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Query Topic: EGFR

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60 ml min 1 73 m2(19)

Clinical significance of the N-terminal pro-brain natriuretic peptide and B-type natriuretic peptide ratio in the acute phase of acute heart failure.
Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) levels are rarely evaluated simultaneously in the acute phase of acute heart failure (AHF). A total of 1207 AHF patients were enrolled, and 1002 patients were analysed. Blood samples were collected within 15 min of admission. Patients were divided into two groups according to the median value of the NT-proBNP/BNP ratio [low-NT-proBNP/BNP group (Group L) vs. high-NT-proBNP/BNP group (Group H)]. A multivariate logistic regression model showed that the C-reactive protein level (per 1-mg/dL increase), Controlling Nutrition Status score (per 1-point increase), and estimated glomerular filtration rate (eGFR, per 10-mL/min/1.73 m2 increase) were independently associated with Group H [odds ratio (OR) 1.049, 95% confidence interval (CI) 1.009-1.090, OR 1.219, 95% CI 1.140-1.304, and OR 1.543, 95% CI 1.401-1.698, respectively]. A Kaplan-Meier curve analysis showed that the prognosis was significantly poorer in Group H than in Group L, and a multivariate Cox regression model revealed Group H to be an independent predictor of 180-day mortality [hazard ratio (HR) 3.084, 95% CI 1.838-5.175] and HF events (HR 1.963, 95% CI 1.340-2.876). The same trend in the prognostic impact was significantly observed in the low-BNP (<810 pg/mL, n = 501), high-BNP (≥810 pg/mL, n = 501), and low-eGFR (<60 mL/min/1.73 m2, n = 765) cohorts, and tended to be observed in normal-eGFR (≥60 mL/min/1.73 m2, n = 237) cohort. A high NT-proBNP/BNP ratio was associated with a non-cardiac condition (e.g. inflammatory reaction, nutritional status, and renal dysfunction) and is independently associated with adverse outcomes in AHF.
Publication Date: 2021-08-26
Journal: European heart journal. Acute cardiovascular care

lung cancer nsclc(289)

Clinical and molecular characteristics of epidermal growth factor receptor exon 20 insertion mutations in non-small-cell lung cancer.
To evaluate the genomic and immune characteristics of non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations from a retrospective dataset with molecular spectrum, tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression, as well as to evaluate the efficacy of immune checkpoint inhibitors (ICIs). A total of 283 patients with EGFR ex20ins mutations who were diagnosed with NSCLC at our hospital from August 2013 to September 2020 were enrolled in this single-center retrospective study. Among the 283 patients with EGFR ex20ins mutations, 182 patients received next-generation sequencing (NGS) test, and 51 different subtypes of insertion variants were recorded. The most common mutations were A767_V769dup (21.4%), S768_D770dup (19.2%) and A763_Y764insFQEA (7.1%). The most common co-occurring mutations were EGFR amplification (37.9%), TP53 mutation (35.0%) and PIK3CA mutation (8.7%). PD-L1 status was available for 141 patients, and 75.9% (107/141) of these samples showed negative PD-L1 expression. In the 36 cases with TMB tested by NGS, the median TMB was 4.6 mutations/Mb. Then 12 patients received ICIs monotherapy or combination therapy. No severe adverse events were observed. Low PD-L1 expression and TMB were observed in NSCLC patients harboring EGFR ex20ins mutations. Further investigations are needed to confirm the therapeutic sensitivity of ICIs in this subgroup of EGFR mutations.
Publication Date: 2021-08-29
Journal: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico

tyrosine kinase inhibitors(199)

Disruption of Cytosolic Folate Integrity Aggravates Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Modulates Metastatic Properties in Non-Small-Cell Lung Cancer Cells.
Patients with advanced-stage non-small-cell lung cancer (NSCLC) are susceptible to malnutrition and develop folate deficiency (FD). We previously found that folate deprivation induces drug resistance in hepatocellular carcinoma; here, we assessed whether disrupted cytoplasmic folate metabolism could mimic FD-induced metastasis and affect the sensitivity of NSCLC cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We examined whether cytosolic folate metabolism in NSCLC cells was disrupted by FD or the folate metabolism blocker pemetrexed for 1-4 weeks. Our results revealed an increase in NF-κB overexpression-mediated epithelial-mesenchymal transition biomarkers: N-cadherin, vimentin, matrix metalloproteinases (MMPs), SOX9, and SLUG. This finding suggests that the disruption of folate metabolism can drastically enhance the metastatic properties of NSCLC cells. Cytosolic FD also affected EGFR-TKI cytotoxicity toward NSCLC cells. Because SLUG and N-cadherin are resistance effectors against gefitinib, the effects of SLUG knockdown in folate antagonist-treated CL1-0 cells were evaluated. SLUG knockdown prevented SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance acquisition and significantly reduced pemetrexed-induced gelatinase activity and MMP gene expression. To summarize, our data reveal two unprecedented adverse effects of folate metabolism disruption in NSCLC cells. Thus, the folic acid status of patients with NSCLC under treatment can considerably influence their prognosis.
Publication Date: 2021-08-28
Journal: International journal of molecular sciences

chronic kidney disease(120)

Effects of Bivalirudin and Unfractionated Heparin on Liver and Renal Function in Chinese Patients with Coronary Artery Disease Undergoing Coronary Angiography with/without Percutaneous Coronary Intervention.
Unfractionated heparin (UFH) and bivalirudin are widely used as anticoagulants in cardiovascular medicine, including for thrombosis prevention during coronary angiography (CAG) and percutaneous coronary intervention (PCI). Little is known of the effects of UFH and bivalirudin on liver and kidney function in patients subjected to these procedures. This study compared the effects of bivalirudin and UFH on liver/renal function in patients with coronary artery disease who underwent CAG, with or without PCI. The study comprised 134 consecutive patients (40-89 years-old), who underwent CAG (or CAG and PCI); among them, 66 and 68 patients were subject to, respectively, bivalirudin or UFH. The following indicators of liver/renal function were measured before and after the procedures: plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, estimated glomerular filtration rate (eGFR), creatinine clearance, and serum creatinine. Patients were further stratified by severity of chronic kidney disease (CKD), based on original eGFR. Relative to baseline, in the bivalirudin group, ALT and AST were higher after CAG ( Relative to UFH, bivalirudin may better safeguard the renal function of patients with coronary artery disease who undergo CAG, especially patients with moderate-to-severe renal insufficiency. UFH may cause less liver damage than bivalirudin.
Publication Date: 2021-08-28
Journal: Journal of clinical and translational hepatology

non-small-cell lung cancer(110)

EGFR transcription in non-small-cell lung cancer tumours can be revealed in ctDNA by cell-free chromatin immunoprecipitation (cfChIP).
Determination of tumour-specific transcription based on liquid biopsies possesses a large diagnostic and prognostic potential in non-small cell lung cancer (NSCLC). Cell-free DNA (cfDNA) packed in nucleosomes mirrors the histone modification profiles present in the cells of origin. H3 lysine 36 trimethylation (H3K36me3)-modified nucleosomes are associated with active genes and, therefore, cell-free chromatin immunoprecipitation (cfChIP) of H3K36me3-associated cfDNA has the potential to delineate whether transcription of a particular gene is occurring in the cells from which its cfDNA originates. We hypothesized that cfChIP can delineate transcriptional status of genes harbouring somatic cancer mutations and analysed the recurrently observed EGFR-L858R mutation as an example. In representative NSCLC cell lines, the relationship between wild type (WT) and mutated EGFR transcriptional activity and mRNA expression levels was analysed using H3K36me3 ChIP and EGFR mRNA reverse transcription quantitative PCR (RT-qPCR), respectively. The ChIP analysis showed that both WT and mutated EGFR are transcribed, and that mRNA is similarly expressed per EGFR copy. Based on this observation, we proceeded with EGFR cfChIP using blood plasma from NSCLC patients harbouring the EGFR-L858R mutation. EGFR-WT fragments can originate from both non-tumour cells with no or low EGFR transcription and tumour cells with active EGFR transcription, whereas EGFR-L858R fragments must specifically originate from tumour cells. H3K36me3 cfChIP followed by droplet digital PCR (ddPCR) revealed significantly higher enrichment of EGFR-L858R compared to EGFR-WT fragments. This is in alignment with EGFR-L858R being actively transcribed in the NSCLC tumour cells. This study is proof-of-principle that cfChIP can be used to identify tumour-specific transcriptional activity of mutated alleles, which can expand the utility of liquid-biopsy-based cfDNA analyses to enhance tumour diagnostics and therapeutics.
Publication Date: 2021-08-29
Journal: Molecular oncology

kinase inhibitors tkis(90)

Transformation From Adenocarcinoma to Pleomorphic Carcinoma as an Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.
Pulmonary pleomorphic carcinoma is a very rare histological type of primary lung cancer, and usually provides aggressive clinical courses. A 65-year-old Japanese woman was diagnosed by transbronchial biopsy of the primary tumor as c-stage IV (cT4N3M1b) of adenocarcinoma harboring L858R point mutation in the exon 21 of epidermal growth factor receptor (EGFR). She received EGFR tyrosine kinase inhibitors (TKIs) (gefitinib and erlotinib) and subsequently cytotoxic chemotherapies. Gefitinib achieved partial response, but was switched to erlotinib due to elevated serum aspartate transaminase. After resistance to EGFR-TKIs, the second transbronchial re-biopsy revealed pulmonary pleomorphic carcinoma. Both carcinomatous and sarcomatous components retained the L858R mutation, but did not acquire T790M mutation. This case suggested that the histological transformation to pulmonary pleomorphic carcinoma may be one of mechanisms of drug resistance to EGFR-TKIs.
Publication Date: 2021-08-27
Journal: Journal of medical cases

confidence interval ci(45)

The predictive and prognostic effects of PD-L1 expression on TKI treatment and survival of EGFR-mutant NSCLC: A meta-analysis.
Whether programmed death-ligand 1 (PD-L1) expression could predict the outcome of tyrosine kinase inhibitor (TKI) treatment and prognosis of epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer (NSCLC) is remaining controversial.Potential studies were search from PubMed, Embase, and Web of Science databases. Pooled odds ratio of objective response rate was used to describe the relationship between PD-L1 expression and primary resistance to EGFR-TKIs. Pooled hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) were included to assess the effects of PD-L1 status on the outcome of EGFR-TKI treatment and survival of EGFR-mutant NSCLCs.Eighteen eligible studies (1986 EGFR-mutant NSCLCs) were included in this meta-analysis. Positive PD-L1 expression correlated with lower objective response rate of EGFR-TKI treatment (odds ratio [95% confidence interval {CI}] = 0.52 [0.28-0.98], P = .043), while PFS (adjusted HR [95% CI] = 1.49 [0.96-1.89], P = .332) and OS (HR [95% CI] = 1.24 [0.70-2.20], P = .456) of EGFR-TKI treatment did not correlated with PD-L1 status. Furthermore, PD-L1 expression was not a predictive biomarker for the OS (HR [95% CI] = 1.43 [0.98-2.08], P = .062) in overall EGFR-mutant cohort.Positive PD-L1 expression indicated a higher incidence of primary resistance, but did not correlate with the PFS or OS of EGFR-TKI therapy. In addition, PD-L1 expression was unlikely a predictive biomarker for prognosis of EGFR-mutant NSCLCs.
Publication Date: 2021-08-28
Journal: Medicine

egfr mutations(173)

Liquid Biopsy for Disease Monitoring in Non-Small Cell Lung Cancer: The Link between Biology and the Clinic.
Cell-free DNA (cfDNA) analysis offers a non-invasive method to identify sensitising and resistance mutations in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Next-generation sequencing (NGS) of circulating free DNA (cfDNA) is a valuable tool for mutations detection and disease's clonal monitoring. An amplicon-based targeted gene NGS panel was used to analyse 101 plasma samples of advanced non-small cell lung cancer (NSCLC) patients with known oncogenic mutations, mostly EGFR mutations, serially collected at different clinically relevant time points of the disease. The variant allelic frequency (VAF) monitoring in consecutive plasma samples demonstrated different molecular response and progression patterns. The decrease in or the clearance of the mutant alleles was associated with response and the increase in or the emergence of novel alterations with progression. At the best response, the median VAF was 0% (0.0% to 3.62%), lower than that at baseline, with a median of 0.53% (0.0% to 9.9%) ( The targeted NGS of circulating tumour DNA (ctDNA) has clinical utility to monitor treatment response in patients with advanced lung adenocarcinoma.
Publication Date: 2021-08-28
Journal: Cells

lung adenocarcinoma(151)

EGFR DNA Methylation Correlates With EGFR Expression, Immune Cell Infiltration, and Overall Survival in Lung Adenocarcinoma.
The epidermal growth factor receptor (EGFR) is a primary target of molecular targeted therapy for lung adenocarcinoma (LUAD). The mechanisms that lead to epigenetic abnormalities of EGFR in LUAD are still unclear. The purpose of our study was to evaluate the abnormal methylation of EGFR CpG sites as potential biomarkers for LUAD. To assess the differentially methylation CpG sites of EGFR in LUAD, we used an integrative study of Illumina HumanMethylation450K and RNA-seq data from The Cancer Genome Atlas (TCGA). We evaluated and compared EGFR multiple-omics data to explore the role of CpG sites located in EGFR promoter regions and gene body regions and the association with transcripts, protein expression levels, mutations, and somatic copy number variation. We calculated the correlation coefficients between CpG sites of EGFR and immune infiltration fraction (by MCPcounter and ESTIMATE) and immune-related pathways in LUAD. Finally, we validated the differential methylation of clinically and prognostically relevant CpG sites using quantitative methylation-specific PCR (qMSP). We found that the methylation level of many EGFR CpGs in the promoter region was negatively correlated with the transcription level, protein expression, and SCNV, while the methylation at the gene body region was positively correlated with these features. The methylation level of EGFR CpGs in the promoter region was positively correlated with the level of immune infiltration and IFN-γ signature, while the opposite was found for methylation of the gene body region. The qMSP results showed that cg02316066 had a high methylation level, while cg02166842 had a low methylation level in LUAD. There was a high degree of co-methylation between cg02316066 and cg03046247. Our data indicate that EGFR is an epigenetic regulator in LUAD acting through DNA methylation. Our research provides a theoretical basis for the further detection of EGFR DNA methylation as a predictive biomarker for LUAD survival and immunotherapy.
Publication Date: 2021-08-28
Journal: Frontiers in oncology

serum creatinine(123)

Clinical Characteristics and Outcomes of Adults with Nephrotic Syndrome Due to Minimal Change Disease.
Minimal change disease (MCD) is considered a relatively benign glomerulopathy, as it rarely progresses to end-stage kidney disease. The aim of this study was to describe the characteristics and outcomes of adults with MCD and identify potential risk factors for relapse. We retrospectively studied a cohort of adults with biopsy-proven MCD in terms of clinical features and treatment outcomes. Baseline characteristics and outcomes were recorded and predictors of relapse were analyzed using logistic regression multivariate analysis. 59 patients with adult-onset primary MCD with nephrotic syndrome were included. Mean serum creatinine at diagnosis was 0.8 mg/dL (±2.5) and estimated GFR (eGFR) was 87 mL/min/1.73 m In this series of patients, almost 46% of adult-onset nephrotic MCD patients experienced a relapse, although their renal progression was rare. Younger onset age was an independent risk factor for relapse in adult-onset MCD patients.
Publication Date: 2021-08-28
Journal: Journal of clinical medicine

cancer cells(77)

Synergistic Antitumor Activity of SH003 and Docetaxel via EGFR Signaling Inhibition in Non-Small Cell Lung Cancer.
Epidermal growth factor receptor (EGFR) is overexpressed in lung cancer patients. Despite treatment with various EGFR tyrosine kinase inhibitors, recurrence and metastasis of lung cancer are inevitable. Docetaxel (DTX) is an effective conventional drug that is used to treat various cancers. Several researchers have studied the use of traditional herbal medicine in combination with docetaxel, to improve lung cancer treatment. SH003, a novel herbal mixture, exerts anticancer effects in different cancer cell types. Here, we aimed to investigate the apoptotic and anticancer effects of SH003 in combination with DTX, in human non-small-cell lung cancer (NSCLC). SH003, with DTX, induced apoptotic cell death, with increased expression of cleaved caspases and cleaved poly (ADP-ribose) polymerase in NSCLC cells. Moreover, SH003 and DTX induced the apoptosis of H460 cells via the suppression of the EGFR and signal transducer and activator of transcription 3 (STAT3) signaling pathways. In H460 tumor xenograft models, the administration of SH003 or docetaxel alone diminished tumor growth, and their combination effectively killed cancer cells, with increased expression of apoptotic markers and decreased expression of p-EGFR and p-STAT3. Collectively, the combination of SH003 and DTX may be a novel anticancer strategy to overcome the challenges that are associated with conventional lung cancer therapy.
Publication Date: 2021-08-28
Journal: International journal of molecular sciences

baseline egfr(75)

Risk of Renal Dysfunction Following Heart Transplantation in Patients Bridged with a Left Ventricular Assist Device.
Acute renal failure (ARF) and chronic kidney disease (CKD) are associated with short- and long-term morbidity and mortality following heart transplantation (HT). We investigated the incidence and risk factors for developing ARF requiring hemodialysis (HD) and CKD following HT specifically in patients with a left ventricular assist device (LVAD). We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry for heart transplant patients between January 2000 and June 2015. We compared patients bridged with durable continuous-flow LVAD to those without LVAD support. Primary outcomes were ARF requiring HD before discharge following HT and CKD (defined as creatinine >2.5 mg/dl, permanent dialysis, or renal transplant) within 3 years. There were 18,738 patients, with 4,535 (24%) bridged with LVAD support. Left ventricular assist device patients had higher incidence of ARF requiring HD and CKD at 1 year, but no significant difference in CKD at 3 years compared to non-LVAD patients. Among LVAD patients, body mass index (BMI) (odds ratio [OR] = 1.79, p < 0.001), baseline estimated glomerular filtration rate (eGFR) (OR = 0.43, p < 0.001), and ischemic time (OR = 1.28, p = 0.014) were significantly associated with ARF requiring HD. Similarly, BMI (hazard ratio [HR] = 1.49, p < 0.001), baseline eGFR (HR = 0.41, p < 0.001), pre-HT diabetes mellitus (DM) (HR = 1.37, p = 0.011), and post-HT dialysis before discharge (HR = 3.93, p < 0.001) were significantly associated with CKD. Left ventricular assist device patients have a higher incidence of ARF requiring HD and CKD at 1 year after HT compared with non-LVAD patients, but incidence of CKD is similar by 3 years. Baseline renal function, BMI, ischemic time, and DM can help identify LVAD patients at risk of ARF requiring HD or CKD following HT.
Publication Date: 2021-08-23
Journal: ASAIO journal (American Society for Artificial Internal Organs : 1992)

95 confidence(72)

Ticagrelor or Prasugrel in Patients With Acute Coronary Syndrome in Relation to Estimated Glomerular Filtration Rate.
The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs). The outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined. Patients (n = 4,012) were categorized into 3 groups: low eGFR (<60 mL/min/1.73 m Patients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted hazard ratio [HR]: 1.89; 95% confidence interval [CI]: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding. These results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800).
Publication Date: 2021-08-28
Journal: JACC. Cardiovascular interventions

egfr exon(72)

Technical Evaluation of the COBAS EGFR Semiquantitative Index (SQI) for Plasma cfDNA Testing in NSCLC Patients with EGFR Exon 19 Deletions.
The cobas
Publication Date: 2021-08-28
Journal: Diagnostics (Basel, Switzerland)

inhibitors egfr-tkis(68)

Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC).
T790M mutation is the most common mechanism of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed. However, the clinical application of these irreversible inhibitors is limited due to its narrow selectivity against L858R/T790M mutant EGFR. In an attempt to develop potent and selective EGFR T790M inhibitors, we have designed and synthesized two series of novel acrylamide linked quinazolines. Among them, compounds 2i (IC
Publication Date: 2021-08-17
Journal: Bioorganic chemistry

disease ckd(56)

Meta-Analysis of Transradial Versus Transfemoral Access for Percutaneous Coronary Intervention in Patients With Chronic Kidney Disease.
Data comparing outcomes of transradial (TR) versus transfemoral (TF) access for percutaneous coronary intervention (PCI) in chronic kidney disease (CKD) including patients with eGFR< 30 ml/min/1.73m
Publication Date: 2021-08-15
Journal: The American journal of cardiology

blood pressure(52)

Data driven evaluation of healthy volunteer characteristics at screening for phase I clinical trials to inform on study design and optimize screening processes.
Protocols for clinical trials describe inclusion and exclusion criteria based on general and compound-specific considerations to ensure subject safety and data quality. In phase I clinical trials, healthy volunteers (HVs) are screened against these criteria that often specify predefined eligibility ranges for vital signs, electrocardiogram, and laboratory tests. HVs are excluded if baseline parameters deviate from these ranges even though this may not indicate underlying pathology, which could delay trial execution. Data from 3365 HVs participating in 9670 screening visits for 94 phase I HV trials, conducted between December 2008 and May 2019 at the Janssen Clinical Pharmacology Unit, were retrospectively analyzed. Commonly predefined protocol ranges were overlaid with HV data to estimate predicted screen failure rates (SFRs). Of the overall population, 91% was White and 64% were men with mean age of 42.8 ± 12.5 years. High predicted SFRs are related to cardiovascular/metabolic (body mass index, heart rate [HR], blood pressure [BP], and corrected QT Fridericia's formula [QTcF]), renal (estimated glomerular filtration rate [eGFR]), liver (alanine aminotransferase [ALT], and total bilirubin), and coagulation (prothrombin time [PT]) parameters. Predicted SFRs increased with age for high systolic and diastolic BP, QTcF interval, and eGFR. In contrast, lower SFRs in the older age groups were seen for low diastolic BP, liver function test, ALT, PT, and total bilirubin. This analysis can be used to inform on study design, protocol inclusion and exclusion criteria, and to optimize the screening process. Data-driven critical appraisal of proposed inclusion and exclusion criteria using a risk-based approach may significantly reduce screen failure rates without compromising subjects' safety.
Publication Date: 2021-08-12
Journal: Clinical and translational science

odds ratio(39)

Metabolic Differences Between Unilateral and Bilateral Renal Stones and Their Association with Markers of Kidney Injury.
Urinary stone disease (USD) has been associated with an increased risk for chronic kidney disease (CKD) and end-stage renal disease (ESRD) in Western populations. However, the metabolic disorders associated with unilateral and bilateral renal stones and the association of these types of stones with CKD and kidney tubular injury markers, such as urine N-acetyl-ß-D-glucosaminidase (NAG) and alpha-1-microglobulin (α1-MG), have not been fully examined. We performed a cross-sectional study of 10,281 participants in rural China in 2014. All the subjects underwent renal ultrasound to detect USD; stone formers were divided into groups with unilateral or bilateral renal stones by ultrasound exams. CKD was defined as a decreased estimated glomerular filtration rate (eGFR, <60 mL/min/1.73 m Among all the participants, 4.9% (n=507) had unilateral renal stones, and 0.7% (n=75) had bilateral renal stones. The proportion of CKD in the non-stone, unilateral and bilateral renal stone formers was 11.0%, 19.2%, and 29.7%, respectively (p for trend <0.001). Individuals with bilateral renal stones had the highest proportion of metabolic components, such as elevated blood pressure and serum glucose. In multivariate analyses after adjustment for multiple confounders, bilateral renal stones were significantly associated with an increased risk of decreased eGFR (odds ratio (OR) 3.38; 95% CI 1.05-10.90), albuminuria (OR 3.01; 95% CI 1.76-5.13), CKD (OR 3.18; 95% CI 1.88-5.36), increased urine NAG/Cr (OR 1.95; 95% CI 1.21-3.16) and α1-MG/Cr levels (OR 2.54; 95% CI 1.56-4.12) compared with the lack of stones. Bilateral renal stones were associated with a higher risk of CKD and higher levels of kidney tubular injury markers. Clinicians should pay attention to metabolic disorders in bilateral renal stone formers.
Publication Date: 2021-08-26
Journal: The Journal of urology

kinase alk(38)

Diagnostic Performance of Electromagnetic Navigation Bronchoscopy-Guided Biopsy for Lung Nodules in the Era of Molecular Testing.
Electromagnetic navigation bronchoscopy (ENB) is an emerging technique used to evaluate peripheral lung lesions. The aim of this study was to determine the diagnostic yield, safety profile, and adequacy of specimens obtained using ENB for molecular testing. This single-center, prospective pilot study recruited patients with peripheral pulmonary nodules that were not suitable for biopsy via percutaneous transthoracic needle biopsy methods. The possibility of molecular testing, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and programmed death ligand 1 (PD-L1), was identified with non-small cell lung cancer (NSCLC) tissue obtained using ENB. ENB-guided biopsy was performed on 30 pulmonary nodules in 30 patients. ENB-guided biopsy was successfully performed in 96.6% (29/30) of cases, but one case failed to approach the target lesion. The diagnostic accuracy of ENB-guided biopsy was 68.0% (17/25). Biopsy-related pneumothorax occurred in one patient and there was no major bleeding or deaths related to the procedure. Among 13 patients diagnosed with NSCLC, molecular testing was successfully performed in 92.3% (12/13). ENB-guided biopsy demonstrated acceptable accuracy and excellent sample adequacy, with a high possibility of achieving molecular testing and a good safety profile to evaluate peripheral pulmonary nodules, even when the percutaneous approach was difficult and/or dangerous.
Publication Date: 2021-08-28
Journal: Diagnostics (Basel, Switzerland)

egfr tyrosine(36)

Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression.
Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm
Publication Date: 2021-08-14
Journal: Oncology letters

age sex(34)

Association of autosomal dominant polycystic kidney disease with cerebral small vessel disease.
Cilia dysfunction in autosomal-dominant polycystic kidney disease (ADPKD) may impair the integrity of glymphatic system and be implicated in the progression of cerebral small vessel disease (SVD), although the link between the two diseases has not been investigated. We evaluated the association of ADPKD pathology with SVD pattern and severity. Overall, 304 individuals in an ADPKD (chronic kidney disease stage ≤4 and age ≥50 years) cohort and their age, sex, and estimated glomerular filtration rate (eGFR)-matched controls were retrospectively included. ADPKD severity was classified into 1 A-B, 1 C, and 1 D-E, according to age and height-adjusted total kidney volume. SVD parameters included white-matter hyperintensity (WMH) severity scale, enlarged perivascular space (ePVS) score, and degree of lacunes or cerebral microbleeds (CMBs). After adjustments for age, sex, eGFR, and cerebrovascular risk factor parameters, ADPKD was associated with higher ePVS scores (
Publication Date: 2021-08-21
Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

months 95(9)

Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure.
Acquired resistance to TKI is an important unmet need in the management of EGFR mutated lung cancer. Recent clinical trial IMPower150 suggested that combination approach with VEGF inhibitor, check point inhibitor immunotherapy and platinum-based chemotherapy was effective in oncogene driven lung cancer. The current trial examined the efficacy of a modified regimen in an EGFR mutated cohort. An open-labelled, single arm, phase II study was conducted in patients with EGFR mutated NSCLC who had progressed on at least one EGFR TKI. For those with T790M mutation, radiological progression on osimertinib was required for enrolment. Patients were treated with combination atezolizumab (1200 mg), bevacizumab (7.5 mg/kg), pemetrexed (500 mg/m2) and carboplatin (AUC 5) given once every 3 weeks until progression. Forty patients were enrolled. Median age was 62 (range 45-76) years. More than one half (23/40, 57.5%) had progressed on osimertinib. PD-L1 expression was < 1% in 52.5%. Median follow-up time was 17.8 months. ORR was 62.5%. Median PFS was 9.4 months (95% CI: 7.6 - 12.1). One year OS was 72.5% (95% CI: 0.56-0.83). Treatment related grade 3 or above adverse events (AE) occurred in 37.5% (15/40). Immune-related AE occurred in 32.5% (13/40) patients. Quality of life measures of function and symptoms did not change significantly throughout the course of treatments. Post-trial rechallenge with EGFR TKI containing regimen resulted in PFS of 5.8 months (95% CI 3.9-10.0 months). Combination approach of atezolizumab, bevacizumab, pemetrexed and carboplatin achieved promising efficacy in metastatic EGFR mutated NSCLC after TKI failure. The results were comparable with taxane based regimen of IMPower150 while toxicity profile was improved.
Publication Date: 2021-07-25
Journal: Lung cancer (Amsterdam, Netherlands)


Prognostic Impact of Membranous/Nuclear Epidermal Growth Factor Receptor Localization in Clear Cell Renal Cell Carcinoma.
EGFR is overexpressed in the majority of clear cell renal cell carcinomas (CCRCCs). Although EGFR deregulation was found to be of great significance in CCRCC biology, the EGFR overexpression is not associated with EGFR-targeted therapy responsiveness. Moreover, the prognostic role of EGFR expression remains controversial. In the present study, we evaluated the role played by EGFR overexpression in CCRCC and its prognostic significance associated with different immunohistochemical localization patterns. In our study, the Total Score (TS) related to membranous-cytoplasmic EGFR expression showed a significant correlation with grade, pathologic stage (pT), and Stage, Size, Grade, and Necrosis (SSIGN) score, and a negative correlation with nuclear EGFR expression. No significant correlations were shown between nuclear EGFR and clinic-pathological features. Additionally, a correlation between SGLT1 expression levels and pT was described. Multivariate analysis identifies pT and SSIGN score as independent prognostic factors for CCRCC. A significantly increased survival rate was found in the case of positive expression of nuclear EGFR and SGLT1. Based on our findings, SGLT1 and nuclear EGFR overexpression defines a subgroup of CCRCC patients with good prognosis. Membranous-cytoplasmic EGFR expression was shown to be a poor prognostic factor and could define a CCRCC subgroup with poor prognosis that should be responsive to anti-EGFR therapies.
Publication Date: 2021-08-28
Journal: International journal of molecular sciences


Elastography ultrasound with machine learning improves the diagnostic performance of traditional ultrasound in predicting kidney fibrosis.
Noninvasively predicting kidney tubulointerstitial fibrosis is important because it's closely correlated with the development and prognosis of chronic kidney disease (CKD). Most studies of shear wave elastography (SWE) in CKD were limited to non-linear statistical dependencies and didn't fully consider variables' interactions. Therefore, support vector machine (SVM) of machine learning was used to assess the prediction value of SWE and traditional ultrasound techniques in kidney fibrosis. We consecutively recruited 117 CKD patients with kidney biopsy. SWE, B-mode, color Doppler flow imaging ultrasound and hematological exams were performed on the day of kidney biopsy. Kidney tubulointerstitial fibrosis was graded by semi-quantification of Masson staining. The diagnostic performances were accessed by ROC analysis. Tubulointerstitial fibrosis area was significantly correlated with eGFR among CKD patients (R = 0.450, P < 0.001). AUC of SWE, combined with B-mode and blood flow ultrasound by SVM, was 0.8303 (sensitivity, 77.19%; specificity, 71.67%) for diagnosing tubulointerstitial fibrosis (>10%), higher than either traditional ultrasound, or SWE (AUC, 0.6735 [sensitivity, 67.74%; specificity, 65.45%]; 0.5391 [sensitivity, 55.56%; specificity, 53.33%] respectively. Delong test, p < 0.05); For diagnosing different grades of tubulointerstitial fibrosis, SWE combined with traditional ultrasound by SVM, had AUCs of 0.6429 for mild tubulointerstitial fibrosis (11%-25%), and 0.9431 for moderate to severe tubulointerstitial fibrosis (>50%), higher than other methods (Delong test, p < 0.05). SWE with SVM modeling could improve the diagnostic performance of traditional kidney ultrasound in predicting different kidney tubulointerstitial fibrosis grades among CKD patients.
Publication Date: 2021-08-29
Journal: Journal of the Formosan Medical Association = Taiwan yi zhi


Expression of Cancer Stem Cell Markers EpCAM and CD90 Is Correlated with Anti- and Pro-Oncogenic EphA2 Signaling in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Additionally, the efficacy of targeted molecular therapies with multiple tyrosine kinase inhibitors is limited. In this study, we focused on the cellular signaling pathways common to diverse HCC cells and used quantitative reverse phase protein array (RPPA) and statistical analyses to elucidate the molecular mechanisms determining its malignancy. We examined the heterogeneity of 17 liver cancer cell lines by performing cluster analysis of their expression of CD90 and EpCAM cancer stem cell markers. Gaussian mixture model clustering identified three dominant clusters: CD90-positive and EpCAM-negative (CD90+), EpCAM-positive and CD90-negative (EpCAM+) and EpCAM-negative and CD90-negative (Neutral). A multivariate analysis by partial least squares revealed that the former two cell populations showed distinct patterns of protein expression and phosphorylation in the EGFR and EphA2 signaling pathways. The CD90+ cells exhibited higher abundance of AKT, EphA2 and its phosphorylated form at Ser
Publication Date: 2021-08-28
Journal: International journal of molecular sciences


Urinary phthalate metabolites mixture, serum cytokines and renal function in children: A panel study.
Epidemiological evidence regarded the relations of phthalates with children's renal function and its underlying mechanism were largely unknown. We conducted a panel study using 287 paired urine-blood samples by repeated measurements of 103 children (4-13 years) across 3 seasons to explore effects of urinary phthalate metabolites on estimated glomerular filtration rate (eGFR) and the potential role of multiple cytokines. We found that mono-ethyl phthalate (MEP), monobutyl phthalate (MBP), mono-benzyl phthalate (MBzP) and mono-n-octyl phthalate (MOP) were significantly associated with eGFR reduction. Compared with the lowest quartile, MBP, MBzP and MEP in the third and fourth quartiles exhibited a graded decrease in eGFR. Meanwhile, weighted quantile sum regression analyses showed an inverse association of metabolites mixture with eGFR, to which MEP, MBzP, MOP were the major contributors. MEP also remained robust in multiple-phthalate model. Age and weight status might modify such relationships with significant interactions. Furthermore, eGFR related phthalate metabolites were associated with increased multiple cytokines, and CCL27, CXCL1 might be potential mediators between MEP and eGFR with mild mediated proportions. Accordingly, urinary phthalate metabolites were related to eGFR reduction in dose-response manner and multiple cytokines elevation, of which CCL27 and CXCL1 might partly mediate phthalate-associated decreased renal function among children.
Publication Date: 2021-08-28
Journal: Journal of hazardous materials


Effects of Sex and Seasonal Climatic Changes on the Risk of Incidence of Anti-EGFR Therapy-Induced Rash in Cancer Patients: A Retrospective Study.
Publication Date: 2021-08-28
Journal: Medicina (Kaunas, Lithuania)


Association of EGFR Tyrosine Kinase Inhibitor Treatment With Progression-Free Survival Among Taiwanese Patients With Advanced Lung Adenocarcinoma and EGFR Mutation.
Publication Date: 2021-08-27
Journal: Frontiers in pharmacology


Sodium-glucose cotransporter 2 inhibitors as the first universal treatment of chronic kidney disease.
In the last five years, the medical community was astonishingly surprised by the sequential large outcome trials that displayed the renal effects of sodium glucose co-transporter inhibitors (SGLT2Is) in type 2 diabetes mellitus (T2DM) patients with or without chronic kidney disease (CKD). This favorable effect was later disclosed in non-diabetic CKD patients. The EMPA-REG OUTCOME trial was the first trial that showed a reduction for the need for dialysis in patients suffering diabetic kidney disease (DKD) by 55%. This figure is double the score achieved by the angiotensin receptor blocker, Losartan, in RENAAL trial. The need for dialysis in DAPA-CKD trial was reduced in diabetic and non-diabetic CKD patients by 33%. The renal-specific composite outcome was reduced by 39% in EMPA-REG trial, 40% in CANVAS study, 47% in DECLARE-TIMI 58 study, 34% in CREDENCE trial, and 44% in DAPA-CKD trial. The greater surprise is the significant favorable effect of SGLT2Is on overall mortality in CKD patients with or without T2DM. Similar survival benefit was not previously encountered with any of the medications used in CKD patients with or without diabetes. In this review, we disclose the results of the DAPA-CKD trial, the CREDENCE trial and those of several cardiovascular outcome trials (CVOT) that used different SGLT2Is and showed that patients with lower eGFR levels may have greater benefit with respect to cardiovascular morbidity than patients with normal kidney function. In addition, we discuss the different mechanisms of action that explain the renal beneficial effects of SGLT2Is.
Publication Date: 2021-08-29
Journal: Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia


Angiotensin II-Induced Vasoconstriction via Rho Kinase Activation in Pressure-Overloaded Rat Thoracic Aortas.
Angiotensin II (Ang II) induces vasoconstriction through myosin light chain (MLC) kinase activation and MLC phosphatase inactivation via phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) by Rho kinase. However, the detailed mechanism underlying Rho kinase activation by Ang II is still unknown. We investigated the mechanism of Ang II-induced vasoconstriction mediated by Rho kinase in pressure-overloaded rat thoracic aortas. Pressure-overloaded rats were produced by coarctation of the suprarenal abdominal aorta in four-week-old male Wistar rats. The contractile response to Ang II was significantly enhanced in the pressure-overloaded rats. Ang II-induced vasoconstriction was attenuated by inhibitors of Rho kinase, extracellular signal-regulated kinase 1 and 2 (Erk1/2), and epidermal growth factor receptor (EGFR) in both the sham-operated and pressure-overloaded rats. The Ang II-induced vasoconstriction was attenuated by a Janus kinase 2 (JAK2) inhibitor in only the pressure-overloaded rats. The protein levels of MYPT1 and JAK2 increased only in the pressure-overloaded rat thoracic aortas. These results suggested that Ang II-induced contraction is mediated by Rho kinase activation via EGFR, Erk1/2, and JAK2 in pressure-overloaded rat thoracic aortas. Moreover, Ang II-induced contraction was enhanced in pressure-overloaded rats probably because the protein levels of MYPT1 and JAK2 increased in the thoracic aortas.
Publication Date: 2021-08-28
Journal: Biomolecules


Relationship of the Intake of Water and Other Beverages With Renal Endpoints: Cross-Sectional and Longitudinal Data-Observational, Population-Based Study.
The relationship of water intake with kidney function in the population is uncertain. This study investigated cross-sectionally and longitudinally the relationship of the intake of water and other beverages with kidney function within an adult Italian population sample. In 4,554 Gubbio Study examinees (54.4% women, age 18-95 years), data collection at baseline included demographics, anthropometry, questionnaires on habitual intakes of water and other beverages (non-water fluids), a timed overnight urine collection, estimated glomerular filtration rate (eGFR), decreased eGFR (<60 mL/minute/1.73 m In multivariable analyses, higher water intake is independently related to higher urine flow (beta = 0.163, P < .001), lower urine osmolality (beta = 0.184, P < .001), lower eGFR (beta = 0.030, P = .002), and higher prevalence of decreased eGFR (logistic coefficient ± standard error = 1.13 ± 0.32, P < .001). Water intake did not relate to kidney function change over time. Intake of non-water fluids did not independently relate to urinary indices nor to kidney function. In the general population, water intake relates cross-sectionally to urine flow, urine concentration, and kidney function but it does not relate to kidney function change over time. The intake of other beverages does not relate to urinary indices or kidney function. Results do not support a role of water intake in kidney function decline over time in the population.
Publication Date: 2021-08-29
Journal: Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation


EphB4 as a Novel Target for the EGFR-Independent Suppressive Effects of Osimertinib on Cell Cycle Progression in Non-Small Cell Lung Cancer.
Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.
Publication Date: 2021-08-28
Journal: International journal of molecular sciences


Interaction between SCP3 and JAB1 Confers Cancer Therapeutic Resistance and Stem-like Properties through EGF Expression.
Synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, has been implicated in cancer progression, and therapeutic resistance, as well as cancer stem cell (CSC)-like properties. Previously, we demonstrated that SCP3 promotes these aggressive phenotypes via hyperactivation of the AKT signaling pathway; however, the underlying mechanisms responsible for SCP3-induced AKT activation remain to be elucidated. In this study, we demonstrated that the EGF-EGFR axis is the primary route through which SCP3 acts to activate AKT signaling. SCP3 triggers the EGFR-AKT pathway through transcriptional activation of EGF. Notably, neutralization of secreted EGF by its specific monoclonal antibody reversed SCP3-mediated aggressive phenotypes with a concomitant reversal of EGFR-AKT activation. In an effort to elucidate the molecular mechanisms underlying SCP3-induced transcriptional activation of EGF, we identified Jun activation domain-binding protein 1 (JAB1) as a binding partner of SCP3 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that SCP3 induces EGF transcription through physical interaction with JAB1. Thus, our findings establish a firm molecular link among SCP3, EGFR, and AKT by identifying the novel roles of SCP3 in transcriptional regulation. We believe that these findings hold important implications for controlling SCP3
Publication Date: 2021-08-28
Journal: International journal of molecular sciences


Stronger Association of Albuminuria with the Risk of Vascular Complications than Estimated Glomerular Filtration Rate in Type 2 Diabetes.
Albuminuria is a risk factor for macro- and microvascular complications of type 2 diabetes (T2D).With an increasing trend of normoalbuminuria, however, of the 2 predictors - estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) - which one is a better predictor of vascular complications of T2D is not clear. This study aimed to compare the impacts of albuminuria and eGFR on patients with T2D associated with micro- and macrovascular complications. This retrospective study recruited 4,715 patients with T2D and grouped them based on the values of UACR (high UACR: ≥30 mg/g, low UACR: <30 mg/g) and eGFR (mL/[min × 1.73 m2]) (G1: eGFR ≥ 90; G2: eGFR = 60-89; G3-5: eGFR < 60) from April 2008 to November 2018. Logistic regression analysis was carried out for risk factors in patients with diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD), left ventricular remodeling, diastolic disorders, and carotid atherosclerotic plaque in 6 different groups: low UACR + G1 (control group), low UACR + G2, low UACR + G3-5, high UACR + G1, high UACR + G2, and high UACR + G3-5. Patients were grouped according to the change in the UACR value (UACR-decreased group: ≤-30%, UACR-stable group: -30 to 30%, and UACR-increased group ≥30%), eGFR value (eGFR-decreased group: >3%, and eGFR-stable group: ≤3%) and followed up. Compared with the control group, patients with higher albuminuria and lower eGFR had higher adjusted odds ratio (OR) trends of complications, especially in the high UACR + G3-5 group. The OR of 2.010, 3.444, 1.633, 2.742, and 3.014 were obtained for DR, DPN, PAD, left ventricular remodeling, and diastolic disorders, respectively. No statistically significant difference was found in the risk of complications within each one of 2 phenotypes, regardless of the change in the eGFR. After grouping by eGFR, the regression analysis of the urinary protein level in each stage revealed that a majority of complications had a statistically significant difference, except for DR and PAD in the high UACR + G3-5 group. DR in the follow-up study had a higher risk in the UACR-stable/increased group than the UACR-decreased group (UACR stable: OR = 2.568; 95% confidence interval (CI): 1.128-5.849; p = 0.025; UACR increased: OR = 2.489; 95% CI: 1.140-5.433; p = 0.022). UACR is a more predictive risk factor for diabetic complications compared with a reduced eGFR.
Publication Date: 2021-08-25
Journal: Kidney & blood pressure research


Low Albumin, Low Bilirubin, and High Alfa-Fetoprotein Are Associated with a Rapid Renal Function Decline in a Large Population Follow-Up Study.
A rapid decline in renal function is associated with high cardiovascular morbidity and mortality, and therefore it is important to identify those at high-risk of rapid renal function decline. The relationship between liver function and renal function is unclear. Therefore, in this longitudinal study, we aimed to investigate associations between liver function and rapid renal function decline. A total of 27,116 participants were enrolled from the Taiwan Biobank and followed for 3.8 years. A rapid decline in renal function was defined as a decline in estimated glomerular filtration rate (eGFR) of ≥25%. Binary logistic regression analysis was used to identify associations between liver function parameters (glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, albumin, α-fetoprotein [AFP], total bilirubin, and gamma-glutamyl transpeptidase) and eGFR decline ≥ 25%. The rate of eGFR decline of ≥25% was 4.7%. Multivariable analysis showed that low albumin (odds ratio [OR], 0.173;
Publication Date: 2021-08-28
Journal: Journal of personalized medicine


The Association of Annexin A1 and Chemosensitivity to Osimertinib in Lung Cancer Cells.
Annexin A1 (ANXA1) has been reported to promote tumor growth and resistance to chemotherapy drugs in lung cancer cells. In this study, we focused on the association of ANXA1 and chemosensitivity with a third generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), Osimertinib, in lung cancer cells with EGFR mutations. The overexpression of ANXA1 was observed in the lung cancer cells studied. The downregulation of ANXA1 with small interference RNA (siRNA) decreased the growth of lung cancer cells. In lung cancer cells with EGFR mutations, the knockdown of ANXA1 increased the chemosensitivity to Osimertinib, and decreased the tumorigenesis, invasion and migration of lung cancer cells. Further study showed that the knockdown of ANXA1 inhibited the phosphorylation of EGFR and down-stream Akt pathways and promoted apoptosis in lung cancer cells treated with Osimertinib. A mice xenograft lung cancer model was established in our study and showed that ANXA1 siRNA enhanced the effects of Osimertinib in vivo. Our study results showed that ANXA1 plays critical roles in chemosensitivity to EGFR-TKI in lung cancer cells with the EGFR mutation. Our efforts may be used in the development of lung cancer treatment strategies in the future.
Publication Date: 2021-08-28
Journal: Cancers


Kidney Biopsy Chronicity Grading in Antineutrophil Cytoplasmic Antibody Associated Vasculitis.
Kidney biopsy is valuable for prognostic assessment of renal outcomes in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) but the impact of chronic changes is not determined. A retrospective cohort study of MPO- or PR3-ANCA positive patients with AAV and active renal disease. We applied the Mayo Clinic Chronicity Score (MCCS), validated and evaluated its implications on outcome prediction in AAV-GN. We analyzed 329 patients with kidney biopsies available to score. The extent of chronicity was graded by MCCS as (i) minimal - 102 (31.0%), (ii) mild - 106 (32.2%), (iii) moderate - 86 (26.1%), and (iv) severe - 35 (10.6%). The MCCS grades correlated with the degree of renal function impairment at presentation (mean eGFR: 48.3 vs. 29.2 vs. 23.7 vs. 18.5 mL/min/1.73 m2, p < 0.0001). Higher degrees of the individual components of the MCCS (glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriosclerosis) were associated with lower median eGFR (p < 0.0001) and decreased event free (kidney failure (KF) and death) survival (p = 0.002, p < 0.0001, p < 0.0001 and p = 0.017, respectively). Patients with lower MCCS grades recovered renal function more frequently (p < 0.0001). Increasing MCCS grades were associated with decreased renal recovery (p = 0.001), more frequent events and shorter time to KF (p < 0.0001), KF and death (p < 0.0001), and death (p = 0.042), independently of remission-induction treatment used (CYC or RTX). The MCCS stratified renal outcomes for each MCCS grade and can be used in clinical practice as a cut-off for KF prediction (MCCS≥4). Chronic changes on kidney histology independently predict renal function, outcomes and response to treatment in AAV-GN.
Publication Date: 2021-08-27
Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association


EGFR analysis on scrapings from cytology smears in lung carcinoma, an effective alternative to testing on trucut biopsies.
Lung carcinomas are a leading cause of cancer morbidity and mortality. Many cases present at an advanced stage of disease where definitive treatment by surgical resection is not feasible. Molecular testing using materials derived from minimally invasive procedures aid in targeted therapy with least iatrogenic burden to the patient. Cases diagnosed as non-small cell lung carcinoma (NSCLC) on cytology were included in the study. Scrapings from the smears with adequate tumor cell load were submitted for molecular testing. The DNA was extracted and quantified. Mutations in exons 18, 19, 20, and 21 of the EGFR gene were detected using Sanger sequencing. DNA quantity and EGFR mutation status on equal number of consecutive trucut biopsy specimens were also analyzed. Seventy cases of NSCLC tested for EGFR mutation had a median DNA concentration of 40.2 ng/μl and 31% cases showed mutation. Majority of mutations (14/21, 66.66%) were identified in exon 19. Among 70 trucut biopsy samples, DNA concentration was 41.42 ng/μl and 30% cases showed mutation. No significant difference was seen in DNA quantity and EGFR mutation between cytology smears and trucut biopsies. EGFR testing on cytology smears provides adequate DNA yield with minimal invasiveness and is equally effective as biopsies. Testing on samples like pleural effusion allows for concomitant diagnosis, staging, and molecular testing in one procedure. Tests done on the smears rather than on cell block or trucut biopsies ensures superior quality DNA from the tumor cells as they are unexposed to cross linking formalin fixative.
Publication Date: 2021-08-26
Journal: Diagnostic cytopathology


Molecular Engineering of Curcumin, an Active Constituent of
Cancer is the world's second leading cause of death, accounting for nearly 10 million deaths and 19.3 million new cases in 2020. Curcumin analogs are gaining popularity as anticancer agents currently. We reported herein the isolation, molecular engineering, molecular docking, antiproliferative, and anti-epidermal growth factor receptor (anti-EGFR) activities of curcumin analogs. Three curcumin analogs were prepared and docked against the epidermal growth factor receptor (EGFR), revealing efficient binding. Antiproliferative activity against 60 NCI cancer cell lines was assessed using National Cancer Institute (NCI US) protocols. The compound
Publication Date: 2021-08-29
Journal: Plants (Basel, Switzerland)


Nephrotoxic Metal Mixtures and Preadolescent Kidney Function.
Exposure to metals including lead (Pb), cadmium (Cd), and arsenic (As), may impair kidney function as individual toxicants or in mixtures. However, no single medium is ideal to study multiple metals simultaneously. We hypothesized that multi-media biomarkers (MMBs), integrated indices combining information across biomarkers, are informative of adverse kidney function. Levels of Pb, Cd, and As were quantified in blood and urine in 4-6-year-old Mexican children (n = 300) in the PROGRESS longitudinal cohort study. We estimated the mixture effects of these metals, using weighted quantile sum regression (WQS) applied to urine biomarkers (Umix), blood biomarkers (Bmix), and MMBs, on the cystatin C-based estimated glomerular filtration rate (eGFR) and serum cystatin C assessed at 8-10 years of age, adjusted for covariates. Quartile increases in Umix and the MMB mixture were associated with 2.5% (95%CI: 0.1, 5.0) and 3.0% (95%CI: 0.2, 5.7) increased eGFR and -2.6% (95% CI: -5.1%, -0.1%) and -3.3% (95% CI: -6.5%, -0.1%) decreased cystatin C, respectively. Weights indicate that the strongest contributors to the associations with eGFR and serum cystatin C were Cd and Pb, respectively. MMBs detected mixture effects distinct from associations with individual metals or media-type, highlighting the benefits of incorporating information from multiple exposure media in mixtures analyses.
Publication Date: 2021-08-28
Journal: Children (Basel, Switzerland)


Associations of Estimated Glomerular Filtration Rate with All-Cause Mortality and Cardiovascular Mortality in Patients with Diabetic Foot Osteomyelitis.
The purpose of this study was to explore the association between estimated glomerular filtration rate (eGFR) and clinical outcomes in patients with diabetic foot osteomyelitis (DFO). This was a retrospective observational study. A total of 199 patients with DFO were recruited and divided into three groups by eGFR: normal kidney function group (eGFR ≥ 90), mildly decreased kidney function group (eGFR 60-89) and moderately to severely decreased kidney function group (eGFR < 60). The patients were followed-up for a median of 36 months, and the study outcomes were all-cause mortality and major cardiovascular adverse events (MACE). Cox proportional hazard models were used to assess the association between eGFR and the outcomes, and a stratified analysis by sex was conducted. During follow-up, all-cause mortality occurred in 51 (25.63%) patients among 199 participants, 54 (28.72%) had MACE in 188 participants and 26 (48.15%) of them died. After fully adjusting for potential confounders, compared to eGFR < 90 mL/min/1.73 m In conclusion, decreased eGFR is a risk factor for all-cause mortality and MACE in individuals with DFO. Additionally, male with decreased eGFR had a higher risk of all-cause mortality and MACE, but female did not.
Publication Date: 2021-08-26
Journal: International journal of general medicine


Real-world efficacy of osimertinib in previously EGFR-TKI treated NSCLC patients without identification of T790M mutation.
The efficacy of osimertinib in previously EGFR-TKI-treated NSCLC without identification of T790M mutational status remains unclear in real-world practice. 417 patients had stage III-IV NSCLC harboring EGFR mutation and 154 out of 417 patients receiving osimertinib as ≥ second-line EGFR-TKI were identified. The time to treatment failure and risk of death were analyzed. Higher risk of death was found in EGFR-mutant patients with age ≥ 65 years, non-adenocarcinoma, no surgery or radiation, non-exon 19 deletion/exon 21 L858R, higher ECOG PS (2-4), PD-L1 expression ≥ 50%, and bone/liver/adrenal metastasis (all p < 0.05). Osimertinib as ≥ second-line TKI in patients with/without identification of T790M revealed lower risk of death compared to first-line first/second generation TKI without subsequent osimertinib (p = 0.0002; 0.0232, respectively). However, osimertinib-treated patients with T790M did not have superior survival than those without (p = 0.2803). A higher risk of treatment failure for osimertinib was found in males, patients with first-line TKI duration ≤ 12 months, BMI drop > 10%, and PD-L1 expression ≥ 50% (All p < 0.05). Nonetheless, osimertinib as ≥ second-line TKI in patients without identification of 790 M did not have higher risk of treatment failure than those with T790M (p = 0.1236). This study demonstrates that osimertinib as second line or subsequent TKI in EGFR-TKI-treated patients without identification of T790M revealed lower risk of death compared to first-line first/second generation TKI without subsequent osimertinib, in real-world practice. Additionally, EGFR-mutant patients with PD-L1 expression ≥ 50% had a higher risk of treatment failure for osimertinib and worse overall survival than those with PD-L1 expression < 50%. These results suggest that osimertinib as second line or subsequent TKI may be a potential alternative option for the treatment of patients without identification of T790M and PD-L1 expression ≥ 50% is associated with a significantly poor outcome in patients receiving osimertinib.
Publication Date: 2021-08-27
Journal: Journal of cancer research and clinical oncology


Association between autophagy and KRAS mutation with clinicopathological variables in colorectal cancer patients.
Autophagy is a host defensive mechanism responsible for eliminating harmful cellular components through lysosomal degradation. Autophagy has been known to either promote or suppress various cancers including colorectal cancer (CRC). KRAS mutation serves as an important predictive marker for epidermal growth factor receptor (EGFR)-targeted therapies in CRC. However, the relationship between autophagy and KRAS mutation in CRC is not well-studied. In this single-centre study, 92 formalin-fixed paraffin-embedded (FFPE) tissues of CRC patients (42 Malaysian Chinese and 50 Indonesian) were collected and KRAS mutational status was determined by quantitative PCR (qPCR) (n=92) while the expression of autophagy effector (p62, LC3A and LC3B) was examined by immunohistochemistry (IHC) (n=48). The outcomes of each were then associated with the clinicopathological variables (n=48). Our findings demonstrated that the female CRC patients have a higher tendency in developing KRAS mutation in the Malaysian Chinese population (p<0.05). Expression of autophagy effector LC3A was highly associated with the tumour grade in CRC (p<0.001) but not with other clinicopathological parameters. Lastly, the survival analysis did not yield a statistically significant outcome. Overall, this small cohort study concluded that KRAS mutation and autophagy effectors are not good prognostic markers for CRC patients.
Publication Date: 2021-08-28
Journal: The Malaysian journal of pathology


Use of SGLT-2 Inhibitors in Patients with Chronic Kidney Disease.
• Chronic kidney disease (CKD) is common, occurring in 1 of 7 adults in the United States. • 9 out of 10 adults with CKD are unaware of it. • People with CKD have the same risk for cardiovascular (CV) death as people with known atherosclerotic heart disease. • The risk for CV events and death increases with worsening albuminuria and estimated glomerular filtration rate (eGFR). • Patients with risk factors for CKD (hypertension, diabetes, family history of CKD, or advancing age) should be screened by measuring both eGFR and urinary albuminto-creatinine ratio. • Sodium-glucose cotransporter-2 inhibitors are first-line agents for treatment of patients with type 2 diabetes mellitus and CKD or a history of atherosclerotic CV disease. • Dapagliflozin has demonstrated equivalent efficacy for reducing kidney events in patients with CKD irrespective of diabetes status, and a similar, ongoing trial with empagliflozin may provide potential confirmation.
Publication Date: 2021-08-26
Journal: The Journal of family practice


Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2.
Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of cancer, and recently, differences in affinity depending on active or inactive states of EGFR or HER2 have been identified. In this study, we first identified FDA-approved compounds with similar structures in the DrugBank to lapatinib and gefitinib, two known inhibitors of EGFR and HER2. The selected compounds were submitted to docking and molecular dynamics MD simulations with the molecular mechanics generalized Born surface area approach to discover the conformational and thermodynamic basis for the recognition of these compounds on EGFR and HER2. These theoretical studies showed that compounds reached the ligand-binding site of EGFR and HER2, and some of the repurposed compounds did not interact with residues involved in drug resistance. An in vitro assay performed on two different breast cancer cell lines, MCF-7, and MDA-MB-23, showed growth inhibitory activity for these repurposed compounds on tumorigenic cells at micromolar concentrations. These repurposed compounds open up the possibility of generating new anticancer treatments by targeting HER2 and EGFR.
Publication Date: 2021-08-29
Journal: Pharmaceuticals (Basel, Switzerland)


Absence of renal remission portends poor long-term kidney outcome in lupus nephritis.
The very long-term consequences of absence of remission in lupus nephritis (LN) remain understudied. In this retrospective analysis, we studied a selected cohort of 128 patients with biopsy-proven class III, IV or V incident LN followed for a median period of 134 months (minimum 25). Remission was defined as a urine protein to creatinine (uP:C) ratio <0.5 g/g and a serum creatinine value <120% of baseline. Renal relapse was defined as the reappearance of a uP:C >1 g/g, leading to a repeat kidney biopsy and treatment change. Poor long-term renal outcome was defined as the presence of chronic kidney disease (CKD). Twenty per cent of patients never achieved renal remission. Their baseline characteristics did not differ from those who did. Absence of renal remission was associated with a threefold higher risk of CKD (48% vs 16%) and a 10-fold higher risk of end-stage renal disease (20% vs 2%). Patients achieving early remission had significantly higher estimated glomerular filtration rate (eGFR) at last follow-up compared with late remitters. Accordingly, patients with CKD at last follow-up had statistically longer time to remission. Among patients who achieved remission, 32% relapsed, with a negative impact on renal outcome, that is, lower eGFR values and higher proportion of CKD (33% vs 8%). Early remission should be achieved to better preserve long-term renal function.
Publication Date: 2021-08-28
Journal: Lupus science & medicine


Triplet Succeeds in Colorectal Cancer.
A drug trio consisting of BRAF, MEK, and EGFR inhibitors may become the new standard of care in
Publication Date: 2019-12-01
Journal: Cancer discovery


The potential targeted drugs for fusion genes including NRG1 in pancreatic cancer.
Pancreatic cancer (PC) remains an incurable disease with few treatment options Recently, promising targets have been identified and novel therapeutic drugs are currently under development in KRAS wild-type PC. It has been reported that KRAS wild-type PC has the genomic alterations such as oncogenic derivers and kinase fusions. NRG1 fusion, which encodes the neuregulin 1 and is the main ligands for ERRB3, has been identified in approximately half of younger patients with PC with KRAS -wild-type tumors by RNA sequencing. There are several promising targeted therapies for NRG1 fusion-positive tumors, such as EGFR-tyrosine kinase inhibitor,HER3, HER2 antibodies. BRAF, NTRK, and ALK fusion are also potentially actionable alterations in KRAS -wild-type PC and novel therapies targeting certain aberrations have shown activity in clinical trials.
Publication Date: 2021-08-29
Journal: Critical reviews in oncology/hematology


Multiplexed electrokinetic sensor for detection and therapy monitoring of extracellular vesicles from liquid biopsies of non-small-cell lung cancer patients.
Liquid biopsies based on extracellular vesicles (EVs) represent a promising tool for treatment monitoring of tumors, including non-small-cell lung cancers (NSCLC). In this study, we report on a multiplexed electrokinetic sensor for surface protein profiling of EVs from clinical samples. The method detects the difference in the streaming current generated by EV binding to the surface of a functionalized microcapillary, thereby estimating the expression level of a marker. Using multiple microchannels functionalized with different antibodies in a parallel fluidic connection, we first demonstrate the capacity for simultaneous detection of multiple surface markers in small EVs (sEVs) from NSCLC cells. To investigate the prospects of liquid biopsies based on EVs, we then apply the method to profile sEVs isolated from the pleural effusion (PE) fluids of five NSCLC patients with different genomic alterations (ALK, KRAS or EGFR) and applied treatments (chemotherapy, EGFR- or ALK-tyrosine kinase inhibitors). The vesicles were targeted against CD9, as well as EGFR and PD-L1, two treatment targets in NSCLC. The electrokinetic signals show detection of these markers on sEVs, highlighting distinct interpatient differences, e.g., increased EGFR levels in sEVs from a patient with EGFR mutation as compared to an ALK-fusion one. The sensors also detect differences in PD-L1 expressions. The analysis of sEVs from a patient prior and post ALK-TKI crizotinib treatment reveals significant increases in the expressions of some markers (EGFR and PD-L1). These results hold promise for the application of the method for tumor treatment monitoring based on sEVs from patient liquid biopsies.
Publication Date: 2021-08-25
Journal: Biosensors & bioelectronics


EGFR-plasma mutations in prognosis for non-small cell lung cancer treated with EGFR TKIs: A meta-analysis.
The plasma-based epidermal growth factor receptor (EGFR) mutation testing is approved recently to use in clinical practice. However, it has not been used as a prognostic marker yet because of contradictory results. This meta-analysis aims to clarify the role of the EGFR-plasma test in prognosis for non-small cell lung cancer (NSCLC) who have mutant tumors and receive EGFR tyrosine kinase inhibitors (TKIs). The PubMed/MEDLINE, Web of Science, Cochrane Library, and Google Scholar databases were searched for relevant studies by April 10, 2021. The hazard ratio (HR) from reports was extracted and used to assess the correlation of EGFR-plasma status with progression-free survival (PFS) and overall survival (OS). A total of 35 eligible studies with 4106 patients were enrolled in the final analysis. Patients with concurrent EGFR mutations in pretreatment plasma have shorter PFS (HR = 2.00, 95% confidence interval [CI]: 1.73-2.31, p < .001) and OS time (HR = 2.31, 95% CI: 1.89-2.83, p < .001) compared to the tumor-only mutation cases. Besides, the persistence of EGFR-activating mutations in post-treatment plasma is associated with worse PFS (HR = 3.84, 95% CI: 2.96-4.99, p < .001) and OS outcome (HR = 3.22, 95% CI: 2.35-4.42, p < .001) compared to others. Notably, the prognostic value of the EGFR-plasma test is also validated in treatment with third-generation EGFR TKI and significance regardless of different detection methods. The presence of EGFR-plasma mutations at pretreatment and after EGFR TKI initiation is the worse prognostic factor for PFS and OS in NSCLC.
Publication Date: 2021-08-25
Journal: Cancer reports (Hoboken, N.J.)


Muscle mass and grip strength in relation to carotid intima-media thickness and plaque score in patients with type 2 diabetes.
In this study, we examined the relationships of appendicular skeletal muscle mass (ASM) and grip strength (GS) with carotid intima-media thickness (CIMT) and plaque score (PS) in patients with type 2 diabetes. A total of 1185 patients were recruited. High CIMT and high PS were defined as ≥ 75 percentile of maximal CIMT of each sex and PS ≥ 3. Patients in the lowest ASM/body mass index (BMI) or GS/BMI tertile were older and had lower HDL cholesterol, and eGFR, but higher BMI, waist circumference (WC), HOMA-IR, and C-reactive protein than those in the highest tertile. Meanwhile, individuals in the lowest ASM or GS tertile group had lower BMI and WC than those in the highest one. CIMT and PS and the prevalence of high CIMT, carotid plaques, and high PS gradually increased with decreasing tertiles of ASM, ASM/BMI, GS, and GS/BMI (p < 0.001). After adjusting for age and sex, odds ratios (ORs) and 95% confidence intervals (CIs) for high CIMT and high PS were 0.98 (0.68-1.42), 1.64 (1.14-2.36), 2.000 (1.33-3.01), and 1.77 (1.22-2.58) and 1.63 (1.16-2.30), 1.78 (1.28-2.54), 1.91 (1.33-2.75), and 1.61 (1.13-2.28) in the lowest tertile of ASM, ASM/BMI, GS, and GS/BMI, respectively. After further adjusting for potential confounders, ORs and 95% CI for high CIMT and high PS remained significant in the lowest tertile group. Low ASM and low GS may be independent risk factors for high CIMT and high PS in patients with type 2 diabetes.
Publication Date: 2021-08-24
Journal: Nutrition, metabolism, and cardiovascular diseases : NMCD


Population Epidemiology of Hyperkalemia: Cardiac and Kidney Long-term Health Outcomes.
The population burden and long-term implications of hyperkalemia have not been comprehensively studied. We studied how often and where hyperkalemia occurs as well as its independent association with survival and long-term cardiac and kidney health. Population-based cohort study of adults residents of Grampian, UK (adult population 468,594). Among the 468,594 adult residents, 2012-2014, 302,630 people with at least one blood test were followed until 2019. Hyperkalemia was defined as serum potassium ≥5.5 mmol/L. Adjustment for comorbidities, demographics, KDIGO measures of acute and chronic kidney function, and medications prescribed prior to measurement of serum potassium. All-cause mortality, cardiac events and kidney failure. Description of the annual incidence of hyperkalemia and the characteristics associated with its occurrence. Adjusted Cox proportional hazards (PH) analysis to evaluate the independent long-term association of hyperkalemia with all-cause mortality among people who survived >90-days after blood testing. Cause-specific PH models were fit to evaluate the association of hyperkalemia with cardiac events/death, non-cardiac death, and kidney failure. Effect modification by level of eGFR at the time of blood testing was explored. The annual population incidence of hyperkalemia was 0.96 per 100 person-years. This represented 2.3%, 2.1%, and 1.9% of people with at least one blood test in 2012, 2013 and 2014, respectively. Two-thirds of episodes of hyperkalemia occurred in the community. The hyperkalemia rate was two-fold higher for each 10-year greater age. Those with hyperkalemia were 20 times more likely to have concurrent AKI, and 17 times more likely to have eGFR <30 ml/min/1.73m The observational nature of this study limits evaluation of causal relationships. There is a substantial burden of hyperkalemia in the general population. Hyperkalemia is associated with poorer long-term health outcomes, especially kidney outcomes, that are independent of other established risk factors.
Publication Date: 2021-08-23
Journal: American journal of kidney diseases : the official journal of the National Kidney Foundation


Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease.
We sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants (n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = -0.75, P = 2.37 × 10
Publication Date: 2021-08-21
Journal: Leukemia