bluuebunny/crossref_metadata_2025 huggingface dataset:
Income-related inequality in distribution of health human resource among districts of Pakistan
Authors: Nawaz Rashed , Zhou Zhongliang , Khalid Neelum , Cao Dan , Liu Guanping , Ren Yangling , Zhao Dantong , Zhao Yaxin , Chen Yaru
Published: February 2021

Background

Solving inequality of health human resource (HHR) is one of the motives of Pakistan health policies, however, there is still exists a massive quantity of HHR inequality in almost every district of Pakistan. The main goal of this research is to scrutinize the disparity in allocation of human health resources among 114 regions of Pakistan from the year 2012 to 2016 and to expose the foundations and aspects of HHR inequality.

Methods

The data regarding this research has been obtained from Pakistan Statistical Bureau from the year 2012 to 2016. The statistics had also been collected from United Nation Development Program (UNDP) Pakistan 2017, Pakistan economic surveys, Ministry of finance Islamabad, Pakistan, Pakistan Social and Living standards Measurement (PSLM) Surveys from 2012 to 2016. The information incorporates district wise; the number of specialists and medical caretakers those are doctors and nurses, number of hospitals, number of beds, number of dispensaries, number of beds in dispensaries, urbanization, total estimated GNI per capita, infant mortality rate, geographical area, and population size. The concentration index is used to compute the extent of disparity in allocation of human health resources and decomposition analysis is also carried out to enumerate the contribution of each variable towards total inequality. Furthermore, the horizontal concentration was used to measure the participation of the need variable.

Results

7. The consequent Concentration Indexes (CI) of the doctors and nurses for the year 2016 are 0.60 (95% CI= 0.42, 0.78) and 0.67 (95% CI= 0.42, 0.92) respectively. Decomposition of the concentration indexes exposed that the monetary status accounts are the leading percentage contributor in doctors disparity (77.5, 44.9, 30.6, − 11.6% and 13%) and population size (− 20.7,-10.5%, 4.6, 49.8, 19.7%). Furthermore, the monetary status formulates the superior contribution HHR disparity from nurses inequality (104.5, 75.1, 59.2, − 54.3%, − 40.1%), and population size (− 53.7, − 53.6%, − 36.3, 83.8, 65.3%). Moreover, after the identification of the need variable the Horizontal Concentration Index (HCI) values of doctors from the year 2012 to 2016 are 0.62, 0.64, 0.63, 0.62 and 0.61 and HCI of the nurses are 0.69, 0.70, 0.69, 0.68 and 0.67.

Conclusion

The pro-rich disparity in allocation of HHR has been scrutinized from the year 2012 to 2016 among 114 districts of Pakistan. The hard concern of HHR disparity should be concentrated by the complete procedures from a multidisciplinary approach.
Impact of pharmacist-conducted anticoagulation patient education and telephone follow-up on transitions of care: a randomized controlled trial
Authors: Karaoui Lamis R. , Ramia Elsy , Mansour Hanine , Haddad Nisrine , Chamoun Nibal
Published: February 2021

Background

There is limited published data in Lebanon evaluating the impact of supplemental education for anticoagulants use, especially DOACs, on clinical outcomes such as bleeding. The study aims to assess the impact of pharmacist-conducted anticoagulation education and follow-up on bleeding and readmission rates.

Methods

This study was a randomized, non-blinded interventional study conducted between August 2017 and July 2019 in a tertiary care teaching Lebanese hospital. Participants were inpatients ≥18 years discharged on an oral anticoagulant for treatment. Block randomization was used. The control group received the standard nursing counseling while the intervention group additionally received pharmacy counseling. Phone call follow-ups were done on day 3 and 30 post-discharge. Primary outcomes included readmission rates and any bleeding event at day 3 and 30 post-discharge. Secondary outcomes included documented elements of education in the medical records and reported mortality upon day 30 post-discharge.

Results

Two hundred patients were recruited in the study (100 patients in each study arm) with a mean age of 73.9 years. In the pharmacist-counseled group, more patients contacted their physician within 3 days (14% versus 4%; p = 0.010), received explicit elements of education (p < 0.001) and documentation in the chart was better (p < 0.05). In the standard of care group, patients were more aware of their next physician appointment date (52% versus 31%, p < 0.001). No difference in bleeding rates at day 3 and 30 post-discharge was observed between the groups.

Conclusions

Although pharmacist-conducted anticoagulation education did not appear to reduce bleeding or readmission rates at day 30, pharmacist education significantly increased patient communication with their providers in the early days post-discharge.

Trial registration

Lebanon Clinical Trial Registry LBCTR2020033424. Retrospectively registered. Date of registration: 06/03/2020.
Characterizing RNA stability genome-wide through combined analysis of PRO-seq and RNA-seq data
Authors: Blumberg Amit , Zhao Yixin , Huang Yi-Fei , Dukler Noah , Rice Edward J. , Chivu Alexandra G. , Krumholz Katie , Danko Charles G. , Siepel Adam
Published: February 2021

Background

The concentrations of distinct types of RNA in cells result from a dynamic equilibrium between RNA synthesis and decay. Despite the critical importance of RNA decay rates, current approaches for measuring them are generally labor-intensive, limited in sensitivity, and/or disruptive to normal cellular processes. Here, we introduce a simple method for estimating relative RNA half-lives that is based on two standard and widely available high-throughput assays: Precision Run-On sequencing (PRO-seq) and RNA sequencing (RNA-seq).

Results

Our method treats PRO-seq as a measure of transcription rate and RNA-seq as a measure of RNA concentration, and estimates the rate of RNA decay required for a steady-state equilibrium. We show that this approach can be used to assay relative RNA half-lives genome-wide, with good accuracy and sensitivity for both coding and noncoding transcription units. Using a structural equation model (SEM), we test several features of transcription units, nearby DNA sequences, and nearby epigenomic marks for associations with RNA stability after controlling for their effects on transcription. We find that RNA splicing-related features are positively correlated with RNA stability, whereas features related to miRNA binding and DNA methylation are negatively correlated with RNA stability. Furthermore, we find that a measure based on U1 binding and polyadenylation sites distinguishes between unstable noncoding and stable coding transcripts but is not predictive of relative stability within the mRNA or lincRNA classes. We also identify several histone modifications that are associated with RNA stability.

Conclusion

We introduce an approach for estimating the relative half-lives of individual RNAs. Together, our estimation method and systematic analysis shed light on the pervasive impacts of RNA stability on cellular RNA concentrations.
LncRNA LINC00342 contributes to the growth and metastasis of colorectal cancer via targeting miR-19a-3p/NPEPL1 axis
Authors: Shen Peng , Qu Lili , Wang Jingjing , Ding Quchen , Zhou Chuanwen , Xie Rui , Wang Honggang , Ji Guozhong
Published: February 2021

Background

Long intergenic non-protein coding RNA 00342 (LINC00342) has been identified as a novel oncogene. However, the functional role of LINC00342 in colorectal cancer (CRC) remains unclear.

Methods

The expression of LINC00342 is detected by real-time PCR (RT-PCR) analysis. Cell proliferation, migration and invasion and xenograft model are examined to analyze the biological functions of LINC00342 in vitro and in vivo using colony formation, would healing and transwell analyses. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays are used to identify the target interactions between LINC00342, miR-19a-3p and aminopeptidase like 1 (NPEPL1).

Results

LINC00342 was highly expressed in CRC. Down-regulation of LINC00342 inhibited cell proliferation and metastasis of CRC cells. Moreover, knocking down LINC00342 inhibited the tumor growth in vivo. Mechanistic investigation revealed that LINC00342 might sponge miR-19a-3p to regulate NPEPL1 expression. Further investigation indicated that the ontogenesis facilitated by LINC00342 was inhibited due to the depletion of NPEPL1.

Conclusion

LINC00342 promotes CRC progression by competitively binding miR-19a-3p with NPEPL1.
The biological function of m6A reader YTHDF2 and its role in human disease
Authors: Wang Jin-yan , Lu Ai-qing
Published: February 2021

N6-methyladenosine (m6A) modification is a dynamic and reversible post-transcriptional modification and the most prevalent internal RNA modification in eukaryotic cells. YT521-B homology domain family 2 (YTHDF2) is a member of m6A “readers” and its role in human diseases remains unclear. Accumulating evidence suggests that YTHDF2 is greatly implicated in many aspects of human cancers and non-cancers through various mechanisms. YTHDF2 takes a great part in multiple biological processes, such as migration, invasion, metastasis, proliferation, apoptosis, cell cycle, cell viability, cell adhesion, differentiation and inflammation, in both human cancers and non-cancers. Additionally, YTHDF2 influences various aspects of RNA metabolism, including mRNA decay and pre-ribosomal RNA (pre-rRNA) processing. Moreover, emerging researches indicate that YTHDF2 predicts the prognosis of different cancers. Herein, we focus on concluding YTHDF2-associated mechanisms and potential biological functions in kinds of cancers and non-cancers, and its prospects as a prognostic biomarker.
Circular RNA CDR1as promotes tumor progression by regulating miR-432-5p/E2F3 axis in pancreatic cancer
Authors: Xiong Xingcheng , Feng Jiarui , Yang Xiao , Li Hanjun , Shi Qiao , Tao Jing , Chang Jian
Published: February 2021

Background

Pancreatic cancer (PC), characterized with high growth rate and metastatic rate. It’s urgently necessary to explore new mechanism of PC. Circular RNA/miRNA/mRNA network was widely reported to participate in the cancer progression.

Methods

In this research, circular RNA CDR1as (circCDR1as) was identified by microarray analysis and detected in pancreatic cancer (PC) tissues and cells. Transwell, colony-forming assay, nude mouse tumorigenicity assay were used to determine the function of circCDR1as in PC. Western blot, dual luciferase reporting test were applied to investigate the mechanism.

Results

We found that circCDR1as was highly expressed in PC tissues. The levels of circCDR1as in PC tissues and cells were higher than those in controls. CircCDR1as promoted the migration, invasion and proliferation of PC cells in vitro and tumor growth in vivo via mediating E2F3 expression by sponging miR-432-5p.

Conclusions

In conclusion, circCDR1as could promote the development of PC and might be a novel diagnostic target for PC.
Characterization of γδT cells in lung of Plasmodium yoelii-infected C57BL/6 mice
Authors: Wei Haixia , Jin Chenxi , Peng Anping , Xie Hongyan , Xie Shihao , Feng Yuanfa , Xie Anqi , Li Jiajie , Fang Chao , Yang Quan , Qiu Huaina , Qi Yanwei , Yin Zhinan , Wang Xinhua , Huang Jun
Published: February 2021

Background

Malaria has high morbidity and mortality rates in some parts of tropical and subtropical countries. Besides respiratory and metabolic function, lung plays a role in immune system. γδT cells have multiple functions in producing cytokines and chemokines, regulating the immune response by interacting with other cells. It remains unclear about the role of γδT cells in the lung of mice infected by malaria parasites.

Methods

Flow cytometry (FCM) was used to evaluate the frequency of γδT cells and the effects of γδT cells on the phenotype and function of B and T cells in Plasmodium yoelii-infected wild-type (WT) or γδTCR knockout (γδT KO) mice. Haematoxylin-eosin (HE) staining was used to observe the pathological changes in the lungs.

Results

The percentage and absolute number of γδT cells in the lung increased after Plasmodium infection (p < 0.01). More γδT cells were expressing CD80, CD11b, or PD-1 post-infection (p < 0.05), while less γδT cells were expressing CD34, CD62L, and CD127 post-infection (p < 0.05). The percentages of IL-4+, IL-5+, IL-6+, IL-21+, IL-1α+, and IL-17+ γδT cells were increased (p < 0.05), but the percentage of IFN-γ-expressing γδT cells decreased (p < 0.05) post-infection. The pathological changes in the lungs of the infected γδT KO mice were not obvious compared with the infected WT mice. The proportion of CD3+ cells and absolute numbers of CD3+ cells, CD3+ CD4+ cells, CD3+ CD8+ cells decreased in γδT KO infected mice (p < 0.05). γδT KO infected mice exhibited no significant difference in the surface molecular expression of T cells compared with the WT infected mice (p > 0.05). While, the percentage of IFN-γ-expressing CD3+ and CD3+ CD8+ cells increased in γδT KO infected mice (p < 0.05). There was no significant difference in the absolute numbers of the total, CD69+, ICOS+, and CD80+ B cells between the WT infected and γδT KO infected mice (p > 0.05).

Conclusions

The content, phenotype, and function of γδT cells in the lung of C57BL/6 mice were changed after Plasmodium infection. γδT cells contribute to T cell immune response in the progress of Plasmodium infection.
Genetic variation in the immune system and malaria susceptibility in infants: a nested case–control study in Nanoro, Burkina Faso
Authors: Natama Hamatandi Magloire , Rovira-Vallbona Eduard , Krit Meryam , Guetens Pieter , Sorgho Hermann , Somé M. Athanase , Traoré-Coulibaly Maminata , Valéa Innocent , Mens Petra F. , Schallig Henk D. F. H. , Berkvens Dirk , Kestens Luc , Tinto Halidou , Rosanas-Urgell Anna
Published: February 2021

Background

Genetic polymorphisms in the human immune system modulate susceptibility to malaria. However, there is a paucity of data on the contribution of immunogenetic variants to malaria susceptibility in infants, who present differential biological features related to the immaturity of their adaptive immune system, the protective effect of maternal antibodies and fetal haemoglobin. This study investigated the association between genetic variation in innate immune response genes and malaria susceptibility during the first year of life in 656 infants from a birth cohort survey performed in Nanoro, Burkina Faso.

Methods

Seventeen single nucleotide polymorphisms (SNPs) in 11 genes of the immune system previously associated with different malaria phenotypes were genotyped using TaqMan allelic hybridization assays in a Fluidigm platform.Plasmodium falciparuminfection and clinical disease were documented by active and passive case detection. Case–control association analyses for both alleles and genotypes were carried out using univariate and multivariate logistic regression. For cytokines showing significant SNP associations in multivariate analyses, cord blood supernatant concentrations were measured by quantitative suspension array technology (Luminex).

Results

Genetic variants in IL-1β (rs1143634) and FcγRIIA/CD32 (rs1801274)—both in allelic, dominant and co-dominant models—were significantly associated with protection from bothP. falciparuminfection and clinical malaria. Furthermore, heterozygote individuals with rs1801274 SNP in FcγRIIA/CD32 showed higher IL-1RA levels compared to wild-type homozygotes (P = 0.024), a cytokine whose production is promoted by the binding of IgG immune complexes to Fcγ receptors on effector immune cells.

Conclusions

These findings indicate that genetic polymorphisms in genes driving innate immune responses are associated to malaria susceptibility during the first year of life, possibly by modulating production of inflammatory mediators.
Reduced circulating dendritic cells in acute Plasmodium knowlesi and Plasmodium falciparum malaria despite elevated plasma Flt3 ligand levels
Authors: Loughland Jessica R. , Woodberry Tonia , Oyong Damian , Piera Kim A. , Amante Fiona H. , Barber Bridget E. , Grigg Matthew J. , William Timothy , Engwerda Christian R. , Anstey Nicholas M. , McCarthy James S. , Boyle Michelle J. , Minigo Gabriela
Published: February 2021

Background

Plasmodium falciparummalaria increases plasma levels of the cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), a haematopoietic factor associated with dendritic cell (DC) expansion. It is unknown if the zoonotic parasitePlasmodium knowlesiimpacts Flt3L or DC in human malaria. This study investigated circulating DC and Flt3L associations in adult malaria and in submicroscopic experimental infection.

Methods

Plasma Flt3L concentration and blood CD141+DC, CD1c+DC and plasmacytoid DC (pDC) numbers were assessed in (i) volunteers experimentally infected withP. falciparumand in Malaysian patients with uncomplicated (ii)P. falciparumor (iii)P. knowlesimalaria.

Results

Plasmodium knowlesicaused a decline in all circulating DC subsets in adults with malaria. Plasma Flt3L was elevated in acuteP. falciparumandP. knowlesimalaria with no increase in a subclinical experimental infection. Circulating CD141+DCs, CD1c+DCs and pDCs declined in all adults tested, for the first time extending the finding of DC subset decline in acute malaria to the zoonotic parasiteP. knowlesi.

Conclusions

In adults, submicroscopicPlasmodiuminfection causes no change in plasma Flt3L but does reduce circulating DCs. Plasma Flt3L concentrations increase in acute malaria, yet this increase is insufficient to restore or expand circulating CD141+DCs, CD1c+DCs or pDCs. These data imply that haematopoietic factors, yet to be identified and not Flt3L, involved in the sensing/maintenance of circulating DC are impacted by malaria and a submicroscopic infection. The zoonoticP. knowlesiis similar to otherPlasmodiumspp in compromising DC in adult malaria.
Coupled liquid biopsy and bioinformatics for pancreatic cancer early detection and precision prognostication
Authors: Hou Jun , Li XueTao , Xie Ke-Ping
Published: February 2021

Early detection and diagnosis are the key to successful clinical management of pancreatic cancer and improve the patient outcome. However, due to the absence of early symptoms and the aggressiveness of pancreatic cancer, its 5-year survival rate remains below 5 %. Compared to tissue samples, liquid biopsies are of particular interest in clinical settings with respect to minimal invasiveness, repeated sampling, complete representation of the entire or multi-site tumor bulks. The potential of liquid biopsies in pancreatic cancer has been demonstrated by many studies which prove that liquid biopsies are able to detect early emergency of pancreatic cancer cells, residual disease, and recurrence. More interestingly, they show potential to delineate the heterogeneity, spatial and temporal, of pancreatic cancer. However, the performance of liquid biopsies for the diagnosis varies largely across different studies depending of the technique employed and also the type and stage of the tumor. One approach to improve the detect performance of liquid biopsies is to intensively inspect circulome and to define integrated biomarkers which simultaneously profile circulating tumor cells and DNA, extracellular vesicles, and circulating DNA, or cell free DNA and proteins. Moreover, the diagnostic validity and accuracy of liquid biopsies still need to be comprehensively demonstrated and validated.
Comparative analysis of laparoscopic proximal gastrectomy plus semi-embedded valve anastomosis with laparoscopic total gastrectomy for adenocarcinoma of the esophagogastric junction: a single-center retrospective cohort study
Authors: Wu Yupeng , Zhang Shihao , Wang Liting , Hu Xuya , Zhang Zhanxue
Published: February 2021

Background

We invented a new antireflux anastomosis method for use in proximal gastrectomy for adenocarcinoma of the esophagogastric junction (AEG) and named it semi-embedded valve anastomosis (SEV). This study was conducted to compare and analyze the short-term efficacy and long-term prognosis of this anastomosis reconstruction method versus laparoscopic total gastrectomy (LTG).

Methods

We retrospectively analyzed the general data and surgical outcomes of patients with AEG who underwent three united laparoscopic proximal gastrectomy plus semi-embedded valve anastomosis (TULPG-SEV, N = 20) and LTG (N = 20) at our hospital from January 2015 to September 2017 and investigated the incidence of postoperative reflux esophagitis and postoperative nutritional status between the two groups. Survival analysis was also performed.

Results

The operative time (178.25 ± 15.41 vs 196.5 ± 21.16 min) and the gastrointestinal reconstruction time (19.3 ± 2.53 vs 34.65 ± 4.88 min) of the TULPG-SEV group were significantly less than that of the LTG group. There was no difference in intraoperative blood loss, length of hospital stay, and postoperative complications. There was no difference in the scores on the postoperative reflux disease questionnaires (RDQs) conducted 1 month (P = 0.501), 3 months (P = 0.238), and 6 months (P = 0.655) after surgery between the TULPG-SEV group and LTG group. Gastroscopy revealed 2 cases of reflux esophagitis (grade B or higher) in each group. The postoperative hemoglobin level was better in the TULPG-SEV group than in the LTG group, and the difference was most noticeable at 1 month after surgery (P = 0.024) and 3 months after surgery (P = 0.029). The levels of albumin and total protein were not significantly different between the groups. There were more patients with weight loss over 5 kg after surgery in the LTG group than in the TULPG-SEV group (P = 0.043). There was no significant difference in the 3-year overall survival rate between the two groups (P = 0.356).

Conclusion

SEV has a certain antireflux effect and can reduce the anastomosis time. Proximal gastrectomy may be better than total gastrectomy for maintaining postoperative hemoglobin levels and reducing weight loss.
WHO key access antibiotics prices, availability and affordability in private sector pharmacies in Pakistan
Authors: Saleem Zikria , Saeed Hamid , Akbar Zunaira , Saeed Amna , Khalid Saleha , Farrukh Laiba , Irfan Aleena , Anam Azka , Hassali Mohamed Azmi , Rasheed Huma , Babar Zaheer-Ud-Din
Published: February 2021

Background

Poor availability and unaffordability of key access antibiotics may increase antimicrobial resistance in the community by promoting inappropriate antibiotic selection and abridged therapy compliance.

Objective

To check the prices, availability, and affordability of the World Health Organization (WHO) key access antibiotics in private sector pharmacies of Lahore, Pakistan.

Methodology

A survey of WHO key access antibiotics from WHO essential medicine list 2017 was conducted in private sector pharmacies of 4 different regions of Lahore employing adapted WHO/HAI methodology. The comparison of prices and availability between originator brands (OB) and lowest price generics (LPG) were conducted followed by the effect of medicine price differences on patient’s affordability. The data were analyzed using a preprogrammed WHO Microsoft excel workbook.

Results

The mean availability of OB products was 45.20% and the availability of LPGs was 40.40%. The OBs of co-amoxiclav, clarithromycin and metronidazole and LPGs of azithromycin and ciprofloxacin were easily available (100%) in all private sector pharmacies. Whereas, antibiotics like chloramphenicol, cloxacillin, nitrofurantoin, spectinomycin, and cefazolin were totally unavailable in all the surveyed pharmacies. The OBs and LPGs with high MPRs were ceftriaxone (OB; 15.31, LPG; 6.38) and ciprofloxacin (OB; 12.42, LPG; 5.77). The median of brand premium obtained was 38.7%, which varied between the lowest brand premium of 3.97% for metronidazole and highest for ceftriaxone i.e. 140%. The cost of standard treatment was 0.5 day’s wage (median) if using OB and 0.4 day’s wage (median) for LPG, for a lowest paid unskilled government worker. Treatment with OB and LPG was unaffordable for ciprofloxacin (OB; 2.4, LPG; 1.1) & cefotaxime (OB; 12.7, LPG; 8.1).

Conclusion

There is dire need to properly implement price control policies to better regulate fragile antibiotic supply system so that the availability of both OB and LPG of key access antibiotics should be increased. The prices could be reduced by improving purchasing efficiency, excluding taxes and regulating mark-ups. This could increase the affordability of patients to complete their antibiotic therapy with subsequent reduction in antimicrobial resistance.
Anti-Warburg effect by targeting HRD1-PFKP pathway may inhibit breast cancer progression
Authors: Fan Ya , Wang Jia , Xu Yuemei , Wang Yipin , Song Tao , Liang Xiubin , Jin Feng , Su Dongming
Published: February 2021

Background

Our previous studies have shown that the E3 ubiquitin ligase of HMG-CoA reductase degradation 1 (HRD1) functions as a tumor suppressor, as overexpression of HRD1 suppressed breast cancer proliferation and invasion. However, its role in breast cancer cell glucose metabolism was unclear. Here, our aim was to uncover the role and molecular mechanisms of HRD1 in regulating aerobic glycolysis in breast cancer.

Methods

The effect of HRD1 on robic glycolysis in breast cancer cells were assessed. Then the proliferation, colony formation ability, invasion and migration of breast cancer cells were evaluated. The relationship between HRD1 and PFKP was validated by Mass spectrometry analysis, immunofluorescence and co-immunoprecipitation. The level of PFKP ubiquitination was measured using ubiquitylation assay. Furthermore, the tumor growth and metastasis in mice xenografts were observed.

Results

We found that upregulation of HRD1 clearly decreased aerobic glycolysis, and subsequently inhibited breast cancer proliferation and invasion. Mass spectrometry analysis results revealed a large HRD1 interactome, which included PFKP (platelet isoform of phosphofructokinase), a critical enzyme involved in the Warburg Effect in breast cancer. Mechanistically, HRD1 interacted and colocalized with PFKP in the cytoplasm, targeted PFKP for ubiquitination and degradation, and ultimately reduced PFKP expression and activity in breast cancer cells. HRD1 inhibited breast cancer growth and metastasis in vivo through a PFKP-dependent way

Conclusions

Our findings reveal a new regulatory role of HRD1 in Warburg effect and provide a key contributor in breast cancer metabolism.

Graphic abstract
S-1-propenylcysteine improves TNF-α-induced vascular endothelial barrier dysfunction by suppressing the GEF-H1/RhoA/Rac pathway
Authors: Kunimura Kayo , Miki Satomi , Takashima Miyuki , Suzuki Jun-ichiro
Published: February 2021

Background

Vascular endothelial barrier function is maintained by cell-to-cell junctional proteins and contributes to vascular homeostasis. Various risk factors such as inflammation disrupt barrier function through down-regulation of these proteins and promote vascular diseases such as atherosclerosis. Previous studies have demonstrated that aged garlic extract (AGE) and its sulfur-containing constituents exert the protective effects against several vascular diseases such as atherosclerosis. In this study, we examined whether AGE and its sulfur-containing constituents improve the endothelial barrier dysfunction elicited by a pro-inflammatory cytokine, Tumor-necrosis factor-α (TNF-α), and explored their mode of action on TNF-α signaling pathway.

Methods

Human umbilical vein endothelial cells (HUVECs) were treated with test substances in the presence of TNF-α for various time periods. The endothelial permeability was measured by using a transwell permeability assay. The localization of cell-to-cell junctional proteins and actin cytoskeletons were visualized by immunostaining. RhoA and Rac activities were assessed by using GTP-binding protein pulldown assay. Gene and protein expression levels of signaling molecules were analyzed by real-time PCR and western blotting, respectively.

Results

We found that AGE and its major sulfur-containing constituent, S-1-propenylcysteine (S1PC), reduced hyperpermeability elicited by TNF-α in HUVECs. In addition, S1PC inhibited TNF-α-induced production of myosin light chain (MLC) kinase and inactivation of MLC phosphatase through the suppression of the Rac and RhoA signaling pathways, respectively, which resulted in the dephosphorylation of MLC2, a key factor of actin remodeling. Moreover, S1PC inhibited the phosphorylation and activation of guanine nucleotide exchange factor-H1 (GEF-H1), a common upstream key molecule and activator of Rac and RhoA. These effects of S1PC were accompanied by its ability to prevent the disruption of junctional proteins on the cell–cell contact regions and the increase of actin stress fibers induced by TNF-α.

Conclusions

The present study suggested that AGE and its major constituent, S1PC, improve endothelial barrier disruption through the protection of junctional proteins on plasma membrane.
Role of SIK1 in the transition of acute kidney injury into chronic kidney disease
Authors: Hu Jinxiu , Qiao Jiao , Yu Qun , Liu Bing , Zhen Junhui , Liu Yue , Ma Qiqi , Li Yanmei , Wang Qianhui , Wang Cheng , Lv Zhimei
Published: February 2021

Background

Acute kidney injury (AKI), with a high morbidity and mortality, is recognized as a risk factor for chronic kidney disease (CKD). AKI-CKD transition has been regarded as one of the most pressing unmet needs in renal diseases. Recently, studies have showed that salt inducible kinase 1 (SIK1) plays a role in epithelial-mesenchymal transition (EMT) and inflammation, which are the hallmarks of AKI-CKD transition. However, whether SIK1 is involved in AKI-CKD transition and by what mechanism it regulates AKI-CKD transition remains unknown.

Methods

We firstly detected the expression of SIK1 in kidney tissues of AKI patients and AKI mice by immunohistochemistry staining, and then we established Aristolochic acid (AA)-induced AKI-CKD transition model in C57BL/6 mice and HK2 cells. Subsequently, we performed immunohistochemistry staining, ELISA, real-time PCR, Western blot, immunofluorescence staining and Transwell assay to explore the role and underlying mechanism of SIK1 on AKI-CKD transition.

Results

The expression of SIK1 was down-regulated in AKI patients, AKI mice, AA-induced AKI-CKD transition mice, and HK2 cells. Functional analysis revealed that overexpression of SIK1 alleviated AA-induced AKI-CKD transition and HK2 cells injury in vivo and in vitro. Mechanistically, we demonstrated that SIK1 mediated AA-induced AKI-CKD transition by regulating WNT/β-catenin signaling, the canonical pathway involved in EMT, inflammation and renal fibrosis. In addition, we discovered that inhibition of WNT/β-catenin pathway and its downstream transcription factor Twist1 ameliorated HK2 cells injury, delaying the progression of AKI-CKD transition.

Conclusions

Our study demonstrated, for the first time, a protective role of SIK1 in AKI-CKD transition by regulating WNT/β-catenin signaling pathway and its downstream transcription factor Twist1, which will provide novel insights into the prevention and treatment AKI-CKD transition in the future.
Cross-talk between ANGPTL4 gene SNP Rs1044250 and weight management is a risk factor of metabolic syndrome
Authors: Tong Zhoujie , Peng Jie , Lan Hongtao , Sai Wenwen , Li Yulin , Xie Jiaying , Tan Yanmin , Zhang Wei , Zhong Ming , Wang Zhihao
Published: February 2021

Background

The prevalence of metabolic syndrome (Mets) is closely related to an increased incidence of cardiovascular events. Angiopoietin-like protein 4 (ANGPTL4) is contributory to the regulation of lipid metabolism, herein, may provide a target for gene-aimed therapy of Mets. This observational case control study was designed to elucidate the relationship between ANGPTL4 gene single nucleotide polymorphism (SNP) rs1044250 and the onset of Mets, and to explore the interaction between SNP rs1044250 and weight management on Mets.

Methods

We have recruited 1018 Mets cases and 1029 controls in this study. The SNP rs1044250 was genotyped with blood samples, base-line information and Mets-related indicators were collected. A 5-year follow-up survey was carried out to track the lifestyle interventions and changes in Mets-related indicators.

Results

ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference (OR 1.618, 95% CI [1.119–2.340]; p = 0.011), elevated blood pressure (OR 1.323, 95% CI [1.002–1.747]; p = 0.048), and Mets (OR 1.875, 95% CI [1.363–2.580]; p < 0.001). The follow-up survey shows that rs1044250 CC genotype patients with weight gain have an increased number of Mets components (M [Q1, Q3]: CC 1 (0, 1), CT + TT 0 [− 1, 1]; p = 0.021); The interaction between SNP rs1044250 and weight management is a risk factor for increased systolic blood pressure (β = 0.075, p < 0.001) and increased diastolic blood pressure (β = 0.097, p < 0.001), the synergistic effect of weight management and SNP rs1044250 is negative (S < 1).

Conclusion

ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference and elevated blood pressure, therefore, for Mets. However, patients with wild type SNP 1044250 are more likely to have Mets when the body weight is increased, mainly due to elevated blood pressure.
Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer
Authors: Chen Zijian , Huang Zenghong , Luo Yanxin , Zou Qi , Bai Liangliang , Tang Guannan , Wang Xiaolin , Cao Guangwen , Huang Meijin , Xiang Jun , Yu Huichuan
Published: February 2021

Background

Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value ofNTRKsgene in colorectal cancer (CRC).

Methods

An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP).

Results

The profiles in six CRC cohorts showed thatNTRKsgene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region withinNTRK3promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC.NTRK3promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition ofNTRK3promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64,P = 0.032). Finally,NTRK3promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma.

Conclusions

This study highlights the essential value ofNTRK3methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.
One-tube SARS-CoV-2 detection platform based on RT-RPA and CRISPR/Cas12a
Authors: Sun Yangyang , Yu Lei , Liu Chengxi , Ye Shanting , Chen Wei , Li Dechang , Huang Weiren
Published: February 2021

Background

COVID-19 has spread rapidly around the world, affecting a large percentage of the population. When lifting certain mandatory measures for an economic restart, robust surveillance must be established and implemented, with nucleic acid detection for SARS-CoV-2 as an essential component.

Methods

We tried to develop a one-tube detection platform based on RT-RPA (Reverse Transcription and Recombinase Polymerase Isothermal Amplification) and DNA Endonuclease-Targeted CRISPR Trans Reporter (DETECTR) technology, termed OR-DETECTR, to detect SARS-CoV-2. We designed RT-RPA primers of the RdRp and N genes following the SARS-CoV-2 gene sequence. We optimized reaction components so that the detection process could be carried out in one tube. Specificity was demonstrated by detecting nucleic acid samples from pseudoviruses from seven human coronaviruses and Influenza A (H1N1). Clinical samples were used to validate the platform and all results were compared to rRT-PCR. RNA standards and pseudoviruses diluted by different gradients were used to demonstrate the detection limit. Additionally, we have developed a lateral flow assay based on OR-DETECTR for detecting COVID-19.

Results

The OR-DETECTR detection process can be completed in one tube, which takes approximately 50 min. This method can specifically detect SARS-CoV-2 from seven human coronaviruses and Influenza A (H1N1), with a low detection limit of 2.5 copies/µl input (RNA standard) and 1 copy/µl input (pseudovirus). Results of six samples from SARS-CoV-2 patients, eight samples from patients with fever but no SARS-CoV-2 infection, and one mixed sample from 40 negative controls showed that OR-DETECTR is 100% consistent with rRT-PCR. The lateral flow assay based on OR-DETECTR can be used for the detection of COVID-19, and the detection limit is 2.5 copies/µl input.

Conclusions

The OR-DETECTR platform for the detection of COVID-19 is rapid, accurate, tube closed, easy-to-operate, and free of large instruments.
A nomogram to predict the high-risk RS in HR+/HER2-breast cancer patients older than 50 years of age
Authors: Yu Jing , Wu Jiayi , Huang Ou , He Jianrong , Zhu Li , Chen Weiguo , Li Yafen , Chen Xiaosong , Shen Kunwei
Published: February 2021

Background

The 21-gene recurrence score (RS) testing can predict the prognosis for luminal breast cancer patients. Meanwhile, patients > 50 years with RS > 25 have improved survival with adjuvant chemotherapy. The current study aimed to develop a nomogram with routine parameters to predict RS.

Methods

We included patients diagnosed with hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative who underwent the 21-gene RS testing and aged > 50 years. The primary outcome was high-risk RS (> 25). Univariate and multivariate analyses were performed to identify significant predictors. A predictive nomogram based on logistic model was developed and evaluated with receiver operating characteristic (ROC) curves. The nomogram was internally validated for discrimination and calibration with bootstrapping method, and externally validated in another cohort. We then assessed the nomogram in different subgroups of patients and compared it with several published models.

Results

A total of 1100 patients were included. Five clinicopathological parameters were used as predictors of a high-risk RS, including tumor grade, histologic subtype, ER expression, PR expression, and Ki-67 index. The area under the curve (AUC) was 0.798 (95% CI 0.772–0.825) and optimism adjusted AUC was 0.794 (95% CI 0.781–0.822). External validation demonstrated an AUC value of 0.746 (95% CI 0.685–0.807), which had no significant difference with the training cohort (P = 0.124). Calibration plots indicated that the nomogram-predicted results were well fitted to the actual outcomes in both internal and external validation. The nomogram had better discriminate ability in patients who had tumors > 2 cm (AUC = 0.847, 95% CI 0.804–0.890). When compared with four other existing models, similar AUC was observed between our nomogram and the model constructed by discriminate Lee et al.

Conclusions

We developed a user-friendly nomogram to predict the high-risk RS in luminal breast cancer patients who were older than 50 years of age, which could guide treatment decision making for those who have no access to the 21-gene RS testing.
The potential role of Colchicine in preventing coronary vascular disease in childhood‐onset lupus: a new view on an old drug
Authors: Abel Dori , Ardoin Stacy P. , Gorelik Mark
Published: February 2021

Background

Patients with systemic lupus erythematous have a significantly increased risk of cardiovascular disease, which is not fully explained by traditional cardiovascular disease risk factors. Despite increasing life expectancy in patients with systemic lupus erythematous, mortality due to cardiovascular disease, the major cause of death in these patients, has not changed. Children with lupus suffer from more aggressive disease compared to their adult counterparts, and there is a growing concern for their increased risk of cardiovascular disease as they age.

Body:

There is an unmet need for therapies to address the increased risk of cardiovascular disease in childhood-onset lupus. Colchicine has many anti-inflammatory and cardiovascular protective properties, including inhibition of IL-1β and IL-18 activity, key proinflammatory cytokines that are predictive of future adverse cardiovascular events. In the Colchicine Cardiovascular Outcomes Trial (COLCOT), colchicine was recently found to have significant benefit with minimal risk in adults with previous myocardial infarction for prevention of secondary vascular disease. While adult studies are promising, no studies have been conducted in pediatric patients to investigate colchicine’s potential for cardiovascular protection in children and adolescents with lupus.

Conclusions

Studies investigating colchicine’s potential role for cardiovascular protection are needed in pediatric patients with systemic lupus erythematous.
Impact of gestational diabetes mellitus on the duration of breastfeeding in primiparous women: an observational cohort study
Authors: Laine Merja K. , Kautiainen Hannu , Gissler Mika , Pennanen Pirjo , Eriksson Johan G.
Published: February 2021

Background

The impact of gestational diabetes mellitus (GDM) on the duration of breastfeeding varies between shortening and no impact. Breastfeeding seems to reduce both maternal and offspring risk for type 2 diabetes and offspring risk for overweight or obesity later in life. The aim of our study was to evaluate in primiparous women whether GDM had an influence on the duration of breastfeeding, and further, to evaluate the factors that influenced on the duration of breastfeeding.

Methods

The study cohort (N = 1089) consisted of all primiparous women with a Finnish background excluding women with pre-existing diabetes mellitus who lived in the city of Vantaa, Finland, gave birth to a singleton living child between 2009 and 2015, and with valid data on breastfeeding available. The diagnosis of GDM was based on a standard 75 g 2-h oral glucose tolerance test. Data were obtained from Finnish national registers and from the medical records of the city of Vantaa.

Results

No differences were observed in the duration of breastfeeding between women diagnosed with GDM and without GDM, 7.5 (Standard Deviation [SD] 3.7) months versus 7.9 (SD 3.5) months (p = 0.17). Women diagnosed with GDM breastfed boys for a longer duration than girls (maternal age, pre-pregnancy body mass index, marital status, educational attainment, duration of pregnancy, and smoking habits adjusted p = 0.042). Women who breastfed < 6 months were younger, were more likely smokers, had shorter education, and higher pre-pregnancy body mass index than women who breastfed over 6 months (p <  0.001 for linearity).

Conclusions

In primiparous women GDM did not influence breastfeeding duration. The positive health effects of breastfeeding should be emphasized especially in young, overweight and less educated women in order to minimize the risk of obesity and type 2 diabetes for themselves and their offspring.
‘Resurgent’, ‘twin’ or ‘silent’ epidemic? A select data overview and observations on increasing psycho-stimulant use and harms in North America
Authors: Fischer Benedikt , O’Keefe-Markman Caroline , Lee Angelica , Daldegan-Bueno Dimitri
Published: February 2021

In the early 2000s, increasing prevalence of psycho-stimulant (e.g., crack/cocaine, methamphetamine) use and related harms, including severe adverse health outcomes, was observed among - mostly marginalized - populations of persons using illicit drugs in North America, underscoring an urgent need for interventions options towards improved prevention and treatment. By about 2010, however, the ‘opioid crisis’, featuring unprecedented use and public health burden, had accelerated into full force in North America, largely muting attention to the psycho-stimulant issue until recently. Recent surveillance data on drug use and related mortality/morbidity from the present decade has documented a marked resurgence of psycho-stimulant use and harms especially in at-risk populations, commonly in direct combination with opioids, across North America, resulting in a ‘twin epidemic’ comprised of opioids and psycho-stimulants We briefly review select epidemiological data indicators for these developments from the United States and Canada; in the latter jurisdiction, related evidence has been less prevalent and systematic but corroborating the same trends. Evidently, the (widely ongoing) focus on the ‘opioid epidemic’ as a ‘mono-type’ drug problem has become an anachronism that requires urgent and appropriate correction. We then briefly consider existing, evidence-based options for – prevention and treatment – interventions targeting psycho-stimulant use and harms, which are substantially more limited and/or less efficacious than those available for problematic opioid use, while presenting major gaps and challenges. The observed resurgence of psycho-stimulants may, indirectly, relate to recent efforts towards curtailing (medical) opioid availability, thereby accelerating demand and supply for both illicit opioids and psycho-stimulants. The presently unfolding ‘twin epidemic’ of opioids and psycho-stimulants, combined with limited intervention resources, presents an acute challenge for public health and may crucially undermine actively extensive efforts to reduce opioid-related health harms in North America.