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An Official Publication of the Indian Association of Oral and Maxillofacial Pathologists
Tumor necrosis factor-like weak inducer of apoptosis expression in healthy oral mucosa, oral dysplasia and oral squamous cell carcinoma
Swetha Acharya1, Prashant Prabhu1, Vidya Patil2, Anirudh B Acharya3, Anil Desai4, Krithi Nikhil5
1 Department of Oral Pathology and Microbiology, SDM College of Dental Sciences and Hospital, A Constituent Unit of Shri Dharmasthala Manjunatheswara University, Dharwad, Karnataka, India
2 Department of Biochemistry, SDM College of Dental Sciences and Hospital, A Constituent Unit of Shri Dharmasthala Manjunatheswara University, Dharwad, Karnataka, India
3 Department of Periodontics, College of Dentistry, Majmaah University, Zulfi, Kingdom of Saudi Arabia
4 Department of Oral and Maxillofacial Surgery, SDM College of Dental Sciences and Hospital, A Constituent Unit of Shri Dharmasthala Manjunatheswara University, Dharwad, Karnataka, India
5 Consultant, Biostatistician, Dharwad, Karnataka, India
Date of Acceptance 19-Jul-2019
Date of Web Publication 19-Dec-2019
Swetha Acharya
Department of Oral Pathology and Microbiology, SDM College of Dental Sciences and Hospital, A Constituent Unit of Shri Dharmasthala Manjunatheswara University, Dharwad - 580 009, Karnataka
DOI: 10.4103/jomfp.JOMFP_151_19
Objective: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of cancer, as it participates in the progression of internal malignancies. However, its role in the biology of squamous cell carcinoma (SCC) is uncertain. Studies regarding TWEAK in SCC have shown inconsistent results. We aimed to study the expression of TWEAK in healthy oral mucosa, oral dysplastic lesions and in oral SCC (OSCC).
Methods: Immunohistochemistry for TWEAK was performed on one hundred oral mucosal tissues, healthy control (HC) (n = 20), oral dysplasia (OD) (n = 20) and OSCC (n = 60). Staining intensity, extent of staining (ES) and immunoreactive Score (IRS) were assessed for each sample. Kruskal–Wallis ANOVA, Mann–Whitney U, Chi-square and Spearman's rank correlation coefficient were applied.
Results: TWEAK was expressed in 55% of HC, 90% of OD and in all cases of OSCC, with variable intensities. A significant difference in the ES and IRS of TWEAK was noted among the three groups. ES and IRS were highest in OSCC group. ES of TWEAK was significantly higher at invasive tumor front (ITF) than in the whole tumor, with a significant positive correlation. TWEAK expression showed a significant association with invasive front grading, pattern of invasion and surgical margins of OSCC.
Conclusions: TWEAK may contribute to the progression of OSCC. It might also sustain altered differentiation, invasion and migration of tumor cells at ITF.
Keywords: Clinicopathologic parameters, oral squamous cell carcinoma, tumor necrosis factor-like weak inducer of apoptosis
Acharya S, Prabhu P, Patil V, Acharya AB, Desai A, Nikhil K. Tumor necrosis factor-like weak inducer of apoptosis expression in healthy oral mucosa, oral dysplasia and oral squamous cell carcinoma. J Oral Maxillofac Pathol 2019;23:369-77
Acharya S, Prabhu P, Patil V, Acharya AB, Desai A, Nikhil K. Tumor necrosis factor-like weak inducer of apoptosis expression in healthy oral mucosa, oral dysplasia and oral squamous cell carcinoma. J Oral Maxillofac Pathol [serial online] 2019 [cited 2020 Jan 18];23:369-77. Available from: http://www.jomfp.in/text.asp?2019/23/3/369/273481
Biomarkers are progressively employed in managing cancer patients.[1] Current investigations have made evident that the tumor necrosis factor (TNF)-like weak inducer of apoptosis-fibroblast growth factor inducible 14 (TWEAK-Fn14) has a task in the progression of malignant tumors.[2] TWEAK is a multifunctional cytokine that, through its specific receptor Fn14, directs several cellular activities, including proliferation, adhesion and migration, differentiation, survival, apoptosis, angiogenesis and inflammation.[3] Overexpression of TWEAK has been detected in cancer of esophageal, liver, pancreatic, colorectal, ovarian, bladder and prostate, whereas prominent Fn14 upregulation has been noted in brain glioma, cancer of lung, breast, colorectal and prostate and melanoma.[2],[4] Recently, TWEAK has been researched as a marker of the outcome after treatment in head-and-neck squamous cell carcinoma (HNSCC). Patients with HNSCC without local, regional or distant tumor recurrence presented higher TWEAK levels than patients with a poor prognosis. Furthermore, it has been observed that the expression levels of TWEAK and Fn14 are closely associated with the grading and prognosis of HNSCC.[1],[5] Hence, TWEAK-Fn14 signals participate in the tumorigenicity of various malignancies.[6]
Even the gene expression pattern showed a gradual and significant increase in the expression pattern of TWEAK and Fn14 genes from control to cancerous tissue. Gene expression of TWEAK increased in HNSCC.[5] On the other hand, immunohistochemical (IHC) analysis has supported that both TWEAK and Fn14 are upregulated in cutaneous SCC although TWEAK expression is sometimes weak in these tissue samples.[7],[8] For HNSCC, both TWEAK and Fn14 are expressed more in the tumor tissue than that in the adjacent and distal tissue.[5] Hence, it is ambiguous whether TWEAK-Fn14 activation provides a contributive or protective role in the development of SCC.[6]
In a few reports, expression of TWEAK in SCC ranged from strong to completely absent. In biopsies of SCC, expression of TWEAK greatly varied depending on the level of tumor differentiation.[7] IHC expression of TWEAK significantly decreased in oral SCC (OSCC) compared to healthy mucosa.[9] It was also reported that TWEAK expression is decreased, whereas Fn14 expression is increased significantly in cervical carcinoma and intraepithelial neoplasm specimens compared with normal control.[10] Thus, the literature lacks clarity regarding the expression of TWEAK in the mucosal tissue samples both in health and disease. Reviews imply that TWEAK levels are different in mucosal pathologies as compared to healthy mucosa. In addition, the aforementioned studies revealed inconsistent results pertaining to the role of TWEAK-Fn14 signaling in SCC. Furthermore, the expression of TWEAK in tumor tissue and their potential function in OSCC has been barley investigated. Hence, the study aimed to analyze the expression and distribution of TWEAK in the oral mucosal tissues of healthy controls (HCs), oral dyplasias (ODs) and in OSCCs.
An IHC analysis was undertaken to evaluate and compare the expression of TWEAK in hundred oral mucosal tissue samples obtained from HC (n = 20), patients with OD (n = 20) and with OSCC (n = 60). Department of Oral Surgery and Craniofacial Unit (CFU) of the institution provided the mucosal samples from patients who underwent treatment. The ethical clearance for the proposal was obtained from the Institutional Ethical Committee (IRB. No. 2016/S/OP/51). Histopathologically confirmed cases of OD and OSCC were included in the study. For the control group, HC samples were obtained from systemically healthy participants without carcinoma and dysplasia who were undergoing minor oral surgical procedures or extraction for orthodontic treatment or impacted teeth. Following OSCC cases were excluded: participants with systemic diseases and allergic conditions, participants treated elsewhere before reporting to our institution, participants with preoperative chemotherapy or radiotherapy before surgery and participants with local resection without neck dissection.
Clinical data were obtained by examining the participants in the Department of Oral Medicine, and histopathological details were analyzed in the Department of Oral Pathology by reviewing the hematoxylin and eosin-stained sections obtained from participants' tissue samples. Treatment and recurrence details of OSCC cases were obtained from the database of the department and CFU of the institution.
Tissue sections were dewaxed with xylene, hydrated using graded alcohol and treated with hydrogen peroxide in methanol for 10 min to eliminate endogenous peroxidase activity. Antibody TWEAK/TNFSF12 (CAT#NBP1-76695, Novus Biologicals, CO, USA) was used after antigen retrieval using microwave. The secondary antibody was obtained from Thermo Scientific-Quanto Detection system. Standardization was performed as per the manufacturer's instructions. Staining was performed according to the manufacturer's protocol using automatic stainer. Sections of skin with known TWEAK expression were used as a positive control. Negative control was made by omission of each primary antibody. A brown precipitate seen in the cytoplasm confirmed the presence of TWEAK. The IHC stained slides were examined imaged and analyzed using a Leica microscope. The number of samples stained, localization, staining intensity (SI) and extent of staining (ES) were assessed. All the hundred TWEAK stained sections were analyzed by two observers who followed uniform criterion and were blinded to the final outcome. Before the commencement of the principal investigation, a pilot analysis was carried out to assess intra- and interobserver consistency with few TWEAK-stained sections.
The percentage of TWEAK immunopositive cells was obtained from 20 random fields per section using a 20× objective lens. Results were classified as follows for the percentage of positive tumor cells (PC): Score 0 = no immunoreactivity; Score 1+ = <10% PC; Score 2+ = 10%–50% PC; Score 3+ = >50%–80% PC and Score 4+ = >80%–100% PC. The SI was evaluated by two independent observers, in a random order, at ×200. Overall epithelial expression of TWEAK was scored from 0 (no staining), 1+ (mild staining), 2+ (moderate staining) and 3+ (strong staining). Results for PC and SI were multiplied, resulting in an immunoreactive score (IRS) 0–12. IRS 9–12 was defined as TWEAKHigh and IRS 0–8 was defined as TWEAKLow.
The data were analyzed using SPSS 19.0 (IBM ® SPSS ® Inc., Armonk, NY, USA). The data were tabulated as mean ± standard deviation, median, range and percentages. The normality of continuous variable distribution was assessed using the Kolmogorov–Smirnov test. Kruskal–Wallis ANOVA, Mann–Whitney U test, Chi-square test and Spearman's rank correlation coefficient tests were applied. P < 0.05 were regarded as statistically significant.
Immunoreactivity to TWEAK appeared as diffuse brown cytoplasmic staining. TWEAK was expressed in 55% of HC, 90% of OD, and in all cases of OSCC, with variable intensities. There was no statistically significant difference in the SI among HC, OD and OSCC groups [Figure 1]. ES showed a significant difference among HC, OD and OSCC groups. ES was highest in the OSCC group, followed by OD and HC. Pair-wise comparison showed a significant difference between HC and OD, OD and OSCC and HC and OSCC groups [Table 1]. IRS score showed a significant difference among HC, OD and OSCC groups. Pair-wise comparison showed a significant difference between HC and OD groups and HC and OSCC [Table 2].
Figure 1: Photomicrograph depicting the staining intensity of tumor necrosis factor-like weak inducer of apoptosis in mucosal samples. (a) Healthy mucosa, (b) dysplasia, (c) oral squamous cell carcinoma. (Objective magnification 10×, 20×, 3,3' Diaminobenzidine chromogen, tumor necrosis factor-like weak inducer of apoptosis monoclonal antibody)
Table 1: Extent of TWEAK expression in the study groups
Table 2: IRS of TWEAK in the study groups
Among twenty oral dysplastic lesions, ten cases were with moderate dysplasia and severe dysplasia in ten. The ES and IRS of TWEAK were higher in severe dysplasia than moderate. However, the difference was not statically significant (45.50 ± 23.85 vs. 38.76 ± 27.20) (P > 0.05).
Among 60 OSCC cases, 43 cases were well differentiated and 17 cases were moderate to poorly differentiated, according to Broder's grading. There was no significant association between IRS scores and tumor grading (P = 0.901) [Table 3]. ES of TWEAK was higher in moderate-to-poorly differentiated tumors than well-differentiated tumor. The difference was not statistically significant (80.10 vs. 73.86) (P = 0.850) [Table 4]. According to invasive front grading (IFG), 23 cases were well differentiated, 16 moderate and 21 poorly differentiated. There was a significant association between TWEAK IRS and IFG (P = 0.001) [Table 3]. There was a significant association between ES of TWEAK and IFG (P = 0.001) [Table 4].
Table 3: The association between tumor necrosis factor-like weak inducer of apoptosis IRS and clinicopathologic parameters of oral squamous cell carcinoma patients
Table 4: Relation between the extent of staining of tumor necrosis factor-like weak inducer of apoptosis and the clinicopathologic parameters of oral squamous cell carcinoma
TWEAK IRS showed also significant association with parameters like IFG [Figure 2] and surgical margins [Table 3]. ES of TWEAK revealed a significant difference in the following parameters such as IFG, pattern of invasion (POI) and surgical margins [Table 4]. Tumors with positive surgical margins, infiltrative type POI and poorly differentiated based on IFG showed significantly higher ES than their counterparts. Statistically significant difference in the ES was noted between tumors with positive and negative surgical margins, infiltrative and pushing POI and between grades of IFG.
Figure 2: Photomicrograph depicting the extent of tumor necrosis factor-like weak inducer of apoptosis staining among various grades of oral squamous cell carcinoma. (a) Well differentiated, (b) moderately differentiated, (c) poorly differentiated. (objective magnification 20×, 3,3' Diaminobenzidine chromogen, tumor necrosis factor-like weak inducer of apoptosis monoclonal antibody)
ES of TWEAK was significantly higher at the invasive tumor front (ITF) than the whole tumor (WT), a significant positive correlation (r = 0.83, P = 0.001) [Figure 3].
Figure 3: Photomicrograph depicting the extent of tumor necrosis factor-like weak inducer of apoptosis staining in oral squamous cell carcinoma sample. (a) Superficial tumor, (b) invasive tumor front. (objective magnification 20×, 3,3' Diaminobenzidine chromogen, tumor necrosis factor-like weak inducer of apoptosis monoclonal antibody)
The role of TNF–alpha in HNSCC has been investigated in the past. It has been a protein with potential for diagnostic utility in OSCC, an extensively expressed pro-inflammatory cytokine in the course of transformation and progression of oral cancer.[11] TWEAK is a member of the TNF ligand superfamily (TNFSF12) that was originally described as a weak inducer of apoptosis in the interferon gamma-treated tumor cell lines.[8],[12],[13] TWEAK which acts generally as both type II transmembrane proteins and cleaved biologically active soluble molecule which binds with high affinity to the Fn14.[8] Fn14 ligand-receptor pair likely plays an important role in variety of cellular processes and in pathogenesis of several human diseases, including cancer.[3],[4],[12] However, the full biological effects of TWEAK on cancer remain largely unknown because cells lacking Fn14 have also been shown to be TWEAK sensitive.[5]
TWEAK expression has been detected in many different cell lines and tissues.[10],[14],[15] In most cancers, TWEAK expression is increased in tumor tissues compared with normal ones,[14],[15] as observed in this investigation. In this analysis, both ES and IRS of TWEAK significantly differed among the study groups and with highest expression in OSCCs. Even Alaoui et al. and Hu et al. found increased expression of TWEAK in cutaneous SCC than normal tissue samples.[6],[8] This increased expression may trigger the proliferation or migration activity, but there are exceptions.[14],[15]
Soluble TWEAK is produced mainly by inflammatory cells, such as macrophages, which intensively infiltrate the local tissue of SCC. TWEAK-Fn14 activation can recruit more macrophages in a feedback manner. TWEAK-Fn14 inhibition is associated with reduced macrophages infiltration in SCC xenografts, coinciding with the fact that macrophages are one of the major TWEAK-secreting cells. Hence, it is evident that intratumoral TWEAK expression increases in SCC.[6],[16],[17] Its expression also increases significantly in tumor tissues during cancer progression, which is associated with infiltration of inflammatory cells and activation of resident immune cells.[18],[19]
Contradictory to the above findings, El-Meadawy et al. found that TWEAK expression was significantly downregulated in OSCC compared with that in normal mucosa.[9] Peternel et al. found that the TWEAK expression ranged from strong to completely absent in cutaneous SCC.[7] Zou et al. reported that TWEAK messenger RNA (mRNA) expression was significantly downregulated in cervical cancer compared with that in normal tissues.[10] A few researchers detected that TWEAK expression significantly decreased in carcinoma compared with normal tissue, and this may be owing to its consumption in the process of Fn14 synthesis.[3]
In certain cell lines, TWEAK also acts as a death-inducing factor. The role of TWEAK on tumor cells is inconclusive, as some studies show that TWEAK alone is able to promote cell proliferation, while others show that TWEAK promotes cell death.[1] In most studies, TWEAK was just one component of a death-inducing cytokine cocktail.[3] TWEAK has been known to be an inducer of apoptosis of keratinocytes by engaging the Fn14 receptor. TWEAK-induced cell death is not well understood but appears to involve multiple context-dependent mechanisms.[4]
Fn14–TNF receptor (TNFR)-associated factor 2 (TRAF2)–TNFR axis regulates the apoptosis and proliferation of tumor cells. TWEAK-Fn14 interaction activates the TRAF2 (anti-apoptotic protein) signaling pathway. Fn14–TRAF2–TNFR1 may play a role in the apoptosis of cells, and Fn14–TRAF2–TNFR2 may be responsible for cell proliferation. TWEAK has been reported to promote the proliferation of normal endothelial cells and keratinocytes infected by human papillomavirus (HPV).[2] HPV16-induced keratinocyte immortalization has been shown to be closely related to epidermis originated malignancies, and TWEAK-Fn14 activation accompanies HPV16 infection inducing the proliferation of keratinocytes.[2],[20] There is a causal relationship between HPV and OSCC.[21] Normal keratinocytes mostly express TNFR1 and reveal promoted apoptosis and unmoved proliferation upon TWEAK stimulation. However, HPV infection switches keratinocytes from an apoptotic to proliferative fate under TWEAK-Fn14 interaction through upregulating TNFR2 expression.[6],[20] HPV16 E6/E7-harboring keratinocytes express high levels of Fn14, which interacts with TWEAK causing proliferation of keratinocytes.
In this analysis, TWEAK showed significant association with parameters such as IFG, POI and surgical margins. Expression of TWEAK was significantly higher in poorly differentiated tumors (based on IFG), tumors with infiltrative growth pattern and tumors with positive surgical margins than their counterparts, respectively. The differentiation status mirrors the clinical behavior of SCC and scores a biological inequality between low-risk and high-risk SCC.[6] Fn14 is expressed more in undifferentiated or less-differentiated cells, including HPV-infected keratinocytes.[20] Fn14 expression prefers to be stronger in the poorly differentiated subtypes. It is possible that TWEAK-Fn14 signaling contributes more to the tumors with poor differentiation stage. However, Hu et al. found no significant difference in Fn14 or TWEAK expression between the well- and poorly-differentiated SCC samples.[6] Contradictory to the above-mentioned results, El-Meadawy et al. found the expression of TWEAK in OSCC to be inversely proportional to the histologic grades.[9] Zou et al. demonstrated a close correlation between reduced expression of TWEAK and increased histological grades and interstitial invasive depth in cervical carcinoma. In the view of downregulated TWEAK being closely related to grade and depth, but not with size and lymph node metastasis, the authors of one investigation hypothesized that TWEAK acts on local cancer tissue permeation than a distant metastasis.[10] Peternel et al. found that although TWEAK was regularly expressed in moderately- and well-differentiated SCC, it was completely absent in poorly-differentiated tumors and stated that TWEAK might serve as a novel differentiation marker whose expression in atypical and malignant epidermal neoplasms with squamous differentiation inversely correlates with the degree of atypia. As TWEAK is shown to be downregulated in proliferating keratinocytes and also found to be reduced in pathologies with altered keratinocyte differentiation. One group of researchers concluded that downregulation of TWEAK expression might be an early indicator of disturbed differentiation or pathologic proliferation of keratinocytes in cutaneous neoplasias.[7]
Invasion and migration are the most vital qualities of malignant tumors and are intimately related to prognosis of the tumor. Several studies have stated that TWEAK-Fn14 pathway plays a significant part in the invasion and migration of tumors. TWEAK-Fn14 signaling fuels the invasion and migration of tumor cells through TNFR-associated factor 2. TWEAK augments the mRNA level of matrix metalloproteinase (MMP)-9, which supports the invasiveness of tumor cells.[2] In the present study, we found the expression of TWEAK to be higher at the invasive front than the WT and extent of TWEAK expression was higher in moderate- and poorly-differentiated OSCC than well-differentiated tumors based on IFG. Thus, it is opined that TWEAK may promote the cellular expressions of MMP-2 and MMP-9, which are suggested to contribute to the invasion of SCC cells.[6],[22] MMPs can assist the movement of tumor cells by degrading some constituents of the extracellular matrix.[22] It is also cited that TWEAK lessens the expression of E-cadherin in cultured SCC cells. E-cadherin is an elementary transmembrane glycoprotein and functions in the calcium-dependent homotypic cell-cell adhesions. The downregulation of E-cadherin can increase SCC metastasis through reducing intercellular constraints.[6] Downregulation of E-cadherin is a crucial step in epithelial–mesenchymal transition which occurs at the ITF.[2] Thus, TWEAK may bring phenotypic transformation of epithelial cells. Therefore, TWEAK-Fn14 activation helps the invasion and migration of SCC cells via multiple downstream pathways.[6]
TWEAK was considerably expressed in the epithelium of oral mucosal samples. TWEAK expression significantly increased in mucosal pathologies compared with that in the normal oral mucosa. Increased expression in mucosal pathologies might suggest that they aid in altered proliferation and differentiation, which accompanies inflammatory or neoplastic process. Results suggest that TWEAK-Fn14 signals contribute to the progression of OSCC, most likely via Fn14–TRAF2–TNFR2 axis. It might also sustain altered differentiation, invasion and migration of tumor cells at the ITF, as TWEAK expression was substantial. TWEAK expression also showed significant association with few histopathologic prognosticators.
TWEAK can be considered as a potential target for anticancer therapy, as it is expressed in the tumor microenvironment and currently known to play a part in the tumor biology. This protein can be a new molecular target for cancer drug development. Rationale exists for inhibition of the TWEAK-Fn14 pathway as an approach to cancer treatment; blocking antibodies to TWEAK have been described in the literature. Additional studies are required to determine TWEAK as a novel molecular target for anticancer therapy in humans.
Further explorations are required to establish the function and mode of action of TWEAK in OSCC development. In this study, IHC expression of TWEAK was assessed in a small group of oral mucosal samples with and without pathologies, which may be a limitation. Simultaneous assessment of TWEAK and Fn14 expression in a larger cluster would better the understanding about their role in OSCC.
The authors thank the Department of Oral Pathology, Department of Oral and Maxillofacial Surgery and Dr. Srinath Thakur, Principal, SDM College of Dental Sciences and Hospital, Dharwad, India. This study was funded by Rajiv Gandhi University of Health Sciences (RGUHS) Advanced Research Wing, Bengaluru, India. Our sincere thanks to Dr. G.S Venkatesh, Director of RGUHS Advanced Research Wing, Bengaluru, India. The authors express gratitude to Dr. Sanjay Navani, LabSurgpath, Mumbai, India, for his expertise in IHC, Mrs. Hemalatha Gudgudi, Dr. Jyothi Kale and Dr. Dewin Arnold for procuring the tissue samples and data.
This work was supported by the Rajiv Gandhi University of Health Sciences (RGUHS) Advanced Research Wing (Grant Number (project Code): D010, year: 2016-2017) Bengaluru, India.
Terra X, Gómez D, García-Lorenzo J, Flores JC, Figuerola E, Mora J, et al. External validation of sTWEAK as a prognostic noninvasive biomarker for head and neck squamous cell carcinoma. Head Neck 2016;38 Suppl 1:E1358-63.
Hu G, Zeng W, Xia Y. TWEAK/Fn14 signaling in tumors. Tumour Biol 2017;39:1010428317714624.
Winkles JA. The TWEAK-Fn14 cytokine-receptor axis: Discovery, biology and therapeutic targeting. Nat Rev Drug Discov 2008;7:411-25.
Burkly LC, Michaelson JS, Hahm K, Jakubowski A, Zheng TS. TWEAKing tissue remodeling by a multifunctional cytokine: Role of TWEAK/Fn14 pathway in health and disease. Cytokine 2007;40:1-6.
Avilés-Jurado FX, Terra X, Gómez D, Flores JC, Raventós A, Maymó-Masip E, et al. Low blood levels of sTWEAK are related to locoregional failure in head and neck cancer. Eur Arch Otorhinolaryngol 2015;272:1733-41.
Hu G, Liang L, Liu Y, Liu J, Tan X, Xu M, et al. TWEAK/Fn14 interaction confers aggressive properties to cutaneous squamous cell carcinoma. J Invest Dermatol 2019;139:796-806.
Peternel S, Manestar-Blažić T, Brajac I, Prpić-Massari L, Kaštelan M. Expression of TWEAK in normal human skin, dermatitis and epidermal neoplasms: Association with proliferation and differentiation of keratinocytes. J Cutan Pathol 2011;38:780-9.
Sabour Alaoui S, Dessirier V, de Araujo E, Alexaki VI, Pelekanou V, Lkhider M, et al. TWEAK affects keratinocyte G2/M growth arrest and induces apoptosis through the translocation of the AIF protein to the nucleus. PLoS One 2012;7:e33609.
EI-Meadawy SH, Salama NM, EL-Nagdy SY, Zyada MM. Immunohistochemical study of TNF like weak inducer of apoptosis (TWEAK) in oral squamous cell carcinoma tissues & its relation to 8-hydroxy-2-deoxyguanosine (8-OHDG) expression in saliva. EDJ 2013;59:481-94.
Zou H, Wang D, Gan X, Jiang L, Chen C, Hu L, et al. Low TWEAK expression is correlated to the progression of squamous cervical carcinoma. Gynecol Oncol 2011;123:123-8.
Krishnan R, Thayalan DK, Padmanaban R, Ramadas R, Annasamy RK, Anandan N. Association of serum and salivary tumor necrosis factor-α with histological grading in oral cancer and its role in differentiating premalignant and malignant oral disease. Asian Pac J Cancer Prev 2014;15:7141-8.
Winkles JA, Tran NL, Brown SA, Stains N, Cunliffe HE, Berens ME, et al. Role of TWEAK and Fn14 in tumor biology. Front Biosci 2007;12:2761-71.
Pettersen I, Baryawno N, Abel F, Bakkelund WH, Zykova SN, Winberg JO, et al. Expression of TWEAK/Fn14 in neuroblastoma: Implications in tumorigenesis. Int J Oncol 2013;42:1239-48.
Dai L, Gu L, Ding C, Qiu L, Di W. TWEAK promotes ovarian cancer cell metastasis via NF-kappaB pathway activation and VEGF expression. Cancer Lett 2009;283:159-67.
Nakayama M, Ishidoh K, Kayagaki N, Kojima Y, Yamaguchi N, Nakano H, et al. Multiple pathways of TWEAK-induced cell death. J Immunol 2002;168:734-43.
Li X. TIPE2 regulates tumor-associated macrophages in skin squamous cell carcinoma. Tumour Biol 2016;37:5585-90.
Wang X, Xiao S, Xia Y. Tumor necrosis factor receptor mediates fibroblast growth factor-inducible 14 signaling. Cell Physiol Biochem 2017;43:579-88.
Gu L, Dai L, Cao C, Zhu J, Ding C, Xu HB, et al. Functional expression of TWEAK and the receptor Fn14 in human malignant ovarian tumors: Possible implication for ovarian tumor intervention. PLoS One 2013;8:e57436.
Winkles JA, Tran NL, Berens ME. TWEAK and Fn14: New molecular targets for cancer therapy? Cancer Lett 2006;235:11-7.
Cheng H, Zhan N, Ding D, Liu X, Zou X, Li K, et al. HPV type 16 infection switches keratinocytes from apoptotic to proliferative fate under TWEAK/Fn14 interaction. J Invest Dermatol 2015;135:2427-36.
Shafer, Hine, Levy. Benign and malignant tumors of the oral cavity. In: Rajendran R, Sivapathasundharam B, editors. Shafer's Text Book of Oral Pathology. 7th ed. New Delhi: Elsevier; 2012. p. 106-7.
Lee JH, Piao MS, Choi JY, Yun SJ, Lee JB, Lee SC. Up-regulation of cyclooxygenase 2 and matrix metalloproteinases-2 and -9 in cutaneous squamous cell carcinoma: Active role of inflammation and tissue remodeling in carcinogenesis. Ann Dermatol 2013;25:145-51.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]
Acharya S
Prabhu P
Patil V
Acharya AB
Desai A
Nikhil K
Clinicopathologic parameters
oral squamous cell carcinoma
tumor necrosis factor-like weak inducer of apoptosis
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Expected =Error: Invalid administrator login attempt.
9) Test Case: Check communication between different browsers.
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CrossFit One World: DOING WORK!!!!
The 16 brave souls who participated in the first CrossFit One World Competitors Training Session. It was as fun for them as it was for me! Great job everyone. Any thoughts or feedback you can provide me would be awesome. freddy@crossfitoneworld.com OR 510-209-8990. Rest up!


text:
Yankees Link Roundup
Rookie pitcher hopes to impress.
By John Amato Apr 26, 2005, 12:35pm EDT
Share All sharing options for: Rookie pitcher hopes to impress.
The NY Post has a good article about Chien-Ming Wang, a 25-year-old right-hander from Taiwan, on the way to take Wright's spot and face the Blue Jays on Saturday.
"The two biggest things are that he throws strikes and isn't afraid of bat contact," Columbus pitching coach Gil Patterson said last night.
"And stuff around him doesn't bother him. What separates Wang from other pitchers who have come through the Yankees system is that he can fire off a 94-mph fastball.
"His next pitch is a slider, but he has a change-up and split-fingered fastball," Patterson said. "If the slider is on, it can be a big help. He can throw it down and away to right-handers and we have been working on a back-door to lefties. He has four pitches and I would guess all four are major league caliber."

redpajama_set_name: RedPajamaCommonCrawl


text:
set -eu

SCRIPT_DIR=$(cd "$(dirname "${BASH_SOURCE[0]}")" && pwd)
source ${SCRIPT_DIR}/testenv.sh || { echo "testenv.sh not found!" >&2; exit 1; }

### Setup a git repository
setup_git_repository

### Load the relnotes script
source ${SCRIPT_DIR}/relnotes.sh || { echo "relnotes.sh not found!" >&2; exit 1; }

### Tests method

function set_up() {
  cd ${MASTER_ROOT}
}

function test_format_release_notes() {
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  assert_equals "${expected}" "$(format_release_notes "${input[@]}")"
}

function test_get_release_notes_commits() {
  # Generated with git log --grep RELNOTES.
  # Only 6d98f6c 53c0748 are removed (rollback).
  commits="0188971 957934c 7a99c7f b5ba24a c9041bf 8232d9b 422c731 e9029d4 \
cc44636 06b09ce 29b05c8 67944d8 e8f6647 6d9fb36 f7c9922 5c0e4b2 9e387dd \
98c9274 db4d861 a689f29 db487ce 965c392 bb59d88 d3461db cef25c4 14d905b"
  assert_equals "$commits" "$(get_release_notes_commits 00d7223 | xargs)"
  assert_equals "$(echo "$commits" | sed 's/957934c //')" \
      "$(get_release_notes_commits 00d7223 957934c | xargs)"
}

TEST_INC_CHANGE='Incompatible changes:

  - Remove deprecated "make var" INCDIR

'
TEST_NEW_CHANGE='New features:

  - added --with_aspect_deps to blaze query, that prints additional
    information about aspects of target when --output is set to {xml,
    proto, record}.

'
TEST_CHANGE='Important changes:

  - Use a default implementation of a progress message, rather than
    defaulting to null for all SpawnActions.
  - Attribute error messages related to Android resources are easier
    to understand now.'

function test_release_notes() {
  assert_equals "$TEST_INC_CHANGE$(echo)$TEST_NEW_CHANGE$(echo)$TEST_CHANGE" \
      "$(release_notes 965c392)"
  assert_equals "$TEST_NEW_CHANGE$(echo)$TEST_CHANGE" \
      "$(release_notes 965c392 bb59d88)"
}

function test_get_last_release() {
  rm -f ${TEST_TMPDIR}/CHANGELOG.md
  if (get_last_release "${TEST_TMPDIR}/CHANGELOG.md"); then
    fail "Should have returned false for initial release"
  fi
  cat <<EOF >${TEST_TMPDIR}/CHANGELOG.md
## No release
EOF
  if (get_last_release "${TEST_TMPDIR}/CHANGELOG.md"); then
    fail "Should have returned false when no release exists"
  fi
  cat <<EOF >${TEST_TMPDIR}/CHANGELOG.md
## New release

Baseline: 965c392

Initial release without cherry-picks

EOF
  assert_equals "965c392" \
      "$(get_last_release "${TEST_TMPDIR}/CHANGELOG.md")"

  mv ${TEST_TMPDIR}/CHANGELOG.md ${TEST_TMPDIR}/CHANGELOG.md.bak
  cat <<EOF >${TEST_TMPDIR}/CHANGELOG.md
## Cherry-picking bb59d88

Baseline: 965c392
   + bb59d88: RELNOTES[INC]: Remove deprecated "make var" INCDIR

$TEST_INC_CHANGE
EOF
  cat ${TEST_TMPDIR}/CHANGELOG.md.bak >>${TEST_TMPDIR}/CHANGELOG.md
  rm ${TEST_TMPDIR}/CHANGELOG.md.bak
  assert_equals "965c392 bb59d88" \
      "$(get_last_release "${TEST_TMPDIR}/CHANGELOG.md")"

  mv ${TEST_TMPDIR}/CHANGELOG.md ${TEST_TMPDIR}/CHANGELOG.md.bak
  cat <<EOF >${TEST_TMPDIR}/CHANGELOG.md
## Cherry-picking bb59d88 and 14d905b

Baseline: 965c392
   + bb59d88: RELNOTES[INC]: Remove deprecated "make var" INCDIR
   + 14d905b: Add --with_aspect_deps flag to blaze query. This flag
              should produce additional information about aspect
              dependencies when --output is set to {xml, proto}.

$TEST_INC_CHANGE
$TEST_NEW_CHANGE
EOF
  cat ${TEST_TMPDIR}/CHANGELOG.md.bak >>${TEST_TMPDIR}/CHANGELOG.md
  rm ${TEST_TMPDIR}/CHANGELOG.md.bak
  assert_equals "965c392 bb59d88 14d905b" \
      "$(get_last_release "${TEST_TMPDIR}/CHANGELOG.md")"

}

function test_create_release_notes() {
  cat <<EOF >${TEST_TMPDIR}/CHANGELOG.md
## New release

Baseline: 965c392

Initial release without cherry-picks

EOF
  assert_equals "$TEST_INC_CHANGE$(echo)$TEST_NEW_CHANGE$(echo)$TEST_CHANGE" \
      "$(create_release_notes ${TEST_TMPDIR}/CHANGELOG.md)"

  cat <<'EOF' >${TEST_TMPDIR}/CHANGELOG.md
## Cherry-picking bb59d88

```
Baseline: 965c392
   + bb59d88: RELNOTES[INC]: Remove deprecated "make var" INCDIR
```

EOF
  cat <<EOF >>${TEST_TMPDIR}/CHANGELOG.md
$TEST_INC_CHANGE
EOF
  assert_equals "$TEST_NEW_CHANGE$(echo)$TEST_CHANGE" \
      "$(create_release_notes ${TEST_TMPDIR}/CHANGELOG.md)"
  assert_equals "965c392 bb59d88" \
      "$(get_last_release "${TEST_TMPDIR}/CHANGELOG.md")"

  cat <<'EOF' >${TEST_TMPDIR}/CHANGELOG.md
## Cherry-picking bb59d88 and 14d905b

```
Baseline: 965c392
   + bb59d88: RELNOTES[INC]: Remove deprecated "make var" INCDIR
   + 14d905b: Add --with_aspect_deps flag to blaze query. This flag
              should produce additional information about aspect
              dependencies when --output is set to {xml, proto}.
```

EOF
  cat <<EOF >>${TEST_TMPDIR}/CHANGELOG.md
$TEST_INC_CHANGE
$TEST_NEW_CHANGE
EOF
  assert_equals "$TEST_CHANGE" \
      "$(create_release_notes ${TEST_TMPDIR}/CHANGELOG.md)"
}

function test_create_revision_information() {
  expected='Baseline: 965c392
   + bb59d88: RELNOTES[INC]: Remove deprecated "make var" INCDIR
   + 14d905b: Add --with_aspect_deps flag to blaze query. This flag
              should produce additional information about aspect
              dependencies when --output is set to {xml, proto}.'
   assert_equals "$expected" \
		 "$(create_revision_information 965c392 bb59d88 14d905b)"
}

run_suite "Release notes generation tests"

redpajama_set_name: RedPajamaGithub


Sant Esteve Church is a Romanesque and partially Gothic church, located at the entrance to the old quarter of the capital city of the small Principality of Andorra, Andorra la Vella.
The church dates back from 12th century, however, it was considerably modified in 20th century. Since it has been through significant alterations and enlargements, from the original church there only remains the semicircular apse, part of the walls of the nave and a small apse.
The apse is the largest and the most richly decorated in sculptures of the Romanesque apses preserved in Andorra, where it has two double slit windows and the quarter sphere roof is made of pumice stone. Outside, beneath the slate roof, there is a saw tooth frieze from one side to the other and below this another of blind arches, all in Lombard style, supported by a small table with geometrical decorations.
All of the walls have been decorated with murals, most likely from 13th century, where today some of them are partially preserved in the National Art Museum of Catalonia. There are also some mural paintings in two private collections, nonetheless, really important to be noted inside the church is the Painting of the Souls from 18th century.
The major restoration from 20th century happened in 1940, which was made by the modernist architect Josep Puig. Visible from various points of the capital city, Sant Esteve Church nowadays is a great symbol for this small country which is high in the Pyrenees Mountains, and greets every visitor who would like to learn more about the rich history of Andorra.


Articulation as an Act of Futility: A Deconstructive Exploration of Textual Articulation as It Functions within a First-Person Narrative Structure.
The inability of language to convey complete meaning and truth is a central point of address for much post-structuralist literary theory and criticism. When these theories are applied to a first-person narrative structure, whether it is a work of fiction or non-fiction, certain specific incongruities arise. When a narrative seeks to recall certain events, a presupposed reexamination takes place as the narrative unfolds text comes into being. If a narractice is contructed in this way then the intent of the text then is to convey comprehensive meanings or truths of those cataloged experiences. According Deconstructive Theory, it is language's inherent nature to resist ultimate meaning. This focus on the articulation of truth is futile because meaning, like language, is always already in a state of fragmentation. This project explores five individual works from different literary traditions-ranging from the canonical to the relatively obscure. The works exhibit various approaches to articulation; including varying degrees of self-definition, personal fiction, and narrative movement toward inarticulation.


text:
Walkthru: The three QB question
Wondering if the Bengals will keep three quarterbacks again this year and the dominoes the decision will set off.
Walkthru: The three QB question Wondering if the Bengals will keep three quarterbacks again this year and the dominoes the decision will set off. Check out this story on cincinnati.com: http://cin.ci/2x4pLEc
Paul Dehner Jr., pdehnerjr@enquirer.com Published 11:26 a.m. ET Aug. 16, 2017
Cincinnati Bengals quarterback Jeff Driskel (6) scores a touchdown in the third quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. (Photo: Kareem Elgazzar)
The Walkthru is a daily look at the Bengals, your questions and whatever else spills from the brains of beat writers Paul Dehner Jr. and Jim Owczarski. You can follow them on Twitter (@pauldehnerjr, @JimOwczarski), Instagram (@enqbengals) as well as Enquirer Sports on Facebook for behind the scenes and breaking news.
On this week's Bengals Beat Podcast, Jim and I got into a healthy discussion about the need to keep three quarterbacks.
Last year, the Bengals swooped in picking up Jeff Driskel off the waiver wire when he was cut by San Francisco following final cuts. The 2016 sixth-round pick of the 49ers spent all year on the team's 53. This marked the first year since gameday rosters were expanded to 46 and the third-QB restriction rule was lifted that the Bengals kept more than two quarterbacks on the roster.
With the Cincinnati tenure of backup AJ McCarron coming to an end in the coming years, the Bengals want to get a long look at potential future backups. So they used an extra roster spot on the 53 to make it happen.
With only seven draft picks last year and a light back-end of the roster, they had the space to stash a developmental QB.
Can they afford to do that again? It's a question many teams are asking themselves. On last year's opening day rosters, 17 teams kept three quarterbacks, 14 kept two and one kept four (Jets, you are always a comical delight).
The teams keeping three weren't necessarily those with unsure QB situations. Green Bay, Kansas City, Pittsburgh, Washington, Carolina and Tennessee were all among those keeping three.
Bengals win preseason opener over Tampa Bay, Aug. 11
Bengals fans smile and cheer as players warmup before kickoff of the Preseason Week 1 game with the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. Sam Greene
Fans cheer as AJ MCCarron and Andy Dalton take the field for warmups before the Preseason Week 1 game with the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. Sam Greene
Landon Gevedon, 8, of Huber Heights, Ohio, waits for the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
A young fan gives a thumbs down at the Tampa Bay Buccaneers take the field in the first quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. After one quarter, the Buccaneers led 3-0. Sam Greene
The Cincinnati Bengals take the field before the first quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. After one quarter, the Buccaneers led 3-0. Sam Greene
Cincinnati Bengals runnings back coach holds his son, Olsen, before the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Fans await the start of the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Zack Powell, 12, left, and Jack Pullen, 11, both of Union, Ky., await the start of the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
The Cincinnati Bengals defense closes in on Tampa Bay Buccaneers wide receiver Mike Evans (13) on a catch in the first quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. After one quarter, the Buccaneers led 3-0. Sam Greene
Cincinnati Bengals outside linebacker Vontaze Burfict (55) shouts down Tampa Bay Buccaneers wide receiver Adam Humphries (10) after a play in the first quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. After one quarter, the Buccaneers led 3-0. Sam Greene
Cincinnati Bengals cornerback Adam Jones (24) breaks up a pass in the end zone intended for Tampa Bay Buccaneers wide receiver Mike Evans (13) in the first quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. After one quarter, the Buccaneers led 3-0. Sam Greene
Cincinnati Bengals outside linebacker Vontaze Burfict (55) and cornerback Adam Jones (24) celebrate after a third down stop in the first quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. After one quarter, the Buccaneers led 3-0. Sam Greene
Cincinnati Bengals wide receiver Brandon LaFell (11) runs after a catch in the first quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. After one quarter, the Buccaneers led 3-0. Sam Greene
Tampa Bay Buccaneers cornerback Vernon Hargreaves (28) intercepts a pass in the end zone intended for Cincinnati Bengals wide receiver Brandon LaFell (11) in the first quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. After one quarter, the Buccaneers led 3-0. Sam Greene
Tampa Bay Buccaneers defensive back Marqueston Huff (34) is tracked by Cincinnati Bengals outside linebacker Vincent Rey (57) on a carry in the second second quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. At half time the Buccaneers led 9-6. Sam Greene
A Cincinnati police officer salutes as the national anthem is played before the the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Tampa Bay Buccaneers running back Peyton Barber (43) is brought down by Cincinnati Bengals cornerback KeiVarae Russell (20) short of the end zone in the second second quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. At half time the Buccaneers led 9-6. Sam Greene
Tampa Bay Buccaneers quarterback Ryan Fitzpatrick (14) strides into the end zone a a QB keeper in the second second quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. At half time the Buccaneers led 9-6. Sam Greene
Cincinnati Bengals defensive tackle Geno Atkins (97), center, is blocked as he tries to make the tackle of Tampa Bay Buccaneers running back Doug Martin (22) in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Tampa Bay Buccaneers wide receiver Mike Evans (13) comes down with a catch as Cincinnati Bengals cornerback Darqueze Dennard (21) and Cincinnati Bengals strong safety Shawn Williams (36) defend in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals running back Joe Mixon (28) breaks through the line on a carry in the second second quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. At half time the Buccaneers led 9-6. Sam Greene
Cincinnati Bengals kicker Jake Elliott (3) kicks a 45 yard field goal in the second second quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. At half time the Buccaneers led 9-6. Sam Greene
Cincinnati Bengals cornerback Darqueze Dennard (21), right, and Cincinnati Bengals cornerback William Jackson (22), high five after a defensive stop in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals defensive end Carlos Dunlap (96), center, reacts after a defensive stop in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals linebacker Carl Lawson (58) is wrapped up as he breaks through to rush Tampa Bay Buccaneers quarterback Ryan Griffin (4) in the second second quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. At half time the Buccaneers led 9-6. Sam Greene
Cincinnati Bengals outside linebacker Vontaze Burfict (55) talks to referee Gene Steratore (114) in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals running back Jeremy Hill (32) carries the ball as Tampa Bay Buccaneers outside linebacker Devante Bond (59) defends in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals running back Jeremy Hill (32) stiff arms Tampa Bay Buccaneers cornerback Ryan Smith (29) in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals wide receiver A.J. Green (18) makes a catch in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals defensive end Carlos Dunlap (96) steps away from the bench to greet young football players in the second quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. At half time the Buccaneers led 9-6. Sam Greene
Cincinnati Bengals tight end Tyler Eifert (85) comes down with a catch in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals wide receiver Brandon LaFell (11) runs after making a reception in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals linebacker Kevin Minter (51) lines up in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals safety Clayton Fejedelem (42) tackled Tampa Bay Buccaneers running back Jacquizz Rodgers (32) in the first quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals running back Tra Carson (33) is brought down by Tampa Bay Buccaneers safety Justin Evans (21) on a carry in the third quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Cincinnati Bengals quarterback Jeff Driskel (6) scrambles out of the pocket in the third quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Cincinnati Bengals quarterback Jeff Driskel (6) scrambles away from Tampa Bay Buccaneers defensive end Ryan Russell (95) in the third quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Cincinnati Bengals tight end Cethan Carter (82) runs deep on a catch in the third quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Cincinnati Bengals running back Tra Carson (33) runs to the outside in the third quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Fireworks explode over the Ohio River during the third quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Cincinnati Bengals head coach Marvin Lewis watches a play unfold in the fourth quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Tampa Bay Buccaneers quarterback Ryan Fitzpatrick (14) is rushed by Cincinnati Bengals defensive end Chris Smith (94) who breaks up the pass in the fourth quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Cincinnati Bengals offensive tackle Cedric Ogbuehi (70) sits on the bench in the fourth quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Cincinnati Bengals wide receiver Alex Erickson (12) runs a catch up the sideline in the fourth quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Cincinnati Bengals wide receiver Alex Erickson (12) turns downfield after making a catch in the third quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals quarterback Jeff Driskel (6) scores a touchdown in the third quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Tampa Bay Buccaneers head coach Dirk Koetter and Cincinnati Bengals head coach Marvin Lewis shake hands after the fourth quarter of the NFL Preseason Week 1 game between the Cincinnati Bengals and the Tampa Bay Buccaneers at Paul Brown Stadium in downtown Cincinnati on Friday, Aug. 11, 2017. The Bengals won the preseason opener, 23-12. Sam Greene
Cincinnati Bengals running back Tra Carson (33) finds running room in the third quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals wide receiver Josh Malone (80) comes down with a touchdown catch in the third quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals wide receiver Josh Malone (80), center, is congratulated after scoring a touchdown in the third quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals kicker Jake Elliott (3) kicks a point after touchdown in the third quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals cornerback Josh Shaw (26) makes a tacklein the third quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals defensive back Demetrious Cox (37) gets down to make a tackle on Tampa Bay Buccaneers running back Jeremy McNichols (33) in the third quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals defensive back Demetrious Cox (37) returns an interception in the third quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Tampa Bay Buccaneers running back Russell Hansbrough Brown (44) makes a catch in the fourth quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals linebacker Hardy Nickerson (56) makes a tackle on Tampa Bay Buccaneers running back Russell Hansbrough Brown (44) in the fourth quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals wide receiver Kermit Whitfield (13) turns downfield after making a catch in the fourth quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
Cincinnati Bengals defensive end Chris Smith (94) is double-teamed in the fourth quarter during the Week 1 NFL preseason game between the Tampa Bay Buccaneers and the Cincinnati Bengals, Friday, Aug. 11, 2017, at Paul Brown Stadium in Cincinnati. Kareem Elgazzar
It's as much about the big picture of the roster as anything.
The Bengals thought the development of Driskel was worth the spot last year and after his impressive debut against Tampa Bay there could be even more reason to keep him around. But this roster isn't like the 2016 version. The Bengals now have 11 draft picks they would like to keep (10 with Brandon Wilson likely starting year on NFI), plus two picks from last year (William Jackson III and Andrew Billings) who weren't on the roster due to injury.
They need to make a determination if Driskel could be the answer at No. 2 for whenever McCarron is gone. And if they come to the conclusion he's at that point now (which would have to be one heck of a preseason), perhaps they'd be more willing to deal McCarron to a prospective team sooner and save the roster spot. That's a more unlikely scenario, but more reason to give him reps earlier in these games with more of the starters in the game.
All of these play into the roster decision that will come at the end of this preseason and serve as a big domino in how the roster ends up constructed entering the opener against Baltimore.
ON TAP TODAY
Bengals final full practice of training camp – at least open to the media – will be today. Next week will be the standard regular season game schedule with media kicked out 30 minutes into practice.
TWITTER QUESTION OF THE DAY
Hey since you love Karaoke like I do, what kind of songs do you sing? I usually sing 50's-70's songs.
— Shelby T Mitchell (@ShelbyTMitchell) August 16, 2017
Great question. I'm always ready to talk karaoke. There is one primary rule of karaoke often overlooked and so often dooms the performer before the first note ever hits.
Commit this to memory, OK.
It's. Not. About. You.
That's right. When picking your song always be thinking about what this particularly audience would like to hear. You want a crowd pleaser. Don't try to fit your round peg song into a square peg venue. So, for that matter, you want to have a diverse portfolio of go-to songs.
With an older crowd, I'll go with Strokin', by Clarence Carter, for the 30s crowd I love doing Gin & Juice by Snoop and you can always go to the ultimate fallback crutch for any audience anywhere, and that's Sweet Caroline by Neil Diamond. Sing-a-longs are ideal. And when that song comes on, you don't even need to be in the room. The bar will take it from there.
This week's edition is on the offensive roster and features interviews with Trey Hopkins, Cedric Ogbuehi, Jake Fisher and wide receivers coach James Urban.
Day at camp included the return of safety George Iloka and a rough day of deep passes for Andy Dalton.
Running back Tra Carson is looking for a spot somewhere entering the second preseason game. Jim with more on his story.
Only one more of these left, so soak in our faces while you can.
AROUND THE DIVISION
Steelers: Tennessee's Josh Dobbs will be starting the second Pittsburgh preseason game with Ben Roethlisberger shelved.
Ravens: In our daily update of the state of the falling sky in Baltimore, WR Breshad Perriman probably won't play in the preseason with a hamstring and there's doubt he'll play the season opener against the Bengals.
Browns:Safety Jabrill Peppers had a breakout practice, apparently.
BENGALS TWITTER POSTS OF THE DAY
The Bengals were locked to the screen watching FC Cincinnati last night.
Great run @fccincinnati!
— Tyler Eifert (@EiferTy85) August 16, 2017
WOW!!! @fccincinnati up 2-0 on NY. LETS GO!!
— CJ Uzomah (@cjuzomah81) August 16, 2017
Let's Go #FCC
— Carlos Dunlap (@Carlos_Dunlap) August 16, 2017
GRAPH OF THE DAY
I think I will pin this at the top of my twitter page and also post it every day in the month of March as fans relentlessly ask why the Bengals aren't making a splash in free agency.
#Broncos really the only team over last few years to win via free agency, rather than draft. pic.twitter.com/B7QaJ00Rdh
— Benjamin Allbright (@AllbrightNFL) August 15, 2017
Nobody likes keeping up with their HOA until they forget to pay taxes and somebody buys your street.
This version of Groundhog Day thankfully never made it to theaters.
You never know how what you write will affect someone. Such an interesting reaction and reaction to his reaction from golfer Shaun Micheel for being called the worst golfer to win a major.
Nice fit with our quarterback discussion from Blind Melon.
Houshmandzadeh: Burrow can't if Carson couldn't
As caravan begins, Reds expecting more moves
Doc: OBJ must be such a shallow dude
Trevor Bauer fuels allegations that Astros players wore buzzers
FC Cincinnati moving on from Emmanuel Ledesma


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All relationships involve sacrifice. Many people include the concept of sacrifice in their definition of true love. Research shows that couples report feeling happier, and are more likely to stay in the relationship if the partners routinely make sacrifices for each other. Sometimes those sacrifices are life-changing. Other times they're smaller and may even seem mundane. Either way, they're inevitable. But when it comes time to make a sacrifice, it may not be easy.
Sacrifice raises power issues. If you're willing to sacrifice frequently early on in a relationship but your partner doesn't reciprocate, you may become trapped in a pattern in which you are always the one expected to give up or to give in. Over time, this lopsided pattern leads to a power imbalance, which is a recipe for long-term resentment and unhappiness.
Studies by social psychologists including Caryl Rusbult, Paul Van Lange, and Emily Impett suggest that making sacrifices for somebody you love shows them that you care and makes you feel better about yourself. But the research also shows that if you're always the one to sacrifice, or that you feel forced to sacrifice, that you should proceed with caution.
To discern whether or not the sacrifices are worth it, try answering these six questions:
How invested are you? One of the most significant forerunners to sacrifice is commitment. For a significant sacrifice to be worthwhile, you need to be sure you're committed the relationship and have confidence regarding your future together. Sacrifice can feel more palatable when it's helping you draw closer to somebody you plan to be with for the rest of your lives.
Would your partner sacrifice for you? Sacrifice is a two-way street. As you and your partner discuss whether to make a sacrifice or not, studies suggest that it's important to explore whether your partner has the same level of commitment in the situation as you do, and is going through a similar thought process to yours. If your partner is assuming that you're automatically the one who will make the sacrifice without taking similar responsibility on his or her end, you need to consider the situation more thoroughly.
Does one of you want the outcome more than the other wants it? When a situation would require sacrifice from just one of you, the other may not be as heavily invested in the end result. As you work through the details of the situation, be certain that you're both clear regarding your own priorities and desires.
Does your partner realize that you're making a sacrifice? If not, she or he will not be able to fully appreciate your selfless act. And if your partner doesn't understand that you're paying a price for the relationship's sake, he or she won't grasp why you're expecting a favor to be returned the next time that a sacrifice is involved. Also, it's important for you to know if your partner doesn't agree with you and therefore doesn't consider your actions to be a sacrifice.
Is there a superior solution? Rather than deciding from only among the choices at hand, you should work with your partner to discover if there's a solution that wouldn't require as significant a sacrifice from either of you. Close relationships involve giving when it's needed. But this doesn't mean that you and your partner can't reach an arrangement that would suit each of you equally well. Things may even work out in this way when bigger sacrifices are involved.
What is your motivation? This may be the most important question that you should ask yourself. Studies show that people make sacrifices for a wide variety of reasons, and they don't all guarantee a happy ending.
Are you moving across the country to keep your relationship intact and to make your partner happy? Or are you just attempting to avoid possible conflict? Avoidance-motivated sacrifices can undermine satisfaction and happiness in a relationship. If you're sacrificing to avoid conflicts, you may think, "I feel bad right now, but at least we're not fighting and our relationship isn't going to suffer." But this is not the case. People who believe that their partner's sacrifice was motivated by conflict avoidance tend to report less satisfaction regarding the relationship.
Thankfully, there is another option. When you're sacrificing to make your partner happy, the happiness and trust in the relationship can potentially increase. People who sacrifice for reasons such as long-term gain as a couple or helping to achieve your partner's dreams tend to be more satisfied and to have stronger relationships.
Sacrificing to increase your partner's happiness can be a positive thing. But it may be troublesome if you're constantly sacrificing because you want to be a "good" partner and to please your partner at the cost of your own happiness. In the long run, people who constantly prioritize their partner's needs over their own pay a price in terms of mental health and self-esteem. Sacrifice is a component of close relationships, but sacrificing should not force you to perpetually neglect your own needs.
Relationships include sacrifice. But before we give up or give in, we need to think things through: consider both the pros and the cons, communicate clearly with your partner, ask all the questions, and be sure you're not sacrificing for the wrong reasons. Properly sacrificing can draw couples closer. But making sacrifices for the wrong reasons can be worse than not sacrificing at all.


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Oracle rises and a classic villain gets an upgrade!
Nathan Simmons
Batgirl's new creative team drops her right into the fight of her life against … Killer Moth?!
Including the Terrible Trio in this issue is a great choice on the part of new series writer Cecil Castellucci. Since they were the main villains of the Mairghread Scott's final arc on Batgirl, it makes sense to bring them in as a menacing bridge to the next phase of Babs' life. We even get to see how expendable their members really are, since they're able to almost immediately hire a new Shark. It's an almost comedic moment when they remind Shark of the fact that he's just the muscle, but it's chilling when we remember just how horrific the original Shark's final moments were.
The fight between Killer Moth and Batgirl is beautifully drawn by Carmine Di Giandomenico. There's a lightness to Babs we haven't seen in a while in not only her poses and facial expressions, but in her general demeanor during the battle. Between the malfunction of her spinal implant and her general aggression in recent issues, it's been a minute since Barbara has seemed to actually enjoy fighting crime. Her narration is funny and sarcastic, which makes the fact that she's fighting a villain she's put down dozens of times (and her surprise as his new capabilities) even more apparent. The illustrations bring home the idea that Barbara has found a new peace with herself.
The acrobatic fight in the air is really exciting, as are the designs for Moth's different gadgets. The sequence in which the ground crumbles and Barbara loses her footing uses perspective in interesting ways, with Killer Moth looking more triumphant than he has in his entire career and Barbara's descent bleeding out of the panel and into the white space. It's a very effective moment.
As always, Jordie Bellaire's colors make every panel pop, particularly in the first few panels of Batgirl chasing Killer Moth, with the two of them standing out in colorful contrast against the city backdrop.
This issue also picks up the threads of Jason Bard's reform and kind of makes him adorable. I'm still so surprised by this change in character, but it really doesn't feel like an act. I can't imagine how Babs will respond when she starts to understand how Jason feels, but this issue does a good job of showing how much he has surprised himself with the way he feels.
What works against this issue is honestly its status as a tie-in to Year of the Villain. These scenes aren't bad by any means, but I'd imagine they're a little harder to follow for anyone who hasn't been following along with that event. The result is that we get a lot of foreshadowing and check-ins with at least one character who may or may not have a strong presence in this particular book going forward, at the expense of it feeling like we spend very little time with our lead character in comparison.
This isn't necessarily a failing of the new creative team. It's just kind of a shame that they had to begin their run with a tie-in issue. It almost feels like we'll have to wait until after Year of the Villain to see their true intentions for this character and her supporting cast. In the meantime, however, this issue is still a strong start that shows a firm grasp on Batgirl's identity.
Batgirl #37
Batgirl's new creative team hits the ground running with a solid Year of the Villain tie-in that will have you afraid of Killer Moth for the first time.
The action is fun and beautifully drawn, while Barbara looks like she's enjoying crimefighting for the first time in a while
The return of the Terrible Trio is a pleasant surprise that bridges this creative team's run to the previous one
The dialogue is snappy and fun, but never at the expense of raising the stakes
All of the Year of the Villain stuff kind of puts Babs on the backburner for large parts of the issue
In this article:batgirl, DC
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