XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial.

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

CT-guided Radioactive 125I Seed Implantation for Abdominal Incision Metastases of Colorectal Cancer: Safety and Efficacy in 17 Patients.

INTRODUCTION: To retrospectively evaluate the safety and efficacy of computed tomography (CT)-guided iodine-125 (125I) seed implantation for patients with abdominal incision metastases from colorectal cancer. MATERIALS AND METHODS: Data of patients with abdominal incision metastases of colorectal cancer from November 2010 to October 2020 were retrospectively reviewed. Each incisional metastasis was percutaneously treated with 125I seed implantation under CT guidance. Follow-up contrast-enhanced CT was reviewed, and the outcomes were evaluated in terms of objective response rate, complications, and overall survival. RESULTS: A total of 17 patients were enrolled in this study. The median follow-up was 18 months (range, 2.7-22.1 months). At 3, 6, 12, and 18 months after the treatment, objective response rate was 52.9%, 63.6%, 33.3%, and 0%, respectively. A small amount of local hematoma occurred in two patients and resolved spontaneously without any treatment. Two patients experienced a minor displacement of radioactive seeds with no related symptoms. Severe complications, such as massive bleeding and radiation injury, were not observed. No ≥ grade 3 adverse events were identified. By the end of follow-up, 14 patients died of multiple hematogenous metastases. The one-year overall survival rate was 41.6%, and the median overall survival was 8.6 months. CONCLUSION: CT-guided 125I seed implantation brachytherapy is safe and feasible for patients with abdominal incision metastases from colorectal cancer.

Methyltransferase SETD2 inhibits tumor growth and metastasis via STAT1-IL-8 signaling-mediated epithelial-mesenchymal transition in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a major subtype of non-small-cell lung cancer, which is the leading cause of cancer death worldwide. The histone H3K36 methyltransferase SETD2 has been reported to be frequently mutated or deleted in types of human cancer. However, the functions of SETD2 in tumor growth and metastasis in LUAD has not been well illustrated. Here, we found that SETD2 was significantly downregulated in human lung cancer and greatly impaired proliferation, migration, and invasion in vitro and in vivo. Furthermore, we found that SETD2 overexpression significantly attenuated the epithelial-mesenchymal transition (EMT) of LUAD cells. RNA-seq analysis identified differentially expressed transcripts that showed an elevated level of interleukin 8 (IL-8) in STED2-knockdown LUAD cells, which was further verified using qPCR, western blot, and promoter luciferase report assay. Mechanically, SETD2-mediated H3K36me3 prevented assembly of Stat1 on the IL-8 promoter and contributed to the inhibition of tumorigenesis in LUAD. Our findings highlight the suppressive role of SETD2/H3K36me3 in cell proliferation, migration, invasion, and EMT during LUAD carcinogenesis, via regulation of the STAT1-IL-8 signaling pathway. Therefore, our studies on the molecular mechanism of SETD2 will advance our understanding of epigenetic dysregulation at LUAD progression.

Hepatic Artery Infusion Pump Combined With Systemic Chemotherapy for Patients With Liver Metastases From Breast Carcinoma.

Background: When liver metastasis in patients with breast cancer is diagnosed, treatment is generally palliative and usually consists of systemic therapies only. This study aimed to evaluate the efficacy and safety of hepatic arterial infusion (HAI) combined with systemic chemotherapy in patients with breast carcinoma liver metastases (BCLM). Methods: From January 2012 to December 2019, HAI catheter systems were implanted under the guide of digital subtract angiography (DSA) in 19 patients with BCLM. All patients received systemic chemotherapy and HAI gemcitabine plus floxuridine (FUDR). Methods: The overall response rate (ORR) of intrahepatic lesions was 73.7%, including 2 patients (10.5%) with complete remission (CR) and 12 patients (63.2%) with partial remission (PR). Additionally, we found that young patients (age < 55 years) had a higher ORR than the older (100% vs 44.4%, P = .011). The median overall survival (mOS) was 13.1 months. Kaplan-Meier survival curves demonstrated that the mOS was not significantly different between patients with < 9 intrahepatic lesions and those with ≥ 9 lesions (13.7 months vs 10.9 months, P = .225). The mOS was 14.3 and 10.6 months for patients without extrahepatic metastases and with extrahepatic metastases, respectively (P = .016). None of the patients had grade 4 toxicity. The grade 3 toxicities included leucopenia, neutropenia and diarrhea. Conclusions: HAI gemcitabine plus FUDR combined with systemic chemotherapy is effective in achieving a high local response and prolonging mOS for patients with BCLM and is associated with a relatively low rate of toxicity.

LncRNA HCG18 suppresses CD8+ T cells to confer resistance to cetuximab in colorectal cancer via miR-20b-5p/PD-L1 axis.

Aim: We aimed to explore the effect of long noncoding RNA HCG18 in colorectal cancer (CRC). Materials & methods: Relative gene and protein expression were screened. Colony formation and flow cytometry assays were performed to determine proliferation and apoptosis. Dual luciferase and RNA immunoprecipitation assays were conducted to validate the interaction between indicated molecules. Xenograft in nude mice was applied to verify the conclusion in vivo. Results:HCG18 and PD-L1 were upregulated while miR-20b-5p was downregulated in CRC tissue. Functional analysis revealed that lncRNA HCG18 promoted proliferation, migration and resistance to cetuximab of CRC cells via the miR-20b-5p/PD-L1 axis. Conclusion:HCG18 facilitated progress of the tumor, conferred to cetuximab resistance and suppressed CD8+ T cells via the miR-20b-5p/PD-L1 axis.

Lay abstract In the present study, we found a long noncoding RNA (lncRNA), HCG18 (a recently discovered lncRNA that facilitates tumor progression via multiple mechanisms), was upregulated in colorectal cancer (CRC). Further studies revealed that HCG18 suppressed CD8⁺ T-cell (cytotoxic T lymphocyte which kills cancer cell) activation to induce cetuximab (a first-line drug in CRC) resistance. Mechanically, HCG18 elevated expression of PD-L1 (a receptor in T-cell membranes, thus suppressing the proliferation of CD8⁺ cytotoxic T lymphocytes) via sponging (lncRNA binds with miRNA) miR-20b-5p. This study might provide a deeper insight into understanding cetuximab resistance in CRC.

Hsa_circ_0136666 activates Treg-mediated immune escape of colorectal cancer via miR-497/PD-L1 pathway.

PURPOSE: In the rankings of cancer mortality and incidence worldwide, colorectal cancer ranks fourth and the third, respectively. Circular RNA hsa_circ_0136666 (hsa_circ_0136666) is reported to participate in the growth of colorectal cancer. However, the mechanism by which hsa_circ_0136666 regulates the tumorigenesis of colorectal cancer needs to be further explored. In this study, we report here the role of hsa_circ_0136666 in the aberrant activation of Treg cells and immune evasion of tumor cells, providing a new strategy for the treatment of colorectal cancer. METHODS: Western blotting assay and qRT-PCR assay were used to determine protein and mRNA expression levels. Dual-luciferase reporter assay was used to evaluate the targeted regulatory relationship. RNA immunoprecipitation was used to detect RNA binding. Colony formation assay was utilized to measure the cell proliferation. Flow cytometry was used to assess cell apoptosis. Xenograft model was setup to evaluate tumor growth. RESULTS: The results showed that hsa_circ_0136666 and PD-L1 was increased in colorectal cancer cells while miR-497 was decreased in colorectal cancer cells when compared with normal colon epithelial cell line. Hsa_circ_0136666 was demonstrated to directly target miR-497, which also regulated PD-L1 by binding to its 3'UTR. Further mechanistic studies identified that hsa_circ_0136666 controlled cell proliferation and apoptosis via targeting miR-497 and regulating PD-L1 expression. Of note, hsa_circ_0136666 stimulated Treg cells mediated by miR-497/PD-L1 axis and its downstream signal pathway in Treg cells. Finally, hsa_circ_0136666 was found to accelerate the tumor growth in vivo. CONCLUSIONS: Our findings demonstrated that hsa_circ_0136666 promoted the expression of PD-L1 by inhibiting miR-497 level in colorectal cancer, thus inducing the activation of Treg cells and leading to the immune escape of tumor, providing a novel mechanistic insight into the pathogenesis of colorectal cancer.

GPC5 suppresses lung cancer progression and metastasis via intracellular CTDSP1/AhR/ARNT signaling axis and extracellular exosome secretion.

Lung cancer is the leading cause of cancer-related death worldwide. Glypican-5 (GPC5) is a member of heparan sulfate proteoglycans, and its biological importance in initiation and progression of lung cancer remains controversial. In the present study, we revealed that GPC5 transcriptionally enhanced the expression of CTDSP1 (miR-26b host gene) via AhR-ARNT pathway, and such up-regulation of CTDSP1 intracellularly contributed to the inhibited proliferation of lung cancer cells. Moreover, exosomes derived from GPC5-overexpressing human lung cancer cells (GPC5-OE-derived exosomes) had an extracellular repressive effect on human lymphatic endothelial cells (hLECs), leading to decreased tube formation and migration. Comparison between GPC5-WT- and GPC5-OE-derived exosomes showed that miR-26b (embedded within introns of CTDSP1 gene) was significantly up-regulated in GPC5-OE-derived exosomes and critical to the influence on hLECs. On the mechanism, we demonstrated that miR-26b transferred into hLECs directly targeted to PTK2 3'-UTR and led to PTK2 down-regulation, resulting in defects in tube formation and migration of hLECs. By uncovering the regulation network among GPC5, miR-26b, miR-26b host gene (CTDSP1), and target gene (PTK2), our findings demonstrated that GPC5 functioned as a tumor suppressor in human lung cancer.

The hepatic microenvironment promotes lung adenocarcinoma cell proliferation, metastasis, and epithelial-mesenchymal transition via METTL3-mediated N6-methyladenosine modification of YAP1.

The inflammatory microenvironment plays an important role in the onset and progression of lung adenocarcinoma (LUAD), and the liver is a suitable site of metastasis for LUAD cells. However, whether the inflammatory microenvironment of the liver is conducive to the proliferation, invasion, and metastasis of LUAD cells remains unclear. In this study, we confirmed that the hepatic inflammatory microenvironment stimulated by IL-6 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition of LUAD cells, increased the m6A methylation of total RNA, and transcriptionally activated METTL3 expression. Additionally, METTL3 activated the YAP1/TEAD signaling pathway by increasing the m6A modification and expression of YAP1 mRNA. These results indicate that the hepatic inflammatory microenvironment plays a role in regulating the biological functions of LUAD cells. Further, our study identifies a molecular mechanism that may provide a new strategy for the early diagnosis, treatment, and prognosis of liver metastasis in LUAD patients.

Combined assay of Circulating Tumor DNA and Protein Biomarkers for early noninvasive detection and prognosis of Non-Small Cell Lung Cancer.

Purpose: Early diagnosis of lung cancer is critical to curtailing cancer-related deaths. We aimed to develop a highly sensitive assay for the analysis of circulating tumor DNA (ctDNA) to detect non-small cell lung cancer (NSCLC) in the early stages. Materials and Methods: We detected EGFR and KRAS mutations in paired plasma and tumor tissue samples from 147 NSCLC patients. Of these, EGFR/KRAS ctDNA mutations and protein biomarkers were comparatively analyzed in 87 individuals. In addition, tissue samples of 20 patients were subjected to repeat multi-gene detection, and pre- and post-operative paired samples of 28 patients were subjected to multi-gene detection. Clinical information was obtained to complement the prognostic value of the combined assay results and post-operative new ctDNA mutation status. Results: EGFR/KRAS mutations were highly consistent in ctDNA and tumor DNA. Combining the detection of EGFR and KRAS mutations in ctDNA with the detection of protein biomarkers increased cancer detection sensitivity to 74.7% (65/87). None of the healthy controls tested positive using the combined assay (100% specificity). Combined assay results independently associated with recurrence-free survival. Post-operative new ctDNA mutation status independently associated with overall survival and recurrence-free survival. Conclusion: The detection of ctDNA may be exploited for early diagnosis of NSCLC, as highlighted by the developed assay. Further, the combined assay results and post-operative new ctDNA mutation status are promising prognostic indicators in NSCLC patients.

A three serum miRNA panel as diagnostic biomarkers of radiotherapy-related metastasis in non-small cell lung cancer.

Serum microRNAs (miRNAs) have been implicated as noninvasive biomarkers for lung cancer diagnosis. However, there are no sensitive and specific biomarkers for the detection of radiotherapy-related non-small cell lung cancer (NSCLC) metastasis. The present study aimed to investigate the role of three serum miRNAs, namely miRNA (miR)-130a, miR-25 and miR-191*, in diagnosing NSCLC, and their biological functions in radiation-mediated development of metastatic properties in A549 cells. To determine this, serum samples were collected from 84 patients with NSCLC and 42 age- and sex-matched healthy controls. Differential expression of serum miRNAs was analyzed by quantitative PCR. Significant associations between miRNA expression and overall survival of patients with NSCLC were identified using the Cox proportional regression model. A receiver operating characteristic curve was generated to evaluate diagnostic accuracy. The functions of miR-130a, miR-25 and miR-191* in lung cancer cells were studied by transfecting A549 cells with miRNA mimics and inhibitors. The results of the present study demonstrated that the expression levels of miR-130a, miR-25 and miR-191* in the serum of patients with NSCLC were increased compared with those in healthy controls, and these increases were associated with advanced age (≥60 years), radiotherapy, histological type (squamous carcinoma), low survival rate and low median survival time. Additionally, irradiation induced the upregulation of miR-130a, miR-25 and miR-191* expression in A549 cells in vitro and in a xenograft mouse model. Irradiation also promoted the invasiveness of A549 cells in vitro and metastasis in vivo. In conclusion, miR-130a, miR-25 and miR-191* may be potential biomarkers for the diagnosis of patients with NSCLC and may serve oncogenic roles in radiation-mediated metastasis of NSCLC.

Study on efficacy and safety of Huangqi Guizhi Wuwu decoction treatment for oxaliplatin induced peripheral neurotoxicity: A protocol for a randomized, controlled, double-blind, multicenter trial.

BACKGROUND: Oxaliplatin can cause severe peripheral neurotoxicity, which is an important reason for clinical oxaliplatin reduction and cessation of treatment. Oxaliplatin induced peripheral neurotoxicity (OIPN) can cause paresthesia and dysesthesia, even affect the quality life of patients. So far, there are no recognized and effective measures to prevent OIPN. Huangqi Guizhi Wuwu decoction is a classical prescription of ancient Chinese medicine recorded in "the synopsis of the Golden Chamber," which can be used in the treatment of various neurotoxicity. However, there is a lack of large-scale and high-quality clinical studies on the prevention of OIPN by Huangqi Guizhi Wuwu decoction. The purpose of this study is to evaluate the efficacy and safety of Huangqi Guizhi Wuwu decoction on preventing OIPN. METHODS/DESIGN: This study is a randomized, controlled, double-blind, and multicenter clinical trial. Three hundred sixty patients will be randomly assigned into Huangqi Guizhi Wuwu decoction group and Huangqi Guizhi Wuwu decoction mimetic agent group. Patients will receive chemotherapy with FOLFOX of 8 cycles of 3 weeks with Traditional Chinese Medicine (TCM) for 6 months and 1-year follow-up. The primary outcome measure is the differences in the incidence of chronic neurotoxicity of grade 2 and above during and after treatment. The secondary outcome measure is the improvement in other symptoms associated with chemotherapy. Four methods will be used to evaluate the efficacy of neurotoxicity, including oxaliplatin specific toxicity grading standard (Levi classification); CTCAE4.02 version; EORTC QLQ-CIPN20 scale, EORTC QLQ C30 scale, and EORTC QLQ-CR29 scale are used at the same time; Electromyography. DISCUSSION: This study will provide objective evidences to evaluate the efficacy and safety of Huangqi Guizhi Wuwu Decoction on preventing OIPN. TRIAL REGISTRATION: Clinical Trials.gov (Identifier: NCT04261920).

Co-mutations of TP53 and KRAS serve as potential biomarkers for immune checkpoint blockade in squamous-cell non-small cell lung cancer: a case report.

BACKGROUND: Unprecedented durable responses are identified in clinical studies to target the signaling of programmed cell death protein-1 (PD-1) as well as its ligand (PD-L1) in patients with squamous-cell non-small cell lung cancer (NSCLC). However, factors predicting the patient subtypes that are responsive to PD-1/PD-L1inhibitors have not been fully understood yet. Biomarkers, like PD-L1 expression, tumor mutational burden(TMB), DNA mismatch repair deficiency (dMMR), and tumor-infiltrating lymphocytes (TILs), have been utilized to select patients responsive to PD-1/PD-L1inhibitors in the clinic, but each of them has limited use. Lung adenocarcinoma patients with a mutation of TP53 or KRAS, particularly those with co-mutations of TP53 and KRAS, can benefit from anti-PD-1 treatment. CASE PRESENTATION: In this study, the co-mutations of TP53 and KRAS in a 64-year-old non-smoking man with squamous-cell NSCLC patient was described using the next-generation sequencing (NGS) technology. The patient was treated with the pembrolizumab combined with gemcitabine as the salvage therapy, and a marked partial response could be attained, which had persisted for over 7 months. CONCLUSION: In addition to testing common driving genes, like EGFR, ALK, ROS1 and BRAF, both TP53, and KRAS should also be considered in advanced or metastatic squamous-cell NSCLC.TP53 and KRAS co-mutations in squamous-cell NSCLC can be a potential factor to assess possible response to PD-1 blockade immunotherapy, but further studies with more cases are needed to confirm the prediction power.

The prognostic significance of hTERT overexpression in cancers: A systematic review and meta-analysis.

BACKGROUND: Human telomerase reverse transcriptase (hTERT) plays an important role in cancer progression. Recently, several clinical studies investigated how the overexpression of hTERT predicts the poor prognosis of solid tumors. However, the results were inconclusive, partly because of the small numbers of patients included. METHOD: We systematically searched PubMed, Web of Science, and Embase to identify relevant studies until August 2017. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to evaluate the association of hTERT expression and survival outcomes. RESULTS: A total of 27studies enrolling 2530 solid tumor patients were included in this meta-analysis. There were strong significant associations between hTERT overexpression and all endpoints: overall survival (OS) (HR = 1.50, 95% CI: 1.31-1.73, P = .00), disease-free survival (HR = 1.84, 95% CI: 1.38-2.46; P = .00), and recurrence-free survival (HR = 1.79, 95% CI: 1.07-2.99; P = .028). In the subgroup analysis, it was found that the overexpression of hTERT induced poor OS in lung cancer (HR = 1.51, 95% CI: 1.21-1.89; P = .00). CONCLUSION: Our comprehensive systematic review concluded that the overexpression of hTERT was associated with poor survival in human solid tumors. hTERT may be a valuable predictive biomarker for prognosis.

Comparisons of the humoral and cellular immunity induced by live A16R attenuated spore and AVA-like anthrax vaccine in mice.

The live attenuated anthrax vaccine and anthrax vaccine adsorbed (AVA) are two main types of anthrax vaccines currently used in human. However, the immunoprotective mechanisms are not fully understood. In this study, we compared humoral and cellular immunity induced by live A16R spore vaccine and A16R strain derived AVA-like vaccine in mice peripheral blood, spleen and bone marrow. Both A16R spores and AVA-like vaccines induced a sustained IgG antibody response with IgG1/IgG2b subtype dominance. However, A16R spores vaccine induced higher titer of IgG2a compared with AVA-like vaccine, indicating a stronger Th1 response to A16R spores. Using antigen-specific ELISpot assay, we observed a significant response of ASCs (antibody secreting cells) and IL4-CSCs (cytokine secreting cells) in mice. Specially, there was a positive correlation between the frequencies of antigen specific ASCs and IL4-CSCs in bone marrow derived cells, either by A16R spore or AVA-like vaccine vaccination. Moreover, we also found A16R spore vaccine, not AVA-like vaccine, could induce sustained frequency of IFN-γ-CSCs in bone marrow derived cells. Collectively, both the vaccines induced a mixed Th1/Th2 response with Th2 dominance in mice and A16R spore vaccine might provide a more comprehensive protection because of humoral and cellular immunity induced in bone marrow.

High expression of CD11c indicates favorable prognosis in patients with gastric cancer.

AIM: To determine the relationship between CD11c expression level and prognosis in patients with gastric cancer (GC). METHODS: This retrospective survival study was performed from July 31, 2008 to June 30, 2014. Our study inclusion criteria included all the patients with GC who underwent surgical resection between January 1998 and December 2009 in the Third Affiliated Hospital of Soochow University. CD11c expression levels in 140 patients with GC at different UICC stages were evaluated using immunohistochemistry, and GC tissues from 16 cases were further verified by qRT-PCR. The χ (2) test was used to compare the patient- and disease-related factors between the low CD11c expression group and the high expression group. Univariate probabilities of overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method. The log rank test was used to compare survival curves. Different multivariate COX models were used to estimate the association between CD11c expression and both death and recurrence risk in GC patients. RESULTS: The average CD11c expression level was 5.1 ± 1.8/high power field (HPF) in 10 gastritis samples, 4.5 ± 2.3/HPF in 10 gastric polyp samples and 9.7 ± 6.3/HPF in 140 gastric cancer samples, respectively. The CD11c expression level was significantly decreased from UICC stage I to stage IV (stage I: 16.0 ± 7.4, stage II: 10.4 ± 5.5, stage III: 9.4 ± 6.1, stage IV: 5.3 ± 3.2, P < 0.001). Patients in the high CD11c expression group had a greater 3- and 5-year OS probability and longer median survival time compared with the low CD11c expression group, (67.7% vs 39.2%; 51.4% vs 29.0%; 67.0 mo vs 28.0 mo; χ(2) = 6.80, P = 0.009), and had a greater 3- and 5-year DFS probability and longer median DFS time (63.7% vs 24.0%; 49.1% vs 11.9%; 64.0 mo vs 18.0 mo; χ (2) = 15.39, P < 0.001). Patients with high CD11c high expression had a reduced risk of death (HR = 0.56, 95%CI: 0.33-0.98, P < 0.05) and relapse (HR = 0.39, 95%CI: 0.23-0.67, P < 0.01) compared with patients with low CD11c expression after adjustment of potential confounders, with the exception of tumor size. However, the protective effect related to death (HR = 0.90, 95%CI: 0.49-1.67, P = 0.749) and relapse (HR = 0.65, 95%CI: 0.36-1.19, P = 0.160) disappeared when tumor size was incorporated into the model. CONCLUSION: High expression of CD11c decreased the risk of death and relapse, and may be regarded as an alternative indicator of favorable prognosis in patients with GC.

Circadian variability of pharmacokinetics of cisplatin in patients with non-small-cell lung carcinoma: analysis with the NONMEM program.

PURPOSE: The aim of this study was to describe the nonlinear pharmacokinetics of total and unbound plasma cisplatin under different administered time in patients with non-small-cell lung carcinoma. METHODS: Patients receiving chemotherapy with cisplatin were included in this analysis. Patients were divided into two groups depending on the administrated time of cisplatin: 6:00 (Group A) and 18:00 (Group B). The population pharmacokinetics of cisplatin was calculated using nonlinear mixed-effects modeling (NONMEM) method, and the possible influence of covariates on the population pharmacokinetics of cisplatin was also explored. RESULTS: The pharmacokinetics of total and unbound cisplatin could be described well by a linear two-compartment model. The mean population estimates for total and unbound drug were, respectively, 0.463 (17.0 %) and 25.4 (14.0 %) l h⁻¹ for clearance (CL), 24.2 (19.9 %) and 20.5 (27.1 %) l for central distribution volume (V1), 10.2 (18.2 %) and 9.82 (28.1) l h⁻¹ for intercompartmental clearance (Q) and 32.0 (24.1 %) and 6.77 (25.4 %) l for peripheral compartment volume (V2). The CL for total and unbound cisplatin was dependent on body surface area (BSA). When cisplatin was administered at 18:00, the CL was 1.38- and 1.22-fold higher than those administered at 6:00 for total and unbound cisplatin, respectively (P < 0.05). The mean parameter estimates from a nonparametric bootstrap procedure were comparable and within 5 % of the estimates from NONMEM. CONCLUSIONS: The results showed that circadian could influence the metabolism of cisplatin and suggested the conventional dose adjustment of cisplatin based on BSA.

The pivotal roles of the plant S-adenosylmethionine decarboxylase 5' untranslated leader sequence in regulation of gene expression at the transcriptional and posttranscriptional levels.

S-Adenosylmethionine decarboxylase (SAMDC; EC 4.1.1.50) is a key rate-limiting enzyme located in the polyamine biosynthesis pathway. When compared with other organisms, the plant SAMDC genes possess some distinct features because they are devoid of introns in the main open reading frame (ORF) but have an intron(s) in their 5' untranslated leader sequences, in which two overlapping tiny and small upstream ORFs (uORFs) are present. Our results show that the presence of the 5' leader sequence plays important roles in transcriptional and posttranscriptional regulation of SAMDC expression. This sequence may help to keep the transcript of its downstream cistron at a relatively low level and function together with its own promoter in response to external stimuli or internal changes of spermidine and spermine to initiate and regulate SAMDC expression. Under stress and high spermidine or spermine conditions, the tiny uORF shows the same function as its overlapping small uORF, which is involved in translational repression and feedback controlled by polyamines. The presence of introns is necessary for the SAMDC up-regulation process when the internal spermidine level is low. Our results suggest that plants have evolved one network to adjust SAMDC activity through their 5' leader sequences, through which transcriptional regulation is combined with an extensive posttranscriptional control circuit.