Egfr - Epidermal growth factor receptor
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Publication
Journal: Archives of medical science : AMS
November/21/2019
Abstract
Triple negative breast cancer (TNBC) is characterized by a worse prognosis than other breast cancer subtypes. TNBC is defined by lack of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. The aim of this analysis was to evaluate the relationship between immunohistochemical expression of novel prognostic markers (erythropoietin (EPO) and erythropoietin receptor (EPO-R)) and clinicopathological features of TNBC and non-TNBC patients.Our analysis was conducted on a group of 162 patients with breast carcinoma with lymph node metastasis (111 TNBC and 51 non-TNBC). All statistical analyses were performed with SPSS software v 12.0.

Results
Histopathologic subtyping of the 111 triple negative breast cancers identified 89.1% invasive ductal carcinomas of no special type and 10.9% other special types of cancers. TNBC more often presented EPO-R and EPO expression (36%; 37.8%) than non-TNBC (23.5%; 29.4%). Non-TNBC subgroup showed statistically significant correlation only between Ki-67 expression and histological grade (G1-G3) (p < 0.001), while TNBC subgroup demonstrated significant correlation between Ki-67 expression and histological grade (G1-G3) and tumor size (pT1-pT4) as well (p = 0.002; p = 0.042), between the EPO-R expression and histological grade (G1-G3) (p < 0.001).

The relationship between the expression of EPO-R and histological malignancy grade in triple negative breast cancer, suggests that the present EPO-R expression in TNBC may constitute an additional prognostic factor.
Publication
Journal: PloS one
November/15/2019
Abstract
The aim of the study was to examine the associations of uric acid (UA) in blood and urine with subclinical renal damage (SRD) and its progression in a Chinese cohort.1) 2342 participants from our previously established cohort who were followed up in 2017 were included. Cross-sectional analysis was used to examine the relationships between serum and urinary UA and the risk of SRD. 2) A total of 266 participants were recruited from the same cohort in 2013, and followed up in 2017. Longitudinal analysis was used to determine the relationships of serum and urinary UA with progression of SRD, which was defined as urinary albumin-to-creatinine ratio (uACR) progression or estimated glomerular filtration rate (eGFR) decline.In cross-sectional analysis, higher levels of uACR were associated with higher levels of serum uric acid (SUA) and urinary uric acid/creatinine ratio (uUA/Cre). Lower eGFR was associated with higher levels of SUA and fractional excretion of uric acid (FEUA) but lower uUA/Cre levels in all subjects. In addition, the multivariate-adjusted odds ratios for SRD compared with non-SRD were 3.574 (2.255-5.664) for uUA/Cre. Increasing uUA/Cre levels were associated with higher risk of SRD. In longitudinal analysis, 4-year changes of uUA/Cre and SUA were significantly associated with eGFR decline.This study suggested that urinary UA excretion was significantly associated with the risk of SRD in Chinese adults. Furthermore, 4-year changes of serum and urinary UA were associated with SRD progression. These findings suggest that UA, especially urinary UA, may be used as a simple, noninvasive marker for early detection of decreased renal function in otherwise healthy subjects.
Publication
Journal: European journal of clinical nutrition
November/15/2019
Abstract
A high atherogenic index of plasma (AIP) is associated with increased cardiovascular risk and higher serum uric acid levels, but whether AIP is a strong risk factor for developing subclinical renal damage (SRD) is unknown. This study aimed to explore the effect of AIP variations on the prevalence of SRD in a 12-year follow-up study.(1) The cross-sectional study enrolled 2485 participants from the Hanzhong cohort in 2017; (2) A total of 202 participants were included in the small longitudinal cohort from 2005 to 2017. Longitudinal analysis was used to determine whether an elevated AIP predicts the development of SRD.In the cross-sectional analysis, the AIP level was correlated with the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatine ratio (uACR) (P < 0.05). The age-adjusted odds ratio (OR) for prevalent SRD in men in the high AIP group was 1.924 (1.355-2.732) (P < 0.001), while in women, the OR was 1.616 (1.049-2.490) (P = 0.030) in the high AIP group. In the longitudinal analysis, significantly higher uACR levels were found in participants with normal AIP at baseline and elevated AIP in 2013 (P < 0.05). The adjusted OR for prevalent SRD in the incident AIP group was 4.741 (1.668-13.472) (P = 0.003) compared with the control group.Our study indicates that elevated AIP increased the risk of developing SRD and was associated with uACR and eGFR. As a simple marker of CVD risk, AIP may emerge as a novel and reliable indicator of SRD.
Publication
Journal: Drugs
November/12/2019
Abstract
Tacrolimus is the most commonly prescribed medication in initial immunosuppressive regimens to prevent acute rejection in kidney transplant recipients (KTRs). Tacrolimus was originally available as an immediate-release formulation (IR-Tac) given twice daily. Extended-release tacrolimus (ER-Tac) given once daily was later developed with the expectation of improved medication adherence. Data from observational studies, which compared outcomes between ER-Tac and IR-Tac in different populations of KTRs including those who are unlikely to be enrolled in randomized clinical trials, have been reported.To evaluate the incidence of biopsy-proven acute rejection (BPAR) at 12 months together with other outcomes reported in observational studies among adult KTRs who received ER-Tac compared to IR-Tac.In accordance with the recommendations of the Cochrane Collaboration and the Meta-analysis of Observational Studies in Epidemiology, we systematically reviewed all observational studies that compared clinical outcomes between ER-Tac and IR-Tac in KTRs. The systematic searches were conducted on PubMed, EMBASE, Scopus, and Web of Science without language restriction. Reference lists were also searched and reviewed. Data were extracted for BPAR, graft survival, patient survival, estimated glomerular filtration rate (eGFR), serum creatinine (Scr), creatinine clearance (CrCl), at different times after kidney transplantation (KT). A meta-analysis was performed to integrate the results from the eligible studies. This study is registered with PROSPERO, number CRD42019135705.

RESULTS
From the 1401 articles screened, 10 observational studies in KTRs who received tacrolimus were included. The pooled results showed significantly lower BPAR with ER-Tac than with IR-Tac at 12 months post-KT (5 studies, n = 659; RR, 0.69; 95% CI 0.51-0.95; p = 0.02; I2 = 0%). No significant differences in BPAR at other time points after KT were found. Graft survival, patient survival, Scr, and eGFR were comparable between groups at different times over approximately 1 year after transplantation.

Based upon currently available evidence in observational studies, 30% lower risk of BPAR was observed in ER-Tac group compared with IR-Tac group at 12 months post-KT, while there was no significant difference in BPAR risk at any other studied time points. No differences in graft- and patient-survival rates and kidney function were found. Given the limitations of observational studies to make causal inference, as well as quality limitations among the included studies, caution should be exercised in interpreting these findings.
Publication
Journal: The Journal of clinical investigation
November/11/2019
Abstract
The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreERt2 knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing of dedifferentiated cells while measuring the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones coexpressed KIM1, VIMENTIN, SOX9, and KI67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells, rather than fixed tubular progenitor cells, account for repair. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor Foxm1 was induced early in injury, was required for epithelial proliferation in vitro, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair, and we reveal an EGFR/FOXM1-dependent signaling pathway that drives proliferative repair after injury.
Publication
Journal: The Journal of clinical investigation
October/29/2019
Abstract
Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3 (HER3)-targeting antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti-PD-1 therapy, treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd: the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins including HMGB-1 via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor-resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.
Publication
Journal: European journal of cancer (Oxford, England : 1990)
October/21/2019
Abstract
We conducted a double-randomised phase III trial to evaluate a concomitant taxane-anthracycline regimen in node-positive breast cancer and the efficacy of trastuzumab in the human epidermal growth factor receptor 2 (HER2)-positive subpopulation.

METHODS
A total of 3010 patients with node-positive breast cancer were randomly assigned to receive 6 cycles of 500 mg/m2 of fluorouracil, 100 mg/m2 of epirubicin and 500 mg/m2 of cyclophosphamide (FEC) or 75 mg/m2 of epirubicin and 75 mg/m2 of docetaxel (ED). Patients with HER2-positive tumours were secondary randomly assigned to either trastuzumab or observation. The primary end-point was disease-free survival (DFS) in the two chemotherapy arms.

After a 115-month median follow-up, DFS was not significantly better in the ED arm (DFS: 70%, 95% confidence interval [CI]: 67-72) than in the FEC arm (DFS: 68%, 95% CI: 65-70; hazard ratio [HR] = 0.88, 95% CI: 0.77-1.01; p = 0.064). The OS was not different between FEC (OS: 80%, 95% CI: 78-83) and ED (OS: 81%, 95% CI: 79-83); HR = 0.97, 95% CI: 0.81-1.16; p = 0.729). ED appeared more toxic. In the 528 HER2-positive subset, there was trend for a higher DFS, in the intention-to-treat population, in the trastuzumab arm (DFS: 68%, 95% CI: 61-74) than in the observation arm (DFS: 60%, 95% CI: 54-66; HR = 0.77, 95% CI: 0.57-1.03; p = 0.079). In the per-protocol population, DFS was significantly higher in the trastuzumab arm (DFS: 70%, 95% CI: 63-76) than in the observation arm (DFS: 59%, 95% CI: 53-65; HR = 0.69, 95% CI: 0.51-0.94; p = 0.0156). The OS was not different between these 2 arms.This study did not show superiority of the concomitant anthracycline-taxane arm which was more toxic in high-risk node-positive breast cancer patients. Long-term results of the HER2-positive subpopulation are in line with those of the other adjuvant trastuzumab trials but quantitatively less pronounced mostly because of lack of power.
Publication
Journal: The Journal of biological chemistry
October/19/2019
Publication
Journal: Frontiers in oncology
October/14/2019
Abstract
The small leucine-rich proteoglycan (SLRP) family consists of 18 members categorized into five distinct classes, the traditional classes I-III, and the non-canonical classes IV-V. Unlike the other class I SLRPs (decorin and biglycan), asporin contains a unique and conserved stretch of aspartate (D) residues in its N terminus, and germline polymorphisms in the D-repeat-length are associated with osteoarthritis and prostate cancer progression. Since the first discovery of asporin in 2001, previous studies have focused mainly on its roles in bone and joint diseases, including osteoarthritis, intervertebral disc degeneration and periodontal ligament mineralization. Recently, asporin gene expression was also reported to be dysregulated in tumor tissues of different types of cancer, and to act as oncogene in pancreatic, colorectal, gastric, and prostate cancers, and some types of breast cancer, though it is also reported to function as a tumor suppressor gene in triple-negative breast cancer. Furthermore, asporin is also positively or negatively correlated with tumor proliferation, migration, invasion, and patient prognosis through its regulation of different signaling pathways, including the TGF-β, EGFR, and CD44 pathways. In this review, we seek to elucidate the signaling pathways and functions regulated by asporin in different types of cancer and to highlight some important issues that require investigation in future research.
Publication
Journal: Frontiers in oncology
October/14/2019
Abstract
Background: Exosomes are cell-derived vesicles and bear a specific set of nucleic acids including DNA (exoDNA). Thus, this study is to explore whether exoDNA in malignant pleural effusions (MPEs) could be a novel DNA source for mutation detection of epidermal growth factor receptor (EGFR). Methods: In this study, 52 lung adenocarcinoma patients were enrolled, and EGFR mutation status was detected with tumor tissues as well as cell blocks and exosomes in MPEs. The sensitivity, specificity and consistency of EGFR detection using exosomes were evaluated, compared with gene detection using tumor tissues and cell blocks. And the clinical response of patients who were detected as EGFR mutation in exosomes and treated with EGFR tyrosine kinase inhibitor (EGFR-TKI) was explored. Results: Gene detection using exosomes showed sensitivity of 100%, specificity of 96.55% and coincidence rate of 98.08% (Kappa = 0.961, P < 0.001), compared with detection using tumor tissues and cell blocks. After EGFR-TKI treatment, patients detected as EGFR mutation by exosomes showed efficacy rate of 83% and disease control rate of 100%. And patients who were detected as wild type in tumor tissues or cell blocks but EGFR mutation in exosomes turned up as PR or SD. Conclusions: These results demonstrated that exoDNA in MPEs could be used as a DNA source for EGFR detection in lung adenocarcinoma.
Publication
Journal: Renal failure
October/3/2019
Abstract
Purpose: To investigate the potential association between lifestyles, including cigarette smoking, alcohol consumption, and physical exercise at the time of biopsy and the risk for developing end-stage renal failure (ESRF) among IgA nephropathy (IgAN) patients within 10 years. Methods: A case-control study was carried out. Seventy-seven ESRF patients with the primary cause of IgAN were enrolled as cases. Seventy-seven IgAN patients who had not progressed to ESRF after being diagnosed for over 10 years served as controls. Smoking, alcohol consumption and physical exercise related data and baseline clinical features were collected from their medical records and confirmed by phone calls. Results: The case group had higher proportions of males, smokers, drinkers, and physical inactivity individuals than the controls had. Alcohol drinking history (/1 year, OR 1.32, p < .05) is independently associated with an increased risk of ESRF, while physical exercise habits (OR 0.06, p < .05) associated with a decreased risk of ESRF in multivariate logistic analysis. Male gender, lower eGFR, and higher urinary protein at the time of biopsy were also independent risk factors. Moreover, male-non-exercise population seems to be more likely to progress to ESRF than others (male-exercise, female-exercise, and female-none-exercise populations). Conclusion: Physical exercise should be encouraged in IgAN patients, especially in males, for a better renal outcome. Alcohol cessation might have a renal survival benefit in IgAN patients.
Publication
Journal: Biomaterials science
October/2/2019
Abstract
Photodynamic therapy has attracted significant attention due to its localized treatment advantage. However, the non-specific distribution of photosensitizers and the subsequent potential toxicity caused by sunshine exposure hinder its wide adoption in cancer treatment. To minimize these unwanted effects and improve its efficacy, we developed a bioactivatable self-quenched nanogel, which remains in its inactive state in healthy tissues. Anti-EGFR Affibody decorated nanogels can effectively target head and neck cancer and release activated pheophorbide A in a reducing environment, such as in the tumor stroma and cytoplasm. Consequently, the EGFR targeted nanogel coupled with NIR irradiation alleviates tumor burden by 94.5% while not inducing systemic toxicity.
Publication
Journal: World journal of gastrointestinal oncology
September/27/2019
Abstract
Gastric cancer is a leading cause of cancer incidence and death worldwide. Patients with advanced gastric cancer benefit from a multi-modality treatment regimen. Sound oncologic resection with negative margins and complete lymphadenectomy plays a crucial role in long-term survival for patients with resectable disease. The utilization of minimally invasive techniques for gastric cancer has been slowly increasing and is proving to be both technically and oncologically safe. Perioperative chemotherapy is the current standard of care for advanced gastric cancer. A variety of chemotherapy regimens have been used with the combination of docetaxel, oxaliplatin, 5-fluorouracil, and leucovorin being the current recommendation given its superior ability to induce a complete pathologic response and prolong survival. The use of radiation has been more controversial with its optimal place in the treatment sequence being unclear. There are current ongoing studies assessing the impact of radiation as an adjunct or in place of chemotherapy. Targeted treatments (e.g., trastuzumab for human epidermal growth factor receptor 2 positive tumors and pembrolizumab for programmed death-ligand 1 positive tumors) are showing promise and are part of a continued emphasis on individualized care. Intraperitoneal chemotherapy may also play a role in preventing peritoneal recurrences for patients with high risk lesions. The treatment of patients with advanced gastric cancer in the West continues to advance and improve with a better understanding of optimal treatment sequences and the utilization of personalized treatment regimens.
Publication
Journal: PloS one
September/24/2019
Abstract
Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015.Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records.Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision.These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials.
Publication
Journal: Clinical journal of the American Society of Nephrology : CJASN
September/20/2019
Abstract
The risk of hypertension attributable to living kidney donation remains unknown as does the effect of developing postdonation hypertension on subsequent eGFR. We sought to understand the association between living kidney donation, hypertension, and long-term eGFR by comparing donors with a cohort of healthy nondonors.We compared 1295 living kidney donors with median 6 years of follow-up with a weighted cohort of 8233 healthy nondonors. We quantified the risk of self-reported hypertension using a parametric survival model. We examined the association of hypertension with yearly change in eGFR using multilevel linear regression and clustering by participant, with an interaction term for race.

RESULTS
Kidney donation was independently associated with a 19% higher risk of hypertension (adjusted hazard ratio, 1.19; 95% confidence interval, 1.01 to 1.41; P=0.04); this association did not vary by race (interaction P=0.60). For white and black nondonors, there was a mean decline in eGFR (-0.4 and -0.3 ml/min per year, respectively) that steepened after incident hypertension (-0.8 and -0.9 ml/min per year, respectively; both P<0.001). For white and black kidney donors, there was a mean increase in eGFR after donation (+0.4 and +0.6 ml/min per year, respectively) that plateaued after incident hypertension (0 and -0.2 ml/min per year, respectively; P=0.07 and P=0.01, respectively, after hypertension).

Kidney donors are at higher risk of hypertension than similar healthy nondonors, regardless of race. Donors who developed hypertension had a plateau in the usual postdonation increase of eGFR.
Publication
Journal: Molecular oncology
September/18/2019
Abstract
Many advanced cases of cancer show central nervous system (CNS), pleural or peritoneal involvement. In this study, we prospectively analyzed if cerebrospinal fluid (CSF), pleural effusion (PE) and/or ascites can be used to detect driver mutations and guide treatment decisions. We collected 42 CSF, PE and ascites samples from advanced NSCLC and melanoma patients. Cell free DNA (cfDNA) was purified and driver mutations analyzed and quantified by PNA-Q- PCR or NGS. All 42 fluid samples were evaluable; clinically relevant mutations were detected in 41 (97.6%). Twenty-three fluids had paired blood samples, 22 were mutation positive in fluid but only 14 in blood, and the abundance of the mutant alleles was significantly higher in fluids. Of the 34 fluids obtained at progression to different therapies, EGFR resistance mutations were detected in nine and ALK acquired mutations in two. The results of testing of CSF, PE and ascites were used to guide treatment decisions, such as initiation of osimertinib treatment or selection of specific ALK tyrosine-kinase inhibitors. In conclusion, fluids close to metastatic sites are superior to blood for the detection of relevant mutations and can offer valuable clinical information, particularly in patients progressing to targeted therapies.
Publication
Journal: JCO precision oncology
September/13/2019
Abstract
Next-generation sequencing (NGS) for tumor molecular profiling can reveal secondary germline pathogenic and likely pathogenic variants (LPV/PV). The American College of Medical Genetics (ACMG) recommends return of secondary results for a subset of 59 genes, but other genes with evidence of clinical utility are emerging. We previously reported that 4.3% of patients who underwent NGS of a targeted panel of 201 genes had LPV/PV based on the ACMG list. Here we report the frequency of additional germline cancer-related gene variants and discuss their clinical utility.Matched tumor and germline DNA NGS of a targeted panel of 201 genes was performed in a research laboratory on samples from 1000 patients with advanced or metastatic solid tumors enrolled in a molecular testing protocol (NCT01772771). The frequency of germline LPV/PV in 54 cancer-related genes, beyond the genes in ACMG list, were analyzed.

Results
Among 1000 patients who underwent tumor/normal DNA sequencing, 46 (4.6%) were found to have a germline LPV/PV in the following genes: AR-(5), ATM-(4), BAP1-(1), CDH1-(1), CDKN2A-(1), CHEK1-(2), CHEK2-(10), EGFR-(1), ERCC3-(4), ERCC5-(1), HNF1B-(1), HRAS-(1), MITF-(4), MLL3-(1), NF1-(3), PKHD1-(4), PTCH1-(1), and SMARCA4-(1). Thus, a total 8.7% of patients had an LPV/PV with 2 patients having 2 concomitant germline LPV/PV. Five mutations in high-penetrance hereditary cancer predisposition genes were selected to be returned to patients or their representatives: BAP1, CDH1, CDKN2A, EGFR, and SMARCA4.

Broader genomic testing is likely to identify additional secondary pathogenic germline alterations, some with potential clinical utility for return to patients and their relatives. The recommended genes for which germline results should be returned are continually changing, warranting continued study.
Publication
Journal: Nano letters
September/13/2019
Abstract
Cell-surface receptors (e.g., EGFR and integrin) and their interactions play determining roles in signal transduction and cytoskeletal activation, which affect cell attachment/detachment, invasion, motility, metastasis (intracellular), and cell-cell signaling. For instance, the interactions between the EGFR and integrin (α6β4) may cause increased mechanical force and shear stress via enhanced cytoskeleton activation. Here, we design a DNA nanodevice (DNA-ND) that can simultaneously target the EGFR and integrin receptors on the caveolae. The piconewton (pN) forces in response to the EGFR-integrin coactivation can be sensed upon the unfolding of the DNA hairpin structure on the side arm of the device via changes of the fluorescence and plasmonic signals. We find that simultaneous activation of EGFR-integrin receptors causes enhanced signal transduction, contractions of the cells, and initiation of the biochemical pathways, thus resulting in a change of the cell division and endocytosis/exocytosis processes that affect the cell proliferation/apoptosis. The DNA-ND further enables us to visualize the cointernalization and degradation of the receptors by lysosomes, providing a novel approach toward bioimaging and mechano-pharmacology.
Publication
Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany)
September/11/2019
Abstract
Amplification of epidermal growth factor receptor (EGFR) and active mutant EGFRvIII occurs frequently in glioblastoma (GBM) and contributes to chemo/radio-resistance in various cancers, especially in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in GBM could benefit cancer patients. A genome-wide screening under a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library is conducted to identify the genes that confer resistance to TMZ in EGFRvIII-expressing GBM cells. Deep sgRNA sequencing reveals 191 candidate genes that are responsible for TMZ resistance in EGFRvIII-expressing GBM cells. Notably, E2F6 is proven to drive a TMZ resistance, and E2F6 expression is controlled by the EGFRvIII/AKT/NF-κB pathway. Furthermore, E2F6 is shown as a promising therapeutic target for TMZ resistance in orthotopic GBM cell line xenografts and GBM patient-derived xenografts models. After integrating clinical data with paired primary-recurrent RNA sequencing data from 134 GBM patients who received TMZ treatment after surgery, it has been revealed that the E2F6 expression level is a predictive marker for TMZ response. Therefore, the inhibition of E2F6 is a promising strategy to conquer TMZ resistance in GBM.
Publication
Journal: Endocrine
September/10/2019
Abstract
Gigantomastia refers to pathological breast enlargement usually occurring in the peripubertal or peripartum period. Idiopathic gigantomastia, however, is a rare entity with hypotheses citing local expression of hormones and growth factors in causing this disease, none of which have been systemically analysed. The purpose of this study was to delve deeper into the mechanistic pathways causing this condition.Herein, we describe three patients of idiopathic gigantomastia, all of whom had had normal puberty and uneventful pregnancies. Further, one of the patients had postmenopausal gigantomastia which is extremely rare, with only four cases described in the literature. Serum markers of autoimmunity, incriminated hormones and growth factors analysed, were normal in all the cases. Breast tissue specimens were subjected to histopathological examination and immunohistochemistry for ER, PR and Her-2-Neu. Quantitative immunofluorescence for aromatase, IGF2, EGFR, TGF-β, PDGFR-α, β, IGF1 and PTHrP was also performed.Of these, the tissue expression of aromatase, IGF2, EGFR, TGF-β, PDGFR-α and β were found to be upregulated, whereas IGF1 and PTHrP were comparable to normal breast.This observation that paracrine overexpression of these factors is responsible for the pathogenesis of apparently idiopathic gigantomastia may have therapeutic ramifications in the future for patients with this debilitating condition.
Publication
Journal: Methods in molecular biology (Clifton, N.J.)
September/4/2019
Abstract
The introduction of tyrosine-kinase inhibitors (TKI) targeting specific EGFR mutations for the treatment non-small cell lung cancer patients (NSCLC) dramatically increased the clinical outcome in a subset of patients harboring specific activating EGFR mutations. Three different generations of TKI have been developed until now, demonstrating increasing progression-free survival as well as overall survival. However, to benefit of the treatment, the analysis of the genomic content of each patient is mandatory. Additionally, resistance mutations are prevalent and occur frequently and rapidly during treatment. Therefore, tests to detect EGFR mutations at initial diagnosis as well as during treatment, e.g., from liquid biopsies, have been developed and implemented in clinical daily practice for theranostic purpose.As EGFR mutation testing has to be highly reliable, fast, and easy to perform, the automatic qPCR system Idylla™ has been developed and implemented for clinical mutation testing from tissue samples and soon from circulating free DNA. Therefore, we here describe how the Idylla™ system can be used for the analysis of EGFR mutations in NSCLC patients. Importantly, as the results are massively influenced by the preanalytical steps, we also provide information on the correct sample selection to avoid nonconclusive results.
Publication
Journal: Journal of thoracic disease
August/29/2019
Abstract
Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations often develop systemic disease progression during treatment with EGFR-tyrosine kinase inhibitors (TKIs). Droplet digital polymerase chain reaction (ddPCR) and amplification refractory mutation system (ARMS)-PCR are routinely applied for detection of EGFR mutations, including T790M, which is associated with TKI sensitivity. We compared the efficiency of ddPCR and ARMS-PCR in detecting T790M and explored the association between T790M abundance and osimertinib efficacy.Genomic DNA (gDNA) from tissue and cells in hydrothorax and circulating tumor DNA (ctDNA) from peripheral blood (PB), and clinicopathological data were retrospectively collected from 263 patients who visited Sun Yat-sen University Cancer Center for T790M test.

Results
Mean T790M abundance and mutant copy number of cases tested positive by both methods, i.e., the ddPCR+ARMS+ group (19.1%, 636.9), were higher than those in the ddPCR+ARMS- group (0.36%, 12.1), suggesting that ddPCR is more sensitive in detecting samples with low mutant abundance than ARMS-PCR. T790M detection rate was comparable for gDNA and ctDNA samples (44.7% vs. 37.6%, P=0.242); however, gDNA sample tended to show more T790M abundance in ddPCR analysis. T790M coexisted with L858R mutation (8/11) more than with deletions in exon 19 (19del) mutation (3/11) in TKI-naive tumors, while 19del co-occurred as often as L858R in post-TKI tumors. T790M+ patients benefited more from osimertinib and showed longer progression-free survival (PFS) (not achieved vs. 10.1 months, P=0.0399), while lower T790M abundance (<1.065%) was associated with longer PFS (not achieved vs. 8.8 months, P=0.0033).

ddPCR has a higher sensitivity than ARMS-PCR, especially in detecting the less abundant T790M. Although detection rates were comparable for ctDNA and gDNA samples, the mutation abundance was higher in gDNA sample. Finally, low T790M abundance was associated with longer PFS in NSCLC patients receiving osimertinib treatment.
Publication
Journal: Hormones (Athens, Greece)
August/25/2019
Abstract

PURPOSE
The cumulative incidence of hypothyroidism, in 131I-treated patients with hyperthyroidism caused by Graves' disease, has been gradually increasing each year. Meanwhile, the role of the genes that control radiation sensitivity (GCRS) involved in 131I therapy is yet to be defined. The main purpose of the present study is to find GCRS that could indicate hypothyroidism in Graves' disease patients treated with 131I.

Thyroid tissue was collected from 59 patients who were diagnosed with Graves' disease. GCRS (including Bcl-2, NF-κB, Survivin, Ku-70, Tob1, EGFR, Egr-1, TP-53, BRCA-1, and ATM) mRNA levels were analyzed with qRT-PCR before radioiodine therapy. Patients were followed up and then grouped by end-point outcomes. The association of the variation of target genes with susceptibility to hypothyroidism was analyzed.

RESULTS
Altogether 44 patients were enrolled, including 11 men and 33 women with an average age of 44.79 ± 12.94 years. Based on their clinical outcomes after at least 2-year follow-up, 59% (26/44) patients were evaluated as hypothyroid, while the remaining 41% (18/44) patients were non-hypothyroid, including 18% (8/44) with persistent hyperthyroidism. The hypothyroid group showed significantly lower Ku-70 mRNA expression levels than the non-hypothyroid group (p = 0.022), whereas no significance was detected regarding other target genes (p > 0.1). Multivariate analysis showed that Ku-70 was significantly correlated with hypothyroidism after 131I treatment (p = 0.033).

CONCLUSIONS
The opposing changes in mRNA expression levels of Ku-70 in patients with hypothyroidism indicate its potential as a prognostic marker for hypothyroidism induced by 131I treatment.

Publication
Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
August/23/2019
Abstract

PURPOSE
To assess the utility of the cobas® EGFR Mutation Test, with tissue and plasma, for first-line osimertinib therapy for patients with EGFR-mutated (EGFRm) (Ex19del and/or L858R) advanced or metastatic non-small cell lung cancer (NSCLC) from the FLAURA study (NCT02296125).

EXPERIMENTAL DESIGN
Tumor tissue EGFRm status was determined at screening using the central cobas tissue test or a local tissue test. Baseline circulating tumor (ct)DNA EGFRm status was retrospectively determined with the central cobas plasma test.

RESULTS
f 994 patients screened, 556 were randomized (289 and 267 with central and local EGFR test results, respectively) and 438 failed screening. Of those randomized from local EGFR test results, 217 patients had available central test results; 211/217 (97%) were retrospectively confirmed EGFRm positive by central cobas tissue test. Using reference central cobas tissue test results, positive percent agreements with cobas plasma test results for Ex19del and L858R detection were: 79% (95% CI, 74-84) and 68% (95% CI, 61-75), respectively. Progression-free survival (PFS) superiority with osimertinib over comparator EGFR-TKI remained consistent irrespective of randomization route (central/local EGFRm positive tissue test). In both treatment arms, PFS was prolonged in plasma ctDNA EGFRm negative (23.5 and 15.0 months,) vs positive patients (15.2 and 9.7 months).

CONCLUSIONS
Our results support utility of cobas tissue and plasma testing to aid selection of patients with EGFRm advanced NSCLC for first-line osimertinib treatment. Lack of EGFRm detection in plasma was associated with prolonged PFS vs patients plasma EGFRm positive, potentially due to patients having lower tumor burden.

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