bluuebunny/crossref_metadata_2025_split huggingface dataset:
MARCKSL1–2 reverses docetaxel-resistance of lung adenocarcinoma cells by recruiting SUZ12 to suppress HDAC1 and elevate miR-200b
Authors: Jiang Min , Qi Feng , Zhang Kai , Zhang Xiaofei , Ma Jingjing , Xia Suhua , Chen Longbang , Yu Zhengyuan , Chen Jing , Chen Dongqin 
Published: July 2022

Abstract
Background
Long non-coding RNAs (lncRNAs) are implicated in the development of multiple cancers. In our previous study, we demonstrated that HDAC1/4-mediated silencing of microRNA-200b (miR-200b) enhances docetaxel (DTX)-resistance of human lung adenocarcinoma (LAD) cells.

Methods and results
Herein, we probed the function of LncRNA MARCKSL1–2 (MARCKSL1-transcript variant 2, NR_052852.1) in DTX resistance of LAD cells. It was found that MARCKSL1–2 expression was markedly reduced in DTX-resistant LAD cells. Through gain- or loss- of function assays, colony formation assay, EdU assay, TUNEL assay, and flow cytometry analysis, we found that MARCKSL1–2 suppressed the growth and DTX resistance of both parental and DTX-resistant LAD cells. Moreover, we found that MARCKSL1–2 functioned in LAD through increasing miR-200b expression and repressing HDAC1. Mechanistically, MARCKSL1–2 recruited the suppressor of zeste 12 (SUZ12) to the promoter of histone deacetylase 1 (HDAC1) to strengthen histone H3 lysine 27 trimethylation (H3K27me3) of HDAC1 promoter, thereby reducing HDAC1 expression. MARCKSL1–2 up-regulated miR-200b by blocking the suppressive effect of HDAC1 on the histone acetylation modification at miR-200b promoter. Furthermore, in vivo analysis using mouse xenograft tumor model supported that overexpression of MARCKSL1–2 attenuated the DTX resistance in LAD tumors.

Conclusions
We confirmed that MARCKSL1–2 alleviated DTX resistance in LAD cells by abolishing the inhibitory effect of HDAC1 on miR-200b via the recruitment of SUZ12. MARCKSL1–2 could be a promising target to improve the chemotherapy of LAD.

Graphical abstract
Tracking malaria health disbursements by source in Zambia, 2009–2018: an economic modelling study
Authors: Mtalimanja Michael , Abasse Kassim Said , Abbas Muhammad , Mtalimanja James Lamon , Zhengyuan Xu , DuWenwen  , Cote Andre , Xu Wei 
Published: July 2022

Abstract
Background
Zambia has made profound strides in reducing both the incidence and prevalence of malaria followed by reducing malaria related deaths between 2009 and 2018. The number of partners providing malaria funding has significantly increased in the same period. The increasing number of partners and the subsequent reduction of the number of reported malaria cases in the Ministry of Health main data repository Health Management Information System (HMIS) stimulated this research. The study aimed at (1) identifying major sources of malaria funding in Zambia; (2) describe malaria funding per targeted interventions and (3) relating malaria funding with malaria disease burden.

Methods
Data was collected using extensive literature review of institutional strategic document between the year 2009 to 2018, assuming one-year time lag between investment and the health outcome across all interventions. The National’s Health Management Information System (HMIS) provided information on annual malaria admission cases and outpatient clinic record. The statistical package for social sciences (SPSS) alongside Microsoft excel was used to analyze data in the year 2019.

Results
The investigation observed that about 30% of the funding came from PMI/USAID, 26% from the global funds, the government of Zambia contributed 17% and other partners sharing the remaining 27%. Multivariate regression analysis suggests a positive correlation between reducing reported malaria disease burden in HMIS 2009–2018 and concurrent increasing program/intervention funding towards ITNs, IRS, MDA, and Case Management with r2 = 77% (r2 > 0.77; 95% CI: 0.72–0.81). Furthermore, IRS showed a p-value 0.018 while ITNs, Case Management and MDA having 0.029, 0.030 and 0.040 respectively.

Conclusion
Our findings highlight annual funding towards specific malaria intervention reduced the number of malaria admission cases.
Whole-exome sequencing identified mutational profiles of urothelial carcinoma post kidney transplantation
Authors: Lim Lee-Moay , Chung Wen-Yu , Hwang Daw-Yang , Yu Chih-Chuan , Ke Hung-Lung , Liang Peir-In , Lin Ting-Wei , Cheng Siao Muk , Huang A-Mei , Kuo Hung-Tien 
Published: July 2022

AbstractKidney transplantation is a lifesaving option for patients with end-stage kidney disease. In Taiwan, urothelial carcinoma (UC) is the most common de novo cancer after kidney transplantation (KT). UC has a greater degree of molecular heterogeneity than do other solid tumors. Few studies have explored genomic alterations in UC after KT. We performed whole-exome sequencing to compare the genetic alterations in UC developed after kidney transplantation (UCKT) and in UC in patients on hemodialysis (UCHD). After mapping and variant calling, 18,733 and 11,093 variants were identified in patients with UCKT and UCHD, respectively. We excluded known single-nucleotide polymorphisms (SNPs) and retained genes that were annotated in the Catalogue of Somatic Mutations in Cancer (COSMIC), in the Integrative Onco Genomic cancer mutations browser (IntOGen), and in the Cancer Genome Atlas (TCGA) database of genes associated with bladder cancer. A total of 14 UCKT-specific genes with SNPs identified in more than two patients were included in further analyses. The single-base substitution (SBS) profile and signatures showed a relative high T > A pattern compared to COMSIC UC mutations. Ingenuity pathway analysis was used to explore the connections among these genes.GNAQ,IKZF1, andNTRK3were identified as potentially involved in the signaling network of UCKT. The genetic analysis of posttransplant malignancies may elucidate a fundamental aspect of the molecular pathogenesis of UCKT.
Development of a single device to quantify motor impairments of the elbow: proof of concept
Authors: van der Velden Levinia Lara , Onneweer Bram , Haarman Claudia Josephina Wilhelmina , Benner Joyce Lisanne , Roebroeck Marij Eugenie , Ribbers Gerard Maria , Selles Ruud Willem 
Published: July 2022

AbstractBackgroundFor patients with post-stroke upper limb impairments, the currently available clinical measurement instruments are inadequate for reliable quantification of multiple impairments, such as muscle weakness, abnormal synergy, changes in elastic joint properties and spasticity. Robotic devices to date have successfully achieved precise and accurate quantification but are often limited to the measurement of one or two impairments. Our primary aim is to develop a robotic device that can effectively quantify four main motor impairments of the elbow.Methods The robotic device, Shoulder Elbow Perturbator, is a one-degree-of-freedom device that can simultaneously manipulate the elbow joint and support the (partial) weight of the human arm. Upper limb impairments of the elbow were quantified based on four experiments on the paretic arm in ten stroke patients (mean age 65 ± 10 yrs, 9 males, post-stroke) and the non-dominant arm in 20 healthy controls (mean age 65 ± 14 yrs, 6 males). The maximum strength of elbow flexor and elbow extensor muscles was measured isometrically at 90-degree elbow flexion. The maximal active extension angle of the elbow was measured under different arm weight support levels to assess abnormal synergy. Torque resistance was analyzed during a slow (6°/s) passive elbow rotation, where the elbow moved from the maximal flexion to maximal extension angle and back, to assess elastic joint properties. The torque profile was evaluated during fast (100°/s) passive extension rotation of the elbow to estimate spasticity.ResultsThe ten chronic stroke patients successfully completed the measurement protocol. The results showed impairment values outside the 10thand 90thpercentile reference intervals of healthy controls. Individual patient profiles were determined and illustrated in a radar figure, to support clinicians in developing targeted treatment plans.ConclusionThe Shoulder Elbow Perturbator can effectively quantify the four most important impairments of the elbow in stroke patients and distinguish impairment scores of patients from healthy controls. These results are promising for objective and complete quantification of motor impairments of the elbow and monitoring patient prognosis. Our newly developed Shoulder Elbow Perturbator can therefore in the future be employed to evaluate treatment effects by comparing pre- and post-treatment assessments.
TGFβ1-transfected tendon stem cells promote tendon fibrosis
Authors: Yu Hong-Bin , Xiong Jing , Zhang Hui-Zhen , Chen Qin , Xie Xu-Yong 
Published: July 2022

Abstract
Background
In aged people, tendon injuries frequently occur during sporting and daily activities. In clinical practice, typical physiotherapeutic, pharmacotherapeutic, and surgical techniques do not result in the full recovery of injured tendons, which may lead to chronic degenerative disease.

Methods
We first isolated tendon stem cells (TSCs) from rats and transfected them with the TGFβ1 gene, resulting in TGFβ1-TSCs. The proliferation of TSCs was detected using the Cell Counting Kit 8, and TSCs were identified by immunofluorescence analysis and differentiation capacity analysis. Aggrecan, COL2A1, alpha smooth muscle actin (α-SMA), and p-Smad2 expression levels were detected using western blotting and quantitative reverse transcription polymerase chain reaction. Additionally, a tendon injury model was generated to explore the effect of TGFβ1 on the repair of the tendon by TSCs.

Results
Compared with fibrinogen treatment, TSC + fibrinogen or TGFβ1-TSC + fibrinogen treatment significantly promoted the fibrosis of injured tendons, as evidenced by histological analyses, with TGFβ1-TSC + fibrinogen having a greater effect than TSC + fibrinogen. In TGFβ1-TSCs, increased expression levels of aggrecan and COL2A1 indicated that TGFβ1 signaling induced chondrogenic differentiation. Meanwhile, the increased collagen and α-SMA protein levels indicated that TGFβ1 promoted fibrogenesis. Additionally, TGFβ1 stimulated the production of phosphorylated Smad2 in TSCs, which suggested that the chondrogenic and fibrogenic differentiation of TSCs, as well as tissue regeneration, may be associated with the TGFβ1/Smad2 pathway.

Conclusion
TGFβ1-TSC therapy may be a candidate for effective tendon fibrosis.
Synthesis of lanthanide tag and experimental studies on paramagnetically induced residual dipolar couplings
Authors: Yassin Ali , Nehmeh Bilal , Kantar Sally El , Al Kazzaz Yara , Akoury Elias 
Published: July 2022

AbstractNuclear Magnetic Resonance (NMR) spectroscopy is an indispensable technique for the structure elucidation of molecules and determination of their characteristic interactions. Residual Dipolar Coupling (RDC) is an NMR parameter that provides global orientation information of molecules but necessitates the use of an anisotropic orientation medium for the partial alignment of the target molecule with respect to the magnetic field. Importantly, anisotropic paramagnetic tags have been successful as orienting media in biomolecular NMR applications but their use in small organic molecules remains imperfect due to challenges in designing functional lanthanide complexes with varying degrees of bonding in the Ln(III) inner coordination sphere. In this study, we propose a strategy for the synthesis of the lanthanide tag 4-mercaptomethylpyridine-2,6-dicarboxylic acid, 4-MMDPA and the measurement of RDCs in a target molecule using several paramagnetic lanthanide complexes.Graphical Abstract
Metagenomic insights into the microbe-mediated B and K2 vitamin biosynthesis in the gastrointestinal microbiome of ruminants
Authors: Jiang Qian , Lin Limei , Xie Fei , Jin Wei , Zhu Weiyun , Wang Min , Qiu Qiang , Li Zhipeng , Liu Junhua , Mao Shengyong 
Published: July 2022

AbstractBackgroundB and K2vitamins, essential nutrients in host metabolism, can be synthesized by the rumen microbiome in ruminants and subsequently absorbed by the host. However, the B and K2vitamin biosynthesis by the whole gastrointestinal microbiome and their abundances in different dietary strategies are largely unknown. Here, we reanalyzed our previous large-scale metagenomic data on the gastrointestinal microbiome of seven ruminant species and recruited 17,425 nonredundant microbial genomes from published datasets to gain a comprehensive understanding of the microbe-mediated B and K2vitamin biosynthesis in ruminants.ResultsWe identified 1,135,807 genes and 167 enzymes involved in B and K2vitamin biosynthesis. Our results indicated that the total abundances of B and K2vitamin biosynthesis were dominant in the stomach microbiome, while the biosynthesis of thiamine, niacin, and pyridoxine was more abundant in the large intestine. By examining 17,425 nonredundant genomes, we identified 2366 high-quality genomes that were predicted to de novo biosynthesize at least one vitamin. Genomic analysis suggested that only 2.7% of these genomes can synthesize five or more vitamins, and nearly half of genomes can synthesize only one vitamin. Moreover, we found that most genomes possessed cobalamin transporters or cobalamin-dependent enzymes to consume cobalamin directly, and only a few microbial genomes possessed a complete cobalamin biosynthesis pathway. Based on these genomic data, we examined the effect of the high-grain (HG) diet on the vitamin biosynthesis of the rumen microbiome of dairy cattle. We revealed that most vitamin biosynthesis was enhanced in the HG group, while only cobalamin synthesis was inhibited in the HG group, indicating that dietary fiber is vital for cobalamin biosynthesis.ConclusionsWe primarily provided a gene catalog and 2366 microbial genomes involved in B and K2vitamin biosynthesis in ruminants. Our findings demonstrated the regional heterogeneity and dietary effect of vitamin biosynthetic potential in the ruminant gastrointestinal microbiome and interpreted the biosynthesis mechanisms of these microbes and their physiological adaptability. This study expands our understanding of microbe-mediated vitamin biosynthesis in ruminants and may provide novel targets for manipulation to improve the production of these essential vitamins.
Ozone high dose therapy (OHT) improves mitochondrial bioenergetics in peripheral blood mononuclear cells
Authors: König Brigitte , Lahodny Johann 
Published: July 2022

Abstract

Background
The worldwide increasing number of people with chronic diseases is pushing conventional therapy to its limits. The so-called Major AutoHaemo Therapy (MAH) has been used in many practices for years. Despite suspicions, especially the 10-passes ozone-high-dosis Therapy (OHT) has shown substantial benefits in chronic ailments. However, knowledge of scientifically based effects of high ozone concentrations are still rare. The present investigation focussed on verifying whether OHT may be linked to a beneficial effect on mitochondrial bioenergetics which can be expressed as a bioenergetic health index (BHI).

Methods
We report on six patients which received OHT for preventive purposes twice within one week. The BHI in peripheral blood mononuclear cells (PBMC) is calculated from parameters of a cellular mitochondrial function assay, which gives insights into different aspects of mitochondrial function: 1) Basal oxygen consumption rate (OCR); 2) ATP-linked OCR and proton leak; 3) Maximal OCR and reserve capacity; 4) Non-mitochondrial OCR.

Results
The results clearly show that the bioenergetic health index in PBMC improves significantly after just 2 OHT applications over a period of 1 week. The overall improvement of the BHI is based primarily on a significant increase in the reserve capacity and the maximum respiration of the mitochondria. The increase in non-mitochondrial oxygen consumption, which has a negative impact on the BHI value, is indicative for the Nrf-2 dependent activation of antioxidant and detoxifying enzymes activated through OHT.

Conclusion
These data demonstrate for the first time the beneficial effect of OHT on mitochondrial parameters. Thus, the results of this study suggest that OHT could be a safe and effective therapeutic option alone or as integrative and complementary support for pharmacological therapy in a variety of chronic and acute diseases where mitochondrial dysfunction plays a central role.
Identification of KRASG12C Mutations in Circulating Tumor DNA in Patients With Cancer
Authors: Thein Kyaw Z. , Biter Amadeo B. , Banks Kimberly C. , Duda Andrew W. , Saam Jennifer , Roszik Jason , Janku Filip , Skoulidis Ferdinandos , Heymach John V. , Kopetz Scott , Meric-Bernstam Funda , Hong David S. 
Published: July 2022

PURPOSE KRAS is the most mutated proto-oncogene that has been identified in cancer, and treatment of patients with KRAS mutations remains an arduous challenge. Recently, KRAS G12C mutation has attracted special interest because it is now considered potentially druggable with recently developed covalent small-molecule KRAS G12C inhibitors. Nevertheless, to date, there have been no large-scale analyses of liquid biopsy that include testing for KRAS G12C. Here, we performed a comprehensive analysis of KRAS G12C mutations in multiple cancer types, as detected by circulating tumor DNA. METHODS We conducted a 5-year retrospective review of KRAS G12C mutations in patients with cancer who had undergone Guardant360 testing between July 1, 2014, and June 30, 2019; our study included treatment-naive and previously treated patients with metastatic solid tumors. RESULTS KRAS G12C mutations were identified in 2,985 of 80,911 patients (3.7%), across > 40 tumor types. KRAS G12C mutations were detected most frequently in patients with nonsquamous non–small-cell lung cancer (NSCLC; 7.5%), NSCLC of all subtypes (6.9%), cancer of unknown primary (4.1%), colorectal cancer (3.5%), squamous NSCLC (2.0%), pulmonary neuroendocrine tumors (1.9%), and pancreatic ductal adenocarcinoma (1.2%) and cholangiocarcinoma (1.2%). KRAS G12C mutations were predominantly clonal (clonality > 0.9%) in patients with lung adenocarcinoma, non-NSCLC, cancer of unknown primary, NSCLC, and pancreatic ductal adenocarcinoma, and patients with colorectal cancer and breast cancer had bimodal distribution of clonal and subclonal KRAS G12C mutations. CONCLUSION Our study demonstrates the feasibility of using circulating tumor DNA to identify KRAS G12C mutations across solid tumors; the highest detection rate was in lung cancer, as previously reported in the literature.
DPYD*7 as a Predictor of Severe Fluoropyrimidine-Related Adverse Events
Authors: de With Mirjam , Brufau Gemma , van den Berg Laila A. , de Man Femke M. , Trajkovic Marija , Thijs Martine F. , Castel Rob , Vermeer Henricus J. , el Bouazzaoui Samira , van Hemel Amber , Matic Maja , Mathijssen Ron H. J. , Bins Sander , van Schaik Ron H. N. 
Published: July 2022

PURPOSE Around 20%-30% of patients treated with fluoropyrimidines develop severe treatment-related adverse events (AEs). These are mainly caused by deficiency of dihydropyrimidine dehydrogenase, its main metabolizing enzyme. The DPYD*7 variant allele contains a frameshift mutation that leads to absence of dihydropyrimidine dehydrogenase. Clinical studies on this variant in patients treated with fluoropyrimidines are lacking because of its low minor allelic frequency. However, the DPYD*7 minor allelic frequency is 56-times higher in the Dutch compared with the global population. This allowed us to evaluate fluoropyrimidine tolerability in DPYD*7 variant allele carriers. MATERIALS AND METHODS Patients treated with standard-of-care fluoropyrimidine who were pretreatment DPYD genotyped for DPYD*2A, *13, 2846A>T, and 1236G>A single-nucleotide polymorphisms were included for analyses. Patients were additionally screened for the DPYD*7 allele (rs72549309, 295-298delTCAT). AEs were graded if they worsened from baseline, according to Common Terminology Criteria for Adverse Events version 5.0. AEs ≥ grade 3 were considered severe. RESULTS From 3,748 patients, we found 13 patients carrying heterozygous DPYD*7. Relevant clinical data were available for 11 patients. All patients developed fluoropyrimidine-related AEs, of which five patients developed severe AEs (46%). From these five patients, three patients were started with 65% or 50% of standard dose, but apparently still developed severe toxicity. Because of severe AEs, three patients discontinued treatment prematurely (one patient already started with 50% of standard dose) and one patient who started with 50% of standard dose was further reduced to 35% of standard dose. CONCLUSION In this study, the clinical consequences of carrying the DPYD*7 variant allele were confirmed as 46% of the patients developed severe AEs, even in the presence of initial dose reductions. This underlines the need for prospective studies investigating the required fluoropyrimidine dose for DPYD*7 carriers.
TSH and FT4 Reference Intervals in Pregnancy: A Systematic Review and Individual Participant Data Meta-Analysis
Authors: Osinga Joris A J , Derakhshan Arash , Palomaki Glenn E , Ashoor Ghalia , Männistö Tuija , Maraka Spyridoula , Chen Liangmiao , Bliddal Sofie , Lu Xuemian , Taylor Peter N , Vrijkotte Tanja G M , Tao Fang-Biao , Brown Suzanne J , Ghafoor Farkhanda , Poppe Kris , Veltri Flora , Chatzi Lida , Vaidya Bijay , Broeren Maarten A C , Shields Beverley M , Itoh Sachiko , Mosso Lorena , Popova Polina V , Anopova Anna D , Kishi Reiko , Aminorroaya Ashraf , Kianpour Maryam , López-Bermejo Abel , Oken Emily , Pirzada Amna , Vafeiadi Marina , Bramer Wichor M , Suvanto Eila , Yoshinaga Jun , Huang Kun , Bassols Judit , Boucai Laura , Feldt-Rasmussen Ulla , Grineva Elena N , Pearce Elizabeth N , Alexander Erik K , Pop Victor J M , Nelson Scott M , Walsh John P , Peeters Robin P , Chaker Layal , Nicolaides Kypros H , D’Alton Mary E , Korevaar Tim I M 
Published: July 2022

Abstract

Context
Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology.

Objective
(1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts.

Methods
(1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy.

Results
(1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody–positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from –10.8% to –21.8% for TSH and –1.2% to –13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting.

Conclusion
We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.