Stress-induced lncRNA LASTR fosters cancer cell fitness by regulating the activity of the U4/U6 recycling factor SART3

Dysregulated splicing is a common event in cancer even in the absence of mutations in the core splicing machinery. The aberrant long non-coding transcriptome constitutes an uncharacterized level of regulation of post-transcriptional events in cancer. Here, we found that the stress-induced long non-coding RNA (lncRNA), LINCO2657 or LASTR (lncRNA associated with SART3 regulation of splicing), is upregulated in hypoxic breast cancer and is essential for the growth of LASTR-positive triple-negative breast tumors. LASTR is upregulated in several types of epithelial cancers due to the activation of the stress-induced JNK/c-JUN pathway. Using a mass-spectrometry based approach, we identified the RNA-splicing factor SART3 as a LASTR-interacting partner. We found that LASTR promotes splicing efficiency by controlling SART3 association with the U4 and U6 small nuclear ribonucleoproteins (snRNP) during spliceosome recycling. Intron retention induced by LASTR depletion downregulates expression of essential genes, ultimately decreasing the fitness of cancer cells

Efektifitas Penggunaan Model Pembelajaran Probing-prompting terhadap Konsentrasi Belajar Peserta Didik SMAN 14 Gowa pada Mata Pelajaran Fisika

Hasil penelitian menunjukkan adanya peningkatan konsentarsi belajar pada peserta didik yang diajar menggunakan model pembelajaran probing-prompting, diperoleh hasil pada penggunaan model pembelajaran probing-prompting sebesar 0,863 (sig > 0,05). Dan adanya peningkatan konsentarsi belajar pada peserta didik yang diajar menggunakan model pembelajaran konvensional yang diterapkan pada peserta didik kelas XI IPA 1, diperoleh hasil pada model pembelajaran konvensional 0,548 (sig > 0,05). Walaupun perbedaanya hanya selisih sedikit pada satu kelas yang dilakukan secara bergantian selama dua pekan. Hasil ini diperoleh dari hasil pengisian kuesioner dan perhitungan menggunakan aplikasi SPSS versi 20 for windows. Hal ini dapat menunjukkan bahwa model pembelajaran probing-prompting efektif untuk diterapkan dalam proses pembelajaran dibandingan dengan model pembelajaran Konvensional dalam hal konsentrasi belajar

The influence of PI3K inhibition on the radiotherapy response of head and neck cancer cells

Radiotherapy has a central role in the treatment of head and neck squamous cell carcinoma (HNSCC). Activation of the PI3K/AKT/mTOR pathway can decrease the efficiency of radiotherapy via the promotion of cell survival and DNA repair. Here, the influence of PI3K pathway inhibition on radiotherapy response was investigated. Two PI3K inhibitors were investigated and both BKM120 and GDC0980 effectively inhibited cellular and clonogenic growth in 6 HNSCC cells, both HPV-positive as well as HPV-negative. Despite targeted inhibition of the pathway and slight increase in DNA damage, PI3K inhibition did not show significant radiosensitization. Currently only one clinical trial is assessing the effectiveness of combining BKM120 with RT in HNSCC (NCT02113878) of which the results are eagerly awaited.status: publishe

Patient Selection in Human Papillomavirus Related Oropharyngeal Cancer: The Added Value of Prognostic Models in the New TNM 8th Edition Era

Background: With the growing interest in treatment de-intensification trials for human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC), prognostic models have become essential for patient selection. The aim of this paper is to validate and compare the prognostic ability of the TNM 8th edition and previous published risk group classifications of Ang et al. and Rietbergen et al. and to derive a patient selection classification for de-intensification trials. Materials: Patients with HPV+ OPC treated with curative (chemo)radiotherapy between 2004 and 2017 were classified according to the TNM 8th edition, the model of Ang et al. and of Rietbergen et al. HPV status was determined by p16 immunohistochemistry staining. Overall survival was estimated using the Kaplan-Meier method and groups were compared using the log-rank test. Harrell's C-index was used as measure of discriminative performance. Results: A total of 333 OPC were identified of whom 100 were HPV+. The median follow-up was 63.7 months. The 5-year overall survival (5Y-OS) of stage I, II and III were 91.6, 55.2, and 38.0%. There was a significant difference between stage I vs. II and III. The Harrell's C-index for TNM 8th edition stage was 0.67. Including only HPV+ OPC, the Harrell's C-index for the model of Ang and Rietbergen were both 0.62. We combined the main prognostic factors defining the low risk groups in the three models, stage I, low comorbidity and ≤ 10 pack years, into one new low risk group to identify patients who may benefit from de-intensification trials. Intermediate risk was defined as stage I with high comorbidity or >10 pack years, high risk as stage II-III. The 5Y-OS were 100, 85.7, and 51.3%. The Harrell's C-index for the new classification model was 0.67. Conclusion: Although TNM 8th edition provides better OS stratification than the 7th edition, it is not performant enough for patient selection, neither are the models from Ang et al. and Rietbergen et al. Therefore, we propose a patient selection classification for de-intensification trials based on the new TNM classification 8th edition, comorbidity and smoking pack years. In addition, this study emphasizes the importance of patient selection and personalized treatment for HPV+OPC.status: publishe

Prognostic significance of glutathione peroxidase levels (GPx1) in head and neck cancers

Introduction: To date, no reliable prognostic biological marker for all squamous cell carcinoma located in different subsites of the head and neck region has been identified and used in daily routine. In line with our previous studies, in which we showed a role of glutathione and associated enzymes as potential biological markers, we investigated the relationship between GPx1 and prognosis of head and neck squamous cell carcinoma.Methods: The association between GPx1 and patient and tumor related factors were investigated in 87 pretreatment biopsies from head and neck cancer patients treated by (chemo)radiation. Moreover, the influence of GPx1 expression on outcome parameters was assessed.Results: A significant difference was found in the T-stage between the low and high-expressing GPx1 groups. About 75% of the T3-T4 tumors were considered GPx1 low-expressing tumors, while low GPx1 expression was only seen in 25% of the T1-T2 tumors. There was also a significant difference found between the groups when looking at the different tumor sites. Local control, locoregional control, disease-free survival, and overall survival were the same in both groups. All these results indicate that GPx1 expression does not influence the radiotherapy response nor survival.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Nuclear p16INK4a expression predicts enhanced radiation response in head and neck cancers

Immunohistochemistry analysis of p16INK4a in head and neck squamous cell carcinomas (HNSCC) tumor samples revealed that 28% of tumors showed nuclear/cytoplasmic p16INK4a localization, while 37% of tumors had cytoplasmic p16INK4a. Our previous study showed that p16INK4a inhibits the DNA repair response independently of its function in the cell cycle, suggesting that p16INK4a subcellular localization should be considered during stratification of HNSCC patients. Using p16INK4a mutants with different localization signals, we found that expression of nuclear p16INK4a, but not cytoplasmic p16INK4a impaired RAD51 foci formation, indicating that nuclear localization of p16INK4a is crucial for its function in DNA repair. We next investigated the role of p16INK4a subcellular localization in radiation response in a retrospective cohort of 261 HNSCC patients treated with chemoradiation. We found that only HNSCC patients expressing nuclear p16INK4a expression showed better outcome, locoregional control and disease free survival, after chemoradiation. In concordance with the patient data, only expression of nuclear p16INK4a increased radiosensitivity of HNSCC cells. These results implicate nuclear p16INK4a expression as a potent marker to predict radiation response of HNSCC patients and should be taken into account in intensification or de-escalation studies

Prognostic Significance of Glutathione Peroxidase Levels (GPx1) in Head and Neck Cancers

IntroductionTo date, no reliable prognostic biological marker for all squamous cell carcinoma located in different subsites of the head and neck region has been identified and used in daily routine. In line with our previous studies, in which we showed a role of glutathione and associated enzymes as potential biological markers, we investigated the relationship between GPx1 and prognosis of head and neck squamous cell carcinoma.MethodsThe association between GPx1 and patient and tumor related factors were investigated in 87 pretreatment biopsies from head and neck cancer patients treated by (chemo)radiation. Moreover, the influence of GPx1 expression on outcome parameters was assessed.ResultsA significant difference was found in the T-stage between the low and high-expressing GPx1 groups. About 75% of the T3–T4 tumors were considered GPx1 low-expressing tumors, while low GPx1 expression was only seen in 25% of the T1–T2 tumors. There was also a significant difference found between the groups when looking at the different tumor sites. Local control, locoregional control, disease-free survival, and overall survival were the same in both groups. All these results indicate that GPx1 expression does not influence the radiotherapy response nor survival

Randomized clinical trial on reduction of radiotherapy dose to the elective neck in head and neck squamous cell carcinoma; update of the long-term tumor outcome

BACKGROUND AND PURPOSE: A multicenter prospective randomized controlled trial was performed to investigate whether dose reduction to the elective nodal volume (PTVelect) in head and neck carcinoma reduces radiation-induced dysphagia, primary endpoint, without compromising tumor control, secondary endpoint. Here, we report on the long-term follow-up of the secondary endpoint (NCT01812486). MATERIALS AND METHODS: Two hundred patients treated with primary (chemo)radiotherapy (RT) were randomized (1:1) between the standard arm, irradiation to PTVelect up to an equivalent dose (EQD2) of 50 Gy and the experimental arm, irradiation to PTVelect up to EQD2 of 40 Gy. The primary tumor and involved nodes were treated according to the standard of care, EQD2 70 Gy (PTVhigh). Regional recurrences (RR) were projected on the initial RT planning-CT to identify the recurrence localization. RESULTS: The 5-year (5Y) RR was 14.0% (CI95% 7.9; 21.8) in the 40 Gy arm versus 7.5% (CI95% 3.3; 14.0) in the 50 Gy arm (p = 0.10). Majority of RR in the 40 Gy arm (9/13) were projected in PTVhigh and 2 RR were seen outside the treated RT volume. Only 2 RR occurred in PTVelect irradiated up to 40 Gy which was the same number as RR occurring in the 50 Gy PTVelect. The 5Y-overall survival (OS) was 56.5% (CI95% 45.7; 65.9) in the 40 Gy arm versus 49.6% (CI95% 39.0; 59.2) in the 50 Gy arm (p = 0.56). CONCLUSION: At 5-years, no statistically significant differences regarding OS, local recurrence, RR nor distant metastases were observed between both treatment arms. This study is underpowered to undoubtedly demonstrate non-inferiority. However, since in both arms only two RR in the PTVelect were observed, reducing the dose to PTVelect appears safe and should be further investigated.status: publishe

Reduction of the dose of radiotherapy to the elective neck in head and neck squamous cell carcinoma; a randomized clinical trial. Effect on late toxicity and tumor control.

A multi-center prospective randomized clinical trial has been performed investigating whether a reduction of the dose to the elective nodal sites in head and neck cancer delivered by intensity modulated radiotherapy (IMRT) would result in a reduction of late side effects without compromising tumor control

Additional file 2: Figure e2. of In vitro and in vivo evaluation of the radiosensitizing effect of a selective FGFR inhibitor (JNJ-42756493) for rectal cancer

Effect on FGFR mRNA levels. (A) Quantification of FGFR mRNA expression in NCI-H716, Caco2, HCT116 and HCA7 cells after 72 h drug incubation. Data = means ± SEM of two independent experiments performed in duplicate. (B) Quantification of FGFR2 mRNA expression in NCI-H716 tumors isolated after drug treatment (TP1). Data = means ± SEM of three independent experiments. HPRT copy number was used to normalize the data. *Significantly different from control conditions at the appropriate drug concentrations (p < 0.05; Tukey). (PDF 4011 kb