bluuebunny/crossref_metadata_2025 huggingface dataset:
MiR-30c-5p loss-induced PELI1 accumulation regulates cell proliferation and migration via activating PI3K/AKT pathway in papillary thyroid carcinoma
Authors: Zheng Tingting , Zhou Youxing , Xu Xiaowei , Qi Xin , Liu Jiameng , Pu Yanan , Zhang Shan , Gao Xuerong , Luo Xinkai , Li Mei , Wang Xuefeng , Dong Liyang , Wang Ying , Mao Chaoming
Published: January 2022

Background

The aberrant expression of E3 ubiquitin ligase Pellino-1 (PELI1) contributes to several human cancer development and progression. However, its expression patterns and functional importance in papillary thyroid cancer (PTC) remains unknown.

Methods

PELI1 expression profiles in PTC tissues were obtained and analyzed through the starBase v3.0 analysis. Real-time PCR, Immunohistochemical assays (IHC) and Western blot were used to investigate the mRNA and protein levels of PELI1 in PTC. The effects of PELI1 on PTC cell progression were evaluated through CCK-8, colony formation, Transwell, and Wound healing assay in vitro, and a PTC xenograft mouse model in vivo. The downstream target signal of PELI1 in PTC was analyzed by using Kyoto encyclopedia of genes and genomes (KEGG), and bioinformatics tools were used to identify potential miRNAs targeting PELI1. Human umbilical cord mesenchymal stem cells were modified by miR-30c-5p and the miR-30c-5p containing extracellular vesicles were collected (miR-30c-5p-EVs) by ultra-high-speed centrifugation method. Then, the effects of miR-30c-5p-EVs on PELI1 expression and PTC progression were evaluated both in vitro and in vivo.

Results

Both mRNA and protein expression of PELI1 were widely increased in PTC tissues, and overexpression of PELI1 was positively correlated with bigger tumor size and lymph node metastases. PELI1 promoted PTC cell proliferation and migration in vitro. While, PELI1 silencing significantly suppressed PTC growth in vivo accompanied with reduced expression of Ki-67 and matrix metallopeptidase 2 (MMP-2). Mechanistically, PI3K-AKT pathway was identified as the downstream target of PELI1, and mediated the functional influence of PELI1 in PTC cells. Moreover, we found that the expression of miR-30c-5p was inversely correlated with PELI1 in PTC samples and further confirmed that miR-30c-5p was a tumor-suppressive miRNA that directly targeted PELI1 to inhibit PTC cell proliferation and migration. Furthermore, we showed that miR-30c-5p-EVs could effectively downregulate PELI1 expression and suppress the PTC cell growth in vitro and in vivo.

Conclusion

This study not only supported the first evidence that miR-30c-5p loss-induced PELI1 accumulation facilitated cell proliferation and migration by activating the PI3K-AKT pathway in PTC but also provided novel insights into PTC therapy based on miR-carrying-hUCMSC-EVs.
Nafamostat reduces systemic inflammation in TLR7-mediated virus-like illness
Authors: Yates Abi G. , Weglinski Caroline M. , Ying Yuxin , Dunstan Isobel K. , Strekalova Tatyana , Anthony Daniel C.
Published: January 2022

Background

The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to an ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model.

Methods

CD-1 mice received an intraperitoneal injection of R848 (200 μg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100 μL, 3 mg/kg in 5% dextrose) or 5% dextrose alone. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 h post-challenge to measure markers of peripheral and central inflammation by blood analysis, immunohistochemistry and qPCR.

Results

R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment.

Conclusions

Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19.
Microbial pathogens induce neurodegeneration in Alzheimer’s disease mice: protection by microglial regulation
Authors: Ganz Tal , Fainstein Nina , Elad Amit , Lachish Marva , Goldfarb Smadar , Einstein Ofira , Ben-Hur Tamir
Published: January 2022

Background

Neurodegeneration is considered the consequence of misfolded proteins’ deposition. Little is known about external environmental effects on the neurodegenerative process. Infectious agent-derived pathogen-associated molecular patterns (PAMPs) activate microglia, key players in neurodegenerative diseases. We hypothesized that systemic microbial pathogens may accelerate neurodegeneration in Alzheimer’s disease (AD) and that microglia play a central role in this process.

Methods

We examined the effect of an infectious environment and of microbial Toll-like receptor (TLR) agonists on cortical neuronal loss and on microglial phenotype in wild type versus 5xFAD transgenic mice, carrying mutated genes associated with familial AD.

Results

We examined the effect of a naturally bred environment on the neurodegenerative process. Earlier and accelerated cortical neuron loss occurred in 5xFAD mice housed in a natural (“dirty”) environment than in a specific-pathogen-free (SPF) environment, without increasing the burden of Amyloid deposits and microgliosis. Neuronal loss occurred in a microglia-rich cortical region but not in microglia-poor CA regions of the hippocampus. Environmental exposure had no effect on cortical neuron density in wild-type mice. To model the neurodegenerative process caused by the natural infectious environment, we injected systemically the bacterial endotoxin lipopolysaccharide (LPS), a TLR4 agonist PAMP. LPS caused cortical neuronal death in 5xFAD, but not wt mice. We used the selective retinoic acid receptor α agonist Am580 to regulate microglial activation. In primary microglia isolated from 5xFAD mice, Am580 markedly attenuated TLR agonists-induced iNOS expression, without canceling their basic immune response. Intracerebroventricular delivery of Am580 in 5xFAD mice reduced significantly the fraction of (neurotoxic) iNOS + microglia and increased the fraction of (neuroprotective) TREM2 + microglia. Furthermore, intracerebroventricular delivery of Am580 prevented neurodegeneration induced by microbial TLR agonists.

Conclusions

Exposure to systemic infections causes neurodegeneration in brain regions displaying amyloid pathology and high local microglia density. AD brains exhibit increased susceptibility to microbial PAMPs’ neurotoxicity, which accelerates neuronal death. Microglial modulation protects the brain from microbial TLR agonist PAMP-induced neurodegeneration.
MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes
Authors: Kieran Nicholas W. , Suresh Rahul , Dorion Marie-France , MacDonald Adam , Blain Manon , Wen Dingke , Fuh Shih-Chieh , Ryan Fari , Diaz Roberto J. , Stratton Jo Anne , Ludwin Samuel K. , Sonnen Joshua A. , Antel Jack , Healy Luke M.
Published: January 2022

Background

Astrocytes are the most numerous glial cell type with important roles in maintaining homeostasis and responding to diseases in the brain. Astrocyte function is subject to modulation by microRNAs (miRs), which are short nucleotide strands that regulate protein expression in a post-transcriptional manner. Understanding the miR expression profile of astrocytes in disease settings provides insight into the cellular stresses present in the microenvironment and may uncover pathways of therapeutic interest.

Methods

Laser-capture microdissection was used to isolate human astrocytes surrounding stroke lesions and those from neurological control tissue. Astrocytic miR expression profiles were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Primary human fetal astrocytes were cultured under in vitro stress conditions and transfection of a miR mimic was used to better understand how altered levels of miR-210 affect astrocyte function. The astrocytic response to stress was studied using qPCR, enzyme-linked immunosorbent assays (ELISAs), measurement of released lactate, and Seahorse.

Results

Here, we measured miR expression levels in astrocytes around human ischemic stroke lesions and observed differential expression of miR-210 in chronic stroke astrocytes compared to astrocytes from neurological control tissue. We also identified increased expression of miR-210 in mouse white matter tissue around middle cerebral artery occlusion (MCAO) brain lesions. We aimed to understand the role of miR-210 in primary human fetal astrocytes by developing an in vitro assay of hypoxic, metabolic, and inflammatory stresses.A combination of hypoxic and inflammatory stresses was observed to upregulate miR-210 expression. Transfection with miR-210-mimic (210M) increased glycolysis, enhanced lactate export, and promoted an anti-inflammatory transcriptional and translational signature in astrocytes. Additionally, 210M transfection resulted in decreased expression of complement 3 (C3) and semaphorin 5b(Sema5b).

Conclusions

We conclude that miR-210 expression in human astrocytes is modulated in response to ischemic stroke disease and under in vitro stress conditions, supporting a role for miR-210 in the astrocytic response to disease conditions. Further, the anti-inflammatory and pro-glycolytic impact of miR-210 on astrocytes makes it a potential candidate for further research as a neuroprotective agent.
Introducing the hormonal Intrauterine Device in Madagascar, Nigeria, and Zambia: results from a pilot study
Authors: Danna Kendal , Jaworski Grace , Rahaivondrafahitra Bakoly , Rasoanirina Francia , Nwala Anthony , Nqumayo Masauso , Smith Gina , Moon Pierre , Jackson Ashley , Thurston Sarah , Kalamar Amanda
Published: January 2022

Background

The hormonal Intrauterine Device (IUD) is a highly effective contraceptive option growing in popularity and availability in many countries. The hormonal IUD has been shown to have high rates of satisfaction and continuation among users in high-income countries. The study aims to understand the profiles of clients who choose the hormonal IUD in low- and middle-income countries (LMICs) and describe their continuation and satisfaction with the method after 12 months of use.

Methods

A prospective longitudinal study of hormonal IUD acceptors was conducted across three countries—Madagascar, Nigeria, and Zambia—where the hormonal IUD had been introduced in a pilot setting within the of a broad mix of available methods. Women were interviewed at baseline immediately following their voluntary hormonal IUD insertion, and again 3 and 12 months following provision of the method. A descriptive analysis of user characteristics and satisfaction with the method was conducted on an analytic sample of women who completed baseline, 3-month, and 12-month follow-up questionnaires. Kaplan–Meier time-to-event models were used to estimate the cumulative probability of method continuation rates up to 12 months post-insertion.

Results

Each country had a unique demographic profile of hormonal IUD users with different method-use histories. Across all three countries, women reported high rates of satisfaction with the hormonal IUD (67–100%) and high rates of continuation at the 12-month mark (82–90%).

Conclusions

Rates of satisfaction and continuation among hormonal IUD users in the study suggest that expanding method choice with the hormonal IUD would provide a highly effective, long-acting method desirable to many different population segments, including those with high unmet need.
Prevalence and correlates of Kaposi’s sarcoma-associated herpesvirus and herpes simplex virus type 2 infections among adults: evidence from the NHANES III data
Authors: Zhang Xin , Xu Yiyun , Li Yi , Yuan Huangbo , Liu Zhenqiu , Zhang Tiejun
Published: January 2022

Background

Kaposi’s sarcoma-associated herpes virus (KSHV) prevalence and risk factors exhibit considerable variations across populations in different geographic regions. Determinants and the transmission routes of KSHV infection are uncertain. We seek to identify the possible risk factors and the transmission routes of KSHV infection in non-endemic areas.

Methods

We collected annual cases and seroprevalence of KSHV and herpes simplex virus type 2 (HSV-2) from the NHANES III sampled individuals from the US general population (1988–1994). We included 13,179 and 10,720 individuals with available remaining serum samples of KSHV and HSV-2. Logistic regression was employed to explore potential risk factors for the seropositivity.

Results

The seroprevalence was 2.05% for KSHV infection and 31.03% for HSV2 infection among this population. All risk factors of sexual behaviors included were strongly associated with HSV-2 positive, however, only MSM had an approximately fivefold increased risk of KSHV infection (OR = 4.71; 95%CI 1.61 11.30). Mexican Americans (2.51%) and older (chi-squaretrend =  − 6.71, P < 0.001) individuals had a higher risk of KSHV infection. After adjustment, individuals with higher level of education and economic status had lower KSHV infection.

Conclusions

In non-endemic areas, KSHV transmission may be related to sexual activity in men, especially in male homosexuals. Higher education level and economic status are protective factors for KSHV infection.
Integrative profiling of Epstein–Barr virus transcriptome using a multiplatform approach
Authors: Fülöp Ádám , Torma Gábor , Moldován Norbert , Szenthe Kálmán , Bánáti Ferenc , Almsarrhad Islam A. A. , Csabai Zsolt , Tombácz Dóra , Minárovits János , Boldogkői Zsolt
Published: January 2022

Background

Epstein–Barr virus (EBV) is an important human pathogenic gammaherpesvirus with carcinogenic potential. The EBV transcriptome has previously been analyzed using both Illumina-based short read-sequencing and Pacific Biosciences RS II-based long-read sequencing technologies. Since the various sequencing methods have distinct strengths and limitations, the use of multiplatform approaches have proven to be valuable. The aim of this study is to provide a more complete picture on the transcriptomic architecture of EBV.

Methods

In this work, we apply the Oxford Nanopore Technologies MinION (long-read sequencing) platform for the generation of novel transcriptomic data, and integrate these with other’s data generated by another LRS approach, Pacific BioSciences RSII sequencing and Illumina CAGE-Seq and Poly(A)-Seq approaches. Both amplified and non-amplified cDNA sequencings were applied for the generation of sequencing reads, including both oligo-d(T) and random oligonucleotide-primed reverse transcription. EBV transcripts are identified and annotated using the LoRTIA software suite developed in our laboratory.

Results

This study detected novel genes embedded into longer host genes containing 5′-truncated in-frame open reading frames, which potentially encode N-terminally truncated proteins. We also detected a number of novel non-coding RNAs and transcript length isoforms encoded by the same genes but differing in their start and/or end sites. This study also reports the discovery of novel splice isoforms, many of which may represent altered coding potential, and of novel replication-origin-associated transcripts. Additionally, novel mono- and multigenic transcripts were identified. An intricate meshwork of transcriptional overlaps was revealed.

Conclusions

An integrative approach applying multi-technique sequencing technologies is suitable for reliable identification of complex transcriptomes because each techniques has different advantages and limitations, and the they can be used for the validation of the results obtained by a particular approach.
Identification of equine herpesvirus 8 in donkey abortion: a case report
Authors: Wang Tongtong , Hu Leyu , Wang Yonghui , Liu Wenqiang , Liu Guiqin , Zhu Mingxia , Zhang Wei , Wang Changfa , Ren Huiying , Li Liangliang
Published: January 2022

Background

Equine herpesvirus-8 (EHV-8) is one of the most economically significant viruses that infect mammals of the genus Equus worldwide, which cause severe respiratory diseases and abortion in horses. However, there is no report of abortion caused by EHV-8 in donkeys.

Case presentation

The present case report is about a 4-year-old donkey having an abortion and showing a serious respiratory issue on the 296th day of pregnancy. Bacteriological and molecular tests were used to screen possible bacterial/viral pathogens to detect the etiological agent.Salmonella abortus equi, EHV-1, EHV-4, and EAV were all negative in the current study. EHV-8, on the other hand, was the only agent that was isolated and identified.

Conclusions

This was for the first time that EHV-8 had been isolated from a donkey in China. EHV-8 infection can cause abortion in donkeys; therefore, veterinarians and breeders should be aware of it.
Association between baseline and changes in high-sensitive C-reactive protein and metabolic syndrome: a nationwide cohort study and meta-analysis
Authors: Xue Qingping , Yang Xue , Huang Yuli , Zhu Dongshan , Wang Yi , Wen Ying , Zhao Jian , Liu Yanjun , Yang Chun-Xia , Pan Jay , Yan Tong , Pan Xiong-Fei
Published: January 2022

Background

We aimed to prospectively evaluate the associations between the baseline and changes in high-density C-reactive protein (hs-CRP) and incident metabolic syndrome (MetS) in China and update the evidence based on a meta-analysis of cohort studies in different populations.

Methods

Data from the China Health and Retirement Longitudinal Study among adults aged 45 years or older were analyzed. Participants who were recruited in the study in 2011–2012 without MetS and successfully followed up to 2015–2016 were included in our final analysis. Logistic regressions were applied to examine the prospective associations of baseline and changes in hs-CRP with incident MetS and estimate corresponding odds ratios (ORs) and 95% confidence intervals (95% CIs). A meta-analysis was conducted to synthesize effect estimates from our findings and other cohort studies on this topic.

Results

Among 4,116 participants, 535 developed MetS after a 4-year follow-up. Compared with the participants with hs-CRP in the lowest quartile, those with hs-CRP in the second, third, and highest quartiles had higher odds of MetS, with multivariable-adjusted ORs (95% CIs) of 1.51 (1.12, 2.06), 1.50 (1.11, 2.04), and 1.83 (1.37, 2.47). For the hs-CRP changes, ORs (95% CIs) were 3.24 (2.51, 4.02), 3.34 (2.56, 4.38), and 3.34 (2.54, 4.40) respectively. One unit (log of 1 mg/L) increase in hs-CRP was associated with 23% higher risk of MetS (OR 1.23; 95% CI 1.10, 1.38). In a meta-analysis of 6 cohort studies, the pooled relative risk for MetS was 1.63 (1.38, 1.93) for the highest versus lowest level of hs-CRP. In addition, the pooled relative risk for MetS was 1.29 (1.05, 1.59) for each unit increase of hs-CRP after log-transformation.

Conclusions

Both higher baseline hs-CRP and longitudinal hs-CRP increases were associated with higher risks of incident MetS. Individuals with high hs-CRP levels may need to be closely monitored for future risk of MetS.
Efficiency of primary spine care as compared to conventional primary care: a retrospective observational study at an Academic Medical Center
Authors: Bezdjian Serena , Whedon James M. , Russell Robb , Goehl Justin M. , Kazal Louis A.
Published: January 2022

Background

Primary Spine Care (PSC) is an innovative model for the primary management of patients with spine-related disorders (SRDs), with a focus on the use of non-pharmacological therapies which now constitute the recommended first-line approach to back pain. PSC clinicians serve as the initial or early point of contact for spine patients and utilize evidence-based spine care pathways to improve outcomes and reduce escalation of care (EoC; e.g., spinal injections, diagnostic imaging, hospitalizations, referrals to a specialist). The present study examined 6-month outcomes to evaluate the efficiency of care for patients who received PSC as compared to conventional primary care. We hypothesized that patients seen by a PSC clinician would have lower rates of EoC compared to patients who received usual care by a primary care (PC) clinician.

Methods

This was a retrospective observational study. We evaluated 6-month outcomes for two groups seen and treated for an SRD between February 01, 2017 and January 31, 2020. Patient groups were comprised of N = 1363 PSC patients (Group A) and N = 1329 PC patients (Group B). We conducted Pearson chi-square and logistic regression (adjusting for patient characteristics that were unbalanced between the two groups) to determine associations between the two groups and 6-month outcomes.

Results

Within six months of an initial visit for an SRD, a statistically significantly smaller proportion of PSC patients utilized healthcare resources for spine care as compared to the PC patients. When adjusting for patient characteristics, those who received care from the PSC clinician were less likely within 6 months of an initial visit to be hospitalized (OR = .47, 95% CI .23–.97), fill a prescription for an opioid analgesic (OR = .43; 95% CI .29–.65), receive a spinal injection (OR = .56, 95% CI .33–.95), or have a visit with a specialist (OR = .48, 95% CI .35–.67) as compared to those who received usual primary care.

Conclusions

Patients who received PSC in an academic primary care clinic experienced significantly less escalation of their spine care within 6 months of their initial visit. The PSC model may offer a more efficient approach to the primary care of spine problems for patients with SRDs, as compared to usual primary care.
A pilot study of machine-learning based automated planning for primary brain tumours
Authors: Tsang Derek S. , Tsui Grace , McIntosh Chris , Purdie Thomas , Bauman Glenn , Dama Hitesh , Laperriere Normand , Millar Barbara-Ann , Shultz David B. , Ahmed Sameera , Khandwala Mohammad , Hodgson David C.
Published: January 2022

Purpose

High-quality radiotherapy (RT) planning for children and young adults with primary brain tumours is essential to minimize the risk of late treatment effects. The feasibility of using automated machine-learning (ML) to aid RT planning in this population has not previously been studied.

Methods and materials

We developed a ML model that identifies learned relationships between image features and expected dose in a training set of 95 patients with a primary brain tumour treated with focal radiotherapy to a dose of 54 Gy in 30 fractions. This ML method was then used to create predicted dose distributions for 15 previously-treated brain tumour patients across two institutions, as a testing set. Dosimetry to target volumes and organs-at-risk (OARs) were compared between the clinically-delivered (human-generated) plans versus the ML plans.

Results

The ML method was able to create deliverable plans in all 15 patients in the testing set. All ML plans were generated within 30 min of initiating planning. Planning target volume coverage with 95% of the prescription dose was attained in all plans. OAR doses were similar across most structures evaluated; mean doses to brain and left temporal lobe were lower in ML plans than manual plans (mean difference to left temporal, – 2.3 Gy, p = 0.006; mean differences to brain, – 1.3 Gy, p = 0.017), whereas mean doses to right cochlea and lenses were higher in ML plans (+ 1.6–2.2 Gy, p < 0.05 for each).

Conclusions

Use of an automated ML method to aid RT planning for children and young adults with primary brain tumours is dosimetrically feasible and can be successfully used to create high-quality 54 Gy RT plans. Further evaluation after clinical implementation is planned.
An algorithm for thoracic re-irradiation using biologically effective dose: a common language on how to treat in a “no-treat zone”
Authors: Brooks Eric D. , Wang Xiaochun , De Brian , Verma Vivek , Williamson Tyler D. , Hunter Rachel , Mohamed Abdallah S. R. , Ning Matthew S. , Zhang Xiaodong , Chang Joe Y.
Published: January 2022

Background

Re-irradiation (re-RT) is a technically challenging task for which few standardized approaches exist. This is in part due to the lack of a common platform to assess dose tolerance in relation to toxicity in the re-RT setting. To better address this knowledge gap and provide new tools for studying and developing thresholds for re-RT, we developed a novel algorithm that allows for anatomically accurate three-dimensional mapping of composite biological effective dose (BED) distributions from nominal doses (Gy).

Methods

The algorithm was designed to automatically convert nominal dose from prior treatment plans to corresponding BED value maps (voxel size 2.5 mm3 and α/β of 3 for normal tissue, BED3). Following the conversion of each plan to a BED3 dose distribution, deformable registration was used to create a summed composite re-irradiation BED3 plan for each patient who received two treatments. A proof-of-principle analysis was performed on 38 re-irradiation cases of initial stereotactic ablative radiotherapy (SABR) followed by either re-SABR or chemoradiation for isolated locoregional recurrence of early-stage non-small cell lung cancer.

Results

Evaluation of the algorithm-generated maps revealed appropriate conversion of physical dose to BED at each voxel. Of 14 patients receiving repeat SABR, there was one case each of grade 3 chest wall pain (7%), pneumonitis (7%), and dyspnea (7%). Of 24 patients undergoing repeat fractionated radiotherapy, grade 3 events were limited to two cases each of pneumonitis and dyspnea (8%). Composite BED3 dosimetry for each patient who experienced grade 2–3 events is provided and may help guide development of precise cumulative dose thresholds for organs at risk in the re-RT setting.

Conclusions

This novel algorithm successfully created a voxel-by-voxel composite treatment plan using BED values. This approach may be used to more precisely examine dosimetric predictors of toxicities and to establish more accurate normal tissue constraints for re-irradiation.
Astragalus membranaceus (Huangqi) and Rhizoma curcumae (Ezhu) decoction suppresses colorectal cancer via downregulation of Wnt5/β-Catenin signal
Authors: Bian Yong , Wang Gang , Zhou Jing , Yin Gang , Liu Tiantian , Liang Li , Yang Xinyue , Zhang Wen , Ni Kexin , Tang Decai , Yu Yun
Published: January 2022

Background

The decoction of Astragalus membranaceus (Huangqi) and Rhizoma curcumae (Ezhu) has been reported as a potential antitumor agent for colorectal cancer (CRC) in experimental and clinical studies, but its underlying mechanism is still unclear.

Methods

The current research aims to explore the potential of Astragalus membranaceus (Huangqi) and Rhizoma curcumae (Ezhu) decoction (AR decoction) in the treatment of CRC and explore the underlying mechanism. SW620 cells were transient transfection to overexpress or knock down wnt 5 or β-Catenin. Astragalus membranaceus (Huangqi) and Rhizoma curcumae (Ezhu) -containing serum (AR-CS) was used to interfere with SW620 cells. Additional AR-CS, Wnt5 inhibitor (IWP-4), and β-Catenin inhibitor (JW55) were used to intervene in SW620 cells. Furthermore, subcutaneously injection of SW620 cells into the right flank of nude mice replicated xenograft mice, which were treated with AR decoction for 21 days.

Results

AR-CS significantly reduced the mRNA and protein expression levels of Wnt5, β-Catenin, ARF6, and N-Cadherin in SW620 cells, while inhibiting the proliferation and migration of SW620 cells. In cells overexpressing Wnt5 or β-Catenin, these effects of AR-CS were significantly suppressed. On the contrary, the inhibitory effect of AR-CS on the mRNA and protein levels of ARF6 and N-Cadherin and cell proliferation and migration of SW620 was enhanced, when Wnt5 or β-Catenin were knocked down or suppressed by the inhibitors. Moreover, in the mouse model of xenograft tumors, AR decoction not only reduced the tumor volume and inhibited the mRNA levels and protein levels of Wnt5, β-Catenin, ARF6, and N-Cadherin in the tumor, but also inhibit the protein levels of LRP5, LRP6, TCF-4, and LEF1.The histopathology of mice also showed increased apoptosis in tumor tissues, and AR decoction treatment did not cause pathological damage to the kidney and liver.

Conclusions

Our results provide evidence that AR decoction inhibits Wnt5/β-catenin signaling and inhibits the development of CRC, which is a promising traditional medicine in the clinical treatment of CRC.
A retrospective cohort study on European Reference Network for Rare Vascular Diseases 5 outcome measures for Hereditary Haemorrhagic Telangiectasia in Denmark
Authors: Hvelplund Troels , Lange Bibi , Bird Susanne Djernes , Korsholm Malene , Kjeldsen Anette Drøhse
Published: January 2022

Background

Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by several clinical symptoms including epistaxis, arteriovenous malformations (AVM), and telangiectasia. In 2018, European Reference Network for Rare Vascular Diseases (VASCERN) recommended five outcome measures for HHT-patients to guide health care providers, some with limited experience in treating HHT, and thereby maximizing the number of HHT-patients receiving good care. The outcome measures cover the following aspects: (1) 90% of the patients should receive a pulmonary AVM (PAVM) screening; (2) 90% of the patients should receive written advice on nosebleed; (3) 70% should be assessed for iron deficiency; (4) 100% of the patients should receive written advice on antibiotic (AB) prophylaxis prior to dental and surgical procedures, and (5) 100% of relevant patients should receive written advice on pregnancy. We have introduced the outcome measures as Benchmarks in our HHT-centre and wanted to evaluate the extend of implementation we have achieved. We constantly struggle to secure the best possible treatment of our HHT-patients.

Methods

The study was a non-interventional retrospective study. Data was collected manually from patient records and from the Danish HHT-database.

Results

A total of 180 HHT-patients were included, all diagnosed in the period from January 1st, 2016, to December 31st, 2020. All patients were screened for PAVM. We could confirm that 66% of patients who had epistaxis received thoroughly advice. Assessment for iron deficiency was performed in 80% of the adult patients. Thoroughly advice on AB prophylaxis was documented in 75%. Thoroughly advice on pregnancy was documented in 80% of female patients 15–45 years of age. There were no significant differences over time for any of the outcome measures.

Conclusions

The Danish HHT-centre reached the target threshold for outcome measures 1 and 3. It could not be documented that the target thresholds for outcome measures 2, 4, and 5 were achieved. As information and education are a very important part of HHT care, focus on and documentation that all patients receive the relevant advice must be a priority in order to ensure best care.
Molecular and clinical characterization of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) in Iranian non-Jewish patients: report of two novel AIRE gene pathogenic variants
Authors: Setoodeh Aria , Panjeh-Shahi Samareh , Bahmani Fariba , Vand-Rajabpour Fatemeh , Jalilian Nazanin , Sayarifard Fatemeh , Abbasi Farzaneh , Sayarifard Azadeh , Rostami Parastoo , Parvaneh Nima , Akhavan-Niaki Haleh , Ahmadifard Mohamadreza , Tabrizi Mina
Published: January 2022

Objective

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is a rare autosomal recessive systemic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Incidence of this genetic disorder is estimated at 1/90,000–200,000 worldwide and 1/6500–9000 in genetically isolated populations such as Iran. Here, we investigated AIRE gene mutations in eight independent Iranian non-Jewish families.

Methods

We sequenced the coding regions of the AIRE gene and documented mutations which were further confirmed in respective parents.

Results

In total, 11 cases from 8 independent families were recruited. Mucosal candidiasis, Addison’s disease and hypoparathyroidism were the most common clinical manifestations in these patients. One novel homozygous splice acceptor mutation (c.308-1G>C), and one novel heterozygous stop-gain mutation (c.1496delC) combined with a known heterozygous c.232T>C missense mutation were found. Moreover, we observed previously described splice donor (c.1095+2T>A), frameshift (c.967-979del), stop-gain (c.415C>T), and missense (c.62C>T) mutations among the patients. All results were co-segregated in parents.

Conclusion

Here, we reported two novel mutations in the AIRE gene leading to APECED. Our data could provide insight into the phenotypic and genotypic spectrum of APECED in the non-Jewish Iranian population. These findings, in addition to future functional assays, can elucidate disease-causing mechanisms related to the AIRE gene and assist in genetic counseling and diagnosis.
Potential impact of the COVID-19 pandemic on japanese patients with eating disorders -a cross-sectional study
Authors: Takakura Shu , Toda Kenta , Yamashita Makoto , Kitajima Tomoko , Suematsu Takafumi , Yokoyama Hiroaki , Asou Chie Suzuyama , Hata Tomokazu , Sudo Nobuyuki
Published: January 2022

Background

The COVID-19 pandemic and associated lockdown had a considerable impact on eating disorders (EDs). We evaluated the clinical features of Japanese ED patients before and after the first COVID-19 outbreak-related state of emergency (April 7, 2020).

Methods

We studied 148 patients who were divided into two groups based on when they arrived at our clinic: before (Before group: n = 86) or after (After group: n = 62) the start of the first state of emergency. All patients completed the Japanese versions of the Eating Disorder Inventory (EDI) and Parental Bonding Instrument (PBI).

Results

The After group was substantially younger than the Before group (p = .0187). Regardless of the ED type, patients who developed an ED during the first state of emergency tended to be significantly younger than those who developed one before. Differences in EDI characteristics were observed between the two groups. The PBI care subscale was notably higher (p = .0177) in the After group. The PBI maternal care subscale was the only statistically significant factor associated with age (β = -0.35, p < .0001).

Conclusions

Home confinement associated with the COVID-19 pandemic and the ensuing increase in parent-child closeness may have influenced the decreased age of ED patients at their initial consultation. Treatment interventions should consider the differences in the clinical features of EDs.
Relief of neuropathic pain by cell-specific manipulation of nucleus accumbens dopamine D1- and D2-receptor-expressing neurons
Authors: Sato Daisuke , Narita Michiko , Hamada Yusuke , Mori Tomohisa , Tanaka Kenichi , Tamura Hideki , Yamanaka Akihiro , Matsui Ryosuke , Watanabe Dai , Suda Yukari , Senba Emiko , Watanabe Moe , Navratilova Edita , Porreca Frank , Kuzumaki Naoko , Narita Minoru
Published: January 2022

Emerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.
Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee
Authors: Januzzi James L. , Garasic Joseph M. , Kasner Scott E. , McDonald Vickie , Petrie Mark C. , Seltzer Jonathan , Mauro Michael , Croce Kevin , Berman Ellin , Deininger Michael , Hochhaus Andreas , Pinilla-Ibarz Javier , Nicolini Franck , Kim Dong-Wook , DeAngelo Daniel J. , Kantarjian Hagop , Xu Jing , Hall Tracey , Srivastava Shouryadeep , Naranjo Daniel , Cortes Jorge
Published: January 2022

Background

The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used.

Methods

To better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions.

Results

A total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93% ≥ 2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE in > 2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors.

Conclusions

This independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 (https://clinicaltrials.gov/ct2/show/NCT01207440).
The CD70-CD27 axis in oncology: the new kids on the block
Authors: Flieswasser Tal , Van den Eynde Astrid , Van Audenaerde Jonas , De Waele Jorrit , Lardon Filip , Riether Carsten , de Haard Hans , Smits Evelien , Pauwels Patrick , Jacobs Julie
Published: January 2022

The immune checkpoint molecule CD70 and its receptor CD27 are aberrantly expressed in many hematological and solid malignancies. Dysregulation of the CD70-CD27 axis within the tumor and its microenvironment is associated with tumor progression and immunosuppression. This is in contrast to physiological conditions, where tightly controlled expression of CD70 and CD27 plays a role in co-stimulation in immune responses. In hematological malignancies, cancer cells co-express CD70 and CD27 promoting stemness, proliferation and survival of malignancy. In solid tumors, only expression of CD70 is present on the tumor cells which can facilitate immune evasion through CD27 expression in the tumor microenvironment. The discovery of these tumor promoting and immunosuppressive effects of the CD70-CD27 axis has unfolded a novel target in the field of oncology, CD70.

In this review, we thoroughly discuss current insights into expression patterns and the role of the CD70-CD27 axis in hematological and solid malignancies, its effect on the tumor microenvironment and (pre)clinical therapeutic strategies.
Biomarkers for sepsis: more than just fever and leukocytosis—a narrative review
Authors: Barichello Tatiana , Generoso Jaqueline S. , Singer Mervyn , Dal-Pizzol Felipe
Published: January 2022

A biomarker describes a measurable indicator of a patient's clinical condition that can be measured accurately and reproducibly. Biomarkers offer utility for diagnosis, prognosis, early disease recognition, risk stratification, appropriate treatment (theranostics), and trial enrichment for patients with sepsis or suspected sepsis. In this narrative review, we aim to answer the question, "Do biomarkers in patients with sepsis or septic shock predict mortality, multiple organ dysfunction syndrome (MODS), or organ dysfunction?" We also discuss the role of pro- and anti-inflammatory biomarkers and biomarkers associated with intestinal permeability, endothelial injury, organ dysfunction, blood–brain barrier (BBB) breakdown, brain injury, and short and long-term mortality. For sepsis, a range of biomarkers is identified, including fluid phase pattern recognition molecules (PRMs), complement system, cytokines, chemokines, damage-associated molecular patterns (DAMPs), non-coding RNAs, miRNAs, cell membrane receptors, cell proteins, metabolites, and soluble receptors. We also provide an overview of immune response biomarkers that can help identify or differentiate between systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and sepsis-associated encephalopathy. However, significant work is needed to identify the optimal combinations of biomarkers that can augment diagnosis, treatment, and good patient outcomes.
Elevated plasma Galectin-3 is associated with major adverse kidney events and death after ICU admission
Authors: Boutin L. , Legrand M. , Sadoune M. , Mebazaa A. , Gayat E. , Chadjichristos C. E. , Dépret F.
Published: January 2022

Background

Galectin-3 (Gal-3) is a proinflammatory and profibrotic protein especially overexpressed after Acute Kidney Injury (AKI). The early renal prognostic value of Gal-3 after AKI in critically ill patients remains unexplored. The objective was to evaluate the prognostic value of plasma level of Gal-3 for Major Adverse Kidney Events (MAKE) and mortality 30 days after ICU admission across AKI stages.

Methods

This is an ancillary study of a prospective, observational, multicenter cohort (FROG-ICU). AKI was defined using KDIGO definition.

Results

Two thousand and seventy-six patients had a Gal-3 plasma level measurement at ICU admission. Seven hundred and twenty-three (34.8%) were females and the median age was 63 [51, 74] years. Eight hundred and seven (38.9%) patients developed MAKE, 774 (37.3%) had AKI and mortality rate at 30 days was 22.4% (N = 465). Patients who developed MAKE had higher Gal-3 level at admission compared to patients without (30.2 [20.8, 49.2] ng/ml versus 16.9 [12.7, 24.3] ng/ml, p < 0.001, respectively. The area under the receiver operating characteristic curve of Gal-3 to predict MAKE was 0.76 CI95% [0.74–0.78], p < 0.001. Gal-3 was associated with MAKE (OR 1.80 CI95% [1.68–1.93], p < 0.001, non-adjusted and OR 1.37 CI95% [1.27–1.49], p < 0.001, adjusted). The use of Gal-3 improved prediction performance of prediction model including SAPSII, Screatadm, pNGAL with a NRI of 0.27 CI95%(0.16–0.38), p < 0.001. Median Gal-3 was higher in non-survivors than in survivors at 30 days (29.2 [20.2, 49.2] ng/ml versus 18.8 [13.3, 29.2] ng/ml, p < 0.001, respectively).

Conclusion

Plasma levels of Gal-3 were strongly associated with renal function, with an increased risk of MAKE and death after ICU admission.

Trial registration ClinicalTrials.gov NCT01367093. Registered on 6 June 2011.

Graphical abstract
JAFFAL: detecting fusion genes with long-read transcriptome sequencing
Authors: Davidson Nadia M. , Chen Ying , Sadras Teresa , Ryland Georgina L. , Blombery Piers , Ekert Paul G. , Göke Jonathan , Oshlack Alicia
Published: January 2022

In cancer, fusions are important diagnostic markers and targets for therapy. Long-read transcriptome sequencing allows the discovery of fusions with their full-length isoform structure. However, due to higher sequencing error rates, fusion finding algorithms designed for short reads do not work. Here we present JAFFAL, to identify fusions from long-read transcriptome sequencing. We validate JAFFAL using simulations, cell lines, and patient data from Nanopore and PacBio. We apply JAFFAL to single-cell data and find fusions spanning three genes demonstrating transcripts detected from complex rearrangements. JAFFAL is available at https://github.com/Oshlack/JAFFA/wiki.
Diurnal RNAPII-tethered chromatin interactions are associated with rhythmic gene expression in rice
Authors: Deng Li , Gao Baibai , Zhao Lun , Zhang Ying , Zhang Qing , Guo Minrong , Yang Yongqing , Wang Shuangqi , Xie Liang , Lou Hao , Ma Meng , Zhang Wei , Cao Zhilin , Zhang Qinghua , McClung C. Robertson , Li Guoliang , Li Xingwang
Published: January 2022

Background

The daily cycling of plant physiological processes is speculated to arise from the coordinated rhythms of gene expression. However, the dynamics of diurnal 3D genome architecture and their potential functions underlying the rhythmic gene expression remain unclear.

Results

Here, we reveal the genome-wide rhythmic occupancy of RNA polymerase II (RNAPII), which precedes mRNA accumulation by approximately 2 h. Rhythmic RNAPII binding dynamically correlates with RNAPII-mediated chromatin architecture remodeling at the genomic level of chromatin interactions, spatial clusters, and chromatin connectivity maps, which are associated with the circadian rhythm of gene expression. Rhythmically expressed genes within the same peak phases of expression are preferentially tethered by RNAPII for coordinated transcription. RNAPII-associated chromatin spatial clusters (CSCs) show high plasticity during the circadian cycle, and rhythmically expressed genes in the morning phase and non-rhythmically expressed genes in the evening phase tend to be enriched in RNAPII-associated CSCs to orchestrate expression. Core circadian clock genes are associated with RNAPII-mediated highly connected chromatin connectivity networks in the morning in contrast to the scattered, sporadic spatial chromatin connectivity in the evening; this indicates that they are transcribed within physical proximity to each other during the AM circadian window and are located in discrete “transcriptional factory” foci in the evening, linking chromatin architecture to coordinated transcription outputs.

Conclusion

Our findings uncover fundamental diurnal genome folding principles in plants and reveal a distinct higher-order chromosome organization that is crucial for coordinating diurnal dynamics of transcriptional regulation.