RRM1 and ERCC1 are determinants of survival after surgical treatment of early-stage, non-small-cell lung cancer.

Purpose: Signal transducers and activators of transcription 3 (Stat3), a member of the STAT family of transcription factors, regulates multiple oncogenic pathways, including pathways regulating tumor cell survival.We evaluated Stat3 activation in early stage non^small cell lung cancers (NSCLC) and how this relates to upstream epidermal growth factor receptor (EGFR) activation, tumor apoptosis, and prognosis. Experimental Design: High-density tissue microarrays using tissues from 176 surgically resected NSCLC were evaluated for expression of phosphorylated Stat3 (pStat3) and epidermal growth factor receptor (pEGFR) along with tumor apoptosis. Using NSCLC cell lines, we evaluated how pStat3 expression relates to EGFR mutations and sensitivity of cells to gefitinib. Results: We identified nuclear pStat3 expression in 54% of tumors. pStat3 expression was correlated with smaller tumors (P < 0.0001) and with limited smoking history (P = 0.02).We identified a trend toward higher pStat3 expression in adenocarcinomas compared with other tumor histology (P = 0.09). No relationship was found between pStat3 and prognosis following surgical resection. Importantly, we found a strong positive correlation between pEGFR expression and pStat3 expression (P <0.0001) and an inverse correlation between pStat3 and apoptosis (P = 0.01) consistent with less apoptosis in tumors expressing high amounts of pStat3. Cell lines with mutant EGFR have increased levels of pStat3 compared with cell lines without mutant EGFR and this correlates with their sensitivity to gefitinib. Finally, antisense-mediated knockdown of Stat3 induces apoptosis in EGFR mutant lung cancer cells. Conclusions: Early-stage NSCLC tumors have activated EGFR-Stat3 signaling with low apoptosis. Our findings suggest that pStat3 expression may be helpful in identifying patients appropriate for treatment with EGFR tyrosine kinase inhibitors.

Transfer RNA is heavily modified and plays a central role in protein synthesis and cellular functions. Here we demonstrate that ALKBH3 is a 1-methyladenosine (m1A) and 3-methylcytidine (m3C) demethylase of tRNA. ALKBH3 can promote cancer cell proliferation, migration and invasion. In vivo study confirms the regulation effects of ALKBH3 on growth of tumor xenograft. The m1A demethylated tRNA is more sensitive to angiogenin (ANG) cleavage, followed by generating tRNA-derived small RNAs (tDRs) around the anticodon regions. tDRs are conserved among species, which strengthen the ribosome assembly and prevent apoptosis triggered by cytochrome c (Cyt c). Our discovery opens a potential and novel paradigm of tRNA demethylase, which regulates biological functions via generation of tDRs.

Purpose We evaluated the efficacy of gemcitabine versus gemcitabine and carboplatin in patients with advanced non–small-cell lung cancer (NSCLC) and a performance status (PS) of 2 and assessed if tumoral RRM1 and ERCC1 protein levels are predictive of response to therapy. Patients and Methods A randomized phase III trial was conducted in community-based oncology practices. Tumor specimens were collected a priori and shipped to a single laboratory for blinded determination of in situ RRM1 and ERCC1 protein expression levels by an automated quantitative immunofluorescent-based technology. Results One hundred seventy patients were randomly assigned. Overall median survival was 5.1 months for gemcitabine and 6.7 months for gemcitabine and carboplatin (P = .24). RRM1 (range, 5.3 to 105.6; median, 34.1) and ERCC1 (range, 5.2 to 131.3; median, 34.7) values were significantly and inversely correlated with disease response (r = −0.41; P = .001 for RRM1; r = −0.39; P = .003 for ERCC1; ie, response was better for patients with low levels of expression). A model for response prediction that included RRM1, ERCC1, and treatment arm, was highly predictive of the treatment response observed (P = .0005). We did not find statistically significant associations between survival and RRM1 or ERCC1 levels. Conclusion Single-agent chemotherapy remains the standard of care for patients with advanced NSCLC and poor PS. Quantitative analysis of RRM1 and ERCC1 protein expression in routinely collected tumor specimens in community oncology practices is predictive of response to gemcitabine and gemcitabine and carboplatin therapy. Oncologists should consider including in situ expression analysis for these proteins into their therapeutic decisions.

A B S T R A C T PurposeWe assessed whether chemotherapy selection based on in situ ERCC1 and RRM1 protein levels would improve survival in patients with advanced non-small-cell lung cancer (NSCLC). Patients and MethodsEligible patients were randomly assigned 2:1 to the trial's experimental arm, which consisted of gemcitabine/carboplatin if RRM1 and ERCC1 were low, docetaxel/carboplatin if RRM1 was high and ERCC1 was low, gemcitabine/docetaxel if RRM1 was low and ERCC1 was high, and docetaxel/vinorelbine if both were high. In the control arm, patients received gemcitabine/ carboplatin. The trial was powered for a 32% improvement in 6-month progression-free survival (PFS). ResultsOf 331 patients registered, 275 were eligible. The median number of cycles given was four in both arms. A tumor rebiopsy specifically for expression analysis was required in 17% of patients. The median time from informed consent to expression analysis was 11 days. We found no statistically significant differences between the experimental arm and the control arm in PFS (6.1 months v 6.9 months) or overall survival (11.0 months v 11.3 months). A subset analysis revealed that patients with low levels for both proteins who received the same treatment in both treatment arms had a statistically better PFS (P ϭ .02) in the control arm (8.1 months) compared with the experimental arm (5.0 months). ConclusionThis demonstrates that protein expression analysis for therapeutic decision making is feasible in newly diagnosed patients with advanced-stage NSCLC. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% (47 of 53) of patients.

The identification of molecular markers, useful for therapeutic decisions in pancreatic cancer patients, is crucial for advances in disease management. Gemcitabine, although a cornerstone of current therapy, has limited efficacy. RRM1 is a key molecule for gemcitabine efficacy and is also involved in tumor progression. We determined in situ RRM1 and excision repair cross complementation group 1 (ERCC1) protein levels in 68 pancreatic cancer patients. All had R0 resections without preoperative therapy. Protein levels were determined by automated quantitative analysis (AQUA), a fluorescence-based immunohistochemical method. The relationship between protein expressions and clinical outcomes, including response to gemcitabine at the time of disease recurrence, was determined. Patients with high RRM1 showed significantly better overall survival than patients with low expression (P=0.0196). There was a trend toward better overall survival for patient with high ERCC1 (P=0.0552). When both markers were considered together, patients with both high RRM1 and ERCC1 faired the best in terms of overall and disease-free survival (P=0.0066, P=0.0127). In addition, treatment benefit from gemcitabine in patients with disease recurrence was observed only in patients with low RRM1. The combination of RRM1 and ERCC1 expression is prognostic in pancreatic cancer patients after a complete resection. On disease recurrence, only patients with low RRM1 derive benefit from gemcitabine.

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Currently, we are on a global pandemic of Coronavirus disease-2019 (COVID-19) which causes fever, dry cough, fatigue and acute respiratory distress syndrome (ARDS) that may ultimately lead to the death of the infected. Current researches on COVID-19 continue to highlight the necessity for further understanding the virus-host synergies. In this study, we have highlighted the key cytokines induced by coronavirus infections. We have demonstrated that genes coding interleukins (Il-1α, Il-1β, Il-6, Il-10), chemokine (Ccl2, Ccl3, Ccl5, Ccl10), and interferon (Ifn-α2, Ifn-β1, Ifn2) upsurge significantly which in line with the elevated infiltration of T cells, NK cells and monocytes in SARS-Cov treated group at 24 hours. Also, interleukins (IL-6, IL-23α, IL-10, IL-7, IL-1α, IL-1β) and interferon (IFN-α2, IFN2, IFN-γ) have increased dramatically in MERS-Cov at 24 hours. A similar cytokine profile showed the cytokine storm served a critical role in the infection process. Subsequent investigation of 463 patients with COVID-19 disease revealed the decreased amount of total lymphocytes, CD3+, CD4+, and CD8+ T lymphocytes in the severe type patients which indicated COVID-19 can impose hard blows on human lymphocyte resulting in lethal pneumonia. Thus, taking control of changes in immune factors could be critical in the treatment of COVID-19.