Phase I/Ib dose-escalation study of avelumab in Chinese patients with advanced solid tumors.

Aim: Data for avelumab (anti-PD-L1 antibody) in Chinese patients are limited. Patients & methods: Phase I/Ib, open-label, dose-escalation study of Chinese patients with advanced solid tumors. Primary study objectives were to evaluate the maximum tolerated dose (MTD) and pharmacokinetics (PK) of avelumab. Results: 24 patients received avelumab 3 mg/kg every 2 weeks (Q2W; n = 3), 10 mg/kg Q2W (n = 7), 20 mg/kg Q2W (n = 6) or 10 mg/kg weekly for 12 weeks and then Q2W thereafter (n = 8). MTD was not reached. Avelumab exposure was increased in higher dose groups. Partial responses occurred in two patients (confirmed in one patient); best overall response was stable disease in nine patients. Conclusion: Data for avelumab in Chinese patients with advanced solid tumors were consistent with previous global studies.

Avelumab is a form of medicine that falls under the category of immunotherapy. This means that it can help the immune system find and destroy cancer cells. In this study, researchers looked at the safety of avelumab in a small group of Chinese people with different types of cancer. Researchers also looked at blood levels of avelumab after treatment. Different doses of avelumab were given to different groups of people. Overall, study results for avelumab in Chinese people were similar to results from earlier studies in other countries.  Clinical trial registration: NCT03523390 (ClinicalTrials.gov).

High-Throughput Salivary Metabolite Profiling on an Ultralow Noise Tip-Enhanced Laser Desorption Ionization Mass Spectrometry Platform for Noninvasive Diagnosis of Early Lung Cancer.

Lung cancer (LC) is a widespread cancer that is the cause of the highest mortality rate accounting for 25% of all cancer deaths. To date, most LC patients are diagnosed at the advanced stage owing to the lack of obvious symptoms in the early stage and the limitations of current clinical diagnostic techniques. Therefore, developing a high throughput technique for early screening is of great importance. In this work, we established an effective and rapid salivary metabolic analysis platform for early LC diagnosis and combined metabolomics and transcriptomics to reveal the metabolic fluctuations correlated to LC. Saliva samples were collected from a total of 150 volunteers including 89 patients with early LC, 11 patients with advanced LC, and 50 healthy controls. The metabolic profiling of noninvasive samples was investigated on an ultralow noise TELDI-MS platform. In addition, data normalization methods were screened and assessed to overcome the MS signal variation caused by individual difference for biomarker mining. For untargeted metabolic profiling of saliva samples, around 264 peaks could be reliably detected in each sample. After multivariate analysis, 23 metabolites were sorted out and verified to be related to the dysfunction of the amino acid and nucleotide metabolism in early LC. Notably, transcriptomic data from online TCGA repository were utilized to support findings from the salivary metabolomics experiment, including the disorder of amino acid biosynthesis and amino acid metabolism. Based on the verified differential metabolites, early LC patients could be clearly distinguished from healthy controls with a sensitivity of 97.2% and a specificity of 92%. The ultralow noise TELDI-MS platform displayed satisfactory ability to explore salivary metabolite information and discover potential biomarkers that may help develop a noninvasive screening tool for early LC.

Development of nomograms to predict therapeutic response and prognosis of non-small cell lung cancer patients treated with anti-PD-1 antibody.

BACKGROUND: Anti-programmed death-1 (PD-1) antibody changed the treatment of non-small cell lung cancer (NSCLC), however, reliable predictive markers were lacking. We aimed to explore factors associated with response and survival, and develop predictive models. METHODS: This multicenter retrospective study included a training cohort (n = 92) and validation cohort (n = 111) with NSCLC patients received anti-PD-1 antibody monotherapy in eight Chinese hospitals, and a control cohort (n = 124) with NSCLC patients received chemotherapy. Logistic and Cox models were used to identify factors associated with response and survival respectively. Nomograms were developed based on significant factors, and evaluated by Concordance-index (C-index), area under the curve (AUC) and calibration curve. RESULT: In training cohort, smoking history (P = 0.027) and higher absolute lymphocyte count (P = 0.038) were associated with response. Female (P < 0.001), age ≥ 65 years (P = 0.004) and higher lactate dehydrogenase (LDH, P < 0.001) were associated with shorter progression-free survival (PFS). Higher LDH (P < 0.001) and derived neutrophil-to-lymphocyte ratio (P = 0.035) were associated with poorer overall survival (OS). While these factors were nonsignificant in chemotherapy cohort. Three nomograms to predict response at 6-week after treatment, PFS and OS at 6-, 12- and 18-months were developed, and validated in validation cohort. The C-indices of each nomogram in both cohorts were as follow (training vs validation): 0.706 vs 0.701; 0.728 vs 0.701; 0.741 vs 0.709; respectively. AUC showed a good discriminative ability. Calibration curves demonstrated a consistence between actual results and predictions. CONCLUSION: We developed predictive nomograms based on easily available factors to help clinicians early assess response and prognosis for NSCLC patients received anti-PD-1 antibody.

The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells.

Pancreatic cancer has one of worst prognosis among all human malignancies around the world, the development of novel and more efficient anti-cancer agents against this disease is urgent. In the current study, we tested the potential effect of INK-128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells in vitro. Our results demonstrated that INK-128 concentration- and time-dependently inhibited the survival and growth of pancreatic cancer cells (both primary cells and transformed cells). INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. Further, INK-128 dramatically inhibited phosphorylation of 4E-binding protein 1 (4E-BP1), ribosomal S6 kinase 1 (S6K1) and Akt at Ser 473 in pancreatic cancer cells. Meanwhile, it downregulated cyclin D1 expression and caused cell cycle arrest. Finally, we found that a low concentration of INK-128 significantly increased the sensitivity of pancreatic cancer cells to gemcitabine. Together, our in vitro results suggest that INK-128 might be further investigated as a novel anti-cancer agent or chemo-adjuvant for pancreatic cancer treatment.

Comparison of long-term effectiveness and complications of radiofrequency ablation with hepatectomy for small hepatocellular carcinoma.

BACKGROUND AND AIM: To determine and compare the adverse events and long-term effectiveness for patients with small hepatocellular carcinoma (HCC) (≤ 3 cm) treated by percutaneous radiofrequency ablation (RFA) or hepatectomy. METHODS: Small HCC from 120 patients were randomized into either percutaneous RFA therapy or hepatectomy group, and the effectiveness and complications of two treatment modalities were analyzed. The complications of post-RFA or hepatectomy, the complete treatment rate, treatment-related mortality, and disease-free and overall survival rate were followed up and conducted. RESULTS: In patients with small HCC, complete remission rates were achieved in 95% and 96.7% in the percutaneus RFA and hepatectomy groups, respectively (P > 0.05). Hepatic function at day-7 status post-treatment, including albumin and bilirubin levels, were significantly worse in the hepatectomy group (P < 0.01). Compared with the RFA group, the incidence of postoperative complications (27.5% vs 5.0%) and hospital stay (11.8 ± 3.1 vs 4.3 ± 1.5) were significantly higher in the hepatectomy group (P < 0.01). After a mean follow-up of 40 months, 22 patients (36.6%) in the RFA group and 21 patients (35.0%) in the hepatectomy group developed a recurrence (P > 0.05). There was no significant difference of the disease-free and overall survival rates at 1, 2, and 3 years between the RFA group and the surgical hepatectomy group (P = 0.443 and P = 0.207, respectively). CONCLUSIONS: In patients with small HCC, percutaneous RFA showed similar local control and long-term survival compared with hepatectomy. Importantly, percutaneous RFA are accompanied with a lower complication rate and shorter hospital stay day.

Effects of Patient-Controlled Transcutaneous Electrical Acupoint Stimulation on Cancer Induced Bone Pain Relief in Patients with Non-Small Cell Lung Cancer: Study Protocol for a Randomized Controlled Trial.

Background: Transcutaneous Electrical Acupoint Stimulation (TEAS) therapy opens up the possibility for individuals with Cancer-induced bone pain (CIBP) to receive a home-based, patient-controlled approach to pain management. The aim of this study is designed to evaluate the efficacy of patient-controlled TEAS (PC-TEAS) for relieving CIBP in patients with non-small cell lung cancer (NSCLC). Methods/Design: This is a study protocol for a prospective, triple-blind, randomized controlled trial. We anticipate enrolling 188 participants with NSCLC bone metastases who are also using potent opioid analgesics from 4 Chinese medical centers. These participants will be randomly assigned in a 1:1 ratio to either the true PC-TEAS or the sham PC-TEAS group. All participants will receive standard adjuvant oncology therapy. The true group will undergo patient-controlled TEAS intervention as needed, while the sham group will follow the same treatment schedule but with non-conductive gel patches. Each treatment course will span 7 days, with a total of 4 courses administered. There will be 4 assessment time points: baseline, the conclusion of weeks 4, 8, and 12. The primary outcome of this investigation is the response rate of the average pain on the Brief Pain Inventory (BPI) scale at week 4 after treatment. Secondary outcomes include pain related indicators, quality of life scale, mood scales, and routine blood counts on the assessment days. Any adverse events will be promptly addressed and reported if they occur. We will manage trial data using the EDC platform, with a data monitoring committee providing regular quality oversight. Discussion: PC-TEAS interventions offer an attempt to achieve home-based acupuncture treatment and the feasibility of achieving triple blinding in acupuncture research. This study is designed to provide more rigorous trial evidence for the adjuvant treatment of cancer-related pain by acupuncture and to explore a safe and effective integrative medicine scheme for CIBP. Trial Registration: ClinicalTrials.gov NCT05730972, registered February 16, 2023.

Inhibition of the angiogenesis and growth of Aloin in human colorectal cancer in vitro and in vivo.

BACKGROUND: Angiogenesis has been an attractive target for drug therapy. Aloin (AL), an natural compound derived from Aloe barbadensis Miller leaves, has been shown to possess anti-cancer potential activities. However, its roles in tumor angiogenesis and the involved molecular mechanism are unknown. METHOD: To evaluate the antiangiogenic and anticancer activities of AL, endothelial cell scratch, modified Boyden chamber inserts and tube formation assays were done in HUVECs, and MTT and Live-Dead assays were used to determine the proliferation inhibition and apoptosis induction of colorectal cancer cells in vitro. The inhibition effects of AL were further confirmed by a mouse xenograft model in vivo. The expression levels of STAT3 signaling pathway and that mediated-target genes were measured in HUVECs and SW620 cells by Western blots. RESULTS: Here, we demonstrated that AL significantly inhibited HUVECs proliferation, migration and tube formation in vitro. Western blotting showed that AL suppressed activation of VEGF receptor (VEGFR) 2 and STAT3 phosphorylation in endothelial cells. In addition, the constitutively activated STAT3 protein, and the expression of STAT3-regulated antiapoptotic (Bcl-xL), proliferative (c-Myc), and angiogenic (VEGF) proteins were also down-regulated in response to AL in human SW620 cancer cells. Consistent with the above findings, AL inhibited tumor cell viability and induced cell apoptosis in vitro, and substantially reduced tumor volumes and weight in vivo mouse xenografts, without obviously toxicity. CONCLUSION: Our studies provided the first evidence that AL may inhibit tumor angiogenesis and growth via blocking STAT3 activation, with the potential of a drug candidate for cancer therapy.

A phase Ia dose-escalation trial of Ametumumab (a fully human monoclonal antibody against epidermal growth factor receptor) in patients with advanced solid malignancies.

Background: Epidermal growth factor receptor (EGFR) is a well-known target for cancer treatment. However, the authorized anti-EGFR monoclonal antibodies generally cause several toxic effects, especially severe cutaneous toxicities as well as infusion reactions, and the clinical indications are limited. Here we developed Ametumumab, a fully human recombinant anti-EGFR monoclonal antibody. Objectives: To assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of Ametumumab. Design: A first-in-human phase Ia dose escalation study of Ametumumab in patients with advanced solid malignancies. Methods: An open-label, first-in-human dose escalation study was done in 22 patients with advanced malignancies who received six ascending dosages ranging from 75 to 750 mg/m2. Following a single dosage and a 28-day dose-limiting toxicity (DLT) monitoring period, patients were given repeated doses weekly. Blood samples were taken to determine the PK parameters of Ametumumab and anti-drug antibody concentrations. Every 8 weeks, radiographic tumor evaluations were conducted. Results: In this trial, no DLT was observed, and the maximum tolerated dose was not reached at doses up to 750 mg/m2. There were no severe adverse events but mild and moderate adverse effects, such as headache, proteinuria, and rash. Single-dose PK results demonstrated a straightforward linear relationship with dosage escalation. The medication concentrations accumulated and attained steady-state after four rounds of injections. It was calculated that 10 patients with disease control would be observed in the 22 evaluable patients. The disease control rate was 45.5%. Conclusion: The Ametumumab was well tolerated and safe in patients with advanced solid malignancies, exhibiting minimal immunogenicity, a long half-life, high levels of drug exposure in the blood, and preliminary effectiveness. Registration: The trial was registered with CTR20170343 on 10 April 2017, The China Center for Drug Evaluation.

Comprehensive Molecular Profiling of Colorectal Cancer With Situs Inversus Totalis by Next-Generation Sequencing.

Background: Colorectal cancer (CRC) is one of the most prevalent malignances worldwide. However, CRC with situs inversus totalis (SCRC) is extremely rare, and molecular characterization of this disease has never been investigated. Methods: Tumor tissue samples from 8 patients with SCRC and 33 CRC patients without situs inversus totalis (NSCRC) were subjected to multigene next-generation sequencing. Results: The most frequently mutated genes in SCRC were APC, TP53, CHEK2, MDC1, GNAQ, KRAS, and SMAD4. A high frequency of SCRC tumors had mutations in DNA damage repair genes. Single amino acid substitutions in the DNA damage repair genes caused by continuous double base substitution was identified in the majority of this population. Furthermore, mutational profiles showed notable differences between the SCRC and NSCRC groups. In particular, CHEK2, MDC1, GNAQ, SMAD4, BRCA1, HLA-B, LATS2, and NLRC5 mutations were more frequently observed in SCRC patients. The mutation loci distributions of KRAS in the SCRC cohort differed from that of the NSCRC cohort. Additionally, differences in the targeted genomic profiles and base substitution patterns were observed between the two groups. Conclusions: These findings comprehensively revealed a molecular characterization of SCRC, which will contribute to the development of personalized therapy and improved clinical management of SCRC patients.

Complete Response to Pembrolizumab in Advanced Colon Cancer Harboring Somatic POLE F367S Mutation with Microsatellite Stability Status: A Case Study.

BACKGROUND: Polymerase epsilon (POLE) mutations are considered as one of the most potential and promising biomarkers for immune checkpoint inhibitors (ICIs) in patients with colorectal cancer. However, the treatment of ICIs sometimes also resulted in unsatisfactory results in patients with POLE mutations, which revealed that not all mutations on POLE contribute to tumor regression in colorectal cancer. CASE PRESENTATION: We herein reported a case in which the patient with advanced colon cancer harboring somatic POLE F367S mutation, along with microsatellite stability status, has achieved efficacy of complete response to the programmed cell death 1 (PD-1) receptor inhibitor pembrolizumab, as well as a progression-free survival more than 49 months, and still in extension. CONCLUSION: Somatic POLE F367S mutation might be presented as a sensitive predictor to pembrolizumab in patients with colon cancer.

Comparison of circulating tumor cell (CTC) detection rates with epithelial cell adhesion molecule (EpCAM) and cell surface vimentin (CSV) antibodies in different solid tumors: a retrospective study.

PURPOSE: Status of epithelial-mesenchymal transition (EMT) varies from tumors to tumors. Epithelial cell adhesion molecule (EpCAM) and cell surface vimentin (CSV) are the most common used targets for isolating epithelial and mesenchymal CTCs, respectively. This study aimed to identify a suitable CTC capturing antibody for CTC enrichment in each solid tumor by comparing CTC detection rates with EpCAM and CSV antibodies in different solid tumors. METHODS: Treatment-naive patients with confirmed cancer diagnosis and healthy people who have performed CTC detection between April 2017 and May 2018 were included in this study. CTC detection was performed with CytoSorter® CTC system using either EpCAM or CSV antibody. In total, 853 CTC results from 690 cancer patients and 72 healthy people were collected for analysis. The performance of CTC capturing antibody was determined by the CTC detection rate. RESULTS: EpCAM has the highest CTC detection rate of 84.09% in CRC, followed by BCa (78.32%). CTC detection rates with EpCAM antibody are less than 40% in HCC (25%), PDAC (32.5%) and OC (33.33%). CSV has the highest CTC detection rate of 90% in sarcoma, followed by BC (85.71%), UC (84.62%), OC (83.33%) and BCa (81.82%). CTC detection rates with CSV antibody are over 60% in all 14 solid tumors. Except for CRC, CSV has better performances than EpCAM in most solid tumors regarding the CTC detection rates. CONCLUSION: EpCAM can be used as a target to isolate CTCs in CRC, LC, GC, BCa, EC, HNSCC, CC and PCa, especially in CRC, while CSV can be used in most solid tumors for isolating CTCs.

Novel Nutrition-Based Nomograms to Assess the Outcomes of Lung Cancer Patients Treated With Anlotinib or Apatinib.

BACKGROUND: Previous studies have indicated that the changes in body composition during treatment are prognostic in lung cancer. The question which follows is it may be too late to identify vulnerable patients after treatment and to improve outcomes for these patients. In our study, we sought to explore the alterations of body composition and weight before the outset of the antiangiogenic treatment and its role in predicting clinical response and outcomes. METHODS: In this retrospective study, 122 patients with advanced lung cancer treated with anlotinib or apatinib were analyzed. The changes in weight and body composition including skeletal muscle index (SMI), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) for 3 months before the outset of antiangiogenic treatment and other clinical characteristics were evaluated with LASSO Cox regression and multivariate Cox regression analysis, which were applied to construct nomograms. The performance of the nomograms was validated internally by using bootstrap method with 1,000 resamples models and was assessed by the concordance index (C-index), calibration plots, decision curve analysis (DCA). RESULTS: The median progression-free survival (PFS) and overall survival (OS) were 128 (95% CI 103.2-152.8) days and 292 (95% CI 270.9-313.1) days. Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastases, the Glasgow Prognostic Score (GPS), clinical response, therapeutic regimen, and ΔL1SMI per 90 days were significantly associated with PFS, while ECOG PS, GPS, clinical response, therapeutic regimen, ΔL1SMI per 90 days were identified for OS. The C-index for the nomograms of PFS and OS were 0.763 and 0.748, respectively. The calibration curves indicated excellent agreement between the predicted and actual survival outcomes of 3- and 4-month PFS and 7- and 8-month OS. DCA showed the considerable value of the model. CONCLUSION: Nomograms were developed from clinical features and nutritional indicators to predict the probability of achieving 3-month and 4-month PFS and 7-month and 8-month OS with antiangiogenic therapy for advanced lung cancer. Dynamic changes in body composition before the initiation of treatment contributed to early detection of poor outcome.

A Novel Nutrition-Based Nomogram to Predict Prognosis After Curative Resection of Gastric Cancer.

Objective: We sought to investigate the prognostic significance of body composition and weight change during the first 6 months of adjuvant chemotherapy after R0 resection and develop novel nomograms to accurately predict relapse-free survival (RFS) and overall survival (OS). Methods: This retrospective study included 190 patients who underwent curative radical gastrectomy for gastric cancer and received adjuvant chemotherapy. The changes in weight and body composition including skeletal muscle index (SMI), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were analyzed for 6 months. LASSO Cox regression and multivariate Cox regression were conducted to evaluate other clinical characteristics, which were used to construct a nomogram for the prediction of 3- and 5-year RFS and OS. The constructed nomogram was subjected to 1,000 resamples bootstrap for internal validation. The Concordance index (C-index) and time-dependent receiver operating characteristic (t-ROC) curves were used to evaluate and compare the discriminative abilities of the new nomograms, non-nutritional nomograms, and pTNM stage. Results: The median follow-up duration was 42.0 (25.2-55.1) months. Factors included in the newly-built nomogram for RFS were pT stage, pN stage, tumor site, tumor size, nerve invasion or not, surgery type, and change of L3SMI, while factors included in the nomogram for OS were pT stage, pN stage, tumor size, nerve invasion or not, surgery type, and change of L3SMI. The C-index and t-ROC indicated that our newly-built nomograms had greater potential to accurately predict prognosis than the non-nutritional nomograms and pTNM stage system. Besides, oral nutritional supplements can reduce the degree of weight and L3SMI loss. Conclusion: Change in skeletal muscle mass during adjuvant chemotherapy can be incorporated into predictive prognostic nomograms for RFS and OS in GC patients after radical resection. Dynamic changes in body composition and weight during adjuvant chemotherapy contribute to the early detection of poor outcomes.

Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes.

BACKGROUND: Recently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy. METHODS: Genomic tumor DNA was isolated from 98 Chinese patients with advanced BTC and used for targeted next-generation sequencing of 416 cancer-related genes to identify the genomic alterations common to advanced BTC. Thirty-four patients had received ICI camrelizumab plus gemcitabine and oxaliplatin (from the NCT03486678 trial) as a first-line treatment. Tumor-infiltrating immune cells were evaluated using immunofluorescence staining. RESULTS: KRAS and TP53 mutations were much more frequent in the advanced-stage BTC cohort than in other cohorts with mostly early stage disease. Specifically, KRAS-TP53 co-mutations were favored in advanced CHOL, with a favorable response to immunotherapy, while single KRAS mutations predicted poor prognosis and immunotherapy outcomes for CHOL. Compared with GBC, CHOL had more mutations in genes involved in KRAS signaling; a high mutation load in these genes correlated with poor immunotherapy outcomes and may subsequently cause inferior immunotherapy outcomes for CHOL relative to GBC. Furthermore, a genomic signature including 11 genes was developed; their mutated subtype was associated with poor prognosis and immunotherapy outcomes in both CHOL and GBC. Transcriptome analyses suggested immune dysfunction in the signature mutated subtype, which was validated by tumor microenvironment (TME) evaluation based on detection of immune cell infiltration. Importantly, the signature wild-type subtype with favorable TME may be an advantageous population of immunotherapy. CONCLUSIONS: Genomic alterations in advanced BTC were associated with specific prognosis and immunotherapy outcomes. Combining genomic classification with TME evaluation further improved the stratification of immunotherapy outcomes.

NF1 germline mutation in a Chinese family with colon cancer.

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Recent advances in genomic medicine have identified novel gene mutations that contribute to an increased risk of CRC. Here, we describe a diagnosis of colon cancer in a 63-year-old woman and also in her brother. Next-generation sequencing showed that both patients harbored a germline mutation in NF1. The female patient also carried co-mutations in KRAS and NRAS. Furthermore, the NF1 germline mutation was identified in a healthy offspring of the brother. The female patient received three cycles of bevacizumab plus capecitabine/oxaliplatin therapy and achieved stable disease of the primary lesion in the colon and partial response of metastasis in the right abdominal cavity. This study highlights the association of NF1 germline mutations with colon cancer.

[Retracted] p53 suppresses stress­induced cellular senescence via regulation of autophagy under the deprivation of serum.

Following the publication of this article, an interested reader drew to the Editor's attention that certain GAPDH control bands were strikingly similar, comparing between two different figures in the paper. Two GAPDH bands in Fig. 1D appeared to be duplicates of two GAPDH bands featured in Fig. 3B, although different conditions were represented by these figures. Furthermore, the protein bands featured in the two lanes in the left p62 panel in Fig. 1D, when flipped horizontally, looked remarkably similar to the Cyclin B lanes featured in the right-hand gel of Fig. 3B. Finally, the same protein bands were also strikingly similar to bands featured in Fig. 4B, albeit in a different experimental context. The Editor of Molecular Medicine Reports has investigated this matter, and we were able to confirm that the two sets of data bands featured in this trio of figures were indeed the same ones, beyond all reasonable doubt. Consequently, the Editor has decided that this article should be retracted from the publication on the basis of an overall lack of confidence in the presented data. The Editor apologizes to the readership of the Journal for any inconvenience caused. [the original article was published in Molecular Medicine Reports 11: 1214-1220, 2015; DOI: 10.3892/mmr.2014.2853].

MADD Expression in Lung Adenocarcinoma and its Impact on Proliferation and Apoptosis of Lung Adenocarcinoma Cells.

OBJECTIVE: This study investigated the expression of MAPK-activating death domaincontaining protein (MADD) in lung adenocarcinoma and its impact on lung adenocarcinoma SPCA- 1 cell proliferation and apoptosis. METHODS: Clinicopathological lung specimens were collected. MADD expression levels in normal human lung and human lung adenocarcinoma tissues were detected by immunohistochemistry. Lung adenocarcinoma SPC-A-1 cells were cultured, and IG20 gene expression in the SPC-A-1 cells was detected using reverse-transcription PCR. SPC-A-1 cells were transfected with a plasmid carrying the MADD gene and a lentiviral vector capable of silencing MADD expression. CCK-8 assay, western blot and flow cytometry were performed to detect MADD expression, proliferation and apoptosis in the SPC-A-1 cells. RESULTS: MADD expression levels in the lung adenocarcinoma tissue were significantly higher than those in the normal lung tissue and lung squamous carcinoma cells. MADD can be expressed in lung adenocarcinoma SPC-A-1 cells. High MADD expression can inhibit SPC-A-1 cell apoptosis and enhance SPC-A-1 cell proliferative activity, while silencing MADD expression can promote apoptosis and reduce SPC-A-1 cell proliferation. CONCLUSION: MADD expression is significantly upregulated in lung adenocarcinoma tissue. MADD can promote lung adenocarcinoma cell growth by inhibiting apoptosis. This study may improve lung adenocarcinoma levels in patients and, thus, is worthy of clinical promotion.

Inhibition of G9a promoted 5-fluorouracil (5-FU) induced gastric cancer cell apoptosis via ROS/JNK signaling pathway in vitro and in vivo.

A histone methyltransferase G9a, encoded by euchromatic histone-lysine N-methyltransferase 2 (EHMT2), is up-regulated in various cancers, and is involved in their poor prognosis. In the study reported here, the abnormal expression of G9a in gastric cancer it was investigated in vitro and in vivo. Furthermore, the expression of G9a was revealed to have a negative correlation with chemotherapy response in gastric cancer patients. Next, the effect of G9a knockdown on fluorouracil (5-FU) induced cell apoptosis in gastric cancer cells was focused on. The results demonstrated that G9a knockdown significantly activated the expression level of phospho c-Jun N-terminal kinase (p-JNK) and increased the intracellular reactive oxygen species (ROS) levels in the gastric cancer cells. Inhibition of the ROS/JNK signaling partial reversed the effect of G9a knockdown on 5-FU treated gastric cancer cells. Down-regulation of G9a enhanced the sensitivity of 5-FU to the gastric cancer cells in vitro and in vivo, which was involved in the activation of the ROS/JNK signaling pathway. These results demonstrated that G9a could play a critical role in the sensitivity of chemotherapy for gastric cancer and might be a novel method for treating gastric cancer in the clinic.

A robust gene expression-based prognostic risk score predicts overall survival of lung adenocarcinoma patients.

Identification of reliable predictive biomarkers and new therapeutic targets is a critical step for significant improvement in patient outcomes. Here, we developed a multi-step bioinformatics analytic strategy to mine large omics and clinical data to build a prognostic scoring system for predicting the overall survival (OS) of lung adenocarcinoma (LuADC) patients. In latter we first identified 1327 significantly and robustly deregulated genes, 600 of which were significantly associated with the OS of LuADC patients. Gene co-expression network analysis revealed the biological functions of these 600 genes in normal lung and LuADCs, which were found to be enriched for cell cycle-related processes, blood vessel development, cell-matrix adhesion and metabolic processes. Finally, we implemented a multiple resampling method combined with Cox regression analysis to identify a 27-gene signature associated with OS, and then created a prognostic scoring system based on this signature. This scoring system robustly predicted OS of LuADC patients in 100 sampling test sets and was further validated in four independent LuADC cohorts. In addition, in comparison to other existing prognostic gene signatures published in the literature, our signature was significantly superior in predicting OS of LuADC patients. In summary, our multi-omics and clinical data integration study created a 27-gene prognostic risk score that can predict OS of LuADC patients independent of age, gender and clinical stage. This score could guide therapeutic selection and allow stratification in clinical trials.