regions, there has been a dearth of research on their neurovascular responses. Blood oxygen level dependent (BOLD) functional MRI (fMRI) experiments can help fill this gap in our understanding. The BOLD hemodynamic response function (HRF) evoked by brief (<4 s) neural activation is crucial for the interpretation of fMRI results because linear analysis between neural activity and the BOLD response relies on the HRF. Moreover, the HRF is a consequence of underlying local blood flow and oxygen metabolism, so characterization of the HRF enables understanding of neurovascular and neurometabolic coupling. We measured the subcortical HRF at 9.4T and 3T with high spatiotemporal resolution using protocols that enabled reliable delineation of HRFs in individual subjects. These results were compared with the HRF in visual cortex. The HRF was faster in subcortical regions than cortical regions at both field strengths. There was no significant undershoot in subcortical areas while there was a significant post-stimulus undershoot that was tightly coupled with its peak amplitude in cortex. The different BOLD temporal dynamics indicate different vascular dynamics and neurometabolic responses between cortex and subcortical nuclei.
Regulation of sleep disorders in patients with traumatic brain injury by intestinal flora based on the background of brain-gut axis
Authors: Zhanfeng Niu , Liang Wu , Jing Kang , Jinbo Bai , Yanjun Chen , Hechun Xia
Published: October 2022

Objective

This study investigates whether people with sleep disorders following traumatic brain injury exhibit altered intestinal flora. The changes may allow us to gain a better understanding of the role of intestinal flora in patients with sleep disorders after traumatic brain injury, which may give us insights into curing the sleep disorder after traumatic brain injury (TBI).

Method

We analyzed the intestinal microbial colony structure in the feces of the 28 patients in the normal sleep group and the sleep disorder group by 16SrDNAsequencing technology. The bioinformatics method was used to analyze the intestinal flora change in the v3-v4 region of patients with biorhythm disorder and to observe the difference between the two groups.

Results

Group grouping comparison and analysis of the evolutionary cladistic map showed the intestinal flora of patients with normal sleep after TBI was mainly Bacilli and Lactobacillales, while that of patients with sleep disorders was mainly Lachnospiraceae and Bacteroidales. The histogram of group value distribution by grouping comparison and analysis showed that Lachnospiraceae, Bacteroidales, Bacteroidia, and Bacteroidetes were dominant in the sleep disorder group. A relative abundance map of species with significant differences by group grouping comparison showed the main manifestations of intestinal flora are Firmicutes, Bacilli, Lactobacillales, Streptococcaceae, and Bacteroidetes. The normal sleep group was dominated by Bacilli, Lactobacillales, Streptococcus, and Veillonella, while in the sleep disorder group, Lachnospiraceae, Bacteroidales, Bacteroidia, and Bacteroidetes were the main species. It was found that there were also significant differences in intestinal flora abundance between the two groups after TBI. After statistics processing, it was compared with the normal sleep group, Lactobacillus, Streptococcus, Oribacterium and Rothia, Actinomyces, Streptophyta, TM7-3 bacteria, and Serratia, showing a significant reduction in the sleep disorder group (P < 0.05). However, Odoribacter, Lachnospiraceae, and Bilophila increased significantly (P < 0.05).

Conclusion

The sleep disorders of patients after TBI can be closely related to intestinal flora disturbance, and its internal mechanism needs further study. Intestinal flora has the potential to be a new therapeutic target.
The emerging role of circular RNAs in drug resistance of non-small cell lung cancer
Authors: Yan Tinghao , Tian Xinchen , Liu Fen , Liu Qingbin , Sheng Qing , Wu Jianlin , Jiang Shulong
Published: October 2022

Due to the characteristics of aggressiveness and high risk of postoperative recurrence, non-small cell lung cancer (NSCLC) is a serious hazard to human health, accounting for 85% of all lung cancer cases. Drug therapies, including chemotherapy, targeted therapy and immunotherapy, are effective treatments for NSCLC in clinics. However, most patients ultimately develop drug resistance, which is also the leading cause of treatment failure in cancer. To date, the mechanisms of drug resistance have yet to be fully elucidated, thus original strategies are developed to overcome this issue. Emerging studies have illustrated that circular RNAs (circRNAs) participate in the generation of therapeutic resistance in NSCLC. CircRNAs mediate the modulations of immune cells, cytokines, autophagy, ferroptosis and metabolism in the tumor microenvironment (TME), which play essential roles in the generation of drug resistance of NSCLC. More importantly, circRNAs function as miRNAs sponges to affect specific signaling pathways, directly leading to the generation of drug resistance. Consequently, this review highlights the mechanisms underlying the relationship between circRNAs and drug resistance in NSCLC. Additionally, several therapeutic drugs associated with circRNAs are summarized, aiming to provide references for circRNAs serving as potential therapeutic targets in overcoming drug resistance in NSCLC.
The extracellular matrix protein fibulin-3/EFEMP1 promotes pleural mesothelioma growth by activation of PI3K/Akt signaling
Authors: Roshini Arivazhagan , Goparaju Chandra , Kundu Somanath , Nandhu Mohan S. , Longo Sharon L. , Longo John A. , Chou Joan , Middleton Frank A. , Pass Harvey I. , Viapiano Mariano S.
Published: October 2022

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited therapeutic options. The extracellular matrix protein fibulin-3/EFEMP1 accumulates in the pleural effusions of MPM patients and has been proposed as a prognostic biomarker of these tumors. However, it is entirely unknown whether fibulin-3 plays a functional role on MPM growth and progression. Here, we demonstrate that fibulin-3 is upregulated in MPM tissue, promotes the malignant behavior of MPM cells, and can be targeted to reduce tumor progression. Overexpression of fibulin-3 increased the viability, clonogenic capacity and invasion of mesothelial cells, whereas fibulin-3 knockdown decreased these phenotypic traits as well as chemoresistance in MPM cells. At the molecular level, fibulin-3 activated PI3K/Akt signaling and increased the expression of a PI3K-dependent gene signature associated with cell adhesion, motility, and invasion. These pro-tumoral effects of fibulin-3 on MPM cells were disrupted by PI3K inhibition as well as by a novel, function-blocking, anti-fibulin-3 chimeric antibody. Anti-fibulin-3 antibody therapy tested in two orthotopic models of MPM inhibited fibulin-3 signaling, resulting in decreased tumor cell proliferation, reduced tumor growth, and extended animal survival. Taken together, these results demonstrate for the first time that fibulin-3 is not only a prognostic factor of MPM but also a relevant molecular target in these tumors. Further development of anti-fibulin-3 approaches are proposed to increase early detection and therapeutic impact against MPM.
A systemic review of taxanes and their side effects in metastatic breast cancer
Authors: Lai Jiun-I. , Chao Ta-Chung , Liu Chun-Yu , Huang Chi-Cheng , Tseng Ling-Ming
Published: October 2022

Taxanes-containing chemotherapy constitutes an essential backbone for both early and metastatic breast cancer (mBC). However, the two major taxane drugs—paclitaxel and docetaxel—have distinct safety profiles. In this review, we summarize the safety outcome and management following treatment with both taxanes from selected clinical trials. We utilized PubMed to perform literature search before April 2021. Five phase III randomized controlled trials with reports of individual taxane adverse events (AEs) were included in this review. Grade 3/4 AEs were summarized and discussed extensively. The rates of grade 3/4 neutropenia were higher with docetaxel than with paclitaxel. For non-hematologic grade 3/4 AEs, peripheral neuropathy was more frequent with paclitaxel while fluid retention was more frequent with docetaxel. Compared to paclitaxel, docetaxel had a higher rate of grade 3/4 gastrointestinal AEs. Grade 3/4 myalgia were generally comparable between the two taxanes. Except for neutropenia, the incidence rate of grade 3/4 AEs of taxanes was generally manageable. Peripheral neuropathy was more common with paclitaxel while grade 3/4 neutropenia was more common with docetaxel.
Development and validation of a m6A -regulated prognostic signature in lung adenocarcinoma
Authors: Chen Yaxin , Xia Lei , Peng Yuxuan , Wang Gang , Bi Liyun , Xiao Xue , Li Cui , Li Weimin
Published: October 2022

Lung adenocarcinoma (LUAD) is the most frequent subtype of lung cancer, with a 5-year survival rate of less than 20%. N6-methyladenosine (m6A) is the most prevalent RNA epigenetic modification in eukaryotic cells, and post-transcriptionally regulates gene expression and function by affecting RNA metabolism. The alterations of functionally important m6A sites have been previously shown to play vital roles in tumor initiation and progression, but little is known about the extent to which m6A-regulated genes play in prognostic performance for patients with LUAD. Here, we presented an overview of the m6A methylome in LUAD tissues using transcriptome-wide m6A methylation profiles, and found that differentially methylated transcripts were significantly enriched in tumor-related processes, including immune response, angiogenesis and cell-substrate adhesion. Joint analysis of m6A modification and gene expression suggested that 300 genes were regulated by m6A. Furthermore, we developed a m6A-regulated prognosis-associated signature (m6A-PPS) by performing a multi-step process. The m6A-PPS model, a 15-gene set, was qualified for prognosis prediction for LUAD patients. By regrouping the patients with this model, the OS of the high-risk group was shorter than that of the low-risk group across all datasets. Importantly, patients with high m6A-PPS scores respond better to immunotherapeutic. Our results provide a valuable resource for understanding the important role of epitranscriptomic modifications in the pathogenesis of LUAD, and obtain potential prognostic biomarkers.
In vitro neutrophil migration is associated with inhaled corticosteroid treatment and serum cytokines in pediatric asthma
Authors: Lemmel Solveig , Weckmann Markus , Wohlers Anna , Jirmo Adan Chari , Grychtol Ruth , Ricklefs Isabell , Nissen Gyde , Bachmann Anna , Singh Shantanu , Caicedo Juan , Bahmer Thomas , Hansen Gesine , Von Mutius Erika , Rabe Klaus F. , Fuchs Oliver , Dittrich Anna-Maria , Schaub Bianca , Happle Christine , Carpenter Anne E. , Kopp Matthias Volkmar , Becker Tim ,   the ALLIANCE Study Group as part of the German Centre for Lung Research (DZL)
Published: October 2022

Background: Different asthma phenotypes are driven by molecular endotypes. A Th1-high phenotype is linked to severe, therapy-refractory asthma, subclinical infections and neutrophil inflammation. Previously, we found neutrophil granulocytes (NGs) from asthmatics exhibit decreased chemotaxis towards leukotriene B4 (LTB4), a chemoattractant involved in inflammation response. We hypothesized that this pattern is driven by asthma in general and aggravated in a Th1-high phenotype.

Methods: NGs from asthmatic nd healthy children were stimulated with 10 nM LTB4/100 nM N-formylmethionine-leucyl-phenylalanine and neutrophil migration was documented following our prior SiMA (simplified migration assay) workflow, capturing morphologic and dynamic parameters from single-cell tracking in the images. Demographic, clinical and serum cytokine data were determined in the ALLIANCE cohort.

Results: A reduced chemotactic response towards LTB4 was confirmed in asthmatic donors regardless of inhaled corticosteroid (ICS) treatment. By contrast, only NGs from ICS-treated asthmatic children migrate similarly to controls with the exception of Th1-high donors, whose NGs presented a reduced and less directed migration towards the chemokines. ICS-treated and Th1-high asthmatic donors present an altered surface receptor profile, which partly correlates with migration.

Conclusions: Neutrophil migration in vitro may be affected by ICS-therapy or a Th1-high phenotype. This may be explained by alteration of receptor expression and could be used as a tool to monitor asthma treatment.
Combinatorial regimens of chemotherapeutic agents: A new perspective on raising the heat of the tumor immune microenvironment
Authors: Liu Jingyang , Yu Yang , Liu Cun , Gao Chundi , Zhuang Jing , Liu Lijuan , Wu Qibiao , Ma Wenzhe , Zhang Qiming , Sun Changgang
Published: October 2022

Harnessing the broad immunostimulatory capabilities of chemotherapy in combination with immune checkpoint inhibitors has improved immunotherapy outcomes in patients with cancer. Certain chemotherapeutic agents can extensively modify the tumor microenvironment (TME), resulting in the reprogramming of local immune responses. Although chemotherapeutic agents with an enhanced generation of potent anti-tumor immune responses have been tested in preclinical animal models and clinical trials, this strategy has not yet shown substantial therapeutic efficacy in selected difficult-to-treat cancer types. In addition, the efficacy of chemotherapeutic agent-based monotherapy in eliciting a long-term anti-tumor immune response is restricted by the immunosuppressive TME. To enhance the immunomodulatory effect of chemotherapy, researchers have made many attempts, mainly focusing on improving the targeted distribution of chemotherapeutic agents and designing combination therapies. Here, we focused on the mechanisms of the anti-tumor immune response to chemotherapeutic agents and enumerated the attempts to advance the use of chemo-immunotherapy. Furthermore, we have listed the important considerations in designing combinations of these drugs to maximize efficacy and improve treatment response rates in patients with cancer.
Hypertension in chronic kidney disease: What lies behind the scene
Authors: Ameer Omar Z.
Published: October 2022

Hypertension is a frequent condition encountered during kidney disease development and a leading cause in its progression. Hallmark factors contributing to hypertension constitute a complexity of events that progress chronic kidney disease (CKD) into end-stage renal disease (ESRD). Multiple crosstalk mechanisms are involved in sustaining the inevitable high blood pressure (BP) state in CKD, and these play an important role in the pathogenesis of increased cardiovascular (CV) events associated with CKD. The present review discusses relevant contributory mechanisms underpinning the promotion of hypertension and their consequent eventuation to renal damage and CV disease. In particular, salt and volume expansion, sympathetic nervous system (SNS) hyperactivity, upregulated renin–angiotensin–aldosterone system (RAAS), oxidative stress, vascular remodeling, endothelial dysfunction, and a range of mediators and signaling molecules which are thought to play a role in this concert of events are emphasized. As the control of high BP via therapeutic interventions can represent the key strategy to not only reduce BP but also the CV burden in kidney disease, evidence for major strategic pathways that can alleviate the progression of hypertensive kidney disease are highlighted. This review provides a particular focus on the impact of RAAS antagonists, renal nerve denervation, baroreflex stimulation, and other modalities affecting BP in the context of CKD, to provide interesting perspectives on the management of hypertensive nephropathy and associated CV comorbidities.
Sanguinarine protects against indomethacin-induced small intestine injury in rats by regulating the Nrf2/NF-κB pathways
Authors: Lin Xiu-lian , Shi Ya-ning , Cao Yu-ling , Tan Xi , Zeng Ya-ling , Luo Shi-teng , Li Ya-mei , Qin Li , Xia Bo-hou , Fu Rong-geng , Lin Li-mei , Li Kai , Cao Deliang , Zeng Jian-guo , Liao Duan-fang
Published: October 2022

In recent years, small intestine as a key target in the treatment of Inflammatory bowel disease caused by NSAIDs has become a hot topic. Sanguinarine (SA) is one of the main alkaloids in the Macleaya cordata extracts with strong pharmacological activity of anti-tumor, anti-inflammation and anti-oxidant. SA is reported to inhibit acetic acid-induced colitis, but it is unknown whether SA can relieve NSAIDs-induced small intestinal inflammation. Herein, we report that SA effectively reversed the inflammatory lesions induced by indomethacin (Indo) in rat small intestine and IEC-6 cells in culture. Our results showed that SA significantly relieved the symptoms and reversed the inflammatory lesions of Indo as shown in alleviation of inflammation and improvement of colon macroscopic damage index (CMDI) and tissue damage index (TDI) scores. SA decreased the levels of TNF-α, IL-6, IL-1β, MDA and LDH in small intestinal tissues and IEC-6 cells, but increased SOD activity and ZO-1 expression. Mechanistically, SA dose-dependently promoted the expression of Nrf2 and HO-1 by decreasing Keap-1 level, but inhibited p65 phosphorylation and nuclear translocation in Indo-treated rat small intestine and IEC-6 cells. Furthermore, in SA treated cells, the colocalization between p-p65 and CBP in the nucleus was decreased, while the colocalization between Nrf2 and CBP was increased, leading to the movement of gene expression in the nucleus to the direction of anti-inflammation and anti-oxidation. Nrf2 silencing blocked the effects of SA. Together our results suggest that SA can significantly prevent intestinal inflammatory lesions induced by Indo in rats and IEC-6 cells through regulation of the Nrf2 pathway and NF-κBp65 pathway.
Mapping volumes to planes: Camera-based strategies for snapshot volumetric microscopy
Authors: Engelhardt Moritz , Grußmayer Kristin
Published: October 2022

Optical microscopes allow us to study highly dynamic events from the molecular scale up to the whole animal level. However, conventional three-dimensional microscopy architectures face an inherent tradeoff between spatial resolution, imaging volume, light exposure and time required to record a single frame. Many biological processes, such as calcium signalling in the brain or transient enzymatic events, occur in temporal and spatial dimensions that cannot be captured by the iterative scanning of multiple focal planes. Snapshot volumetric imaging maintains the spatio-temporal context of such processes during image acquisition by mapping axial information to one or multiple cameras. This review introduces major methods of camera-based single frame volumetric imaging: so-called multiplane, multifocus, and light field microscopy. For each method, we discuss, amongst other topics, the theoretical framework; tendency towards optical aberrations; light efficiency; applicable wavelength range; robustness/complexity of hardware and analysis; and compatibility with different imaging modalities, and provide an overview of applications in biological research.
Receptor subunit compositions underly distinct potencies of a muscle relaxant in fast and slow muscle fibers
Authors: Yamashita Manami , Egashira Yoshihiro , Nakamura Shuntaro , Sakata Souhei , Ono Fumihito
Published: October 2022

A line of studies in the 1960s–1980s suggested that muscle relaxants do not work uniformly on all skeletal muscles, though its mechanism has not been clarified. We showed here that a classical non-depolarizing muscle relaxant pancuronium inhibits fast muscle fibers at lower concentration compared to slow muscle fibers in zebrafish. The difference of effective concentration was observed in locomotion caused by tactile stimulation as well as in synaptic currents of the neuromuscular junction induced by motor neuron excitation. We further showed that this difference arises from the different composition of acetylcholine receptors between slow and fast muscle fibers in the neuromuscular junction of zebrafish. It will be interesting to examine the difference of subunit composition and sensitivity to muscle relaxants in other species.
Hemodynamics-driven mathematical model of third heart sound generation
Authors: Shahmohammadi Mehrdad , Huberts Wouter , Luo Hongxing , Westphal Philip , Cornelussen Richard N. , Prinzen Frits W. , Delhaas Tammo
Published: October 2022

The proto-diastolic third heart sound (S3) is observed in various hemodynamic conditions in both normal and diseased hearts. We propose a novel, one-degree of freedom mathematical model of mechanical vibrations of heart and blood that generates the third heart sound, implemented in a real-time model of the cardiovascular system (CircAdapt). To examine model functionality, S3 simulations were performed for conditions mimicking the normal heart as well as heart failure with preserved ejection fraction (HFpEF), atrioventricular valve regurgitation (AVR), atrioventricular valve stenosis (AVS) and septal shunts (SS). Simulated S3 showed both qualitative and quantitative agreements with measured S3 in terms of morphology, frequency, and timing. It was shown that ventricular mass, ventricular viscoelastic properties as well as inflow momentum play a key role in the generation of S3. The model indicated that irrespective of cardiac conditions, S3 vibrations are always generated, in both the left and right sides of the heart, albeit at different levels of audibility. S3 intensities increased in HFpEF, AVR and SS, but the changes of acoustic S3 features in AVS were not significant, as compared with the reference simulation. S3 loudness in all simulated conditions was proportional to the level of cardiac output and severity of cardiac conditions. In conclusion, our hemodynamics-driven mathematical model provides a fast and realistic simulation of S3 under various conditions which may be helpful to find new indicators for diagnosis and prognosis of cardiac diseases.
Identification of long non-coding RNA-microRNA-mRNA regulatory modules and their potential roles in drought stress response in wheat (Triticum aestivum L.)
Authors: Li Ning , Liu Tongtong , Guo Feng , Yang Jinwen , Shi Yugang , Wang Shuguang , Sun Daizhen
Published: October 2022

Drought is one of the most severe abiotic stresses that influence wheat production across the globe. Understanding the molecular regulatory network of wheat in response to drought is of great importance in molecular breeding. Noncoding RNAs influence plant development and resistance to abiotic stresses by regulating gene expression. In this study, whole-transcriptome sequencing was performed on the seedlings of two wheat varieties with contrasting levels of drought tolerance under drought and control conditions to identify long noncoding RNAs (lncRNAs), micro RNAs (miRNAs), and mRNAs related to drought stress and explore the potential lncRNA-miRNA-mRNA regulatory modules in controlling wheat drought stress response. A total of 1515 differentially expressed lncRNAs (DELs), 209 differentially expressed miRNAs (DEMs), and 20462 differentially expressed genes (DEGs) were identified. Of the 20462 DEGs, 1025 were identified as potential wheat drought resistance-related DEGs. Based on the regulatory relationship and expression patterns of DELs, DEMs, and DEGs, 10 DEL-DEM-DEG regulatory modules related to wheat drought stress response were screened, and preliminary expression verification of two important candidate modules was performed. Our results revealed the possible roles of lncRNA-miRNA-mRNA modules in regulatory networks related to drought tolerance and provided useful information as valuable genomic resources in molecular breeding of wheat.