bluuebunny/crossref_metadata_2025 huggingface dataset:
Health system impacts of SARS-CoV − 2 variants of concern: a rapid review
Authors: Dol Justine , Boulos Leah , Somerville Mari , Saxinger Lynora , Doroshenko Alexander , Hastings Stephanie , Reynolds Bearach , Gallant Allyson , Shin Hwayeon Danielle , Wong Helen , Crowther Daniel , Macdonald Marilyn , Martin-Misener Ruth , McCulloch Holly , Tricco Andrea C. , Curran Janet A.
Published: April 2022

Background

As of November 25th 2021, four SARS-CoV − 2 variants of concern (VOC: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2)) have been detected. Variable degrees of increased transmissibility of the VOC have been documented, with potential implications for hospital and health system capacity and control measures. This rapid review aimed to provide a synthesis of evidence related to health system responses to the emergence of VOC worldwide.

Methods

Seven databases were searched up to September 27, 2021, for terms related to VOC. Titles, abstracts, and full-text documents were screened independently by two reviewers. Data were extracted independently by two reviewers using a standardized form. Studies were included if they reported on at least one of the VOC and health system outcomes.

Results

Of the 4877 articles retrieved, 59 studies were included, which used a wide range of designs and methods. Most of the studies reported on Alpha, and all except two reported on impacts for capacity planning related to hospitalization, intensive care admissions, and mortality. Most studies (73.4%) observed an increase in hospitalization, but findings on increased admission to intensive care units were mixed (50%). Most studies (63.4%) that reported mortality data found an increased risk of death due to VOC, although health system capacity may influence this. No studies reported on screening staff and visitors or cohorting patients based on VOC.

Conclusion

While the findings should be interpreted with caution as most of the sources identified were preprints, evidence is trending towards an increased risk of hospitalization and, potentially, mortality due to VOC compared to wild-type SARS-CoV − 2. There is little evidence on the need for, and the effect of, changes to health system arrangements in response to VOC transmission.
Effects of prehospital management in out-of-hospital cardiac arrest: advanced airway and adrenaline administration
Authors: Wang Yu , Zhang Qun , Qu Guang Bo , Fang Fang , Dai Xiao Kang , Yu Liang Xi , Zhang Hong
Published: April 2022

Background

There is uncertainty about the best approaches for advanced airway management (AAM) and the effectiveness of adrenaline treatments in Out-of-hospital cardiac arrest (OHCA). This study aimed to evaluate whether AAM and adrenaline administration provided by Emergency Medical Service (EMS) can improve the outcomes of OHCA.

Methods

This study was a prospective analysis of collected data based on OHCA adult patients treated by the EMS in China from January 2019 to December 2020.The patients were divided into AAM group and no AAM group, and into subgroups according to whether adrenaline was used. The outcome was rate of return of spontaneous circulation (ROSC), survival to admission and hospital discharge.

Results

1533 OHCA patients were reported. The probability of ROSC outcome and survival admission in the AAM group was significantly higher, compared with no AAM group. The probability of ROSC outcome in the AAM group increased by 66% (adjusted OR: 1.66, 95%CI, 1.02–2.71). There were no significant differences in outcomes between the adrenaline and no adrenaline groups. The combined treatment of AAM and adrenaline increased the probability of ROSC outcome by 114% (adjusted OR, 2.14, 95%CI, 1.20–3.81) and the probability of survival to admission increased by 115% (adjusted OR, 2.15, 95%CI, 1.16–3.97).

Conclusions

The prehospital AAM and the combined treatment of AAM and adrenaline in OHCA patients are both associated with an increased rate of ROSC. The combined treatment of AAM and adrenaline can improve rate of survival to admission in OHCA patients.
Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR
Authors: Ueno Takayuki , Kitano Shigehisa , Masuda Norikazu , Ikarashi Daiki , Yamashita Makiko , Chiba Tomohiro , Kadoya Takayuki , Bando Hiroko , Yamanaka Takashi , Ohtani Shoichiro , Nagai Shigenori , Nakayama Takahiro , Takahashi Masato , Saji Shigehira , Aogi Kenjiro , Velaga Ravi , Kawaguchi Kosuke , Morita Satoshi , Haga Hironori , Ohno Shinji , Toi Masakazu
Published: April 2022

Background

Triple-negative breast cancer (TNBC) is a biologically diverse disease, with characteristics such as homologous recombination deficiency (HRD), gene mutation, and immune reactions. Japan Breast Cancer Research Group 22 is a multicenter trial examining TNBC’s response to neoadjuvant chemotherapy (NAC) according to the HRD status. This translational research investigated the clinical significance of the immune microenvironment of TNBC in association with HRD, tumor BRCA1/2 (tBRCA1/2) mutation, and response to NAC.

Methods

Patients aged below 65 years with high HRD or germline BRCA1/2 (gBRCA1/2) mutation randomly received paclitaxel + carboplatin (group A1) or eribulin + carboplatin (A2), followed by anthracycline. Patients aged below 65 years with low HRD or those aged 65 years or older without gBRCA1/2 mutation randomly received eribulin + cyclophosphamide (B1) or eribulin + capecitabine (B2); nonresponders to the first four cycles of the therapy received anthracycline. A pathological complete response (pCR) was defined as the absence of residual cancer cells in the tissues. Pretreatment biopsy specimens were stained by multiplexed fluorescent immunohistochemistry using antibodies against CD3, CD4, CD8, Foxp3, CD204, and pan-cytokeratin. Immune cells with specific phenotypes were counted per mm2 in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response.

Results

This study analyzed 66 samples. T1 tumors had a significantly higher density of intratumoral CD8+ T cells than T2 or larger tumors. The tBRCA1/2 mutation or HRD status was not associated with the density of any immune cell. The density of intratumoral and stromal CD4+ T cells was higher in patients showing pCR than in those without pCR. In a multivariate analysis, intratumoral and stromal CD4+ T cell density significantly predicted pCR independent of age, chemotherapy dose, HRD status, and treatment groups (P = 0.009 and 0.0057, respectively). In a subgroup analysis, the predictive value of intratumoral and stromal CD4+ T cell density persisted in the platinum-containing chemotherapy group (A1+A2) but not in the non-platinum-containing group (B1+B2).

Conclusions

Intratumoral and stromal CD4+ T cell density was an independent predictor of pCR in patients with TNBC. A larger study is warranted to confirm the results.

Trial registration

UMIN000023162
Clinical features and treatment response to differentiate idiopathic peritonitis from non-strangulating intestinal infarction of the pelvic flexure associated with Strongylus vulgaris infection in the horse
Authors: Hedberg-Alm Ylva , Tydén Eva , Tamminen Lena-Mari , Lindström Lisa , Anlén Karin , Svensson Maria , Riihimäki Miia
Published: April 2022

Background

Peritonitis in horses secondary to non-strangulating infarction (NSII) has a guarded prognosis, even after intestinal resection. In contrast, horses with idiopathic peritonitis respond well to medical treatment. Affected horses in both cases often show signs of both colic and systemic inflammation, but early diagnosis is crucial for optimal treatment and an accurate prognosis. One cause of NSII is thrombus formation secondary toStrongylus vulgarislarval migration. There has been a documented increase inS. vulgarisprevalence in Sweden since the implementation of selective anthelmintic treatment in 2007, which subsequently could result in a rise in NSII cases. In a retrospective clinical study, medical records from cases diagnosed with NSII of the pelvic flexure or idiopathic peritonitis from three equine referral hospitals in Sweden during 2017–2020 were reviewed. Information including demographic data, relevant medical history, and clinical- and laboratory parameters were obtained from patient records. To facilitate the differentiation between cases of idiopathic peritonitis and cases with confirmed NSII of the pelvic flexure, the aim of the study was to compare clinical and laboratory parameters, clinical progression and initial response to antimicrobial treatment. A secondary aim was to compare survival-rates.

Results

Horses with NSII (n = 20) were significantly more likely to present during the winter months with a poorer response to medical treatment within 48 h. Cases of idiopathic peritonitis (n = 107) had a 100% survival rate with medical treatment, although one case required surgical correction of a colon displacement. In comparison, all confirmed NSII cases were non-responsive to antimicrobial treatment, with a survival rate to discharge of 50% after colon resection. Specific rectal findings and peripheral blood neutropenia were strongly associated with NSII.

Conclusions

In Sweden, idiopathic peritonitis cases still predominate overS. vulgarisassociated NSII cases and have an excellent survival rate with antimicrobial treatment. However, horses presenting with septic peritonitis during the winter months with a palpable rectal mass and displaying fever and colic signs beyond 48 h of medical treatment are likely to suffer from NSII of the pelvic flexure and should be considered for abdominal surgery.
Integrative analysis of eQTL and GWAS summary statistics reveals transcriptomic alteration in Alzheimer brains
Authors: Varathan Pradeep , Gorijala Priyanka , Jacobson Tanner , Chasioti Danai , Nho Kwangsik , Risacher Shannon L. , Saykin Andrew J. , Yan Jingwen
Published: April 2022

Background

Large-scale genome-wide association studies have successfully identified many genetic variants significantly associated with Alzheimer’s disease (AD), such as rs429358, rs11038106, rs723804, rs13591776, and more. The next key step is to understand the function of these SNPs and the downstream biology through which they exert the effect on the development of AD. However, this remains a challenging task due to the tissue-specific nature of transcriptomic and proteomic data and the limited availability of brain tissue.In this paper, instead of using coupled transcriptomic data, we performed an integrative analysis of existing GWAS findings and expression quantitative trait loci (eQTL) results from AD-related brain regions to estimate the transcriptomic alterations in AD brain.

Results

We used summary-based mendelian randomization method along with heterogeneity in dependent instruments method and were able to identify 32 genes with potential altered levels in temporal cortex region. Among these, 10 of them were further validated using real gene expression data collected from temporal cortex region, and 19 SNPs from NECTIN and TOMM40 genes were found associated with multiple temporal cortex imaging phenotype.

Conclusion

Significant pathways from enriched gene networks included neutrophil degranulation, Cell surface interactions at the vascular wall, and Regulation of TP53 activity which are still relatively under explored in Alzheimer’s Disease while also encouraging a necessity to bind further trans-eQTL effects into this integrative analysis.
Association and mediation analyses among multiple metals exposure, plasma folate, and community-based impaired estimated glomerular filtration rate in central Taiwan
Authors: Chung Mu-Chi , Hsu Hui-Tsung , Mao Yan-Chiao , Wu Chin-Ching , Ho Chih-Te , Liu Chiu-Shong , Chung Chi-Jung
Published: April 2022

Background

Chronic kidney disease (CKD) is increasing, with heavy metal exposure an important risk factor. Additionally, the antioxidant folic acid has been studied for reducing blood arsenic levels and related tissue damage. Therefore, we explored the association and mediation effects among various heavy metal levels in blood, plasma folate, other CKD risk factors, and impaired estimated glomerular filtration rate (eGFR).

Methods

We constructed a community-based cross-sectional study from the Human Biomonitoring and Environmental Health Program in central Taiwan. A total of 1643 participants had lived locally for > 5 years, > 40 years old, and completely received health examinations and biospecimen collections. Impaired eGFR was defined as one single eGFR < 60 mL/min/1.73 m2. Plasma folate and metal levels in blood were determined, as well as urinary 8-hydroxy-2′-deoxyguanosine as an oxidative stress marker. Generalized weighted quantile sum (WQS) regression analysis was used to calculate a WQS score, reflecting overall body-burden of multiple metals (arsenic, cadmium, chromium, nickel, and lead) in blood.

Results

Impaired eGFR was identified in 225 participants. Participants with high WQS scores had increased risk of impaired eGFR (odds ratio = 1.67; 95% confidence interval [CI]: 1.34, 2.07). Of five metals, arsenic, lead, and cadmium were weighted highly in impaired eGFR. Participants with high WQS and folate insufficiency (< 6 ng/mL) had 2.38-fold risk of impaired eGFR compared to those with low WQS and high folate (≥6 ng/mL) (95% CI: 1.55, 5.17). Similar increased 4.16-fold risk of impaired eGFR was shown in participants with high WQS and uric acid levels (95% CI: 2.63, 6.58). However, there were no significant WQS–folate (p = 0.87) or WQS–uric acid (p = 0.38) interactions on impaired eGFR risk. As a mediator, uric acid contributed 24% of the association between WQS score and impaired eGFR risk (p < 0.0001). However, no mediation effect of plasma folate was observed.

Conclusion

WQS analysis could be applied to evaluate the joint effects of multiple metals exposure. High WQS scores may influence impaired eGFR risk through increased uric acid levels. A large-scale and prospective cohort study is necessary to validate these results and demonstrate any causal relationship.
FOXO transcriptional activity is associated with response to chemoradiation in EAC
Authors: Creemers A. , van der Zalm A. P. , van de Stolpe A. , Holtzer L. , Stoffels M. , Hooijer G. K. J. , Ebbing E. A. , van Ooijen H. , van Brussel A. G. C. , Aussems-Custers E. M. G. , van Berge Henegouwen M. I. , Hulshof M. C. C. M. , Bergman J. J. G. H. M. , Meijer S. L. , Bijlsma M. F. , van Laarhoven H. W. M.
Published: April 2022

In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.
IFI16 induces inflammation in hepatitis B virus-associated glomerulonephritis by regulating the Caspase-1/ IL-1 ß pathway
Authors: Liu Li , Xie Shuangshuang , Li Cheng , Guo Yue , Liu Xiaoyan , Zhao Xiuhua , Li Qiang , Du Wenjun
Published: April 2022

Aims and background

IFI16 plays an important role in innate immunity against invasive microbial infection by sensing double-stranded DNA viruses due to caspase-1-dependent inflammasome activation and subsequent maturation and secretion of IL-1β. However, the role of IFI16 in regulating the immune response to viruses in Hepatitis B Virus-Associated Glomerulonephritis (HBV-GN), especially in sensing hepatitis B virus (HBV), has not been determined. In this study, we investigated the inflammatory role of IFI16 in HBV-GN.

Methods

A total 75 kidney tissue including 50 HBV-GN and 25 chronic glomerulonephritis (CCN) were collected to determine the expression of IFI16, Caspase-1 and IL-1β using immunohistochemistry (IHC), then the correlation between them was analyzed. In vitro, the primary human glomerular mesangial (HGM) cells and HEK-293 T cell lines were used in this study. The cell lines were both co-transfected with HBVDNA and overexpression or silencing IFI16. Quantitative Real-time PCR and western blotting were used to determine the expression of IFI16, Caspase-1 and IL-1β.

Results

IFI16 expression in HBV-GN biopsies (80.0%) was significantly higher than in CGN (24.0%) and positively correlated with HBVDNA,caspase-1 and IL-1β expression in HBV-GN. Meanwhile, over expression of IFI16 increased caspase-1 and IL-1β expression in HBV-infected HGM and HEK-293 T cell lines, knockdown of IFI16 mRNA by siRNA resulted in downregulation of the caspase-1 and IL-1β expression in both cell lines.

Conclusions

The elevation of IFI16 during HBV infection or replication may contribute to renal damage due to inflammation, thus providing a putative therapeutic target and a new avenue for researching the pathogenesis of HBV-GN.
Analysis of prognostic factors for in-hospital mortality in patients with unplanned re-exploration after cardiovascular surgery
Authors: Deng Jianying , Zhong Qianjin
Published: April 2022

Objective

To explore the prognostic factors for in-hospital mortality in patients with unplanned re-exploration after cardiovascular surgery.

Methods

We retrospectively analyzed the data of 100 patients who underwent unplanned re-exploration after cardiovascular surgery in our hospital between May 2010 and May 2020. There were 77 males and 23 females, aged (55.1 ± 15.2) years. Demographic characteristics, surgical information, perioperative complications were collected to establish a database. These patients were divided into surviving and non-surviving groups according to in-hospital mortality. Logistic regression was used for multivariable analysis to explore the prognostic factors of in-hospital mortality. These statistically significant indicators were selected for drawing the receiver operating characteristic curve of the evaluation model, calculating the area under the curve (AUC) and evaluating the effectiveness of the new model with Hosmer–Lemeshow C-statistic.

Results

In-hospital mortality in patients with unplanned re-exploration after cardiovascular surgery was 26.0% (26/100). Multivariate logistics regression revealed that the operation time of unplanned re-exploration, the worst blood creatinine value within 48 h before the re-exploration, the worst lactate value within 24 h after the re-exploration, cardiac insufficiency, respiratory insufficiency, and acute kidney injury were independent prognostic factors (P < 0.05). The AUC of the new assessment model constituted by these prognostic factors was 0.910, and the Hosmer–Lemeshow C-statistic was 4.153 (P = 0.762).

Conclusions

Operation time of unplanned re-exploration, worst serum creatinine value within 48 h before re-exploration, worst lactate value within 24 h after re-exploration, cardiac insufficiency, respiratory insufficiency, and acute kidney injury are the main prognostic factors for in-hospital mortality in patients with unplanned re-exploration after cardiovascular surgery. Identifying these prognostic factors can effectively facilitate preventive measures and improve patient outcomes.
Roles of Rufy3 in experimental subarachnoid hemorrhage-induced early brain injury via accelerating neuronal axon repair and synaptic plasticity
Authors: Wang Yang , Xu Jianguo , You Wanchun , Shen Haitao , Li Xiang , Yu Zhengquan , Li Haiying , Chen Gang
Published: April 2022

RUN and FYVE domain-containing 3 (Rufy3) is a well-known adapter protein of a small GTPase protein family and is bound to the activated Ras family protein to maintain neuronal polarity. However, in experimental subarachnoid hemorrhage (SAH), the role of Rufy3 has not been investigated. Consequently, we aimed to investigate the potential role of Rufy3 in an in vivo model of SAH-induced early brain injury (EBI). In addition, we investigated the relevant brain-protective mechanisms. Oxyhemoglobin (OxyHb) stimulation of cultured primary neurons simulated vitro SAH condition. The SAH rat model was induced by infusing autologous blood into the optic chiasma pool and treating the rats with lentivirus-negative control 1 (LV-NC1), lentivirus-Rufy3 shRNA (LV-shRNA), lentivirus-negative control 2 (LV-NC2), lentivirus-Rufy3 (LV-Rufy3), or 8-pCPT-2′-O-Me-cAMP (8p-CPT) (Rap1 agonist). In experiment one, we found that the protein level of Rufy3 decreased and neuronal axon injury in the injured neurons but was rectified by LV-Rufy3 treatment. In experiment two, mRNA and protein levels of Rufy3 were downregulated in brain tissue and reached the lowest level at 24 h after SAH. In addition, the expression of Myelin Basic Protein was downregulated and that of anti-hypophosphorylated neurofilament H (N52) was upregulated after SAH. In experiments three and four, Rufy3 overexpression (LV-Rufy3) increased the interactions between Rufy3 and Rap1, the level of Rap1-GTP, and the ratio of Rap1-GTP/total GTP. In addition, LV-Rufy3 treatment inhibited axon injury and accelerated axon repair by activating the Rap1/Arap3/Rho/Fascin signaling pathway accompanied by upregulated protein expression levels of ARAP3, Rho, Fascin, and Facin. LV-Rufy3 also enhanced synaptic plasticity by activating the Rap1/MEK/ERK/synapsin I signaling pathway accompanied by upregulated protein expression levels of ERK1, p-ERK1, MEK1, p-MEK1, synaspin I, and p-synaspin I. Moreover, LV-Rufy3 also alleviated brain damage indicators, including cortical neuronal cell apoptosis and degeneration, brain edema, and cognitive impairment after SAH. However, the downregulation of Rufy3 had the opposite effect and aggravated EBI induced by SAH. Notably, the combined application of LV-Rufy3 and 8p-CPT showed a significant synergistic effect on the aforementioned parameters. Our findings suggest that enhanced Rufy3 expression may reduce EBI by inhibiting axon injury and promoting neuronal axon repair and synaptic plasticity after SAH.
RORγt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers
Authors: Xia Li , Tian Enming , Yu Mingcheng , Liu Chenglong , Shen Lian , Huang Yafei , Wu Zhongen , Tian Jinlong , Yu Ker , Wang Yonghui , Xie Qiong , Zhu Di
Published: April 2022

Background

The overall response rate to checkpoint blockade remains unsatisfactory, partially due to the immune-suppressive tumor microenvironment. A retinoic acid-related orphan receptor γt (RORγt) agonist (LYC-55716) is currently used in clinical trials combined with anti-PD-1, but how the Th17 cell transcription factor RORγt enhances antitumor immunity of PD-1 in the tumor microenvironment remains elusive.

Methods

The expression of mRNA was analyzed using qPCR assays. Flow cytometry was used to sort and profile cells. Cell migration was analyzed using Transwell assays. Biacore was used to determine the binding affinity to the RORγt protein. The RORγt GAL4 cell-based reporter gene assay was used to measure activity in the RORγt driven luciferase reporter gene expression.

Results

We designed a potent and selective small-molecule RORγt agonist (8-074) that shows robust antitumor efficacy in syngeneic tumor models and improves the efficacy of anti‑PD‑1 in a murine lung cancer model. RORγt agonist treatment increased intratumoral CD8+ T cells, which were correlated with CXCL10 and monocyte-derived dendritic cells (MoDCs). In addition, the RORγt agonist promoted Type 17 T cell migration by upregulating CCL20 and CCR6 expression, and Type 17 T cell tumor infiltration. CCL20 induces MoDCs migration, and CXCL10 derived from MoDCs promotes CD8+ T cell migration.

Conclusion

Our results revealed that the RORγt agonist improved the efficacy of anti-PD-1. The RORγt agonist increased the migration of MoDCs, which increased the local levels of CXCL10, thus promoting CD8+ T cell tumor infiltration. Our findings provide the mechanistic insights implicating the RORγt agonist in immunotherapy and offer a strategy for targeting the RORγt agonist to improve PD-1 antibody efficacy in cancers.
Circular RNA circ-MTHFD1L induces HR repair to promote gemcitabine resistance via the miR-615-3p/RPN6 axis in pancreatic ductal adenocarcinoma
Authors: Chen Zhi-Wen , Hu Jian-Fei , Wang Zu-Wei , Liao Cheng-Yu , Kang Feng-Ping , Lin Cai-Feng , Huang Yi , Huang Long , Tian Yi-Feng , Chen Shi
Published: April 2022

Background

Chemoresistance of pancreatic cancer is the main reason for the poor treatment effect of pancreatic cancer patients. Exploring chemotherapy resistance-related genes has been a difficult and hot topic of oncology. Numerous studies implicate the key roles of circular RNAs (circRNAs) in the development of pancreatic cancer. However, the regulation of circRNAs in the process of pancreatic ductal adenocarcinoma (PDAC) chemotherapy resistance is not yet fully clear.

Methods

Based on the cross-analysis of the Gene Expression Omnibus (GEO) database and the data of our center, we explored a new molecule, hsa_circ_0078297 (circ-MTHFD1L), related to chemotherapy resistance. QRT-PCR was used to detect the expression of circRNAs, miRNAs, and mRNAs in human PDAC tissues and their matched normal tissues. The interaction between circ-MTHFD1L and miR-615-3p/RPN6 signal axis was confirmed by a series of experiments such as Dual-luciferase reporter assay, fluorescence in situ hybridization (FISH) RNA immunoprecipitation (RIP) assays.

Results

Circ-MTHFD1L was significantly increased in PDAC tissues and cells. And in PDAC patients, the higher the expression level of circ-MTHFD1L, the worse the prognosis. Mechanism analysis showed that circ-MTHFD1L, as an endogenous miR-615-3p sponge, upregulates the expression of RPN6, thereby promoting DNA damage repair and exerting its effect on enhancing gemcitabine chemotherapy resistance. More importantly, we also found that Silencing circ-MTHFD1L combined with olaparib can increase the sensitivity of pancreatic cancer to gemcitabine.

Conclusion

Circ-MTHFD1L maintains PDAC gemcitabine resistance through the miR-615-3p/RPN6 signal axis. Circ-MTHFD1L may be a molecular marker for the effective treatment of PDAC.
Genome-wide CRISPR screen identified Rad18 as a determinant of doxorubicin sensitivity in osteosarcoma
Authors: Du Mingrui , Gu Jintao , Liu Chenlin , Liu Nannan , Yu Zhe , Zhou Chengpei , Heng Wei , Cao Zhengcong , Wei Feilong , Zhu Kailong , Wang Yingwen , Zhang Wei , Xue Xiaochang , Zhang Yong , Qian Jixian
Published: April 2022

Background

Osteosarcoma (OS) is a malignant bone tumor mostly occurring in children and adolescents, while chemotherapy resistance often develops and the mechanisms involved remain challenging to be fully investigated.

Methods

Genome-wide CRISPR screening combined with transcriptomic sequencing were used to identify the critical genes of doxorubicin resistance. Analysis of clinical samples and datasets, and in vitro and in vivo experiments (including CCK-8, apoptosis, western blot, qRT-PCR and mouse models) were applied to confirm the function of these genes. The bioinformatics and IP-MS assays were utilized to further verify the downstream pathway. RGD peptide-directed and exosome-delivered siRNA were developed for the novel therapy strategy.

Results

We identified that E3 ubiquitin-protein ligase Rad18 (Rad18) contributed to doxorubicin-resistance in OS. Further exploration revealed that Rad18 interact with meiotic recombination 11 (MRE11) to promote the formation of the MRE11-RAD50-NBS1 (MRN) complex, facilitating the activation of the homologous recombination (HR) pathway, which ultimately mediated DNA damage tolerance and leaded to a poor prognosis and chemotherapy response in patients with OS. Rad18-knockout effectively restored the chemotherapy response in vitro and in vivo. Also, RGD-exosome loading chemically modified siRad18 combined with doxorubicin, where exosome and chemical modification guaranteed the stability of siRad18 and the RGD peptide provided prominent targetability, had significantly improved antitumor activity of doxorubicin.

Conclusions

Collectively, our study identifies Rad18 as a driver of OS doxorubicin resistance that promotes the HR pathway and indicates that targeting Rad18 is an effective approach to overcome chemotherapy resistance in OS.
Are 5-level triage systems improved by using a symptom based approach?—a Danish cohort study
Authors: Kongensgaard Frederik Trier , Fløjstrup Marianne , Lassen Annmarie , Dahlin Jan , Brabrand Mikkel
Published: April 2022

Background

Five-level triage systems are being utilized in Danish emergency departments with and without the use of presenting symptoms. The aim of this study was to validate and compare two 5-level triage systems used in Danish emergency departments: “Danish Emergency Process Triage” (DEPT) based on a combination of vital signs and presenting symptoms and a locally adapted version of DEPT (VITAL-TRIAGE) using vital signs only.

Methods

This was a retrospective cohort using data from five Danish emergency departments. All patients attending an emergency department during the period of 1 April 2012 until 31 December 2015 were included. Validity of the two triage systems was assessed by comparing urgency categories determined by each triage system with critical outcomes: admission to Intensive care unit (ICU) within 24 h, 2-day mortality, diagnosis of critical illness, surgery within 48 h, discharge within 4 h and length of hospital stay.

Results

We included 632,196 ED contacts. Sensitivity for 24-h ICU admission was 0.79 (95% confidence interval 0.78–0.80) for DEPT and 0.44 (0.41–0.47) for VITAL-TRIAGE. The sensitivity for 2-day mortality was 0.69 (0.67–0.70) for DEPT and 0.37 (0.34–0.41) for VITAL-TRIAGE. The sensitivity to detect diagnoses of critical illness was 0.48 (0.47–0.50) for DEPT and 0.09 (0.08–0.10) for VITAL-TRIAGE. The sensitivity for predicting surgery within 48 h was 0.30 (0.30–0.31) in DEPT and 0.04 (0.04–0.04) in VITAL-TRIAGE. Length of stay was longer in VITAL-TRIAGE than DEPT. The sensitivity of DEPT to predict patients discharged within 4 h was 0.91 (0.91–0.92) while VITAL-TRIAGE was higher at 0.99 (0.99–0.99). The odds ratio for 24-h ICU admission and 2-day mortality was increased in high-urgency categories of both triage systems compared to low-urgency categories.

Conclusions

High urgency categories in both triage systems are correlated with adverse outcomes. The inclusion of presenting symptoms in a modern 5-level triage system led to significantly higher sensitivity measures for the ability to predict outcomes related to patient urgency. DEPT achieves equal prognostic performance as other widespread 5-level triage systems.
Central precocious puberty during COVID-19 pandemic and sleep disturbance: an exploratory study
Authors: Umano Giuseppina R , Maddaluno Ivan , Riccio Simona , Lanzaro Francesca , Antignani Rachele , Giuliano Maria , Luongo Caterina , Festa Adalgisa , Miraglia del Giudice Emanuele , Grandone Anna
Published: April 2022

Background

Increased incidence of central precocious puberty (CPP) after coronavirus infectious disease-19 lockdown has been reported. Our study aims in investigating changes in CPP rates and in sleep patterns in CPP and healthy controls.

Methods

CPP were retrospectively evaluated from April 2020 to April 2021. Parents of girls diagnosed with CPP during lockdown and of matched healthy controls filled out a questionnaire about sleep disturbances (SDSC questionnaire) and sleep schedules.

Results

Thirty-five CPP and 37 controls completed the survey. Incidence of new CPP cases significantly increased in 2020–2021 compared to 2017–2020 (5:100 vs 2:100, p = 0.02). Sleep disturbance rates did not differ between CPP and healthy controls before lockdown. During lockdown, CPP reported higher rates of sleep disturbs for total score (p = 0.005), excessive somnolence (p = 0.049), sleep breathing disorders (p = 0.049), and sleep–wake transition disorders (p = 0.005). Moreover, CPP group more frequently shifted toward later bedtime (p = 0.03) during lockdown compared to controls. Hours of sleep and smartphone exposure around bedtime did not differ between groups.

Conclusions

Our study confirms the observation of increased incidence of CPP after lockdown measures. Additionally, CPP showed higher rates of sleep disturbances and later bedtime compared to controls. The causality link between sleep disturbances and CPP should be further investigated to gain knowledge in this association.
Efficacy of thunder-fire moxibustion in treating ankylosing spondylitis of kidney deficiency and governor meridian cold and its influence on TNF-α and RANKL: study protocol for a prospective, nonblinded, single-center, randomized controlled trial
Authors: Liu Yang , Wang Pei , Sun Yan Yan , Qu Jing , Li Min
Published: April 2022

Background

Ankylosing spondylitis (AS) is a common chronic inflammatory spondyloarthropathy. It is considered in traditional Chinese medicine (TCM) that the pathogenesis of AS is mainly due to Yang deficiency of kidney governor meridian and internal prosperity of cold evil. Thunder-fire moxibustion is a kind of moxibustion that is characterized in abundance in drug composition, high heat radiation, and strong penetration. Thunder-fire moxibustion on the spinal segment of the governor meridian in treating AS seems compatible with the main pathogenesis of kidney deficiency and governor meridian cold. The trial aims to explore the efficacy of thunder-fire moxibustion in patients with AS of kidney deficiency and governor meridian cold and its influence on bone metabolism, through a prospective randomized trial.

Methods

Sixty patients with AS of kidney deficiency and governor meridian cold will be recruited and randomly assigned to the treatment group (thunder-fire moxibustion three times a week plus basic treatment) and the control group (basic treatment) at the Center of TCM of Beijing Luhe Hospital Affiliated to Capital Medical University (Beijing, China). Each patient will be treated for 4 weeks. The primary outcome is the efficacy of TCM syndrome, and the secondary outcome indexes will include the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Short-Form-36 Questionnaire (SF-36), tumor necrosis factor-α (TNF-α), and receptor activator of nuclear factor-κB ligand (RANKL). TNF-α and RANKL with observation will be determined once respectively before and after treatment, while the other indexes will be observed once prior to the treatment, 2 weeks post-treatment, and at the end of the treatment. Side effects will be recorded and analyzed as well. Inter-group comparison and analysis will be performed based on the intention-to-treat set and per-protocol set.

Discussion

This prospective randomized trial will help verify the efficacy of thunder-fire moxibustion in treating AS of kidney deficiency and governor meridian cold, discuss preliminarily its mechanism in treating this disease, and provide high-quality evidences for scientific researches on clinical treatment with thunder-fire moxibustion against AS.

Trial registration

Chinese Clinical Trial Registry ChiCTR2100044227. Registered on 12 March 2021
Inhibition of COX-2 ameliorates murine liver schistosomiasis japonica through splenic cellular immunoregulation
Authors: Qi Zhang , Lan Chen , Xiaofang Ji , Juanjuan Tang , Cheng Fu , Ting Huang , Erxia Shen , Zi Li
Published: April 2022

Background

We have reported the positive association of the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) axis with liver fibrosis induced by Schistosoma japonicum (Sj) infection, and TLR4 signaling controlled this axis. However, how COX-2 regulates immune response during Sj infection is still unclear.

Methods

Hematoxylin and eosin staining was used to evaluate the effect of the COX-2-specific inhibitor NS398 on liver granulomatous inflammation and fibrosis. Flow cytometry was used to explore the frequency and amount of different immune cell infiltration in the spleen during Sj infection.

Results

NS398 significantly reduced the size of liver granuloma, spleen, and mesenteric lymph node (MLN) and alleviated chronic granulomatous inflammation. Mechanically, this might be by decreasing the number of Sj-induced macrophages and T helper type 1 (Th1), Th2, T follicular helper (Tfh), T follicular regulatory (Tfr), and germinal center B (GC B) cells. There were no differences in the number of neutrophils, myeloid-derived suppressor cells, Th17 cells, regulatory T cells (Treg), or total B cells in the spleen of the mice with or without NS398 treatment.

Conclusions

COX-2/PGE2 inhibition may represent a potential therapeutic approach for schistosomiasis japonica through splenic cellular immunoregulation.

Graphical Abstract
Genome-wide identification and expression profiling of odorant receptor genes in the malaria vector Anopheles sinensis
Authors: He Zhengbo , Yu Zhengrong , He Xingfei , Hao Youjin , Qiao Liang , Luo Shihui , Zhang Jingjing , Chen Bin
Published: April 2022

Background

The olfactory system plays a crucial role in regulating insect behaviors. The detection of odorants is mainly mediated by various odorant receptors (ORs) that are expressed in the dendrites of olfactory neurons of chemosensilla.Anophelessinensisis a major malaria vector in Eastern Asia and its genome has recently been successfully sequenced and annotated. In this study, we present genome-wide identification and expression profiling of OR genes in different chemosensory tissues ofAn.sinensis.

Methods

The OR genes were identified using the available genome sequences ofAn.sinensis. A series of bioinformatics analyses were conducted to investigate the structure, genome distribution, selective pressure and phylogenetic relationships of OR genes, the conserved domains and specific functional sites in the OR amino acid sequences. The expression levels of OR genes were analyzed from transcriptomic data fromAn.sinensisantennae, proboscis and maxillary palps of both sexes.

Results

A total of 59 putative OR genes have been identified and characterized inAn.sinensis. This number is significantly less than that inAn.gambiae. Whether this difference is caused by the contraction or expansion of OR genes after divergence of the two species remains unknown. The RNA-seq analysis showed thatAsORs have obvious tissue- and sex-specific expression patterns. MostAsORsare highly expressed in the antennae and the expression pattern and number ofAsORs expressed in antennae are similar in males and females. However, the relative levels ofAsORtranscripts are much higher in female antennae than in male antennae, which indicates that the odor sensitivity is likely to be increased in female mosquitoes. Based on the expression patterns and previous studies, we have speculated on the functions of some OR genes but this needs to be validated by further behavioral, molecular and electrophysiological studies. Further studies are necessary to compare the olfactory-driven behaviors and identify receptors that respond strongly to components of human odors that may act in the process of human recognition.

Conclusions

This is the first genome-wide analysis of the entire repertoire of OR genes inAn.sinensis. Characterized features and profiled expression patterns of ORs suggest their involvement in the odorous reception of this species. Our findings provide a basis for further research on the functions of OR genes and additional genetic and behavioral targets for more sustainable management ofAn.sinensisin the future.

Graphical Abstract
Effect of red beetroot juice on oxidative status and islet insulin release in adult male rats
Authors: Sayyar Armin , Oladi Mohammad , Hosseini Mehran , Nakhaee Samaneh , Ataie Zomorrod , Farrokhfall Khadijeh
Published: April 2022

Introduction

Beetroot is rich in inorganic nitrate and it has been shown that inorganic nitrate has beneficial effects on metabolic syndrome. This study aims to investigate the effect of red beetroot juice (RBJ) on carbohydrate metabolism in adult insulin-resistant rats.

Materials and methods

Sixteen male Wistar rats (32 weeks old) were divided into two equal groups: control and RBJ. Treatment with drinking water (control) and 100% RBJ (RBJ) was lasted for 5 weeks. At the end of the 4th week the intraperitoneal glucose tolerance test was performed and at the end of the study period animals were sacrificed and blood and tissue (aorta, heart, and liver) samples were collected. Furthermore, pancreatic islets were isolated and their insulin secretion activity was investigated in different glycemic conditions.

Results

Compared to the control group, RBJ-treated rats showed lower blood glucose and insulin levels in the glucose tolerance test. Serum and tissue levels of nitric oxide in the RBJ group were significantly higher than those in the control group. The liver peroxidation and serum aspartate transaminase levels were significantly increased in the RBJ-treated animals compared to the control group. The islets of RBJ group exhibited lower insulin secretion, especially in 16.7 mM glucose concentration (supraphysiologic condition) than control group.

Conclusions

RBJ consumption improves glucose metabolism in rats via increasing nitric oxide metabolites in an insulin-independent manner. However, future studies are needed to minimize the potential hepatic adverse consequences.
A direct sequencing assay for pharmacogenetic testing of thiopurine-intolerant NUDT15 alleles in an Asian population
Authors: Poon Kok-Siong , Imran Izz Irfan B. , Chew Silvester Kheng-Han , Tan Patrice , Tan Karen Mei-Ling
Published: April 2022

Objective

The nucleoside diphosphate linked moiety X (Nudix)-Type motif 15 (NUDT15) enzyme is involved in thiopurine metabolism. Genetic variants in the NUDT15 gene result in decreased NUDT15 activity, which in addition to decreased thiopurine S-methyltransferase (TPMT) activity, contributes to thiopurine toxicity. Current standard approaches of NUDT15 genetic analysis have mainly been targeting several common variants. We aimed to develop a clinical-grade DNA-based assay for genetic analysis of the NUDT15 gene using Sanger di-deoxy sequencing.

Results

Sanger sequencing results were fully concordant with the expected NUDT15 genotype in all 17 cell line samples with known NUDT15 variants (accuracy = 100%; 95% CI 80.49 to 100.00%). Precision studies showed 100% intra-run repeatability and 100% inter-run reproducibility, respectively. Genetic analysis of the NUDT15 gene was performed for 80 patients of Asian ethnicity with wildtype TPMT. 76% (N = 61) of the studied individuals had NUDT15 *1/*1 diplotype. 25% (N = 14) of Chinese and 36% (N = 5) of Malays were found to carry at least 1 non-functional NUDT15 allele. Our study confirmed a high frequency of NUDT15 c.415C>T and c.55_56insGAGTCG variants in the Chinese and Malay ethnic groups in Singapore, highlighting the importance of determining NUDT15 genotype prior to thiopurine dosing.
Usefulness of a commercial LAMP assay for detection of malaria infection, including Plasmodium knowlesi cases, in returning travelers in Spain
Authors: Martín-Ramírez Alexandra , Lanza Marta , Hisam Shamilah , Perez-Ayala Ana , Rubio José M.
Published: April 2022

Objective

Main malaria diagnosis is based on microscopic examination combined with rapid diagnostic tests. Both methods have low sensitivity and specificity. Loop-mediated isothermal amplification techniques have shown a sensitivity similar to PCR but with lower times of performance. This study aimed to assess a commercial LAMP for the diagnosis of malaria (Alethia® Malaria) against the Nested-Multiplex-Malaria PCR, including the analytical sensitivity and the operational characteristics.

Results

One hundred five samples out of 114 rendered valid results, obtaining 85 positive samples and 18 negative samples with an agreement of 98% compared to the reference method with a sensitivity, specificity and kappa coefficient of 98.84%, 94.74% and 0.94 respectively, with only two discrepant samples. The turnaround time was estimated in 1 h and 30 min, with a cost of 32.67€ per determination. The results showed several advantages of the Alethia® Malaria, as it was easy to perform, minimal training requirement and 40 min run. Moreover, it includes an internal control to avoid false negatives. However, it also showed some limitations such as the need for a specific amplification and detection device, the detection of only Plasmodium spp. and a very high price.
Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with Alzheimer’s disease
Authors: Kivisäkk Pia , Carlyle Becky C. , Sweeney Thadryan , Quinn James P. , Ramirez Christopher E. , Trombetta Bianca A. , Mendes Muriel , Brock Mary , Rubel Carrie , Czerkowicz Julie , Graham Danielle , Arnold Steven E.
Published: April 2022

Background

There is currently a lack of reliable and easily accessible biomarkers predicting cognitive decline in Alzheimer’s disease (AD). Synaptic dysfunction and loss occur early in AD and synaptic loss measured in the brain tissue and by PET are closely linked to cognitive decline, rendering synaptic proteins a promising target for biomarker development.

Methods

We used novel Simoa assays to measure cerebrospinal fluid (CSF) levels of two synaptic biomarker candidates, postsynaptic density protein 95 (PSD-95/DLG4), and the presynaptically localized synaptosomal-associated protein 25 (SNAP-25), as well as neurogranin (Ng), an established postsynaptic biomarker. CSF samples from two well-characterized cohorts (n=178 and n=156) were selected from banked samples obtained from diagnostic lumbar punctures containing subjects with amyloid-ß (Aß) positive AD, subjects with non-AD neurodegenerative diseases, subjects with other neurological conditions, and healthy controls (HC).

Results

All subjects had detectable CSF levels of PSD-95, SNAP-25, and Ng. CSF levels of PSD-95, SNAP-25, and Ng were all correlated, with the strongest correlation between the presynaptic SNAP-25 and the postsynaptic neurogranin. AD subjects had on average higher concentrations of all three synaptic markers compared to those with non-AD neurodegenerative diseases, other neurological disorders, and HCs. Increased CSF levels of PSD-95, SNAP-25, and Ng were, however, not specific for AD and were present in sporadic cases with inflammatory or vascular disorders as well. High CSF levels of PSD-95 were also observed in a few subjects with other neurodegenerative disorders.

Conclusion

The data establishes PSD-95 as a promising CSF marker for neurodegenerative disease synaptic pathology, while SNAP-25 and Ng appear to be somewhat more specific for AD. Together, these synaptic markers hold promise to identify early AD pathology, to correlate with cognitive decline, and to monitor responses to disease-modifying drugs reducing synaptic degeneration.