bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a lncRNA AC011511.5- Mediated Competitive Endogenous RNA Network Involved in the Pathogenesis of Allergic Rhinitis
Authors: Yang Yujuan , Sun Qi , Guo Jing , Liu Zhen , Wang Jianwei , Yao Yao , Yu Pengyi , Cao Jiayu , Zhang Yu , Song Xicheng
Published: May 2022

LncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks are thought to be involved in regulating the development of various inflammatory diseases. Up to now, the mechanism of such a network in allergic rhinitis (AR) remains unclear. In the study, we investigated the differential expression of lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) by performing a microarray analysis of peripheral blood obtained from AR patients and healthy control subjects. StarBase 2.0 was used to predict miRNAs that might interact with various DElncRNAs and DEmRNAs. We constructed a ceRNA network based on potential lncRNA-miRNA-mRNA interactions. The Cluster Profiler R package was used to perform a functional enrichment analysis of the hub-ceRNA, and Molecular Complex Detection (MCODE) was used for further identification of the hub-ceRNA network. The expression levels of genes contained in the hub-ceRNA network were validated by RT-PCR. In total, 247 DEmRNAs and 18 DelncRNAs were aberrantly expressed in the PBMCs of AR patients. A ceRNA network consisting of 3 lncRNAs, 45 miRNAs, and 75 mRNAs was constructed. A GO analysis showed that negative regulation of immune response, response to interferon-beta, and response to interferon-alpha were important terms. A KEGG pathway analysis showed that 75 mRNAs were significantly enriched in “NOD-like receptor signaling pathway” and “tryptophan metabolism”. Ultimately, a hub-ceRNA network was constructed based on 1 lncRNA (AC011511.5), 5 miRNAs (hsa-miR-576-5p, hsa-miR-520c-5p, hsa-miR-519b-5p, hsa-miR-519c-5p, and hsa-miR-518d-5p), and 2 mRNAs (ZFP36L1 and SNX27). Following further verification, we found that overexpression of lncRNA AC011511.5 or inhibitor of miR-576-5p upregulated SNX27 expression. The expression of SNX27 in the lncRNA AC011511.5 overexpression & miR-576-5p inhibitor group was not different from that in the miR-576-5p inhibitor group or lncRNA AC011511.5 overexpression group, indicating that overexpression of lncRNA AC011511.5 could not further upregulate the expression of SNX27 in miR-576-5p inhibitor Jurkat cells. This network may provide new insights to search for biomarkers that can be used for the diagnosis and clinical treatment of AR.
The Evaluation of Genetic Diagnosis on High-Risk Fetal CAKUT
Authors: Liu Wanlu , Shi Xinwei , Li Yuqi , Qiao Fuyuan , Chen Suhua , Feng Ling , Zeng Wanjiang , Deng Dongrui , Wu Yuanyuan
Published: May 2022

Background: It is challenging to make an accurate prenatal diagnosis for congenital anomalies of the kidney and urinary tract (CAKUT) because of its pathologic diversity. This study aims to evaluate the performance of whole-exome sequencing (WES) combined with karyotype analysis and copy number variations (CNVs) in diagnosing high-risk fetal CAKUT.

Methods: We conducted a retrospective study on prenatal diagnoses of CAKUT in our hospital from January 2020 to April 2021. The research studied 24 high-risk fetuses with CAKUT who were scanned by ultrasonography at the prenatal diagnosis center of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. The likely pathogenic gene variants were screened for the patients and their parents by multiple approaches, including karyotype analysis, CNVs and WES, and further verified with Sanger sequencing.

Results: ①We detected abnormal CNVs in 20.8% (5/24) of the fetuses but only 8.3% (2/24) fetuses had abnormal karyotypes. ②Of the 15 CAKUT fetuses, positive findings (40%) were detected by WES. Of the 9 high-risk fetuses with CAKUT (negative findings in ultrasound scan but with family history), we found abnormal variants (77.8%) through WES.

Conclusion: The application of CNVs and WES showed advance in prenatal diagnosis of CAKUT and the pathogenic gene variants were detectable especially for high-risk fetuses with negative ultrasound findings on CAKUT in the preliminary study. The applied strategy could be used to improve the accuracy of prenatal diagnosis for CAKUT in the future.
Contribution of Helicobacter pylori to the Inflammatory Complications of Common Variable Immunodeficiency
Authors: Motta-Raymundo Adriana , Rosmaninho Pedro , Santos Diana F. , Ferreira Ruben D. , Silva Sara P. , Ferreira Cristina , Sousa Ana E. , Silva Susana L.
Published: May 2022

Common Variable Immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, is frequently associated with severe inflammatory complications that determine its morbidity and mortality. We hypothesize that Helicobacter pylori (HP), a very common worldwide infection, may contribute to the clinical and immune phenotype of CVID. We stratified 41 CVID patients into HP+ (n=26) and HPneg (n=15) groups, according to previous urease breath test and/or gastric biopsies, and compared their clinical manifestations and immune profile evaluated by flow cytometry. No genetic variants with known potential impact in HP infection were found upon WES/WGS. Gastric complications were significantly more frequent in HP+ patients. Importantly, the six CVID patients with gastric cancer were infected with HP. In contrast, a significantly higher frequency of cytopenias was observed in the HPneg. Moreover, HP+ did not feature higher prevalence of organ auto-immunity, as well as of lung, liver or intestinal inflammatory manifestations. We observed the same B-cell profiles in HP+ and HPneg groups, accompanied by marked CD4 and CD8 T-cell activation, increased IFNγ production, and contraction of naïve compartments. Notably, HP+ patients featured low CD25 despite preserved Foxp3 levels in CD4 T cells. Overall, HP impact in CVID inflammatory complications was mainly restricted to the gastric mucosa, contributing to increased incidence of early onset gastric cancer. Thus, early HP screening and eradication should be performed in all CVID patients irrespective of symptoms.
Evaluation of Antibody-Dependent Fc-Mediated Viral Entry, as Compared With Neutralization, in SARS-CoV-2 Infection
Authors: Wieczorek Lindsay , Zemil Michelle , Merbah Mélanie , Dussupt Vincent , Kavusak Erin , Molnar Sebastian , Heller Jonah , Beckman Bradley , Wollen-Roberts Suzanne , Peachman Kristina K. , Darden Janice M. , Krebs Shelly , Rolland Morgane , Peel Sheila A. , Polonis Victoria R.
Published: May 2022

Fc-mediated virus entry has been observed for many viruses, but the characterization of this activity in convalescent plasma against SARS-CoV-2 Variants of Concern (VOC) is undefined. In this study, we evaluated Fc-mediated viral entry (FVE) on FcγRIIa-expressing HEK293 cells in the presence of SARS-CoV-2 convalescent plasma and compared it with SARS-CoV-2 pseudovirus neutralization using ACE2-expressing HEK293 cells. The plasma were collected early in the pandemic from 39 individuals. We observed both neutralization and FVE against the infecting Washington SARS-CoV-2 strain for 31% of plasmas, neutralization, but not FVE for 61% of plasmas, and no neutralization or FVE for 8% of plasmas. Neutralization titer correlated significantly with the plasma dilution at which maximum FVE was observed, indicating Fc-mediated uptake peaked as neutralization potency waned. While total Spike-specific plasma IgG levels were similar between plasma that mediated FVE and those that did not, Spike-specific plasma IgM levels were significantly higher in plasma that did not mediate FVE. Plasma neutralization titers against the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2) VOC were significantly lower than titers against the Washington strain, while plasma FVE activity against the VOC was either higher or similar. This is the first report to demonstrate a functional shift in convalescent plasma antibodies from neutralizing and FVE-mediating against the earlier Washington strain, to an activity mediating only FVE and no neutralization activity against the emerging VOC, specifically the Beta (B.1.351) and Gamma (P.1) VOC. It will be important to determine the in vivo relevance of these findings.
Crossing Scales: Data-Driven Determination of the Micro-scale Behavior of Polymers From Non-homogeneous Tests at the Continuum-Scale
Authors: Amores Víctor J. , Montáns Francisco J. , Cueto Elías , Chinesta Francisco
Published: May 2022

We propose an efficient method to determine the micro-structural entropic behavior of polymer chains directly from a sufficiently rich non-homogeneous experiment at the continuum scale. The procedure is developed in 2 stages: First, a Macro-Micro-Macro approach; second, a finite element method. Thus, we no longer require the typical stress-strain curves from standard homogeneous tests, but we use instead the applied/reaction forces and the displacement field obtained, for example, from Digital Image Correlation. The approach is based on the P-spline local approximation of the constituents behavior at the micro-scale (a priori unknown). The sought spline vertices determining the polymer behavior are first pushed up from the micro-scale to the integration point of the finite element, and then from the integration point to the element forces. The polymer chain behavior is then obtained immediately by solving a linear system of equations which results from a least squares minimization error, resulting in an inverse problem which crosses material scales. The result is physically interpretable and directly linked to the micro-structure of the material, and the resulting polymer behavior may be employed in any other finite element simulation. We give some demonstrative examples (academic and from actual polymers) in which we demonstrate that we are capable of recovering “unknown” analytical models and spline-based constitutive behavior previously obtained from homogeneous tests.
Case Report: Massive Hemoptysis From a Spontaneously Regression Inflammatory Bronchial Polyp
Authors: Iwamoto Yuichiro , Takenouchi Haruka , Koyama Katsumasa , Shirai Ryo , Kaneto Hideaki , Tomoda Koichi
Published: May 2022

Background

Bronchial inflammatory polyps are usually treated by surgical operation or with steroids and/or antibiotics, and it is quite rare that such polys spontaneously disappear without any treatment. This report shows a rare case with a bronchial inflammatory polyp which caused massive hemoptysis but spontaneously disappeared without any treatment.

Case Presentation

A 66-year-old man with type 2 diabetes mellitus and a history of cough and asthma suddenly developed massive hemoptysis while smoking and was brought to an emergency room in our institution. In bronchoscopy on admission, a polypoidal elevated lesion was observed in the left upper lobe bifurcation. Pulsatile hemorrhage from a polypoidal elevated lesion was observed upon stimulation of passage of the bronchoscope. Bronchoscopy performed 25 days after discharge showed no evidence of active bleeding and a tendency toward reduction of the elevated lesion. In bronchoscopy performed 106 days after the initial hospitalization, the bronchial inflammatory polyp completely disappeared.

Conclusions

We should bear in mind the possibility of spontaneous disappearance of bronchial inflammatory polyps causing some serious symptoms such as massive hemoptysis and repeated bloody sputum. Finally, we should select the best therapy for bronchial inflammatory polys based on each patient's background and conditions in clinical practice.
A Novel Subfoveal Perfluorocarbon Liquid Removal Technique Combining a 25-Gauge Retrobulbar Needle With a Built-in 30-Gauge Needle
Authors: Yang Yuan , Xiao Haodong , Zhang Xuerui , Mi Wei , Wang Xiaohan , Ye Hongfei , Wen Yanjun , Peng Jie , Zhao Peiquan
Published: May 2022

Introduction

To report a novel combining a 25-gauge retrobulbar needle with a built-in 30-gauge needle surgical technique for subfoveal perfluorocarbon liquid (PFCL) removal.

Materials and Methods

Fourteen eyes of 14 patients who underwent subfoveal PFCL removal with a 25-gauge retrobulbar needle combined with a built-in 30-gauge needle were studied. The 30-gauge needle was inserted into the 25-gauge retrobulbar needle. The bent tip of the built-in 30-gauge needle was used to create a 30-gauge retinotomy at the farthest edge of the subfoveal PFCL droplet. Then, a flute cannula was used to aspirate the PFCL through the previously created retinotomy. The best-corrected visual acuity (BCVA) was determined, previous surgical history and post-operative complications were recorded.

Results

Fourteen cases were analyzed. Most eyes (92.85%) showed an improvement in BCVA after surgery. The mean change in the BCVA was −0.7 ± 0.72 logarithm of the minimum angle of resolution (logMAR) units (p = 0.006). Post-operative complications included a self-healing macular hole in one eye and vitreous hemorrhage in one eye. Post-operative optical coherence tomography confirmed removal of the subfoveal PFCL with restoration of the macular fovea.

Conclusion

Combining a 25-gauge retrobulbar needle with a built-in 30-gauge needle to remove subfoveal PFCL is easy to perform and carries little potential risk of subretinal impairment. This method also provides relatively good macular contour with functional improvement.
Critical Study on the Tube-to-Chip Luer Slip Connectors
Authors: Etxeberria Leire , Aguilera Unai , Garcia de Madinabeitia Pablo , Saez Alberto , Zaldua Ane M. , Vilas-Vilela José L. , Fernández Luis , Llobera Andreu
Published: May 2022

Luer slip is one of the gold standards for chip-to-world interface in microfluidics. They have outstanding mechanical and operational robustness in a broad range of applications using water and solvent-based liquids. Still, their main drawbacks are related to their size: they have relatively large dead volumes and require a significant footprint to assure a leak-free performance. Such aspects make their integration in systems with high microchannel density challenging. To date, there has been no geometrical optimization of the Luer slips to provide a solution to the mentioned drawbacks. This work aims to provide the rules toward downscaling the Luer slips. To this effect, seven variations of the Luer slip male connectors and five variations of Luer slip female connectors have been designed and manufactured focusing on the reduction of the size of connectors and minimization of the dead volumes. In all cases, female connectors have been developed to pair with the corresponding male connector. Characterization has been performed with a tailor-made test bench in which the closure force between male and female connectors has been varied between 7.9 and 55 N. For each applied closure force, the test bench allows liquid pressures to be tested between 0.5 and 2.0 bar. Finally, the analysis of a useful life determines the number of cycles that the connectors can withstand before leakage.
Small and Medium-Sized Aneurysm Outcomes Following Intracranial Aneurysm Treatment Using the Pipeline Embolization Device: A Subgroup Analysis of the PLUS Registry
Authors: Zhang Hongyun , Li Li , Zhang Hongqi , Liu Jianmin , Song Donglei , Zhao Yuanli , Guan Sheng , Maimaitili Aisha , Wang Yunyan , Feng Wenfeng , Wang Yang , Wan Jieqing , Mao Guohua , Shi Huaizhang , Luo Bin , Shao Qiuji , Chang Kaitao , Zhang Qianqian , He Yingkun , Zhang Peng , Yang Xinjian , Li Tian xiao
Published: May 2022

Objective

The purpose of this work was to summarize the real-world safety and efficacy of Pipeline Embolization Device (PED) therapy for small and medium-sized intracranial aneurysms in China.

Methods

Patients from the PED in China post-market multi-center registry study (PLUS) with aneurysms smaller than 12 mm were selected. Radiographic outcomes were assessed using digital subtraction angiography. Clinical outcomes included functional outcomes (modified Rankin Scale, MRS) in the early postoperative period ( ≤ 30 days) and early postoperative complications associated with PED therapy.

Results

A total of 652 patients with a combined 754 aneurysms were included in this study (mean age of 53.9 ± 10.3 years, 68.7% women). Mean aneurysm diameter was 6.78 ± 2.67 mm. Of the 687 stents deployed, 99.7% (685/689) were successfully deployed. In this study, 64.7% (488/754) of aneurysms were treated with only the PED, whereas 35.3% (266/754) were subjected to PED-assisted therapy. Radiographic outcome at the last follow-up (median time: seven months) was available for 64.3% (485/754) of the aneurysms. 82.5% (400/485) of aneurysms demonstrated complete occlusion (Raymond Roy Grade I). 81.4% (395/485) of aneurysms were found to meet the study's primary effectiveness outcome. At the early postoperative period, the mRS score was determined to be 0–2 vs. 3-6 in 98.2% (640/652) vs. 1.8% (12/652) of the cases, respectively. The combined major morbidity and mortality rate was 3.2% (21/652).

Conclusion

In the largest study of PED therapy for small and medium-sized intracranial aneurysms to date, pipeline-assisted coil embolization was chosen more often than multiple stent implantation for aneurysm treatment, demonstrating good results, high surgical success rates, high occlusion rates, and low morbidity and mortality.

Clinical Trial Registration

www.ClinicalTrials.gov, identifier: NCT03831672.
Cerebral Microbleeds and Structural White Matter Integrity in Patients With Traumatic Brain Injury—A Diffusion Tensor Imaging Study
Authors: Dahl Juho , Tenovuo Olli , Posti Jussi P. , Hirvonen Jussi , Katila Ari J. , Frantzén Janek , Maanpää Henna-Riikka , Takala Riikka , Löyttyniemi Eliisa , Tallus Jussi , Newcombe Virginia , Menon David K. , Hutchinson Peter J. , Mohammadian Mehrbod
Published: May 2022

Diffuse axonal injury (DAI) is a common neuropathological manifestation of traumatic brain injury (TBI), presenting as traumatic alterations in the cerebral white matter (WM) microstructure and often leading to long-term neurocognitive impairment. These WM alterations can be assessed using diffusion tensor imaging (DTI). Cerebral microbleeds (CMBs) are a common finding on head imaging in TBI and are often considered a visible sign of DAI, although they represent diffuse vascular injury. It is poorly known how they associate with long-term white matter integrity. This study included 20 patients with TBI and CMBs, 34 patients with TBI without CMBs, and 11 controls with orthopedic injuries. DTI was used to assess microstructural WM alterations. CMBs were detected using susceptibility-weighted imaging (SWI) and graded according to their location in the WM and total lesion load was counted. Patients underwent SWI within 2 months after injury. DTI and clinical outcome assessment were performed at an average of eight months after injury. Outcome was assessed using the extended Glasgow Outcome Scale (GOSe). The Glasgow Coma Scale (GCS) and length of post-traumatic amnesia (PTA) were used to assess clinical severity of the injury. We found that CMB grading and total lesion load were negatively associated with fractional anisotropy (FA) and positively associated with mean diffusivity (MD). Patients with TBI and CMBs had decreased FA and increased MD compared with patients with TBI without CMBs. CMBs were also associated with worse clinical outcome. When adjusting for the clinical severity of the injury, none of the mentioned associations were found. Thus, the difference in FA and MD is explained by patients with TBI and CMBs having more severe injuries. Our results suggest that CMBs are not associated with greater WM alterations when adjusting for the clinical severity of TBI. Thus, CMBs and WM alterations may not be strongly associated pathologies in TBI.
Quality of Life in Teenagers and Adults With Coeliac Disease: From Newly Spanish Coeliac Disease Questionnaire Validation to Assessment in a Population-Based Study
Authors: Moreno María de Lourdes , Sánchez-Muñoz Diego , Sousa Carolina
Published: May 2022

Background

Coeliac disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten in genetically predisposed individuals. Gluten restriction in CD sufferers leads to numerous limitations in various aspects of daily life and can significantly impact the quality-of-life (QoL). The specific and widely used Coeliac Disease Questionnaire (CDQ) is an excellent tool to evaluate QoL in patients with CD, assessing physical, psychological, and social domains. This questionnaire is unavailable in Spain. Therefore, our study is the first to translate, culturally adapt, validate, and apply the Spanish version of CDQ to a representative sample of Spanish teenagers and adults with CD.

Methods

A total of 153 CD participants with biopsy-proven and self-reported gluten-free adherence were included in the cross-sectional study, which included four stages: (1) translation and retranslation of the French CDQ version into Spanish; (2) cultural adaptation and semantic evaluation; (3) CDQ validation through the internal consistency determination and reproducibility of the QoL; and (4) application of the questionnaire to Spanish teenagers and adults with CD and estimation of QoL using EQ-5D.

Results

The internal consistency and test–retest reliability of the Spanish CDQ were satisfactory and no ceiling or floor effects were detected. Significant correlations were identified between the CDQ scales, and the instrument for validation covering similar dimensions of the QoL was identified. The mean CDQ total score was 131.03 ± 24.1, and the social domain had the highest rating. There was no correlation between the time spent on a gluten-free diet and QoL. A significantly higher QoL score was reported among males and adolescents in the 15–17 age groups.

Conclusion

The newly Spanish CDQ is an appropriate tool to assess the QoL of the teenager and adult patients with CD. This study highlights the importance of identifying the affected scales to address actions to reduce the impact of the gluten-free diet burden of the coeliac patients and maintain public health regulations that support patients with chronic diseases such as CD.
The Relationship Between Famine Exposure During Early Life and Left Ventricular Hypertrophy in Adulthood
Authors: Yan Yu-qin , Liu Lin , Sun Shuo , Feng Ying-qing , Li Jie , Huang Yu-qing
Published: May 2022

Background

Although the evidence was still limited, some studies suggested that childhood malnutrition might affect cardiac function and structure in adulthood. To address the knowledge gap, this study investigated if the Great Chinese Famine exposure during early life had affected left ventricular hypertrophy (LVH).

Methods

This research was a cross-sectional study. It included participants who had cardiac ultrasound assessments and were born in Guangdong, China, from 1 October 1952 to 30 September 1964. They were classified according to their exposure period to famine, namely, no exposure, fetal-, early-, mid-, and late childhood. Multivariate logistic regression and subgroup analysis have been conducted to determine the odds ratio (OR) and confidence intervals (CIs) between famine exposure and LVH.

Results

This research included 2,543 participants, 1,612 women, their mean age was 59.07 ± 3.65 years, and 704 participants had LVH. LVH prevalence was 122 (23.6%), 87 (25.1%), 133 (27.3%), 184 (29.2%), and 178 (31.7%), in non-, fetal-, early-, mid-, and late-childhood exposed groups, respectively (p = 0.031), while in the non-exposed group, the ORs for developing carotid plaque as a result of fetal, early-, mid- to late-childhood exposure were 1.08 (95% CI: 0.76, 1.59, p = 0.619), 1.24 (95% CI: 1.03, 1.79, p = 0.031), 1.49 (95% CI: 1.10, 2.01, p = 0.009), and 1.64 (95% CI: 1.25, 2.18, p = 0.001), respectively (p for trend = 0.003). There was no interactive effect between gender, obesity, or hypertension history with how the famine influenced LVH, as the subgroups analyses demonstrated (all p for interaction > 0.05).

Conclusion

This research has demonstrated the potential relationship between Great Chinese Famine exposure during childhood and LVH in adults.
The Influence of EGCG on the Pharmacokinetics and Pharmacodynamics of Bisoprolol and a New Method for Simultaneous Determination of EGCG and Bisoprolol in Rat Plasma
Authors: Zeng Weiwei , Lao Sixian , Guo Yi , Wu Yufeng , Huang Min , Tomlinson Brian , Zhong Guoping
Published: May 2022

Background and Aim

Research has shown that green tea catechins may influence the activity of drug metabolizing enzymes and drug transporters. We examined whether epigallocatechin-3-gallate (EGCG) affected the pharmacokinetics and pharmacodynamics of bisoprolol in rats.

Methods

A sensitive, specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the quantitative determination of EGCG and bisoprolol. The pharmacokinetic parameters of EGCG and bisoprolol in Sprague-Dawley (SD) rats were analyzed using non-compartmental methods with the aid of the computer program WinNolin. Blood pressure (BP) of spontaneously hypertensive rats (SHRs) was monitored by the tail-cuff method. Bisoprolol was given as single doses of 10 mg/kg with or without EGCG 100 mg/kg by gavage or by intravenous injection.

Results

Intake of EGCG with bisoprolol by gavage significantly reduced the Cmax (mean Cmax from 2012.31 to 942.26 ng/mL, P < 0.05) and increased the Tmax (mean Tmax from 0.5 to 0.83 h, P < 0.01) for bisoprolol. After intravenous injection, EGCG significantly increased the apparent volume of distribution of bisoprolol (mean Vz/F from 1629.62 to 2473.27 mL/Kg, P < 0.05) and tended to increase the clearance. The absolute bioavailability of bisoprolol was reduced from 92.04 to 66.05% in rats when bisoprolol was administered with EGCG. Heart rate reduction was less in SHRs when EGCG was given by gavage with bisoprolol whereas BP reduction occurred more rapidly.

Conclusion

This study showed that the simultaneous administration of EGCG by gavage at a dose of 100 mg/kg was associated with decreased Cmax and increased Tmax of bisoprolol, and the Vz/F of bisoprolol was increased when administered with EGCG by intravenous injection in SD rats. Moreover, the early heart rate reduction with bisoprolol was attenuated and BP reduction occurred earlier when EGCG was given with bisoprolol by gavage in SHRs.
Impact of Introducing Intensity Modulated Radiotherapy on Curative Intent Radiotherapy and Survival for Lung Cancer
Authors: Fornacon-Wood Isabella , Chan Clara , Bayman Neil , Banfill Kathryn , Coote Joanna , Garbett Alex , Harris Margaret , Hudson Andrew , Kennedy Jason , Pemberton Laura , Salem Ahmed , Sheikh Hamid , Whitehurst Philip , Woolf David , Price Gareth , Faivre-Finn Corinne
Published: May 2022

Background

Lung cancer survival remains poor. The introduction of Intensity-Modulated Radiotherapy (IMRT) allows treatment of more complex tumours as it improves conformity around the tumour and greater normal tissue sparing. However, there is limited evidence assessing the clinical impact of IMRT. In this study, we evaluated whether the introduction of IMRT had an influence on the proportion of patients treated with curative-intent radiotherapy over time, and whether this had an effect on patient survival.

Materials and Methods

Patients treated with thoracic radiotherapy at our institute between 2005 and 2020 were retrospectively identified and grouped into three time periods: A) 2005-2008 (pre-IMRT), B) 2009-2012 (selective use of IMRT), and C) 2013-2020 (full access to IMRT). Data on performance status (PS), stage, age, gross tumour volume (GTV), planning target volume (PTV) and survival were collected. The proportion of patients treated with a curative dose between these periods was compared. Multivariable survival models were fitted to evaluate the hazard for patients treated in each time period, adjusting for PS, stage, age and tumour volume.

Results

12,499 patients were included in the analysis (n=2675 (A), n=3127 (B), and n=6697 (C)). The proportion of patients treated with curative-intent radiotherapy increased between the 3 time periods, from 38.1% to 50.2% to 65.6% (p<0.001). When stage IV patients were excluded, this increased to 40.1% to 58.1% to 82.9% (p<0.001). This trend was seen across all PS and stages. The GTV size increased across the time periods and PTV size decreased. Patients treated with curative-intent during period C had a survival improvement compared to time period A when adjusting for clinical variables (HR=0.725 (0.632-0.831), p<0.001).

Conclusion

IMRT was associated with to more patients receiving curative-intent radiotherapy. In addition, it facilitated the treatment of larger tumours that historically would have been treated palliatively. Despite treating larger, more complex tumours with curative-intent, a survival benefit was seen for patients treated when full access to IMRT was available (2013-2020). This study highlights the impact of IMRT on thoracic oncology practice, accepting that improved survival may also be attributed to a number of other contributing factors, including improvements in staging, other technological radiotherapy advances and changes to systemic treatment.
Absence of PSA Flare With Apalutamide Administered 1 Hour in Advance With GnRH Agonists: Case Report
Authors: Hu Zhiquan , Liu Zhenghao , Chen Zhiyuan , Zeng Xing , Wang Zhihua , Yang Chunguang
Published: May 2022

Objective

To examine the effects of apalutamide on endocrine function and flare prevention in metastatic hormone-sensitive prostate cancer (mHSPC) patients administered GnRH agonists.

Methods

The first newly diagnosed mHSPC patient took apalutamide for 2 weeks followed by combination with GnRH agonist, as recommended by clinical guidelines. Serum luteinizing hormone (LH), testosterone, and PSA were detected during the oral administration of apalutamide before and after ADT. Eight newly diagnosed mHSPC patients innovatively took apalutamide 1 hour before GnRH agonist administration; LH, testosterone and PSA were detected before and after ADT.

Results

In the first patient, LH and testosterone levels were increased during apalutamide monotherapy, and serum PSA levels decreased rapidly, demonstrating apalutamide effectively blocked AR signaling. In patients on the 1-hour regimen, combined treatment with apalutamide and GnRH agonists led to peak level of testosterone on day 3 and castration level on day 28, while PSA decreased continuously. No one experienced dysuria or bone pain worsen after ADT.

Conclusion

Taking apalutamide 1 hour in advance may effectively prevent the flare-up effect in prostate cancer patients treated with GnRH agonists. Compared with the 2-week regimen, the 1-hour regimen could simplify the treatment process and bring testosterone to castration levels in advance.
β-Boswellic Acid Suppresses Breast Precancerous Lesions via GLUT1 Targeting-Mediated Glycolysis Inhibition and AMPK Pathway Activation
Authors: Bie Fengjie , Zhang Guijuan , Yan Xianxin , Ma Xinyi , Zhan Sha , Qiu Yebei , Cao Jingyu , Ma Yi , Ma Min
Published: May 2022

Breast carcinoma is a multistep progressive disease. Precancerous prevention seems to be crucial. β-Boswellic acid (β-BA), the main component of the folk medicine Boswellia serrata (B. serrata), has been reported to be effective in various diseases including tumors. In this work, we demonstrated that β-BA could inhibit breast precancerous lesions in rat disease models. Consistently, β-BA could suppress proliferation and induce apoptosis on MCF-10AT without significantly influencing MCF-10A. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that β-BA may interfere with the metabolic pathway. Metabolism-related assays showed that β-BA suppressed glycolysis and reduced ATP production, which then activated the AMPK pathway and inhibited the mTOR pathway to limit MCF-10AT proliferation. Further molecular docking analysis suggested that GLUT1 might be the target of β-BA. Forced expression of GLUT1 could rescue the glycolysis suppression and survival limitation induced by β-BA on MCF-10AT. Taken together, β-BA could relieve precancerous lesions in vivo and in vitro through GLUT1 targeting-induced glycolysis suppression and AMPK/mTOR pathway alterations. Here, we offered a molecular basis for β-BA to be developed as a promising drug candidate for the prevention of breast precancerous lesions.
Efficacy and Safety Profile of Histone Deacetylase Inhibitors for Metastatic Breast Cancer: A Meta-Analysis
Authors: Wang Changjun , Lin Yan , Zhu Hanjiang , Zhou Yidong , Mao Feng , Huang Xin , Sun Qiang , Li Chenggang
Published: May 2022

Introduction

Acquired resistance to endocrine therapy (ET) remains a big challenge in the management of metastatic breast cancer (MBC). A novel therapeutic agent, histone deacetylase inhibitors (HDACi), targets the abnormal epigenetic modification and may overcome acquired resistance. However, HDACi efficacy and the safety profile for hormone receptor (HoR)-positive/human epidermal growth factor receptor 2 (HER2)-negative MBC remain controversial.

Methods

Two independent reviewers searched PubMed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies on HDACi and HoR+/HER2- MBC. Demographic and clinicopathological parameters were extracted and presented as means and proportions, and between-group differences were assessed by Pearson chi-square test. Fixed- or random-effects models were used for meta-analysis based on inter-study heterogeneity. Pooled results were presented as L’Abbé plot and forest plot. Funnel plot and Egger’s test were employed for evaluation of publication bias.

Results

Four studies with 1,457 patients were included for meta-analysis. The overall objective response rates (ORRs) of HDACi + ET (HE) and placebo + ET (PE) groups were 11.52% and 6.67%, respectively. The HE regimen significantly increased ORR (odds ratio [OR] 1.633, 95% confidence interval [CI] = 1.103–2.418, p < 0.05) and showed higher clinical benefit rate (CBR) than the PE regimen (HE vs. PE groups: 38.82% vs. 30.58%, OR 1.378, 95% CI = 1.020–1.861, p < 0.05). Additionally, the HE regimen was associated with prolonged progression-free survival (PFS) (hazard ratio [HR] 0.761, 95% CI = 0.650–0.872, p < 0.001) and overall survival (OS) (HR 0.849, 95% CI = 0.702–0.996, p < 0.001). Regarding safety profile, the HE regimen had increasing toxicity in terms of higher overall adverse event (AE), Grade ≥3 AE, dose modification, and discontinuation rate.

Conclusions

This meta-analysis validated that the HE regimen had superior efficacy over control in terms of ORR, CBR, PFS, and OS, but was accompanied with increasing toxicity. HDACi plus ET could serve as an important option in managing HoR+/HER2- MBC. Future studies may focus on the clinical difference among different HDACi and AE managements to enhance tolerability.
Carnosol Induces p38-Mediated ER Stress Response and Autophagy in Human Breast Cancer Cells
Authors: Alsamri Halima , Alneyadi Aysha , Muhammad Khalid , Ayoub Mohammed Akli , Eid Ali , Iratni Rabah
Published: May 2022

We recently reported that carnosol induces ROS-dependent autophagy and apoptosis in breast cancer cells. We also reported that carnosol inhibits breast cancer cell migration, invasion, and in ovo tumor growth, as well as targets STAT3, PCAF, and p300 to proteasome degradation. Here, we investigated the molecular mechanisms underlying its anti-malignant activity in breast cancer. We report that carnosol induces a ROS-dependent type I and type II programmed cell death (PCD-I or PCD-II, respectively), which occurred independently of each other. Indeed, chemical inhibition of autophagy had no effect on the induction of apoptosis, evident by the absence of cleaved PARP. Electron microscopy revealed that carnosol-treated cells exhibited enlarged endoplasmic reticulum, characteristic of ER stress. Markers of the three unfolded protein response pathways (PERK, IRE-1 α, and ATF6), namely ATF4, CHOP, phospho-IRE-1α, XBP1S, and cleaved ATF6 were upregulated in a ROS-dependent manner. In addition, carnosol induced a ROS-dependent activation of p38MAPK, increased the overall level of protein polyubiquitination, and targeted mTOR protein to proteasome degradation. Interestingly, inhibition of p38MAPK, by SB202190 and 203580, reduced cell death, selectively blocked the induction of IRE-1α and ATF6 UPR sensors and inhibited autophagy. In addition, inhibition of p38 reduced the carnosol-induced polyubiquitination and rescued mTOR, PCAF, and STAT3 from proteasomal degradation. Importantly, activation of PERK sensors and induction of apoptosis occurred independently of p38 activation. Taken together, our results suggest that ROS-dependent induced-ER stress contributes to carnosol-induced apoptotic and autophagic cell death in breast cancer cells, and further confirm that carnosol is a promising agent for breast cancer therapy.
A Pilot Study to Assess Opportunistic Use of CT-Scan for Osteoporosis Screening in Chronic Pancreatitis
Authors: McNabb-Baltar Julia , Manickavasagan Hanisha R. , Conwell Darwin L. , Lu Andrew , Yadav Dhiraj , Hart Philip A. , Lara Luis F. , Cruz-Monserrate Zobeida , Ing Steven , Hinton Alice , Mace Thomas A. , Bradley David , Shah Zarine K.
Published: May 2022

Objectives: CT scans are commonly performed in patients with chronic pancreatitis (CP). Osteopathy and fractures are recognized in CP but no osteoporosis screening guidelines are recommended. “Opportunistic” CT scan-derived bone density thresholds are assessed for identifying osteoporosis in CP.

Methods: Retrospective pilot cohort study. CP subjects who had CT scans and dual-energy x-ray absorptiometry (DXA) within 1 year were included. CT-derived bone density was measured at the L1 level. Pearson’s correlation was performed between age and CT-derived bone density in Hounsfield unit (HU). Univariate analysis using HU to identify osteoporosis was performed at various thresholds of bone density. The discriminatory ability of the model was evaluated with the area under the receiver operating characteristic (ROC) curve (AUC). Several HU thresholds were tested.

Results: Twenty-seven CP subjects were included, of whom 11 had normal bone density, 12 osteopenia, and four osteoporosis on DXA. The mean age was 59.9 years (SD 13.0). There was a negative correlation of age with HU (r = −0.519, p = 0.006). CT-derived bone density predicted DXA-based osteoporosis in the univariable analysis (Odds Ratio (OR) = 0.97 95% Confidence Interval (CI) 0.94–1.00, p = 0.03). HU thresholds were tested. A threshold of 106 HU maximized the accuracy (AUC of 0.870).

Conclusions: CT scan may be repurposed for “opportunistic” screening to rule out osteoporosis in CP. A larger study is warranted to confirm these results.
How Egg Storage Duration Prior to Incubation Impairs Egg Quality and Chicken Embryonic Development: Contribution of Imaging Technologies
Authors: Adriaensen Hans , Parasote Vanille , Castilla Ines , Bernardet Nelly , Halgrain Maeva , Lecompte François , Réhault-Godbert Sophie
Published: May 2022

Storing fertilised eggs prior to incubation is a frequent practice in commercial hatcheries to coordinate activities and synchronise hatchings. However, the conditions used to store eggs can have major impacts on egg quality and the subsequent viability of chicken embryos. While storage temperatures of 16–18°C are classically used in hatcheries, the duration of storage varies from three to more than 10 days. We explored the effect of storage duration (zero, three or 10 days; D0, D3 and D10, respectively) at 16°C, 80% relative humidity (RH) on egg quality (Broiler, Ross 308), using computed tomography (CT) and classical measurements (egg weight, eggshell strength, egg white pH, Haugh units, yolk index and colour). The results revealed that a storage duration of up to 10 days negatively affected some egg quality traits (yolk index and volume, air chamber volume and egg white pH). Eggs stored for three or 10 days were further incubated for 11, 13 or 15 days (37.8°C, 55% RH). Eggs were analysed by magnetic resonance imaging (MRI) and CT to assess the development of the embryo and internal egg changes occurring during incubation. First, data showed that the fertility and sex ratio of eggs were not affected by storage duration. However, the mortality of viable eggs was increased in the D10 group compared to the D3 group. Results of non-invasive imaging technologies revealed that the storage of eggs for 10 days impaired embryo growth as early as 11 days of incubation (decrease in brain and embryo volumes). Collectively, these data provide new evidence that the duration of egg storage negatively affects embryonic growth. They further corroborate that this parameter is likely to be crucial to synchronising embryonic stages and maybe reducing the hatching window, hence limiting the time spent by newborn chicks in hatchers. In addition, our results highlight that CT and MRI imaging technologies are useful non-invasive tools to evaluate egg quality prior to incubation and the impact of storage (or incubation) practices on developmental growth of the embryo.
Current Challenges of Mitochondrial Potassium Channel Research
Authors: Kulawiak Bogusz , Szewczyk Adam
Published: May 2022

In this paper, the current challenges of mitochondrial potassium channels research were critically reviewed. Even though recent progress in understanding K+ traffic in mitochondria has been substantial, some basic issues of this process remain unresolved. Here, we focused on the critical discussion of the molecular identity of various mitochondrial potassium channels. This point helps to clarify why there are different potassium channels in specific mitochondria. We also described interactions of mitochondrial potassium channel subunits with other mitochondrial proteins. Posttranslational modifications of mitochondrial potassium channels and their import are essential but unexplored research areas. Additionally, problems with the pharmacological targeting of mitochondrial potassium channel were illustrated. Finally, the limitation of the techniques used to measure mitochondrial potassium channels was explained. We believe that recognizing these problems may be interesting for readers but will also help to progress the field of mitochondrial potassium channels.
UGT440A1 Is Associated With Motility, Reproduction, and Pathogenicity of the Plant-Parasitic Nematode Bursaphelenchus xylophilus
Authors: Wang Min , Du Guicai , Fang Junna , Wang Linsong , Guo Qunqun , Zhang Tingting , Li Ronggui
Published: May 2022

Pine wilt disease (PWD) caused byBursaphelenchus xylophilusis considered a major threat to pine forests worldwide. Uridine diphosphate (UDP)-glycosyltransferases (UGTs) catalyze the conjugation of small lipophilic compounds with sugars and play crucial roles in the detoxification and homeostatic processes in all living organisms. We investigated the molecular characteristics and biological functions of the geneUGT440A1that encodes UGTs inB. xylophilus. Thein situhybridization results indicated thatUGT440A1is expressed in all developmental stages ofB. xylophilus, particularly in the head, intestine, and hypodermis of the second-stage of juveniles (J2), third-stage of juveniles (J3) and fourth-stage of juveniles (J4) females and in almost the whole body of J4 males and adults. Recombinant UGT440A1 was observed mainly in the inclusion bodies, and the enzyme activity assay revealed that UGT440A1 could catalyze the glycosylation reaction of two types of flavonols (kaempferol and quercetin). RNA interference (RNAi) ofUGT440A1suppressed motility, feeding, and reproduction ofB. xylophilus. Furthermore,UGT440A1knockdown caused a delay in the development of PWD symptoms in the pine seedlings inoculated with the nematodes. These results suggest thatUGT440A1is involved in the pathogenic process ofB. xylophilusand the information may facilitate a better understanding of the molecular mechanism of PWD.
Regulation and Function of Metal Uptake Transporter NtNRAMP3 in Tobacco
Authors: Kozak Katarzyna , Papierniak-Wygladala Anna , Palusińska Małgorzata , Barabasz Anna , Antosiewicz Danuta Maria
Published: May 2022

Natural resistance-associated macrophage protein (NRAMP) genes encode proteins with low substrate specificity, important for maintaining metal cross homeostasis in the cell. The role of these proteins in tobacco, an important crop plant with wide application in the tobacco industry as well as in phytoremediation of metal-contaminated soils, remains unknown. Here, we identified NtNRAMP3, the closest homologue to NRAMP3 proteins from other plant species, and functionally characterized it. A NtNRAMP3-GFP fusion protein was localized to the plasma membrane in tobacco epidermal cells. Expression of NtNRAMP3 in yeast was able to rescue the growth of Fe and Mn uptake defective Δfet3fet4 and Δsmf1 mutant yeast strains, respectively. Furthermore, NtNRAMP3 expression in wild-type Saccharomyces cerevisiae DY1457 yeast strain increased sensitivity to elevated concentrations of iron (Fe), manganese (Mn), copper (Cu), cobalt (Co), nickel (Ni), and cadmium (Cd). Taken together, these results point to a possible role in the uptake of metals. NtNRAMP3 was expressed in the leaves and to a lesser extent in the roots of tobacco plants. Its expression occurred mainly under control conditions and decreased very sharply in deficiency and excess of the tested metals. GUS-based analysis of the site-specific activity of the NtNRAMP3 promoter showed that it was primarily expressed in the xylem of leaf blades. Overall, our data indicate that the main function of NtNRAMP3 is to maintain cross homeostasis of Fe, Mn, Co, Cu, and Ni (also Cd) in leaves under control conditions by controlling xylem unloading.
Molecular and Computational Strategies to Increase the Efficiency of CRISPR-Based Techniques
Authors: Mattiello Lucia , Rütgers Mark , Sua-Rojas Maria Fernanda , Tavares Rafael , Soares José Sérgio , Begcy Kevin , Menossi Marcelo
Published: May 2022

The prokaryote-derived Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas mediated gene editing tools have revolutionized our ability to precisely manipulate specific genome sequences in plants and animals. The simplicity, precision, affordability, and robustness of this technology have allowed a myriad of genomes from a diverse group of plant species to be successfully edited. Even though CRISPR/Cas, base editing, and prime editing technologies have been rapidly adopted and implemented in plants, their editing efficiency rate and specificity varies greatly. In this review, we provide a critical overview of the recent advances in CRISPR/Cas9-derived technologies and their implications on enhancing editing efficiency. We highlight the major efforts of engineering Cas9, Cas12a, Cas12b, and Cas12f proteins aiming to improve their efficiencies. We also provide a perspective on the global future of agriculturally based products using DNA-free CRISPR/Cas techniques. The improvement of CRISPR-based technologies efficiency will enable the implementation of genome editing tools in a variety of crop plants, as well as accelerate progress in basic research and molecular breeding.