bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of Angiotensin-Converting Enzyme 2: A Potential Target to Prevent COVID-19?
Authors: Hu Yue , Liu Lihuan , Lu Xifeng
Published: October 2021

The renin–angiotensin system (RAS) is crucially involved in the physiology and pathology of all organs in mammals. Angiotensin-converting enzyme 2 (ACE2), which is a homolog of ACE, acts as a negative regulator in the homeostasis of RAS. ACE2 has been proven to be the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic. As SARS-CoV-2 enters the host cells through binding of viral spike protein with ACE2 in humans, the distribution and expression level of ACE2 may be critical for SARS-CoV-2 infection. Growing evidence shows the implication of ACE2 in pathological progression in tissue injury and several chronic conditions such as hypertension, diabetes, and cardiovascular disease; this suggests that ACE2 is essential in the progression and clinical prognosis of COVID-19 as well. Therefore, we summarized the expression and activity of ACE2 under various conditions and regulators. We further discussed its potential implication in susceptibility to COVID-19 and its potential for being a therapeutic target in COVID-19.
Transcriptome-Based Identification and Functional Characterization of NAC Transcription Factors Responsive to Drought Stress in Capsicum annuum L.
Authors: Borràs Dionis , Barchi Lorenzo , Schulz Karina , Moglia Andrea , Acquadro Alberto , Kamranfar Iman , Balazadeh Salma , Lanteri Sergio
Published: October 2021

Capsicum annuum L. is one of the most cultivated Solanaceae species, and in the open field, water limitation leading to drought stress affects its fruit quality, fruit setting, fruit size and ultimately yield. We identified stage-specific and a common core set of differentially expressed genes, following RNA-seq transcriptome analyses of a breeding line subjected to acute drought stress followed by recovery (rewatering), at three stages of plant development. Among them, two NAC transcription factor (TF) genes, i.e., CaNAC072 and CaNAC104, were always upregulated after drought stress and downregulated after recovery. The two TF proteins were observed to be localized in the nucleus following their transient expression in Nicotiana benthamiana leaves. The expression of the two NACs was also induced by NaCl, polyethylene glycol (PEG) and abscisic acid (ABA) treatments, suggesting that CaNAC072 is an early, while CaNAC104 is a late abiotic stress-responsive gene. Virus-induced gene silencing (VIGS) of CaNAC104 did not affect the pepper plantlet’s tolerance to drought stress, while VIGS of CaNAC072 increased drought tolerance. Heterologous expression of CaNAC072 in Arabidopsis thaliana as well as in plants mutated for its homolog ANAC072 did not increase drought stress tolerance. This highlights a different role of the two NAC homologs in the two species. Here, we discuss the complex role of NACs as transcriptional switches in the response to drought stress in bell pepper.
Assessment of CircRNA Expression Profiles and Potential Functions in Brown Adipogenesis
Authors: Zhang Pengpeng , Sheng Mingxuan , Du Chunyu , Chao Zhe , Xu Haixia , Cheng Xiaofang , Li Cencen , Xu Yongjie
Published: October 2021

Brown adipose tissue (BAT) is specialized for energy expenditure, thus a better understanding of the regulators influencing BAT development could provide novel strategies to defense obesity. Many protein-coding genes, miRNAs, and lncRNAs have been investigated in BAT development, however, the expression patterns and functions of circRNA in brown adipogenesis have not been reported yet. This study determined the circRNA expression profiles across brown adipogenesis (proliferation, early differentiated, and fully differentiated stages) by RNA-seq. We identified 3,869 circRNAs and 36.9% of them were novel. We found the biogenesis of circRNA was significantly related to linear mRNA transcription, meanwhile, almost 70% of circRNAs were generated by alternative back-splicing. Next, we examined the cell-specific and differentiation stage-specific expression of circRNAs. Compared to white adipocytes, nearly 30% of them were specifically expressed in brown adipocytes. Further, time-series expression analysis showed circRNAs were dynamically expressed, and 117 differential expression circRNAs (DECs) in brown adipogenesis were identified, with 77 upregulated and 40 downregulated. Experimental validation showed the identified circRNAs could be successfully amplified and the expression levels detected by RNA-seq were reliable. For the potential functions of the circRNAs, GO analysis suggested that the decreased circRNAs were enriched in cell proliferation terms, while the increased circRNAs were enriched in development and thermogenic terms. Bioinformatics predictions showed that DECs contained numerous binding sites of functional miRNAs. More interestingly, most of the circRNAs contained multiple binding sites for the same miRNA, indicating that they may facilitate functions by acting as microRNA sponges. Collectively, we characterized the circRNA expression profiles during brown adipogenesis and provide numerous novel circRNAs candidates for future brown adipogenesis regulating studies.
Comparative Transcriptome Sequencing of Taro Corm Development With a Focus on the Starch and Sucrose Metabolism Pathway
Authors: Dong Weiqing , He Fanglian , Jiang Huiping , Liu Lili , Qiu Zuyang
Published: October 2021

Taro (Colocasia esculenta) is an important tuber crop and staple food. Taro corms have higher nutritional value and starch contents as compared to most of the other root/tuber crops. However, the growth and development of the taro rhizome have not been critically examined in terms of transcriptomic signatures in general or specific to carbohydrates (starch and sucrose) accumulation. In current study, we have conducted a comprehensive survey of transcripts in taro corms aged 1, 2, 3, 4, 5, and 8 months. In this context, we have employed a whole transcriptome sequencing approach for identification of mRNAs, CircRNAs, and miRNAs in corms and performed functional enrichment analysis of the screened differentially expressed RNAs. A total of 11,203 mRNAs, 245 CircRNAs, and 299 miRNAs were obtained from six developmental stages. The mRNAs included 139 DEGs associated with 24 important enzymes of starch and sucrose metabolism. The expression of genes encoding key enzymes of starch and sucrose metabolism pathway (GBSS, AGPase, UGPase, SP, SSS, βFRUCT and SuSy) demonstrated significant variations at the stage of 4 months (S4). A total of 191 CircRNAs were differentially expressed between the studied comparisons of growth stages and 99 of these were associated with those miRNA (or target genes) that were enriched in starch and sucrose metabolism pathway. We also identified 205 miRNAs including 46 miRNAs targeting DEGs enriched in starch and sucrose biosynthesis pathway. The results of current study provide valuable resources for future exploration of the molecular mechanisms involved in the starch properties of Taro.
Case Report: Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne: A Single-Center Experience and Literature Review
Authors: Wang Yumei , Wu Na , Yu Keyi , Shen Min
Published: October 2021

Objectives

This study aims to describe the characteristics of patients diagnosed with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome at a single center in China and provide an up-to-date literature review.

Methods

The clinical data and genotype of three Chinese Han patients were carefully documented and studied. We also conducted a systematic literature review on PAPA syndrome.

Results

A total of three patients were diagnosed with PAPA syndrome at our center from 2018 to 2020. Arthritis was observed in all three patients, while pyoderma gangrenosum (PG) was found in two patients and acne in one patient. Other manifestations included pathergy reaction, intermittent fever, oral ulcer, keratitis, proteinuria, and hematuria. The PSTPIP1 A230T mutation was identified in two patients, and a novel Y119C variation was revealed in a sporadic patient. A total of 76 patients with PAPA syndrome reported in 29 articles were included in our literature review. The classical triad of arthritis, PG, and acne was visible in only 16 (25.4%) patients, while 24 (38.1%) exhibited only one major symptom. Skin lesions were more commonly seen in patients with adult-onset disease than those with childhood-onset disease (100 vs. 83%), whereas arthritis was less common (50 vs. 98.1%). Steroid and/or biological agents were effective in most patients.

Conclusions

The rarity and phenotypic heterogeneity associated with PAPA syndrome make the diagnosis a huge challenge to physicians, especially in adult patients. A significant portion of patients did not exhibit the full spectrum of the classical triad. Accordingly, gene testing is critically helpful for diagnosis.
Diagnostic Value of sIL-2R, TNF-α and PCT for Sepsis Infection in Patients With Closed Abdominal Injury Complicated With Severe Multiple Abdominal Injuries
Authors: Zhai Guang-hua , Zhang Wei , Xiang Ze , He Li-Zhen , Wang Wei-wei , Wu Jian , Shang An-quan
Published: October 2021

Objective

We aimed to evaluate the diagnostic value of soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and combined detection for sepsis infection in patients with closed abdominal injury complicated with severe multiple abdominal injuries.

Patients and Methods

One hundred forty patients with closed abdominal injury complicated with severe multiple abdominal injuries who were diagnosed and treated from 2015 to 2020 were divided into a sepsis group (n = 70) and an infection group (n = 70).

Results

The levels of sIL-2R, TNF-α, and PCT in the sepsis group were higher than those in the infection group (p < 0.05). The receiver operating characteristic (ROC) curve showed that the areas under the ROC curve (AUCs) of sIL-2R, TNF-α, PCT and sIL-2R+TNF-a+PCT were 0.827, 0.781, 0.821, and 0.846, respectively, which were higher than those of white blood cells (WBC, 0.712), C-reactive protein (CRP, 0.766), serum amyloid A (SAA, 0.666), and IL-6 (0.735). The AUC of the three combined tests was higher than that of TNF-α, and the difference was statistically significant (p < 0.05). There was no significant difference in the AUCs of sIL-2R and TNF-α, sIL-2R and PCT, TNF-α and PCT, the three combined tests and sIL-2R, and the three combined tests and PCT (p > 0.05). When the median was used as the cut point, the corrected sIL-2R, TNF-α, and PCT of the high-level group were not better than those of the low-level group (p > 0.05). When the four groups were classified by using quantile as the cut point, the OR risk values of high levels of TNF-α and PCT (Q4) and the low level of PCT (Q1) after correction were 7.991 and 21.76, respectively, with statistical significance (p < 0.05).

Conclusions

The detection of sIL-2R, TNF-α, and PCT has good value in the diagnosis of sepsis infection in patients with closed abdominal injury complicated with severe multiple abdominal injuries. The high concentrations of PCT and TNF-α can be used as predictors of the risk of septic infection.
Distribution and Abundances of Planktic Foraminifera and Shelled Pteropods During the Polar Night in the Sea-Ice Covered Northern Barents Sea
Authors: Zamelczyk Katarzyna , Fransson Agneta , Chierici Melissa , Jones Elizabeth , Meilland Julie , Anglada-Ortiz Griselda , Lødemel Helene Hodal
Published: October 2021

Planktic foraminfera and shelled pteropods are important calcifying groups of zooplankton in all oceans. Their calcium carbonate shells are sensitive to changes in ocean carbonate chemistry predisposing them as an important indicator of ocean acidification. Moreover, planktic foraminfera and shelled pteropods contribute significantly to food webs and vertical flux of calcium carbonate in polar pelagic ecosystems. Here we provide, for the first time, information on the under-ice planktic foraminifera and shelled pteropod abundance, species composition and vertical distribution along a transect (82°–76°N) covering the Nansen Basin and the northern Barents Sea during the polar night in December 2019. The two groups of calcifiers were examined in different environments in the context of water masses, sea ice cover, and ocean chemistry (nutrients and carbonate system). The average abundance of planktic foraminifera under the sea-ice was low with the highest average abundance (2 ind. m–3) close to the sea-ice margin. The maximum abundances of planktic foraminifera were concentrated at 20–50 m depth (4 and 7 ind. m–3) in the Nansen Basin and at 80–100 m depth (13 ind. m–3) close to the sea-ice margin. The highest average abundance (13 ind. m–3) and the maximum abundance of pteropods (40 ind. m–3) were found in the surface Polar Water at 0–20 m depth with very low temperatures (–1.9 to –1°C), low salinity (<34.4) and relatively low aragonite saturation of 1.43–1.68. The lowest aragonite saturation (<1.3) was observed in the bottom water in the northern Barents Sea. The species distribution of these calcifiers reflected the water mass distribution with subpolar species at locations and depths influenced by warm and saline Atlantic Water, and polar species in very cold and less saline Polar Water. The population of planktic foraminifera was represented by adults and juveniles of the polar speciesNeogloboquadrina pachydermaand the subpolar speciesTurborotalita quinqueloba. The dominating polar pteropod speciesLimacina helicinawas represented by the juvenile and veliger stages. This winter study offers a unique contribution to our understanding of the inter-seasonal variability of planktic foraminfera and shelled pteropods abundance, distribution and population size structure in the Arctic Ocean.
Plasticity of Locomotor Activity Permits Energy Homeostasis During Reproduction in a Female Sea Cucumber
Authors: Ru Xiaoshang , Zhang Libin , Yang Hongsheng
Published: October 2021

Behavioral plasticity in animals allows for moment-by-moment behavioral adjustments to biotic and abiotic uncertainties in the environment. For most aquatic animals, reproduction involves gonadal development and other physiological changes, causing increasing demands in nutrients and energy for females. The aim of this report was to determine how the female sea cucumber, Apostichopus japonicus, accommodates increasing energy demands during reproduction by adopting a behavioral energy conservation strategy. Dynamic changes in feeding activity, total body mass, locomotor activity, energetic condition, and metabolic performance of the females were measured from the non-breeding stage up to the mature stage. Routine metabolic rate analysis showed that reproduction caused a significant increase in energy demands in the adult. However, reproduction also suppressed the appetite of adults resulting in decreased energy intake. Interestingly, combining time-lapse camera and behavioral analysis software, the results showed that sea cucumbers down-regulated their locomotor activities in order to conserve energy effectively. Energy budget analysis and unchanged cortisol level revealed that the reduction in motility offset the increased energy demand for reproduction while helping to maintain energy homeostasis in the maternal body. Altogether, our study suggests that plasticity in the locomotor behavior allows sea cucumbers to cope with the high energy demands of reproduction.
Case Report: Metagenomics Next-Generation Sequencing Can Be Performed for the Diagnosis of Disseminated Mucormycosis
Authors: Sun Yi , Li HuiLing , Chen JiaJun , Ma ZhongHui , Han Pin , Liu YuChen , Wen Jing , Ren Fang , Ma XiaoXu
Published: October 2021

Mucormycosis is an infection caused by a group of filamentous molds with in the order Mucorales. In developing countries, most cases of mucormycosis occur in persons with poorly controlled diabetes mellitus or subjects with normal post-traumatic immune function. Mucormycosis exhibits a marked propensity for invading blood vessels. The mortality rate of invasive mucormycosis is very high (>30–50%), and 90% of mortality is related to disseminated diseases. We report a 62-year-old man with underlying diseases, such as diabetes and psoriatic arthritis, with a history of trauma before admission. Chest CT showed multiple cavities. Based on the suspected clinical manifestation of mucormycosis infection, the patient received a microbiological culture of bronchoalveolar lavage fluid, and metagenomics next generation sequencing (mNGS) was performed. The results suggested Klebsiella pneumoniae infection. However, Rhizopus microsporus strains were shown by the mNGS of transpulmonary puncture tissue. Therefore, we report a case in which rare pathogens are identified by mNGS.
Proximal Tubule p53 in Cold Storage/Transplantation-Associated Kidney Injury and Renal Graft Dysfunction
Authors: Xiang Xiaohong , Zhu Jiefu , Zhang Gang , Ma Zhengwei , Livingston Man J. , Dong Zheng
Published: October 2021

Kidney injury associated with cold storage/transplantation is a primary factor for delayed graft function and poor outcome of renal transplants. p53 contributes to both ischemic and nephrotoxic kidney injury, but its involvement in kidney cold storage/transplantation is unclear. Here, we report that p53 in kidney proximal tubules plays a critical role in cold storage/transplantation kidney injury and inhibition of p53 can effectively improve the histology and function of transplanted kidneys. In a mouse kidney cold storage/transplantation model, we detected p53 accumulation in proximal tubules in a cold storage time-dependent manner, which correlated with tubular injury and cell death. Pifithrin-α, a pharmacologic p53 inhibitor, could reduce acute tubular injury, apoptosis and inflammation at 24 h after cold storage/transplantation. Similar effects were shown by the ablation of p53 from proximal tubule cells. Notably, pifithrin-α also ameliorated kidney injury and improved the function of transplanted kidneys in 6 days when it became the sole life-supporting kidney in recipient mice. in vitro, cold storage followed by rewarming induced cell death in cultured proximal tubule cells, which was accompanied by p53 activation and suppressed by pifithrin-α and dominant-negative p53. Together, these results support a pathogenic role of p53 in cold storage/transplantation kidney injury and demonstrate the therapeutic potential of p53 inhibitors.
Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies
Authors: Qu Weiyi , Ma Tengfei , Cai Jingjing , Zhang Xiaojing , Zhang Peng , She Zhigang , Wan Feng , Li Hongliang
Published: October 2021

Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and this nomenclature MAFLD was proposed to renovate its former name, non-alcoholic fatty liver disease (NAFLD). MAFLD/NAFLD have shared and predominate causes from nutrition overload to persistent liver damage and eventually lead to the development of liver fibrosis and cirrhosis. Unfortunately, there is an absence of effective treatments to reverse MAFLD/NAFLD-associated fibrosis. Due to the significant burden of MAFLD/NAFLD and its complications, there are active investigations on the development of novel targets and pharmacotherapeutics for treating this disease. In this review, we cover recent discoveries in new targets and molecules for antifibrotic treatment, which target pathways intertwined with the fibrogenesis process, including lipid metabolism, inflammation, cell apoptosis, oxidative stress, and extracellular matrix formation. Although marked advances have been made in the development of antifibrotic therapeutics, none of the treatments have achieved the endpoints evaluated by liver biopsy or without significant side effects in a large-scale trial. In addition to the discovery of new druggable targets and pharmacotherapeutics, personalized medication, and combinatorial therapies targeting multiple profibrotic pathways could be promising in achieving successful antifibrotic interventions in patients with MAFLD/NAFLD.
Innovative Artificial-Intelligence- Based Approach for the Biodegradation of Feather Keratin by Bacillus paramycoides, and Cytotoxicity of the Resulting Amino Acids
Authors: Moussa Zeiad , Darwish Doaa B. , Alrdahe Salma S. , Saber WesamEldin I. A.
Published: October 2021

The current study reported a new keratinolytic bacterium, which was characterized as Bacillus paramycoides and identified by 16S rRNA, and the sequence was then deposited in the GenBank (MW876249). The bacterium was able to degrade the insoluble chicken feather keratin (CFK) into amino acids (AA) through the keratinase system. The statistical optimization of the biodegradation process into AA was performed based on the Plackett–Burman design and rotatable central composite design (RCCD) on a simple solid-state fermentation medium. The optimum conditions were temperature, 37°C, 0.547 mg KH2PO4, 1.438 mg NH4Cl, and 11.61 days of incubation. Innovatively, the degradation of the CFK process was modeled using the artificial neural network (ANN), which was better than RCCD in modeling the biodegradation process. Differentiation of the AA by high-performance liquid chromatography (HPLC) revealed the presence of 14 AA including essential and non-essential ones; proline and aspartic acids were the most dominant. The toxicity test of AA on the HepG2 cell line did not show any negative effect either on the cell line or on the morphological alteration. B. paramycoides ZW-5 is a new eco-friendly tool for CFK degradation that could be optimized by ANN. However, additional nutritional trials are encouraged on animal models.
MiRNA-142-3P and FUS can be Sponged by Long Noncoding RNA DUBR to Promote Cell Proliferation in Acute Myeloid Leukemia
Authors: Yin Zhao , Shen HuiJuan , Gu Chun ming , Zhang Ming qi , Liu Zhi , Huang Jing , Zhu Yangmin , Zhong Qi , Huang Yizhen , Wu Feima , Ou Ruiming , Zhang Qing , Liu Shuang
Published: October 2021

Acute myeloid leukemia (AML) represents a frequently occurring adulthood acute leukemia (AL). Great progresses have been achieved in the treatment of AML, but its pathogenic mechanism remains unclear. This study reported the biological functions of lncRNA DUBR in AML pathogenic mechanism. As a result, lncRNA DUBR showed high expression level within AML, resulting in poor prognosis, especially in M4 AML. In vitro studies elucidated that knockdown of DUBR with small interfering RNA (siRNA) resulted in the suppression of survival and colony formation ability, as well as induction of apoptosis, in AML cells. RNA pull-down assay and computational revealed that DUBR could sponge with miRNA-142-3P and interact with FUS protein. MiRNA-142-3P have a negative correlation with DUBR and overexpression of miRNA-142-3P inhibited cell growth in AML. Meanwhile, DUBR promoted the expression of FUS protein, targeting inhibition of FUS significantly promoted cell apoptosis in AML cell lines. In conclusion, these results revealed new mechanism of lncRNA DUBR in AML malignant behavior, and suggested that the manipulation of DUBR expression could serve as a potential strategy in AML therapy.
Meta-Analysis of Neurochemical Changes Estimated via Magnetic Resonance Spectroscopy in Mild Cognitive Impairment and Alzheimer's Disease
Authors: Liu Huanhuan , Zhang Dandan , Lin Huawei , Zhang Qi , Zheng Ling , Zheng Yuxin , Yin Xiaolong , Li Zuanfang , Liang Shengxiang , Huang Saie
Published: October 2021

The changes of neurochemicals in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients has been observed via magnetic resonance spectroscopy in several studies. However, whether it exists the consistent pattern of changes of neurochemicals in the encephalic region during the progression of MCI to AD were still not clear. The study performed meta-analysis to investigate the patterns of neurochemical changes in the encephalic region in the progress of AD. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases, and finally included 63 studies comprising 1,086 MCI patients, 1,256 AD patients, and 1,907 healthy controls. It showed that during the progression from MCI to AD, N-acetyl aspartate (NAA) decreased continuously in the posterior cingulate (PC) (SMD: −0.42 [95% CI: −0.62 to −0.21], z = −3.89, P < 0.05), NAA/Cr (creatine) was consistently reduced in PC (SMD: −0.58 [95% CI: −0.86 to −0.30], z = −4.06, P < 0.05) and hippocampus (SMD: −0.65 [95% CI: −1.11 to −0.12], z = −2.44, P < 0.05), while myo-inositol (mI) (SMD: 0.44 [95% CI: 0.26–0.61], z = 4.97, P < 0.05) and mI/Cr (SMD: 0.43 [95% CI: 0.17–0.68], z = 3.30, P < 0.05) were raised in PC. Furthermore, these results were further verified by a sustained decrease in the NAA/mI of PC (SMD: −0.94 [95% CI: −1.24 to −0.65], z = −6.26, P < 0.05). Therefore, the levels of NAA and mI were associated with the cognitive decline and might be used as potentially biomarkers to predict the possible progression from MCI to AD.

Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42020200308.
Sonographic Features of Pure Mucinous Breast Carcinoma With Micropapillary Pattern
Authors: Zhou Wu , Li Yong-Zhong , Gao Li-Min , Cai Di-Ming
Published: October 2021

Objective

Previous studies have mostly discussed the clinical manifestations and prognosis of mucinous breast carcinoma with a micropapillary pattern. The purposes of this study were to investigate the sonographic features of pure mucinous breast carcinoma with micropapillary pattern (MUMPC) and to identify the role of ultrasound in the differential diagnosis between MUMPC and conventional pure mucinous breast carcinoma (cPMBC).

Materials and Methods

We obtained written informed consent from all patients, and the Ethics Committee of West China Hospital approved this retrospective study. The study was conducted between May and August 2020. We enrolled 133 patients with 133 breast lesions confirmed as mucinous breast carcinoma (MBC) histopathologically between January 2014 and January 2020.We retrospectively assessed sonographic features (margin, shape, internal echogenicity, calcification, posterior acoustic feature, invasive growth, blood flow grade, and rate of missed diagnosis) and clinical characteristics (age, tumor size, tumor texture, initial symptom, and lymph node metastasis). Bivariable analyses were performed using SPSS version 19.0.

Results

The 133 lesions included 11 MUMPCs, 65 cPMBCs, and 57 mixed MBCs (MMBCs). There were significant differences in margin, shape, calcification, posterior acoustic feature, invasive growth, rate of missed diagnosis, average tumor size, and lymph node metastasis among the three groups (p < 0.05). The subsequent pairwise comparisons showed that there were significant differences in lymph node metastasis, margin, and invasive growth between MUMPC and cPMBC (p < 0.05). In patients aged >45 years, there was a significant difference in tumor size among the three groups (p = 0.045), and paired comparison showed that the average tumor size in the cPMBC group was larger than that in the MMBC group (p = 0.014).

Conclusion

MUMPC showed a non-circumscribed margin and invasive growth more frequently than cPMBC did. Lymphatic metastasis was more likely to occur in MUMPC than cPMBC. Ultrasound is helpful to distinguish MUMPC from cPMBC.
Comparison of Efficacy and Safety of Third-Line Treatments for Advanced Gastric Cancer: A Systematic Review With Bayesian Network Meta-Analysis
Authors: Huang Miao , Li Jisheng , Yu Xuejun , Xu Qian , Zhang Xue , Dai Xin , Li Song , Sheng Lei , Huang Kai , Liu Lian
Published: October 2021

Background

Although various third-line treatments of advanced gastric cancer (AGC) significantly improved the overall survival, the optimal regimen has not been determined by now. This study aims to evaluate the efficacy and safety of multiple third-line treatments of AGC via integrated analysis and network meta-analysis (NMA) to provide valuable evidence for the optimal third-line systemic therapy for AGC.

Methods

By searching the databases of PubMed, Embase and the Cochrane Central Register of Controlled Trials from Jan 01, 2005 to Dec 31, 2020, we included phase II/III randomized clinical trials (RCTs) of the third-line treatments for AGC to perform NMA. The main outcomes for NMA were median overall survival (mOS), median progression-free survival (mPFS), disease control rate (DCR) and adverse events (AEs). We also included phase IB/II non-RCTs and II/III RCTs of the third-line immune checkpoint inhibitors (ICIs) for integrated analysis for pooled mOS (POS), pooled mPFS (PPFS) and other outcomes.

Results

Eight phase II/III RCTs and 2 ICIs-related phase IB/II non-RCTs were included for analysis, involving 9 treatment regimens and 3012 AGC patients. In terms of mOS, apatinib (hazard ratio [HR] 0.61, 95% credible interval [CrI] 0.48-0.78) and nivolumab (HR 0.62, 95% CrI 0.51-0.76) were the most effective treatments compared with placebo. Apatinib also significantly improved mPFS versus placebo (HR 0.38, 95% CrI 0.29-0.49). Nivolumab ranked first among all regimens for 1-year OS rate and achieved the best OS in patients with HER-2 positive tumor, patients with gastroesophageal junction (GEJ) cancer and patients without gastrectomy history. TAS-102 (OR 7.46, 95% CrI 4.61-12.51) was the most toxic treatment in terms of AEs of grade 3 and higher (≥3 AEs). Pembrolizumab was more likely to cause immune related adverse event. Finally, the POS, pooled 1-year OS rate, pooled ORR and PPFS of AGC patients treated with third-line ICIs were 5.1 months, 25%, 10% and 1.71 months respectively.

Conclusions

Apatinib and nivolumab are the most effective treatments for the third-line treatment of AGC in contrast to the third-line chemotherapy. For AGC patients with HER-2 positive tumor, patients with GEJ cancer and patients without gastrectomy history, ICIs could be the optimal third-line treatment choice.
Association of Virological Response to Antiviral Therapy With Survival in Intermediate-Stage Hepatitis B Virus-Related Hepatocellular Carcinoma After Chemoembolization
Authors: Jin Meng , Chen Yong , Hu Shuifang , Zhu Meiyan , Wang Yan , Chen Minshan , Peng Zhenwei
Published: October 2021

Introduction

Role of response to antiviral therapies on survival of patients with intermediate-stage hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) undergoing transarterial chemoembolization (TACE) remains unknown. We aimed to determine whether virological response (VR) or prolonged maintained virological response (MVR) to nucelos(t)ide analogues (NA) therapy could result in improved survival in HBV-HCC patients receiving TACE.

Methods

Between January 2012 and October 2018, data of patients with intermediate HBV-HCC who underwent TACE and started NA therapy within one week prior to TACE treatment at our institution were reviewed. Overall survival (OS) was compared using the Kaplan-Meier method with log-rank test between different VR status groups. Univariable and multivariable Cox regression analyses were used to determine the association between achievement of VR or MVR and OS. VR was defined as an undetectable HBV DNA level (<100 IU/ml) on two consecutive measurements during NA treatment. MVR was defined as a persistently undetectable HBV DNA level after achieving a VR.

Results

A total of 1265 patients undergoing TACE with a median follow-up time of 18 months (range, 2-78 months) were included in the analysis. Of 1265 NA-treated patients [1123 (88.8%) male, median (range) age, 56 (18-75) years], 744 patients (58.8%) achieved VR and the remaining patients (41.2%) did not. Patients with achievement of VR showed a significantly longer OS than those without VR (median OS: 21 vs 16 months; HR, 0.707; 95% CI, 0.622-0.804; P<0.001). Among patients with VR, MVR was present in 542 patients (72.8%), while the other 202 patients (27.2%) in the non-MVR group. The OS for the MVR group was significantly higher than the non-MVR group (median OS: 23.2 vs 18 months; HR, 0.736; 95% CI, 0.612-0.885; P=0.001). Additionally, patients with MVR status more than two years showed a better OS than those with just one-year (HR, 0.719; 95% CI, 0.650-0.797; P<0.001) or one-to-two-year MVR (HR, 0.612; 95% CI, 0.471-0.795; P=0.024). On multivariable analyses, splenomegaly and up-to-seven criteria were independent prognostic factors of OS in both VR and MVR cohorts.

Conclusions

In patients with intermediate-stage HBV-HCC, both VR to antiviral therapy and prolonged response are associated with prolonged OS after TACE, especially for those within up-to-seven criteria.
Functional Genomics of PRUNE1 in Neurodevelopmental Disorders (NDDs) Tied to Medulloblastoma (MB) and Other Tumors
Authors: Bibbò Francesca , Sorice Carmen , Ferrucci Veronica , Zollo Massimo
Published: October 2021

We analyze the fundamental functions of Prune_1 in brain pathophysiology. We discuss the importance and maintenance of the function of Prune_1 and how its perturbation influences both brain pathological conditions, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; OMIM: 617481), and tumorigenesis of medulloblastoma (MB) with functional correlations to other tumors. A therapeutic view underlying recent discoveries identified small molecules and cell penetrating peptides to impair the interaction of Prune_1 with protein partners (e.g., Nm23-H1), thus further impairing intracellular and extracellular signaling (i.e., canonical Wnt and TGF-β pathways). Identifying the mechanism of action of Prune_1 as responsible for neurodevelopmental disorders (NDDs), we have recognized other genes which are found overexpressed in brain tumors (e.g., MB) with functional implications in neurodevelopmental processes, as mainly linked to changes in mitotic cell cycle processes. Thus, with Prune_1 being a significant target in NDDs, we discuss how its network of action can be dysregulated during brain development, thus generating cancer and metastatic dissemination.
HIST1H1B Promotes Basal-Like Breast Cancer Progression by Modulating CSF2 Expression
Authors: Liao Ruocen , Chen Xingyu , Cao Qianhua , Wang Yifan , Miao Zhaorui , Lei Xingyu , Jiang Qianjin , Chen Jie , Wu Xuebiao , Li Xiaoli , Li Jun , Dong Chenfang
Published: October 2021

Background

Basal-like breast cancer (BLBC) is associated with a poor clinical outcome; however, the mechanism of BLBC aggressiveness is still unclear. It has been shown that a linker histone functions as either a positive or negative regulator of gene expression in tumors. Here, we aimed to investigate the possible involvement and mechanism of HIST1H1B in BLBC progression.

Experimental design

We analyzed multiple gene expression datasets to determine the relevance of HIST1H1B expression with BLBC. We employed quantitative real-time PCR, transwell assay, colony formation assay, and mammosphere assay to dissect the molecular events associated with the expression of HIST1H1B in human breast cancer. We studied the association of HIST1H1B with CSF2 by ChIP assay. Using tumorigenesis assays, we determine the effect of HIST1H1B expression on tumorigenicity of BLBC cells.

Results

Here, we show that the linker histone HIST1H1B is dramatically elevated in BLBC due to HIST1H1B copy number amplification and promoter hypomethylation. HIST1H1B upregulates colony-stimulating factor 2 (CSF2) expression by binding the CSF2 promoter. HIST1H1B expression promotes, whereas knockdown of HIST1H1B expression suppresses tumorigenicity. In breast cancer patients, HIST1H1B expression is positively correlated with large tumor size, high grade, metastasis and poor survival.

Conclusion

HIST1H1B contributes to basal-like breast cancer progression by modulating CSF2 expression, indicating a potential prognostic marker and therapeutic target for this disease.
Case Report: Paternal Uniparental Isodisomy and Heterodisomy of Chromosome 16 With a Normal Phenotype
Authors: Zhang Xu , Liu Li , Liu Yang , Pan Xin
Published: October 2021

Uniparental disomy (UPD) is a specific type of chromosomal variant that has been detected in both prenatal diagnosis and neonates with advances in molecular genetic testing technologies [mainly chromosome microarray analysis (CMA) technologies containing single-nucleotide polymorphism (SNP) probes]. In this case, we performed non-invasive prenatal genetic testing (NIPT) to screen fetuses for aneuploidy and detected the presence of aneuploidy chimerism and UPD by CMA, including SNP analysis and whole-exome sequencing, to detect pathogenic variants within the genome. The NIPT results suggested an increased number of fetal chromosome 16, and the CMA results indicated that it was the first case of holistic paternal UPD16 with isodisomy combined with heterodisomy, although no abnormal phenotype was seen in the newborn at postnatal follow-up. The homozygous region of the isodimer combined with the heterodimer is smaller than that of the complete isodimer, and it is less prone to recessive genetic diseases. A retrospective analysis of this case of paternally derived UPD16 was used to explore the uniparental diploid origin of chromosome 16 and to provide some reference for genetic counseling and prenatal diagnosis.
Tetrathiomolybdate Treatment Attenuates Bleomycin-Induced Angiogenesis and Lung Pathology in a Sheep Model of Pulmonary Fibrosis
Authors: Derseh Habtamu B. , Perera Kopiyawaththage U. E. , Dewage Sasika N. Vithana , Stent Andrew , Koumoundouros Emmanuel , Organ Louise , Pagel Charles N. , Snibson Ken J.
Published: October 2021

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic lung disease characterized by excessive extracellular matrix (ECM) deposition in the parenchyma of the lung. Accompanying the fibrotic remodeling, dysregulated angiogenesis has been observed and implicated in the development and progression of pulmonary fibrosis. Copper is known to be required for key processes involved in fibrosis and angiogenesis. We therefore hypothesized that lowering bioavailable serum copper with tetrathiomolybdate could be of therapeutic value for treating pulmonary fibrosis. This study aimed to investigate the effect of tetrathiomolybdate on angiogenesis and fibrosis induced in sheep lung segments infused with bleomycin. Twenty sheep received two fortnightly infusions of either bleomycin (3U), or saline (control) into two spatially separate lung segments. A week after the final bleomycin/saline infusions, sheep were randomly assigned into two groups (n= 10 per group) and received twice-weekly intravenous administrations of either 50 mg tetrathiomolybdate, or sterile saline (vehicle control), for 6 weeks. Vascular density, expressed as the percentage of capillary area to the total area of parenchyma, was determined in lung tissue sections immuno-stained with antibodies against CD34 and collagen type IV. The degree of fibrosis was assessed by histopathology scoring of H&E stained sections and collagen content using Masson’s trichrome staining. Lung compliance was measured via a wedged bronchoscope procedure prior to and 7 weeks following final bleomycin infusion. In this large animal model, we show that copper lowering by tetrathiomolybdate chelation attenuates both bleomycin-induced angiogenesis and pulmonary fibrosis. Moreover, tetrathiomolybdate treatment downregulates vascular endothelial growth factor (VEGF) expression, and improved lung function in bleomycin-induced pulmonary fibrosis. Tetrathiomolybdate also suppressed the accumulation of inflammatory cells in bronchoalveolar lavage fluid 2 weeks after bleomycin injury. The molecular mechanism(s) underpinning copper modulation of fibrotic pathways is an important area for future investigation, and it represents a potential therapeutic target for pulmonary fibrosis.
C1q/TNF-Related Protein 9 Attenuates Atherosclerosis by Inhibiting Hyperglycemia-Induced Endothelial Cell Senescence Through the AMPKα/KLF4 Signaling Pathway
Authors: Wang Gang , Han Baihe , Zhang Ruoxi , Liu Qi , Wang Xuedong , Huang Xingtao , Liu Dandan , Qiao Weishen , Yang Mengyue , Luo Xing , Hou Jingbo , Yu Bo
Published: October 2021

Hyperglycemia-induced endothelial cell senescence has been widely reported to be involved in the pathogenesis of type 2 diabetes mellitus‒accelerated atherosclerosis. Thus, understanding the underlying mechanisms and identifying potential therapeutic targets for endothelial cell senescence are valuable for attenuating atherosclerosis progression. C1q/tumor necrosis factor-related protein 9 (CTRP9), an emerging potential cardiokine, exerts a significant protective effect with respect to atherosclerosis, particularly in endothelial cells. However, the exact mechanism by which CTRP9 prevents endothelial cells from hyperglycemia-induced senescence remains unclear. This study aimed to investigate the effects of CTRP9 on hyperglycemia-induced endothelial cell senescence and atherosclerotic plaque formation in diabetic apolipoprotein E knockout (ApoE KO) mice. Human umbilical vein endothelial cells (HUVECs) were cultured in normal glucose (5.5 mM) and high glucose (40 mM) with or without recombinant human CTRP9 protein (3 μg/ml) for 48 h. Purified lentiviruses overexpressing CTRP9 (Lv-CTRP9) and control vectors containing green fluorescent protein (Lv-GFP) were injected via the tail vein into streptozotocin-induced diabetic ApoE KO mice. Results revealed that exposure of HUVECs to HG significantly increased the expression of Krüppel-like factor 4 (KLF4) and cyclin-dependent kinase inhibitor p21 (p21) and decreased that of telomerase reverse transcriptase (TERT). Treatment with recombinant human CTRP9 protein protected HUVECs from HG-induced premature senescence and dysfunction. CTRP9 promoted the phosphorylation of AMP-activated kinase (AMPK), attenuated the expression of KLF4 and p21 induced by HG, and increased the expression of TERT in HUVECs. Furthermore, in the background of AMPKα knockdown or KLF4 activation, the protective effects of CTRP9 were abolished. In-vivo experiments showed that the overexpression of CTRP9 inhibited vascular senescence and reduced atherosclerotic plaque formation in ApoE KO mice with diabetes. In conclusion, we demonstrate that KLF4 upregulation plays a crucial role in HG-induced endothelial senescence. This anti-atherosclerotic effect of CTRP9 may be partly attributed to the inhibition of HG-induced endothelial senescence through an AMPKα/KLF4-dependent mechanism, suggesting that CTRP9 could benefit further therapeutic approaches for type 2 diabetes mellitus‒accelerated atherosclerosis.
CircEpc1 Promotes Ricin Toxin-Induced Inflammation via Activation of NF-κB and MAPK Signaling Pathways by Sponging miR-5114
Authors: Dong Mingxin , Zhang Xiaohao , Yu Haotian , Wang Yan , Chang Ying , Sun Chengbiao , Zhang Jianxu , Zhao Na , Yu Kaikai , Sun Guangchao , Zhao Guiru , Xu Na , Liu Wensen
Published: October 2021

Increasing studies have concentrated on investigating circular RNAs (circRNAs) as pivotal regulators in the progression of numerous diseases and biological processes and abundant evidence shows that circRNAs are participated in the regulation of innate immune responses. Several studies showed that Ricin Toxin (RT) could induce inflammatory injury. There was no research on the particular functions and underlying mechanisms of circRNAs in RT-induced inflammation. In this study, RNA sequencing performed on RT-treated and normal RAW264.7 macrophage cells was used to investigated the differentially expressed circRNAs. Based on the dataset, the expression of circEpc1 (mmu_circ_0,000,842) was identified higher in RT-treated cells. Moreover, gain-and-loss function assays showed that circEpc1 function as a promoter in RT-induced inflammation in vivo and in vitro. Mechanistically, circEpc1 acted as a miR-5114 sponge to relieve the suppressive effect of miR-5114 on its target NOD2 and thereby activating NF-κB and MAPK signaling pathways. Our results illuminated a link between RT-induced inflammation and the circEpc1 regulatory loop and provided novel insight into the functions of circRNA in innate immune, which may emerge as a potential target in immunotherapy to control the RT-induced inflammatory injury.
Ex vivo Validation of Noninvasive Epicardial and Endocardial Repolarization Mapping
Authors: van der Waal Jeanne G. , Meijborg Veronique M. F. , Belterman Charly N. W. , Streekstra Geert J. , Oostendorp Thom F. , Coronel Ruben
Published: October 2021

Background: The detection and localization of electrophysiological substrates currently involve invasive cardiac mapping. Electrocardiographic imaging (ECGI) using the equivalent dipole layer (EDL) method allows the noninvasive estimation of endocardial and epicardial activation and repolarization times (AT and RT), but the RT validation is limited to in silico studies. We aimed to assess the temporal and spatial accuracy of the EDL method in reconstructing the RTs from the surface ECG under physiological circumstances and situations with artificially induced increased repolarization heterogeneity.

Methods: In four Langendorff-perfused pig hearts, we simultaneously recorded unipolar electrograms from plunge needles and pseudo-ECGs from a volume-conducting container equipped with 61 electrodes. The RTs were computed from the ECGs during atrial and ventricular pacing and compared with those measured from the local unipolar electrograms. Regional RT prolongation (cooling) or shortening (pinacidil) was achieved by selective perfusion of the left anterior descending artery (LAD) region.

Results: The differences between the computed and measured RTs were 19.0 ± 17.8 and 18.6 ± 13.7 ms for atrial and ventricular paced beats, respectively. The region of artificially delayed or shortened repolarization was correctly identified, with minimum/maximum RT roughly in the center of the region in three hearts. In one heart, the reconstructed region was shifted by ~2.5 cm. The total absolute difference between the measured and calculated RTs for all analyzed patterns in selectively perfused hearts (n = 5) was 39.6 ± 27.1 ms.

Conclusion: The noninvasive ECG repolarization imaging using the EDL method of atrial and ventricular paced beats allows adequate quantitative reconstruction of regions of altered repolarization.
A Semi-Automated SNP-Based Approach for Contaminant Identification in Biparental Polyploid Populations of Tropical Forage Grasses
Authors: Martins Felipe Bitencourt , Moraes Aline Costa Lima , Aono Alexandre Hild , Ferreira Rebecca Caroline Ulbricht , Chiari Lucimara , Simeão Rosangela Maria , Barrios Sanzio Carvalho Lima , Santos Mateus Figueiredo , Jank Liana , do Valle Cacilda Borges , Vigna Bianca Baccili Zanotto , de Souza Anete Pereira
Published: October 2021

Artificial hybridization plays a fundamental role in plant breeding programs since it generates new genotypic combinations that can result in desirable phenotypes. Depending on the species and mode of reproduction, controlled crosses may be challenging, and contaminating individuals can be introduced accidentally. In this context, the identification of such contaminants is important to avoid compromising further selection cycles, as well as genetic and genomic studies. The main objective of this work was to propose an automated multivariate methodology for the detection and classification of putative contaminants, including apomictic clones (ACs), self-fertilized individuals, half-siblings (HSs), and full contaminants (FCs), in biparental polyploid progenies of tropical forage grasses. We established a pipeline to identify contaminants in genotyping-by-sequencing (GBS) data encoded as allele dosages of single nucleotide polymorphism (SNP) markers by integrating principal component analysis (PCA), genotypic analysis (GA) measures based on Mendelian segregation, and clustering analysis (CA). The combination of these methods allowed for the correct identification of all contaminants in all simulated progenies and the detection of putative contaminants in three real progenies of tropical forage grasses, providing an easy and promising methodology for the identification of contaminants in biparental progenies of tetraploid and hexaploid species. The proposed pipeline was made available through the polyCID Shiny app and can be easily coupled with traditional genetic approaches, such as linkage map construction, thereby increasing the efficiency of breeding programs.