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Vol 15, No 1 (January 31, 2023) /
High expression of FGFR3 predicts a better prognosis for patients with non-small cell lung cancer in a Chinese...
High expression of FGFR3 predicts a better prognosis for patients with non-small cell lung cancer in a Chinese population
Yun-En Lin1#, Hui-Dong Long2#, Cheng-Cong Chen3#, Guan-Cheng Liu4, Feng Li3, Yun-Hong Tian3, Lu Dai5^
1Department of Pathology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China; 2Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China; 3Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China; 4Department of Ultrasound Room, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China; 5Department of Thoracic Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
Contributions: (I) Conception and design: HD Long, YH Tian; (II) Administrative support: YE Lin; (III) Provision of study materials or patients: CC Chen; (IV) Collection and assembly of data: GC Liu; (V) Data analysis and interpretation: F Li, L Dai; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
^ORCID: 0000-0002-6895-9619.
Correspondence to: Lu Dai. Department of Thoracic Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China. Email: docdailu@126.com; Yun-Hong Tian. Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China. Email: tianyunhong2020@gzhmu.edu.cn.
Background: This study sought to examine the expression and mutation status of fibroblast growth factor receptor 3 (FGFR3) in non-small cell lung cancer (NSCLC) tissues and explore the prognostic potential of FGFR3 in NSCLC.
Methods: Immunohistochemistry (IHC) was used to evaluate the FGFR3 protein expression of 116 NSCLC tissues. Sanger sequencing was used to examine the mutation status of exons 7, 10, and 15 in FGFR3. A Kaplan‑Meier survival analysis was conducted to evaluate the association between the expression level of FGFR3 and the overall survival (OS) and disease-free survival (DFS) of NSCLC patients. Univariate and multivariate Cox analyses were conducted to examine the association between the risk score and clinical features.
Results: FGFR3 was immunoreactive in 26 of the 86 NSCLC cases. Further, FGFR3 was positively expressed in 84.6% of the lung adenocarcinoma (AC) cases and 15.4% of the lung squamous cell carcinoma (SCC) cases. FGFR3 mutations were detected in 2 NSCLC patients (2/72, 2.8%), who both harbored the T450M mutation, a novel mutation in exon 10 of FGFR3. In NSCLC, a high expression of FGFR3 was positively correlated with gender, smoking, histology type, T stage, and the epidermal growth factor receptor (EGFR) mutation (P<0.05). FGFR3 expression was also correlated with better OS and DFS. The multivariate analysis revealed that FGFR3 served as an independent prognostic factor (P=0.024) for the OS of NSCLC patients.
Conclusions: This study showed that FGFR3 was highly expressed in NSCLC tissues, and the frequency rate for the FGFR3 mutation at T450 M in NSCLC tissues was low. The survival analysis suggested that FGFR3 may be a useful prognostic biomarker in NSCLC.
Keywords: Fibroblast growth factor receptor 3 (FGFR3); non-small cell lung cancer (NSCLC); immunohistochemistry (IHC); mutation; prognosis
Submitted Sep 05, 2022. Accepted for publication Jan 10, 2023. Published online Jan 16 2023.
doi: 10.21037/jtd-22-1523
• Our study showed that FGFR3 was highly expressed in NSCLC tissues, and the frequency rate for the FGFR3 mutation at T450 M in NSCLC tissues was low.
What is known and what is new?
• Several studies have detected alterations of FGFR3 in NSCLC; however, the frequency of FGFR3 status was discordance. In one study, FGFR3 fusions were detected in 9 of 312 lung SCCs in Chinese patients, and the rate of FGFR3 fusions was even lower in lung ACs (0.6%, 6/1,016).
• Thus, this study sought to examine the alterations of FGFR3 using immunohistochemistry and Sanger sequencing in the NSCLC tissues of 116 patients with surgically resectable NSCLC at the I-IIIA stage. The prognostic role of FGFR3 in NSCLC patients was also explored.
What is the implication, and what should change now?
• FGFR3 may serve as an independent prognostic factor for the OS of NSCLC patients.
Lung cancer is a leading cause of cancer-related deaths worldwide (1). Non-small cell lung cancer (NSCLC) accounts for >75% of all cases of lung cancer and can be further classified into 3 subtypes; that is, adenocarcinoma (AC), squamous cell carcinoma (SCC), and large cell carcinoma (2-5). A number of studies have successfully applied molecular-targeted therapeutic agents and demonstrated their superiority to conventional chemotherapy in treating NSCLC (6-8). For example, the echinoderm microtubule-associated protein like4-anaplasticlymphoma kinase and epidermal growth factor receptor (EGFR) are important treatment modalities for NSCLC (9-12). Despite advances in the multimodality treatment of NSCLC, the prognosis of patients still remains unfavorable with a 5-year overall survival (OS) rate of <15% in China (13,14). To improve the prognosis of NSCLC patients and establish effective treatment modalities, the tumor biology mechanism needs to be deciphered.
Fibroblast growth factor receptors (FGFRs) are 4 highly conserved transmembrane receptor tyrosine kinase (RTK) families, and include FGFR1, FGFR2, FGFR3, and FGFR4 (15). FGFR3 spans 16.5 kb with 18 introns and 19 exons and is situated on chromosome 4p16.3. FGFR3 is a member of the FGFR family and has been found to regulate cell growth, cell differentiation, and migration (16,17). FGFR3 is involved in a variety of biological processes including cell proliferation, differentiation, migration, angiogenesis, and apoptosis. Cellular functions of FGFR3 are activated by ligand-induced dimerization which in turn leads to transphosphorylation of key tyrosine residues in the kinase domain of the receptor Phosphorylated tyrosines act as docking sites for the recruitment of signaling molecules and activation of downstream pathways. Four main signal transduction pathways have been implicated in mediating FGFR3 functions including the MAP kinase, STAT1, PI3K-AKT, and PLCγ (18,19). FGFR3 has been shown to be activated by the mutation or fusion of its own gene in several types of cancers, such as urinary bladder cancer, cervix carcinomas, glioblastoma, rhabdomyosarcoma, and NSCLC (20).
Several studies have detected alterations of FGFR3 in NSCLC (21-23); however, the frequency of FGFR3 status was discordance. In one study, FGFR3 fusions were detected in 9 of 312 lung SCCs in Chinese patients, and the rate of FGFR3 fusions was even lower in lung ACs (0.6%, 6/1,016) (23). In addition to FGFR3 fusions, the mutation alteration is more common in the tumor area, particularly in bladder tumors. A previous study reported that the FGFR3 mutation rate is rare in NSCLC, and is only found in lung SCC (21). To date, no data are available on the distribution rates for FGFR3 expression and mutation, its relation to clinicopathological characteristics, and clinical outcomes in NSCLC. Thus, this study sought to examine the alterations of FGFR3 using immunohistochemistry (IHC) and Sanger sequencing in the NSCLC tissues of 116 patients with surgically resectable NSCLC at the I-IIIA stage. The prognostic role of FGFR3 in NSCLC patients was also explored. The findings of the present study may provide novel insights into the role of FGFR3 in the pathophysiology of NSCLC. We present the following article in accordance with the REMARK reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1523/rc).
This study examined 116 NSCLC surgical tumor tissue samples from patients who had undergone primary and curative resection at the Affiliated Cancer Hospital and Institute of Guangzhou Medical University. The samples were collected between June 2010 and June 2014. None of the patients had previously undergone preoperative chemotherapy or radiotherapy. Patients with surgically resectable NSCLC (stage I–IIIA) were included in this study. The clinicopathological data of the patients are summarized in Table 1. Tumor, node and metastasis (TNM) staging was evaluated based on American Joint Committee on Cancer (AJCC)/International Union against Cancer TNM classification system (24). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of Guangzhou Medical University (No. 50, 2019), and informed consent was obtained from each patient.
Associations between FGFR3 expression and the clinicopathological parameters of NSCLC patients
Case, N=86 (%)
FGFR3 expression
Low, N=26 (%)
High, N=26 (%)
Age (years) 0.595
≥60 50 (58.8) 36 (60.0) 14 (53.8)
<60 36 (41.2) 24 (40.0) 12 (46.2)
Gender 0.002
Male 57 (66.3) 46 (76.7) 11 (42.3)
Female 29 (33.7) 14 (23.3) 15 (57.7)
Smoking <0.001
Ever-smoker 42 (48.8) 38 (63.3) 4 (15.4)
Never-smoker 44 (51.2) 22 (36.7) 22 (84.6)
Histology type <0.001
AC 39 (44.2) 17 (28.3) 22 (84.6)
SCC 47 (55.8) 43 (71.7) 4 (15.4)
T stage 0.017
≤5 cm 65 (75.6) 41 (68.3) 24 (92.3)
>5 cm 21 (24.4) 19 (31.7) 2 (17.7)
N stage 0.082
0 44 (51.2) 27 (45.0) 17 (65.4)
1, 2, 3 42 (48.8) 33 (55.0) 9 (34.6)
Clinical stage 0.934
I, II 59 (68.6) 41 (66.7) 18 (69.2)
III 27 (31.4) 19 (33.3) 8 (30.8)
EGFR mutation <0.001
Yes 39 (45.3) 17 (28.3) 22 (84.6)
No 47 (54.7) 43 (71.7) 4 (15.4)
NSCLC, non-small cell lung cancer; AC, adenocarcinoma; EGFR, epidermal growth factor receptor; FGFR3, fibroblast growth factor receptor 3; SCC, squamous cell carcinoma.
Tissue specimens
Formalin-fixed paraffin-embedded (FFPE) tissue blocks and the corresponding hematoxylin-and-eosin (H&E)-stained slides were overlaid for tissue microarray (TMA) sampling. The slides were assessed by a senior pathologist, who labelled the representative tumor areas. The TMA block (116 lung cancers tissues) was generated by punching representative tumor areas with cylinders (1 mm in diameter).
IHC analysis of NSCLC samples
The TMA slides were deparaffinized and rehydrated, and then incubated for 20 min with 3% hydrogen peroxide to quench endogenous peroxidase activity. Antigen retrieval was performed by 3-min pressure cooking in ethylenediaminetetraacetic acid buffer (pH 8.0). The slides were blocked with 10% normal goat serum for 30 min at room temperature. The slides were then incubated with rabbit FGFR3 monoclonal antibody (1:100, ab137084; Abcam, Cambridge, UK) for 2 h at room temperature, and then incubated with a secondary antibody for 1 h at room temperature. The staining was visualized with 3, 3'-diaminobenzidine. Normal brain and testicular tissues were used as positive control (see Figure S1), while negative control slides were generated by replacing the FGFR3 monoclonal antibody with normal immunoglobulin.
IHC staining evaluation
All the specimens were examined by 2 independent observers blinded to the clinicopathologic data. If inconsistencies arose, the cases were discussed until a consensus was reached. FGFR3-positive staining cancer cells were assessed at 100× magnification. Membranous and/or cytoplasmic staining was considered reactive. Intensity was scored as 3 for strong staining, 2 for moderate staining, 1 for weak staining, and 0 for negative staining. FGFR3 overexpression was defined by a score of 2 or 3. A higher score was selected for analysis if 2 discordant cores were generated for the same patient.
Evaluation of the FGFR3 mutation
A manual micro-dissection procedure on the tissue block was performed using H&E slides as templates. Based on the histological analysis, the dissected samples had >70% tumor cells. A DNAeasy® tissue kit was used for the deoxyribonucleic acid (DNA) extraction. The direct-sequencing method was used to analyze the FGFR3 mutation by choosing exons 7, 10, and 15 according to previous studies (25) and the primers used for the exon amplification have also been described previously (25). Polymerase chain reaction (PCR) products were fractionated by electrophoresis and visualized with ethidium bromide. The bigDye terminator V1.1 cycle sequencing kit was used to perform the sequencing analysis of the purified PCR products. ChromasPro software 1.34 was used for the mutational analysis.
Follow-up study
The follow-up period was defined as the date of diagnosis until any event (e.g., relapse, death, or last known follow-up). OS was defined as the date of diagnosis to tumour-related death. Disease-free survival (DFS) was defined as the date of diagnosis to tumor local recurrence or metastasis. The average follow-up period for the NSCLC patients was 36.46 months (median: 33.44 months; range, 4–45 months).
All the data were analyzed using SPSS software 16.0 (SPSS Inc., Amond, USA). The categorical variables (i.e., the clinicopathologic features, FGFR3 expression, and FGFR3 mutation) were analyzed by the Chi-square test. Associations between the expression levels of FGFR3 and the OS and DFS of the NSCLC patients were evaluated by a Kaplan-Meier survival analysis with a log-rank test. The association between the risk score and clinical features was detected by univariate and multivariate Cox analyses. The Cox regression model was used to calculate the hazard ratios and 95% confidence intervals. A P value <0.05 was considered statistically significant.
A total of 116 cases of NSCLC were included in the preliminary analysis. Among the 116 cases, the complete clinical records of NSCLC patients were available for 86 cases, and those cases were included in the further analysis. The clinical pathological parameters of the 86 NSCLC patients are summarized in Table 1. There were 57 male patients and 29 female patients in this cohort. The patients had a median age of 58 years (range, 41–80 years) at the time of diagnosis. The clinical follow-up period was up to 64 months. Among the patients, 46 were ever-smoking patients. The cases for AC and SCC were 39 and 47, respectively. The cases for early stage (I–II) and late stage (III) tumors were 59 and 27, respectively. In addition, the cases for the EGFR mutation and wild-type EGFR were 39 and 47, respectively.
The expression of FGFR3 in NSCLC tissues
The FGFR3 expression levels of the 86 NSCLC tissues were evaluated by TMA. FGFR3 expression (both cytoplasmic and membranous) was detected by IHC. The non-expression, low expression, and high expression of FGFR3 in the NSCLC tissues are shown in Figure 1. Based on the IHC results, FGFR3 was immunoreactive in 26 of the 86 NSCLC cases. Further, FGFR3 was positively expressed in 84.6% of the lung AC cases and 15.4% of the lung SCC cases. FGFR3 was positively expressed in 42.3% of the male patients and 57.7% of the female patients. Additionally, FGFR3 was positively expressed in 15.4% of the smoking cases and 84.6% of the non-smoking cases. Further, 69.2% of the early stage tumors (I and II) cases and 30.8% of the late stage tumors (III) cases were positive for FGFR3. Among the FGFR3 positive cases, 80.8% of the cases had the EGFR mutation and 19.2% cases had wild-type EGFR.
Figure 1 IHC staining of FGFR3 expression in lung tissues. (A) Negative staining of FGFR3 in normal lung tissues (40× magnification). (B) Low expression of FGFR3 in NSCLC tissues (40× magnification). (C) High expression of FGFR3 in NSCLC tissues (40× magnification). (D) Negative staining of FGFR3 in normal lung tissues (100× magnification). (E) Low expression of FGFR3 in NSCLC tissues (100× magnification). (F) High expression of FGFR3 in NSCLC tissues (100× magnification). IHC, immunohistochemistry; FGFR3, fibroblast growth factor receptor 3; NSCLC, non-small cell lung cancer.
All the samples were further divided into either high or low FGFR3 expression groups. Patients with a smoking history, histology type, T stage, and the EGFR mutation had higher FGFR3 expression rates. However, high FGFR3 expression was not associated with other clinical parameters, such as age, N stage, and clinical stage (see Table 1).
Analysis of FGFR3 mutations in NSCLC samples
DNA was extracted from the paraffin-embedded tissues of 86 NSCLC tissues, and direct sequencing was conducted on exons 7, the extracellular domain, 10 and 15 of FGFR. A total of 72 cases were included in the FGFR3 sequencing analysis. FGFR3 mutations were found in 2/72 (2.8%) NSCLC cases as follows: 1/28 (3.6%) in AC, and 1/44 (2.3%) in SCC. Two cases of the FGFR3 mutation were found in exons 10, but no mutations were found in exons 7 or15 of FGFR3. Among the 70 NSCLC cases with wild-type FGFR3, 20 (28.6%) cases were FGFR3 positive. Due to the small number of FGFR3 mutation cases, the associations between the FGFR fusions and key clinicopathologic characteristics were not assessed.
T450M is a novel mutation in FGFR3 TM domain
The mutational analysis of FGFR3 exon 10 showed the only point mutation at T450M. Figure 2 shows heterozygous substitutions C > T at position 1349 in exon 10 of FGFR3, leading to amino acid substitution T450M. The Database Single Nucleotide Polymorphism (dbSNP) indicated that it was not a polymorphism (see Table S1). The mutation was detected in 2 patients. Of whom, 1 was a 54-year-old female, who had undergone a radical lobectomy, and had stage cT2a N1M0 LA. The patient was alive, and the FGFR3 protein expression was positive. The EGFR had 19 deletion mutations. The other patient was a 78-year-old male, who had been diagnosed with SCC. He had undergone radical lobectomy and had stage T2a N1M0. The molecular analysis revealed the negative staining of FGFR3 and wild-type EGFR. T450M in FGFR3 exon 10 was the only mutation detected in the 2 patients. No other mutations in exons 7 and 15 of FGFR3 were detected.
Figure 2 Sanger sequencing of FGFR3 gene. (A) The wild-type FGFR3 profile, and (B) a T450M-mutated tumor, characterized by a C > T base substitution in codon 450. FGFR3, fibroblast growth factor receptor 3.
The association between FGFR3 expression and the survival of NSCLC patients
The correlation between FGFR3 expression and the OS and DFS of the NSCLC patients was assessed by a Kaplan-Meier survival analysis. High FGFR3 expression was correlated with better OS (log-rank =5.772, P=0.016; see Figure 3A) and DFS (log-rank =4.239, P=0.040; see Figure 3B).
Figure 3 Kaplan-Meier survival analysis of FGFR3 expression in NSCLC patients. Association between FGFR3 expression and the (A) OS and (B) DFS of the NSCLC patients. FGFR3, fibroblast growth factor receptor 3; NSCLC, non-small lung cell cancer; OS, overall survival; DFS, disease-free survival.
Univariate and multivariate analyses of the clinical factors and FGFR3 expression associated with the survival of NSCLC patients
Initially, age, smoking, histology type, T stage, N stage, clinical stage, the EGFR mutation, and the expression of FGFR3 were selected for the univariate analysis. The variables were reduced through forward-stepwise regression. The multivariate analysis revealed that FGFR3 was an independent prognostic factor (P=0.024) for the OS of NSCLC patients (see Table 2).
Univariate and multivariate analyses of the clinicopathological factors and FGFR3 expression associated with the survival of NSCLC patients
Univariate analysis (N=86)
Age ≥60 vs. <60 0.945 (0.447–1.999) 0.883
Smoking Yes vs. no 1.554 (0.734–3.291) 0.249
Gender Male vs. female 2.501 (0.950–6.582) 0.063
Histology type AC vs. SCC 0.523 (0.236–1.157) 0.110
T stage ≤5 vs. >5 cm 0.827 (0.351–1.950) 0.664
N stage 0 vs. 1, 2, 3 1.756 (0.830–3.718) 0.141
Clinical stage I, II vs. III 1.303 (0.601–2.826) 0.503
EGFR mutation Yes vs. no 0.523 (0.236–1.157) 0.110
FGFR3 Low vs. high 0.294 (0.102–0.850) 0.024
Multivariate analysis (N=86)
FGFR3, fibroblast growth factor receptor 3; NSCLC, non-small cell lung cancer; HR, hazard ratio; CI, confidence interval; AC, adenocarcinoma; SCC, squamous cell carcinoma; EGFR, epidermal growth factor receptor.
Clinical trial (NCT01824901) examining FGFR inhibitors in NSCLC is ongoing. New targets for which therapies already exist need to be identified. FGFR3 is a member of the FGFR family, whose alterations may become an effective target for the gene therapy of NSCLC. In this study, the frequencies of protein expression and the FGFR3 mutation in the NSCLC patients were 26/86 (30.2%) and 2/72 (2.8%), respectively. We showed for the first time that FGFR3 is associated with a favorable prognosis and is a novel independent prognostic factor for the OS of NSCLC patients. The high FGFR3 expression group had more females, more non-smokers, more ACs, earlier T stage, fewer lymph node metastases, earlier clinical stage, a higher EGFR mutation rate, and longer OS and DFS. Reasons for the favorable prognosis of NSCLC patients include the small sample size for death events during the follow-up period and the different treatment modalities, which included tyrosine kinase inhibitor (TKI)–treatment and adjuvant chemotherapy. Notably, we discovered that T450M is a novel mutation in the FGFR3 TM domain. T450M in FGFR3 exon 10 was the only mutation detected in 2 patients. No other mutations in exons 7 and 15 of FGFR3 were detected. Further, 2 cases were lung AC with overexpressed FGFR3 and lung SCC with FGFR3 negative staining respectively.
A study reported that the expression rate of FGFR3 was 1.8% (5/275) in lung SCC (26). Conversely, we found that high FGFR3 expression was predominant in lung AC patients, but the positive rate of FGFR3 in lung SCC was low. A previous study has reported that the FGFR3 expression rate is 3.3% (20/612) in NSCLC (27). However, the FGFR3 expression rate was 22.3% (23/103) using the polyclonal antibody from the Abcam company, and 11.7% (12/103) using antibodies from Cell Signaling Technology in 103 lung SCC cases, and the positive expression rate of FGFR3 in NSCLC was not detected. We found a FGRF3-positive expression rate of 15.4% (4/26) using an Abcam monoclonal antibody in lung SCC. There is no unified standard scoring system for FGFR3 expression in NSCLC. However, as FGFR3 in urothelial carcinoma has been widely studied (28) (Table S1), we adopted the scoring system of Cappellen et al. (24). We also reviewed the scoring system for FGFR3 expression from a NSCLC study (29) (Table S2), but the frequency of FGFR3 expression was different in NSCLC. Any discrepancies between previous studies and our findings may be explained by the composition of patients, the heterogeneity of the FGFR3 gene, the cancer stage, antibodies, and the different scoring systems.
Previous studies showed that am EGFR TKI induced FGFR3 signaling by de-repressing FGFR3 expression, and FGFGR3 signaling is a key signaling pathway in the regulation of EGFR TKI resistance (30-32). Thus, de novo FGFR3 high expression may be significantly related to the EGFR mutation state of activation in treatment-naive NSCLC patients. Further, combining EGFR with FGFR specific TKIs may improve the therapeutic effects of EGFR inhibitors.
FGFR3 has been observed to be overexpressed in human hepatocellular carcinoma, oral cancer, and bladder cancer (33). Thus, the overexpression of FGFR3 may play an important role in human carcinogenesis (34). However, little is known about the role of FGFR3 in NSCLC. This study was the first to apply a TMA-based IHC method to examine FGFR3 expression in a cohort of 116 patients. Our results suggest that FGFR3 plays an essential role in NSCLC progression. A recent study showed that miR-100 and FGFR3 protein levels are inversely expressed in the A549 lung cancer cell line (35). However, the mechanisms underlying the upregulation of FGFR3 in A549 cells remain unknown.
High FGFR3 expression is correlated with clinicopathologic factors in lung cancer. Our study showed that FGFR3 was differentially expressed in the lung tissues between the AC and SCC subtypes, which suggests that the tumor behavior may be driven by the morphologic characteristics of tumors (36). The expression of FGFR3 was higher in lung AC than SCC, and higher FGFR3 expression predicted better OS. Additionally, the high FGFR3 expression group had a higher EGFR mutation rate, which suggests that patients in the high FGFR3 expression group received EGFR TKI treatments more than those in the low FGFR3 expression group. Thus, FGFR3 appears to be closely related to AC with the EGFR mutation.
The results of the survival analysis revealed the patients with high FGFR3 expression levels had better OS, which suggests that lower or reduced FGFR3 expression levels may enhance NSCLC progression, while FGFR3 overexpression may attenuate NSCLC progression. FGFR3 overexpression has also been shown to induce the transformation of colon cancer cells (37). FGFR3 upregulation was detected at the messenger ribonucleic acid and protein levels in urinary bladder carcinomas (38). In relation to the role of FGFR3 in the progression of human cancers, some results are contradictory. For example, FGFR3 mutation and expression have been shown to be related to favorable low-grade bladder cancer (39). Conversely, FGFR3 overexpression has also been shown to be a prognostic factor for adverse outcomes for muscle-invasive bladder carcinoma treated with adjuvant chemotherapy (40). FGFR3 expression has also been shown to be associated with a poor prognosis of breast cancer patients (41). Interestingly, in our study, FGFR3 was associated with a favorable prognosis in patients with NSCLC and served as an independent prognostic factor for the OS of NSCLC patients. There are several explanations regarding the contradictory findings among different studies. In the present study, we only included the patients with surgically resectable NSCLC at the I–IIIA stage, and the favorable prognostic role of FGFR3 may only occurred in patients with early-stage NSCLC. This study is a retrospective study, the study is based on the 7th edition of TNM staging classification. However, the current NSCLC staging has been updated to the 8th edition, this staging classification may affect patient management, because many clinicians make management based on stage Therefore, the staging system of this study may affect the judgment of prognostic results and have a certain impact on the treatment plan. Kaplan-Meier survival analysis showed that patients with high FGFR3 expression had significantly improved OS and significantly prolonged DFS compared with patients with low FGFR3 expression. It may be because the expression of FGFR3 in lung adenocarcinoma is higher than that in lung squamous cell carcinoma, and the EGFR mutation rate in the group with high FGFR3 expression is higher, and there is a chance to receive EGFR-TKI treatment in the future. Therefore, it is speculated that patients with high FGFR3 expression have longer OS and DFS, and are closely associated with higher EGFR mutations. However, the mechanistic actions still need to be further investigated.
Our study also found no correlation between protein expression and the FGFR3 mutation. FGFR3 mutations have been described previously in urothelial carcinoma (42,43). However, similar to a previous report (44), the frequency of the FGFR3 mutation in the NSCLC patients in our cohort was low. Studies have reported that FGFR3 aberrations in NSCLC occurred in the FGFR3 fusion gene type (27) (Table S3). Pros et al. did not discover any FGFR3 mutation in 50 cases of NSCLC (45). Shinmura et al. reported that the FGFR3 mutation rate was 0.9% (2/214) in NSCLC (38), which was lower than the rate reported in the present study (Table S4). However, similar to the results of our study, the frequency rate in lung SCC was reported to be 3.2% (2/63). We found that FGFR3 mutations were not associated with the prognosis of NSCLC patients, but this may be due to the limited sample size.
This study had several limitations. First, as a single-center retrospective study, selection bias was unavoidable. Second, IHC and Sanger sequencing were combined to detect FGFR3 status, and the frequency of FGFR3 alterations in China differ to those of other countries. Third, currently, there are no consistent standards, including antibody and scoring system standards. Fourth, this was only a preliminary study, and more thorough studies using human cells or samples need to be conducted to provide further insights into the function of FGFR3 in NSCLC and the progression of NSCLC.
FGFR3 alterations, including expression and mutation alterations, in NSCLC could be promising therapeutic targets. We found that the frequency of FGFR3 expression in NSCLC, especially AC, is high, but the FGFR3 mutation rate is low and is not correlated with the histology type. FGFR3 may serve as an independent prognostic factor for the OS of NSCLC patients.
Funding: This work was supported by grants from the Guangzhou Health Science and Technology Project (Nos. 20202A010014, 20211A011091, and 20212A011024), the Traditional Chinese Medicine Bureau Research Project of Guangdong Province in China (No. 20202111), and the Science and Technology Program of Guangzhou Health Commission (Nos. 20211A011088, 20222A010047).
Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1523/rc
Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1523/dss
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1523/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of Guangzhou Medical University (No. 50, 2019), and informed consent was obtained from each patient.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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Tan AC, Pavlakis N. Anti-Angiogenic Therapy in ALK Rearranged Non-Small Cell Lung Cancer (NSCLC). Int J Mol Sci 2022;23:8863. [Crossref] [PubMed]
Gaughan EM, Costa DB. Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities. Ther Adv Med Oncol 2011;3:113-25. [Crossref] [PubMed]
Ramalingam SS, Owonikoko TK, Khuri FR. lung cancer: new biological insights and recent therapeutic advances. CA Cancer J Clin 2011;61:91-112. [Crossref] [PubMed]
Chew NJ, Nguyen EV, Su SP, et al. FGFR3 signaling and function in triple negative breast cancer. Cell Commun Signal 2020;18:13. [Crossref] [PubMed]
Sakashita T, Yanagitani N, Koike S, et al. Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK-rearranged non-small cell lung cancer. Cancer Sci 2022;113:3888-900. [Crossref] [PubMed]
Liu C, Liu C, Liao J, et al. Genetic correlation of crizotinib efficacy and resistance in ALK- rearranged non-small-cell lung cancer. Lung Cancer 2022;171:18-25. [Crossref] [PubMed]
Hart KC, Robertson SC, Donoghue DJ. Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation. Mol biol cell 2001;12:931-42. [Crossref] [PubMed]
L'Hôte CG, Knowles MA. Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Exp cell res 2005;304:417-31. [Crossref] [PubMed]
Chellaiah AT, McEwen DG, Werner S, et al. fibroblast growth factor receptor (fgfr) 3. alternative splicing in immunoglobulin-like domain iii creates a receptor highly specific for acidic fgf/fgf-1. J Biol Chem 1994;269:11620-7.
Murgue B, Tsunekawa S, Rosenberg I, et al. identification of a novel variant form of fibroblast growth factor receptor 3 (fgfr3 iiib) in human colonic epithelium. Cancer Res 1994;54:5206-11.
Sturla LM, Merrick AE, Burchill SA. fgfr3iiis: a novel soluble fgfr3 spliced variant that modulates growth is frequently expressed in tumour cells. Br J Cancer 2003;89:1276-84. [Crossref] [PubMed]
Acquaviva J, He S, Zhang C, et al. FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism. Mol Cancer Res 2014;12:1042-54. [Crossref] [PubMed]
Cappellen D, De Oliveira C, Ricol D, et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 1999;23:18-20. [Crossref] [PubMed]
Bodoor K, Ghabkari A, Jaradat Z, et al. FGFR3 mutational status and protein expression in patients with bladder cancer in a Jordanian population. Cancer epidemiol 2010;34:724-32. [Crossref] [PubMed]
Kompier LC, Lurkin I, van der Aa MN, et al. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS One 2010;5:e13821. [Crossref] [PubMed]
Majewski IJ, Mittempergher L, Davidson NM, et al. Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing. J Pathol 2013;230:270-6. [Crossref] [PubMed]
Nakanishi Y, Akiyama N, Tsukaguchi T, et al. Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3-BAIAP2L1. Mol Cancer Ther 2015;14:704-12. [Crossref] [PubMed]
Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25. [Crossref] [PubMed]
Parker BC, Engels M, Annala M, et al. Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours. J Pathol 2014;232:4-15. [Crossref] [PubMed]
Chen L, Zhang Y, Yin L, et al. Fibroblast growth factor receptor fusions in cancer: opportunities and challenges. J Exp Clin Cancer Res 2021;40:345. [Crossref] [PubMed]
Carotenuto M, Sacco A, Forgione L, et al. Genomic alterations in cholangiocarcinoma: clinical significance and relevance to therapy. Explor Target Antitumor Ther 2022;3:200-23. [Crossref] [PubMed]
Singh D, Chan JM, Zoppoli P, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 2012;337:1231-5. [Crossref] [PubMed]
Testa U, Castelli G, Pelosi E. Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells. Cancers (Basel) 2018;10:248. [Crossref] [PubMed]
Williams SV, Hurst CD, Knowles MA. Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet 2013;22:795-803. [Crossref] [PubMed]
Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 2013;3:636-47. [Crossref] [PubMed]
Liao RG, Jung J, Tchaicha J, et al. Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma. Cancer Res 2013;73:5195-205. [Crossref] [PubMed]
Shinmura K, Kato H, Matsuura S, et al. A novel somatic FGFR3 mutation in primary lung cancer. Oncol Rep 2014;31:1219-24. [Crossref] [PubMed]
Kim Y, Hammerman PS, Kim J, et al. Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients. J clin oncol 2014;32:121-8. [Crossref] [PubMed]
Wang R, Wang L, Li Y, et al. FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non-small cell lung cancer. Clin cancer res 2014;20:4107-14. [Crossref] [PubMed]
Tsim S, O'Dowd CA, Milroy R, et al. staging of non-small cell lung cancer (nsclc): a review. Respir Med 2010;104:1767-74. [Crossref] [PubMed]
Neuzillet Y, van Rhijn BW, Prigoda NL, et al. FGFR3 mutations, but not FGFR3 expression and FGFR3 copy-number variations, are associated with favourable non-muscle invasive bladder cancer. Virchows arch 2014;465:207-13. [Crossref] [PubMed]
Bernardo P, Budetta M, Aliberti F, et al. Temporal lobe malformations, focal epilepsy, and FGFR3 mutations: a non-causal association? Neurol Sci 2021;42:2063-7. [Crossref] [PubMed]
Turo R, Harnden P, Thygesen H, et al. FGFR3 expression in primary invasive bladder cancers and matched lymph node metastases. J Urol 2015;193:325-30. [Crossref] [PubMed]
Pros E, Lantuejoul S, Sanchez-Verde L, et al. Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer. Int J Cancer 2013;133:898-907. [Crossref] [PubMed]
Cite this article as: Lin YE, Long HD, Chen CC, Liu GC, Li F, Tian YH, Dai L. High expression of FGFR3 predicts a better prognosis for patients with non-small cell lung cancer in a Chinese population. J Thorac Dis 2023;15(1):101-111. doi: 10.21037/jtd-22-1523
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Do the Disabled Really Buy Sporting Goods?
While working on a website we are redesigning, I was seeing some minor usability/accessibility issues that I was concerned about. I brought up those issues, mentioning that the site would be significantly less functional in some cases to those with disabilities, such as the vision-impaired and physically handicapped persons for whom using a mouse is difficult. That was when someone asked, "Do blind people actually buy sporting goods?".


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package org.evm.biz.sys;

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	 * 服务域
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	public static String systemId;
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	public static String dbIp;
	public static String dbPort;
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	public void setServerName(String serverName) {
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	}

	public void setLoginPage(String loginPage) {
		SystemConfig.loginPage = loginPage;
	}

	public void setMainPage(String mainPage) {
		SystemConfig.mainPage = mainPage;
	}

	public void setSystemId(String systemId) {
		SystemConfig.systemId = systemId;
	}

	public void setDbName(String dbName) {
		SystemConfig.dbName = dbName;
	}

	public void setDbIp(String dbIp) {
		SystemConfig.dbIp = dbIp;
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	public void setDbPort(String dbPort) {
		SystemConfig.dbPort = dbPort;
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	public void setDbPassword(String dbPassword) {
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}

redpajama_set_name: RedPajamaGithub


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Home / Elder Law / State of Missouri Shuts Down Nursing Home
State of Missouri Shuts Down Nursing Home
Making the decision to move a loved one into a nursing home is rarely a decision that is made lightly nor easily. Once the need for long-term care has been agreed upon, the search begins for the right facility. From the time you move your loved one into a nursing home you worry that they are being properly cared for and that the facility is free of abuse and neglect. Imagine how you would feel, therefore, if the nursing home your loved one was in was shut down by the State of Missouri? That's exactly what happened at Benchmark Healthcare nursing home in Festus, Missouri, causing the 60 residents to be relocated to other facilities.
The State Steps in — Closes Nursing Home
A recent news story tells a sad story that doesn't end well. According to news reports, by the time the State of Missouri took the drastic step of shutting down the nursing home, the facility's financial problems were so severe that workers at the facility were using their own money to feed the residents. Not surprisingly, trash was also piling up, the lights were shut off, and the building was infested with flies at the time the nursing home was forcefully closed by the state.
Residents of the facility started complaining months ago that they were not getting fed as a result of suspension of food deliveries for non-payment. State investigators conducted an inspection in July, during which a Benchmark employee was seen trying to make a smoothie from seven pieces of dry toast. Although Missouri State health officials petitioned the court to put the nursing home into emergency receivership after that inspection, they backed down when the food deliveries started back up again.
Officials conducted a follow-up visit the next month. During that visit they found four residents were not getting medicines they needed for congestive heart failure, epilepsy and schizophrenia because the pharmacy bills hadn't been paid in months. Finally, on September 13th officials took the unusual step of closing down the facility and relocating the 60 residents still living there at the time.
"It was just a disaster," said Ann Bickel of the Missouri Coalition for Quality Care, which advocates for residents in nursing homes. "Some nursing homes aren't as clean, some don't have as much staff as we'd like them to have, and there is abuse sometimes. But to this extent, I have never heard of this."
The reason for the living conditions at the nursing home? Financial problems faced by the owner, Legacy Health Systems, a Chesterfield-based family business. Legacy Health Systems was started back in 1938 by Clara Sells and has been family run since then. John Sells, Clara's grandson and the current President, decided to expand the business back in 1999 by taking over other nursing home chains. To do so, he borrowed millions of dollars. According to Sells, the company's financial problems stem from discovering in 2014 that its payroll contractor had, for several years, stolen from them by failing to turn payroll taxes over to the IRS. Although the contractor was ordered to make more than $3 million in restitution to dozens of victims, hat may not be the true source of the company's financial problems. Court records indicate that the company was having trouble paying its bills long before the embezzlement occurred. Among the lawsuits filed against the company for unpaid bills prior to 2014 were an insurance company, a pharmacy alleging that Sells' nursing homes owed nearly $2 million, a lawsuit alleging the nursing homes were $900,000 in arrears for therapy goods and services, and a lawsuit claiming the company owed another $900,000 for food services. By 2015, Great Southern Bank took the company to court alleging a debt of over $6 million remained unpaid. The bank eventually sized four of the company's nursing homes.
By the time the State of Missouri closed down the nursing home, staff had not been paid in weeks and were routinely paying for clothes and food for the residents out of their own pockets. Sadly, many of the residents at the facility were also suffering from mental health conditions.
What to Do If You Suspect Neglect at a Nursing Home
At this point you may be wondering how things could possibly have gotten that bad before something was done. The answer remains unclear; however, if you ever suspect neglect at a nursing home where a loved one resides, contact an experienced Missouri elder law attorney right away.
If you have additional questions or concerns regarding nursing home abuse and neglect, contact the experienced Missouri elder law attorneys at Amen, Gantner & Capriano, Your Estate Matters, LLC by calling (314) 966-8077 to schedule an appointment.
Filed Under: Elder Law
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Hemingway Tour
After pick up at your hotel, the excursion starts with a drive to "La Finca Vigía", the former residence of the prominent American writer. "I live in Cuba, because I love Cuba", Hemingway said when he expressed his affection for Cuba. Hemingway made Havana his part-time home for 20 years. His house, "Finca Vigia", was where he wrote (among others) his novel "The Old Man and the Sea", for which he received the Pulitzer Prize in 1953.This work is considered one of the 20th century's most outstanding fiction pieces and possibly his most famous work. When he won the Nobel Prize for his life's work, Hemingway dedicated the award to Cuba. The statue can be seen at the Santuario del Cobre in Santiago de Cuba.
Next stop is Cojimar (14km from Havana), where Hemingway used to dock his yatch El Pilar. A walking tour takes you to Hemingway's statue, made by sculptor Fernando Boada with from old anchors, props, and tools salvaged by local fishermen. Here, you'll visit the restaurant Las Terrazas, the preferred Cojimar hangout of the author and the Captain of his boat (Pilar); Gregorio Fuentes (cocktail included).
From here, we return to the capital to follow Hemingway's trail in Old Havana, having a peek at room 511 in Hotel Ambos Mundos – where Hemingway used to stay in the 1930s. Breathe the atmosphere of those days in the restaurant-bars "la Bodeguita del Medio" and "Floridita", the former is famous for its superb mojitos, the latter for its Daiquiris. In "Floridita" you will find a life-size bronze statue of Hemingway sculpted by Cuban artist José Villa Soberón.
Cubans don't just hold Hemingway's literary work in high esteem, we also praise his regular contact with the people. Hemingway's legacy continues to strengthen the cultural links between the two countries.
Finca Vigía
Cojímar
Restaurante Las Terrazas en Cojímar
Hotel Ambos Mundos, habitación 511
La Bodeguita del Medio
Restaurante El Floridita
After pick up at your hotel, the excursion starts with a drive to "La Finca Vigía", the former resid
Sighseeing


text:
Q: Android. Разрешение установки приложений через USB При попытке включения установки через USB (нажатие на кнопку "Установка через USB Разрешить установку приложений через USB") телефон требует вставить SIM-карту.

В случае если при этом выключить вайфай и повторить нажатие (либо же включить режим полёта) то требуется подключится к сети.

Примечание: до недавнего момента всё работало нормально, приложения через USB устанавливались и без SIM-карты. Случайно выключил режим разработчика, настройки сбросились.
Телефон: Xiaomi Mi Max 32 GB
Версия Android: 7.0 NRD90M
Версия MIUI: MIUI Global 8.5 Стабильная 8.5.1.0(NBCMIED)
Вопрос: Как обратно включить установку через USB?

redpajama_set_name: RedPajamaStackExchange


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Skip to main content Sports Washington Football Team Nationals Capitals Wizards Colleges Mystics D.C. United & Soccer Video Gaming
For Notre Dame, the fourth time is a charm
Notre Dame celebrates its win over Connecticut at Conseco Fieldhouse. (Elsa/Getty Images)
By Gene Wang
Sports reporter covering local and national college football and basketball
Email Bio Follow
INDIANAPOLIS — The Notre Dame women's basketball team drew exactly the adversary it wanted in the Final Four. Call the Fighting Irish stubborn or just plain silly, but that opponent was none other than powerhouse Connecticut, which had upended Notre Dame three straight times this season and 12 in row overall.
Unfazed by that stretch of domination, Notre Dame erased a six-point halftime deficit to log a cathartic 72-63 victory over the two-time defending NCAA champions on Sunday night before 16,421 at Conseco Fieldhouse. The victory sends the Fighting Irish to its second national championship game in its third appearance in the Final Four. Notre Dame, which beat a second straight No. 1 seed, will play Texas A&M on Tuesday.
Sophomore point guard Skylar Diggins led Notre Dame with a team-high 28 points on 10-for-14 shooting, and junior guard Natalie Novosel shot 8 for 13 en route to 22 points. In the final game of her college career, Connecticut's Maya Moore, perhaps the most accomplished player in the history of the sport, finished with 36 points to lead the Huskies, who lost for just the second time this season.
"In the front of our minds was the three losses," said Diggins, who added 6 assists, 4 rebounds and 2 steals. "I just wanted to make sure I stayed poised. I kind of wanted to be the voice of calm even though sometimes I was pretending."
Behind by a point in the early stages of the second half, Notre Dame (31-7) took the lead, 38-37, with 14 minutes 49 seconds to play on Becca Bruszewski's layup after Devereaux Peters converted a three-point play on the previous possession. The Huskies tied it on a free throw from freshman guard Bria Hartley, but another three-point play, this one from Diggins, made it 41-38, and Notre Dame didn't trail the rest of the way.
Senior guard Lorin Dixon sank a jumper to draw Connecticut to 41-40, but Notre Dame scored the next six points, including four foul shots by Novosel, for a 47-40 lead with 9:42 left. Moore uncharacteristically missed two free throws on the Huskies' next possession before teammate Kelly Faris, a sophomore guard, made a jumper to whittle the margin to five.
Diggins then swished a pair of foul shots, but Connecticut (36-2) got a three-pointer from Hartley to make it 49-45. Senior guard Brittany Mallory did the same for Notre Dame, and following Moore's jumper, Novosel hit nothing but net on a three-point attempt, and the Fighting Irish were up, 55-47.
Moments later, the arena erupted when Novosel's jumper gave Notre Dame a 10-point lead with 6:54 to play. The Fighting Irish went ahead 59-47 on freshman forward Natalie Achonwa's jumper and then 61-49 when she made another field goal.
But Connecticut predictably wasn't done. Playing her customary best basketball when the stakes were highest, Moore scored the next seven points, including a three-pointer and then rebounding her three-point miss soon after to score on a short jumper with just over three minutes to play.
Huskies Coach Geno Auriemma immediately called timeout, but out of the stoppage, Novosel collected a rebound and put it back with 2:47 to play. That gave the Fighting Irish a 63-57 advantage.
Not to be outdone, Moore responded with another three-pointer to move Connecticut to 63-60 with 2:28 to go. But again Notre Dame didn't wilt, getting Novosel's jumper before Diggins stole the ball and went in for a layup that all but sealed it with 1:35 remaining.
"It's an incredible victory for our team and our program to beat a quality team with a great player like Maya Moore," Notre Dame Coach Muffet McGraw said. "I thought Skylar was just amazing. She was simply amazing today in both halves. We made big shot after big shot. We answered their runs. We were resilient."
Moore had an opportunity to make it a bit more interesting in the closing seconds, but after being fouled on a three-point attempt, the Big East Player of the Year missed 2 of 3 from the line, and Connecticut was still behind, 67-61. Time then ran out on the Huskies' chances of playing for an NCAA record tying eighth national championship in the program's 12th appearance in the Final Four.
Moore's point total was the third most in a national semifinal game and fourth most in any Final Four game. She scored in double figures in 149 of 153 career games, scored at least 30 points for the 12th time, including her seventh this season, and moved into third all-time in points in the NCAA tournament.
"There are always positives and negatives out of everything," said Moore, whose final line included eight rebounds and four steals but missing 4 of 7 foul shots. "So like Coach said, I'm going to have to choose to remember the great things and really how fortunate I was to be able to be a part of so many record-breaking seasons, games, whatever it may be. It's just tough that is the current taste in my mouth right now, but we'll deal with it."
notre dame u.-conn.
Gene Wang Gene Wang is a sports reporter covering multiple beats, including Virginia and Virginia Tech football and basketball, national college football and basketball, the Wizards, boxing and golf. He has been with The Washington Post sports department since 1990, and has also written about other Washington teams and fantasy football. Follow


What was the symbol for colonial South Carolina?
How many US Senators does South Carolina Have? Reasons for settlement in South Carolina? What is the state song of South Carolina? What is the market cap for Bank of South Carolina Corp - BKSC -? What is the average monthly temperature in the state of South Carolina?


text:
Bible Encyclopedias
Cyclopedia of Biblical, Theological and Ecclesiastical Literature
Resource Toolbox
Nave Topical Bible
Fatted Calf
Thompson Chain Reference
Treasury of Biblical Knowledge
Blood, & Fat Fat
American Tract Society
Fausset Bible Dictionary
Holman Bible Dictionary
Fatlings, Fatted
Hastings' Dictionary of the Bible
King James Dictionary
Fatness
Morrish Bible Dictionary
Wine-Press, Wine-Fat
Hawker's Poor Man's Dictionary
Smith Bible Dictionary
Vines' Expository Dictionary
Fatling, Fatted
Wilson's Bible Types
Webster Dictionary
Otoba Fat
Fatted
(only first 3 shown)
Watson's Theological Dictionary
1911 Encyclopedia Britannica
International Standard Bible Encyclopedia
Fat (Vat)
Kitto Biblical Cyclopedia
McClintock and Strong's Bible Encyclopedia
Collops of Fat
Fatted Fowl
The Jewish Encyclopedia
ܫܽܘܡܢܳܐ
ܫܡܰܢ
πιότης
σιτευτός
אָבַס
אַלְיָה
בָּרָא בָּרָא, , בָּרָא
for receiving wine; an old orthography for VAT (See VAT) (q.v.).
(prop. חֵלֶב , che'leb). [For the use of the word as a verb, (See FATTED FOWL). ] The Hebrews distinguished between the suet, or pure fat of an animal (חֵלֶב ), and the fat which was intermixed with the lean (מִשְׁמִנֵּים, oily pieces, Nehemiah 8:10). Certain restrictions were imposed upon them in' reference to the former: some parts of the suet, viz. about the stomach, the entrails, the kidneys, and the tail of a sheep, which grows to an excessive size in many Eastern countries, and is a special delicacy, were forbidden to be eaten in the case of animals offered to Jehovah in sacrifice (Leviticus 3:3; Leviticus 3:9; Leviticus 3:17; Leviticus 7:3; Leviticus 7:23). The ground of the prohibition was that the fat was the richest part of the animal, and therefore belonged to him (Leviticus 3:16). It has been supposed that other reasons were superadded, as that the use of fat was unwholesome in the hot climate of Palestine (Maimonides, More Nebochimn, part 3, chapter 48). There appears, however, to be no ground for such an' assumption (Bahr, Symbol. 2:382). The presentation of thefat as the richest part of the animal was agreeable to the dictates of natural feeling, and to the analogy in dedicating the first-born and first-fruits to God. This was also the ordinary practice even of heathen nations, as instanced in the Homeric descriptions'of sacrifices (II. 1:460; 2:423; Od. 3:457), and in the customs of the Egyptians (Herod. 2:47), and Persians (Strabo, 15:732); Accordingly, Abel, who brought the first anfimal sacrifice, not only presented to the Lord "the firstlings of his flock," but "the fat thereof," which, by virtue of its being the best part, was as much the firstling of the animal itself as the animal was the firstling of the flock (Genesis 4:4); or if the word here means the fattest of his flock, the same idea is essentially implied. Indeed, the term cheleb is itself significant of the feeling on which the regulation was based, for it sometimes describes the best of any production (Genesis 45:18; Numbers 18:12; Psalms 81:16; Psalms 147:14; compare 2 Samuel 1:22; Judges 3:29; Isaiah 10:16). With regard to the other parts of the fat of sacrifices or the fat of other animals, it might be consumed, with the exception of those dying either by a violent or a natural death (Leviticus 7:24), which might still be used in any other way. The burning of the fat of sacrifices was particularly specified in each kind of offering, whether a peace offering (Leviticus 3:9), consecration offering (Leviticus 8:25), sin offering (Leviticus 4:8), trespass offering (Leviticus 7:3), or redemption offering (Numbers 18:17). The Hebrews fully appreciated the luxury of well-fatted meat, and had their stall-fed oxen and calves (1 Kings 4:23; Jeremiah 46:21; Luke 15:23). This was, however, not a usual practice; and even at this day in the East, domestic cattle seldom undergo any preparatory feeding or fattening before being killed. Hence there is little fat in the carcase except that belonging to the parts specified in the prohibition, which is all more or less of the nature of suet. (See FOOD).
The parts of the fat or suet of the victims which belong to God, and are especially to be appropriated to the altar, are given in Exodus 29:13-22, and Leviticus 3:3-5, as follows:
1. The fat which covers the entrails (הִחֵלֶב חִמְכִסֶּה אֶתאּהִקֶּרֶב ) = ἐπίπλους, as Josephus rightly has it (Ant. 3:9, 2); the omentum, which is only to be found in man and mammals, and is very fat in ruminants (comp. Aristot. Hist. Anim. 1:16; Pliny, Hist. Nat. 11:80).
2. The fat which accumulates around entrails (הִחֵלֶב אֲשֶׁר עִלאּהִקֶּרֶב ), and is easily separated therefrom, i.e., the reticular adherings to the colon.
3. The two kidneys, with the fat on them, at the internal muscles of the loins (הִכְּלָיֹת וְאֶת הִחֵלֶב עֲלֵחֶן אֲשֶׁר עִל הִכְּסָלִים שְׁתֵּי ), as the most fat accumulates near the kidneys (Deuteronomy 32:14; Isaiah 34:6), and to such an extent in sheep that they sometimes die of it (οἱ νεφοὶ μάλιστα τῶασπλάγχνων ἔχονσι πιμελήν , Aristot. De Part. Animn 3:9, and Hist. Anim. 3:16; Pliny, Hist. Nat. 11:81),
4. The יֹתֶרֶת, yothereth, which is taken by the Sept and Josephus (Ant. 3:9, 2) to mean ὁ λοβὸς τοῦ ἣπατος, the greater lobe of the liver, similarly the Syriac and Chaldee (חצרא דעל כבדא ); and is explained by the Talmud (Chulin, 49:6), Rashi, Kimchi, Solomon ben-Melech, etc., as טִרְפְּשָּׂא = τρἀπεζα, whereby the Greeks, according to Hippocrates, understood the greater and thickest of the five segments of the liver (Bahr, Symb. 2:354). This meaning of יוֹתֶרֶת is ably defended by Bochart (Hieroz. lib. 2, c. 45), and followed by Le Clerc, J.D. Rosenmuller, Kalisch (on Exodus 29:13), and others. But the Vulgate, Luther, Tyndale, the Bishops' Bible, the Geneva Bible, the A.V., Piscator, De Wette, Knobel, Furst, etc., take it to denote omentum minus, which is preferable, for the lobes have no accumulation of fat.
5. The tail ( אִלְיָה alyah', A.V. "rump") of a sheep (Leviticus 7:3), which, in a certain species (ovis laticaudata), contains a great quantity of fat. It is for this reason that the eating of fat is forbidden (Leviticus 3:17). It affords a delicate marrowy substance much used in pillaus and other messes which require to be lubricated by animal juices. The Rabbinical Jews maintain that the prohibition of it is restricted to the sacrifices, while the Karaite Jews regard the eating of the tail as absolutely forbidden. (See SHEEP).
One of the metaphorical senses of "fat" (in the Hebrew) is noticed above. By a natural figure,"fat" is occasionally put in Scripture for a dull and torpid state of mind, as if the heart were covered with thick fat, and therefore insensible (Psalms 17:10). (See OIL).
Bibliography Information
McClintock, John. Strong, James. Entry for 'Fat'. Cyclopedia of Biblical, Theological and Ecclesiastical Literature. https://www.studylight.org/encyclopedias/eng/tce/f/fat.html. Harper & Brothers. New York. 1870.
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Cancelled Tron game by the F.E.A.R. 3 dev revealed
Codename "TR2N: Liberation" featured seamless on-foot to lightbike transitions.
News by	Jeffrey Matulef, Contributor
Back in 2008 F.E.A.R. 3 and Fracture developer Day 1 Studios was developing a Tron game to tie into the films sequel, Tron: Legacy. Unfortunately, Disney pulled the plug.
Now Unseen 64 has unearthed prototype footage of Day 1's cancelled Tron title, tentatively titled TR2N: Liberation.
TR2N: Liberation was in development for Xbox 360, PS3 and PC. Had it been greenlit, a Wii port would have been outsourced.
Weirdly, Disney was so secretive about Tron: Legacy that it wouldn't even show concept art for the film to the handful of developers it had asked to whip up prototypes for the tie-in game. As such, Day 1 was flying blind and had to base its aesthetic off the visual stylings of the original film. Coincidentally, both visions ended up being quite similar as the original Tron's art direction is so distinct.
Day 1's Tron game was to be a fairly linear adventure, but one comprised of open-ended levels in which players could swap between being on-foot and on a lightbike at the touch of a button. Enemies could likewise transform into bike-mode and chase you around should you attempt to flee.
TR2N: Liberation's plot would have revolved around a rebel program leading an uprising against Clu and his army.
The on-foot combat was going to be more like a tennis match than the game that actually came out, Tron: Evolution. Where that title opted for more of a hack-and-slash system with multiple enemies and discs zipping about, Day 1's vision was for a slower, more measured pace. Fights would involve fewer foes, mostly being one-on-one affairs, and the focus was on precise timing as you dodge and deflect enemy projectiles.
PvP lightbike combat was going to be a racing affair in which you would also create walls of light in your steed that your opponent could crash into. Unlike the film, players would have a jump function to leap over said walls if they got the timing right.
Reportedly Disney liked Day 1's pitch for TR2N: Liberation, but ultimately Turok (2008) developer Propaganda Games underbid them, claiming it could make its Tron game cheaper and faster, meeting the film's holiday 2010 deadline.
As such TR2N: Liberation wasn't greenlit and Day 1 had to lay off roughly a dozen staffers.
The studio eventually recovered, however, making the surprisingly great F.E.A.R. 3 before getting acquired by Wargaming in 2013 to the tune of $20m. The studio has since been branded Wargaming Chicago-Baltimore, where it works on World of Tanks.
Jeffrey Matulef
Jeffrey Matulef is the best-dressed man in 1984.


Natural Family Planning Talk - Holy Cross Orthodox Church has not.
When married couples are considering issues around child-bearing, fertility, conception, and the spacing of children, they should do so with prayer and in light of the Church's tradition and, when helpful, in consultation with their spiritual father.
To help explore the incredible gift of a couple's fertility, we have invited Julie Tomko, a certified Natural Family Planning (NFP) instructor in the Creighton Fertility Method, to speak about the myriad physical and spiritual benefits of Natural Family Planning.
NFP is an excellent way to not only prevent, achieve, and plan pregnancies, but can also be incredibly helpful in medically diagnosing fertility and other female reproductive health issues, while simultaneously bringing a married couple closer together through God's gift of sexuality. Ms. Tomko will speak after Saturday evening Vespers (approximately 6:00pm on February 18 in the Parish Hall.
For more information and to help us get an idea of how many may attend, please contact contact us.


The class will be conducted by the renowned, talented and versatile Bhutanese artist- Rajesh Gurung. Rajesh is one of the founders of the first contemporary art studio called VAST (Voluntary Artists' Studio Thimphu) and it has been grooming, nurturing and inspiring artists for over 30 years.
Rajesh Charges US$ 50 dollars per head for more than two people and US$ 100 for a single person. The class will be for 2-3 hours.


I'm suspecting Windows Information Protection (WIP) pulled the plug off. Therefore we have to define Microsoft Teams as an managed app in order to work properly. Because we're using our cloud identity (Work- or School account) to access Microsoft Teams, we've to add Microsoft Teams as a managed (trusted) app, allowing to use our corporate identity here. Normally a straight forward process however the current preview version of Microsoft Teams desktop app doesn't have all product properties (product- and file name) embedded in order to configure Windows Information Protection policy properly.
I've created an uservoice item to get this solved in the final version (if it wont be a universal app), so feel free to vote-up!
The (temporary) workaround in our case was to just add the information available (publisher and version) in order to keep the scope tight to only Microsoft Teams. (Chances might be minimum here to hit (allow) another Microsoft desktop apps with the same version).
Additional to Windows Information Protection we bumped in to another challenge: Conditional Access. Once successfully logged in to Microsoft Teams we were facing the message below. Access to Microsoft Teams was prohibited because we didn't met the compliance status. Odd if you asked me, because we didn't set up a particular conditional access policy rule for Microsoft Teams (aka as Skype Teams).
This should be something related to Office 365 as Microsoft Teams is part of that platform. Thanks to fellow MVP Maxime Rastello which pointed me of having configured Conditional Access for SharePoint Online, by Microsoft Intune. We initially enabled Conditional Access for SharePoint Online for all platforms including Android, iOS, Windows 10 Mobile and Windows 10. For some reason Conditional Access can't determine correctly whether a Windows 10 is domain joined and/or compliant. As my Windows 10 laptop is domain joined (Azure AD Joined) we should be good here.
As temporary workaround we disabled Conditional Access for Windows 10, Microsoft Teams desktop app appears to be working as expected. All other (mobile) platforms mentioned before are working fine. I've noticed this behavior also occurs with other SaaS application in combination of Windows 10.
The current preview version of the Teams desktop app seems to be lacking support of device-based authentication/conditional access. Given that this feature is not in the current native app and had to be added, it may be fair to assume that there are some other dependencies in the native apps (possibly ADAL versions or the like) that are involved and that Teams may not have the right login components integrated to allow this to work. Currently Teams seems to be an app framework using the web based log-in framework as you do with a native web browser, however most likely the client user agent isn't determined as Edge or Internet Explorer browser, but Mozilla as Conditional Access doesn't support Chrome as trusted browsers.
Ideally, Microsoft Teams should just work if you had your device registered and (or compliant) there would not be a technology limitation preventing it. The fact that Microsoft Teams is not clearly separated from SharePoint in the policy engine is also a bit of a challenge. While it kind of makes sense that for example One Drive for Business and SharePoint share the same Conditional Access policy, it is much harder to figure out why Teams would get bundled in there.
Many thanks to Maxime Rastello and Joe Kaplan for sharing their insights.
No need to disable the policy. Simply uncheck "Block non-compliant devices on same platform as outlook" found under Outlook Web Access (OWA) in the Intune classic portal (manage.microsoft.com). This will allow users to use the web browser to login to OWA in addition to allowing them to log into teams.microsoft.com, so be aware. Microsoft, fix your shiz…. Teams is not OWA.


It is nature that teaches, and that you, with your art, do nothing more than walk quietly at her side.
Johann Heinrich Pestalozzi (January 12 1746 – February 17 1827) was a Swiss educational reformer.
The ultimate end of education is not a perfection in the accomplishments of the school, but fitness for life; not the acquirement of habits of blind obedience, and of prescribed diligence, but a preparation for independent action. We must bear in mind that whatever class of society a pupil may belong to, whatever calling he may be intended for, there are certain faculties in human nature common to all, which constitute the stock of the fundamental energies of man. We have no right to withhold from any one the opportunities for developing all their faculties. It may be judicious to treat some of them with marked attention, and to give up the idea of bringing others to high perfection. The diversity of talent and inclination, of plans and pursuits, is a sufficient proof of the necessity for such a distinction. But I repeat that we have no right to shut out the child from the development of those faculties also, which we may not for the present conceive to be very essential for his future calling or station in life.
Each of our moral, mental, and bodily powers must have its development based upon its own nature, and not based upon artificial and outside influences.
Faith must be developed by exercises in believing and cannot be developed from the knowledge and understanding, only, of what is to be believed; thought must grow from thinking, for it cannot come simply from the knowledge and understanding of what is to be thought, or the laws of thought; love must be developed by loving, for it does not arise merely from a knowledge and understanding of what love is and of what ought to be loved; art, also, can only be cultivated through doing artistic work and acquiring skill, for unending discussion of art and skill will not develop them. Such a return to the true method of Nature in the method of the development of our powers necessitates the subordination of education to the knowledge of the various laws which govern those powers.
It is life itself that educates.


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NER Interns: Where are they now?
Camille Kellogg
Camille Kellogg '17 talks to NER intern Bel Spelman '23 about editing manuscripts, books as mirrors, and reading widely.
Bel Spelman: What do you remember from your NER internship?
Camille Kellogg: I remember my time at NER vividly. I was so excited to intern there. At the time, I was writing my thesis, so I would leave the library and tramp through the snow over to the NER office, which is this lovely, cozy building full of books. It was a very warm place, in every sense of the word. Everyone who worked there was so kind and friendly and put me at ease right away.
At NER, I got to sort query letters, format website posts, choose art for the website, proofread pieces, and read submissions then discuss them with the team. One of my favorite tasks was editing audio recordings of authors reading at Bread Loaf: I got to listen to incredible readings from Garth Greenwell, Natasha Tretheway, Peter Ho Davies, and more.
Interning at NER convinced me that I wanted to work in publishing. I looked at the NER team and saw a life I wanted to lead. It's a lot of work and it's not all reading and editing (there's plenty of paperwork!) but the work was inspiring and exciting. When I got the issue of the magazine we'd worked on and held it in my hands it made me very sure that this was the kind of future I wanted.
BS: What were some of the steps that brought you to Bloomsbury Publishing?
CK: Once I graduated from Middlebury, I attended the Columbia Publishing Course to get an overview of the publishing industry. When the course ended, I crossed my fingers and moved to New York without a job. I actually had a broken arm at the time from a rugby injury, so I only brought one suitcase with me! I applied to as many editorial assistant jobs as I could find and got hired at HarperCollins Children's Books. A few years later I moved over to Macmillan, but I was only there for about a year before my entire imprint was shut down during the pandemic. They say if you work in publishing long enough, you'll eventually get laid off, so I'm hoping that was my one time! While I was unemployed, I spent my time working on a book of my own, which is being published by Penguin Random House next year. After four months, I was hired at Bloomsbury Children's Books. I'm now an editor here, working with the wonderful Bloomsbury team and acquiring books from truly incredible authors.
BS: How does your work challenge you?
CK: Editing a manuscript is always challenging, no matter how many times you do it, because every book needs something slightly different. The first time you read a manuscript through, you know there are parts that you love and parts that feel off. Then you have to sit down and figure out why things feel off. Is it the pacing, the character development, the plot? Once you can identify the problem, then you can work with the author to come up with a solution.
The biggest challenge in publishing, though, is always time management. There's so much to do! There's always paperwork to fill out, emails to send, and submissions to read. The job is never really "done." I always wish I had more time, especially for reading.
BS: Bloomsbury has a focus on publishing children's and young adult stories. What do you enjoy about working with these stories?
CK: I decided to go into children's books because, as a queer person, I didn't see myself in books growing up. It's so important for kids to see themselves in the stories they read—it helps them develop confidence and feel like they can be the hero of their own story. I wanted to help make sure every kid gets that experience. Being a kid or teen can also be really scary and overwhelming, so I tend to be drawn towards books that don't shy away from the darkness of childhood but instead show readers how to find light when things get dark.
Kids and young adult books are also fun. One of the goals of every book I publish is to teach young people to love reading, to publish stories that they don't want to put down. It's hard to take yourself too seriously when you're editing chapter books about dragons or YA novels about K-pop stars. There's always a note of fun in the work I do.
BS: Any advice for college students looking to enter the publishing industry?
Camille Kellog (right) and a fellow intern in the NER office.
CK: The best advice I can give to anyone who wants to work in publishing is READ. Read a ton of books in the genre you want to work in and read RECENT books. When you go to an interview, you want to be able to talk about books published in the last two to three years, not just the books that you read in your English classes. Read a really wide range of books, too: commercial books, literary books, bestsellers, flops, everything. When you finish a book, think about what worked in the book, what didn't, and what you would suggest changing if you were the editor. Doing this helps you get to know the current publishing market and also develop your editorial skills.
BS: Do you have a long-term goal for your editorial career?
CK: My long-term career goal is to publish a lot of wonderful books, do my absolute best for my authors, and help to put more stories out into the world for people who might not have seen themselves in stories before. That's also the same goal I have for my career as an author: my debut novel, which is a queer adult romcom, comes out in 2023 and is for queer people who feel lost or uncertain about how to navigate the world. It's the book that I desperately needed when I was younger to tell me that things were going to be okay.
Filed Under: Featured, Interns, News & Notes, Where Are They Now Tagged With: Bel Spelman, Camille Kellogg
Megan Fernandes
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