Camrelizumab plus famitinib in previously chemo-immunotherapy treated patients with advanced NSCLC: results from an open-label multicenter phase 2 basket study.

BACKGROUND: The combination of immune checkpoint inhibitors and antiangiogenic agents has been effective in treating multiple cancers. This was further explored in an open-label, multicenter phase 2 basket study (NCT04346381), which evaluated the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients with advanced solid tumors. We herein report the findings from the cohort of advanced NSCLC patients who progressed after treatment with platinum-doublet chemotherapy and immunotherapy. METHODS: Eligible patients were enrolled and treated with camrelizumab (200 mg once every 3 weeks via intravenous infusion) and oral famitinib (20 mg once daily). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled in this cohort, with a median follow-up duration of 11.5 months. Three patients (7.5%) achieved a partial response, and 29 patients (72.5%) achieved stable disease. The ORR and DCR with this combination regimen were 7.5% (95% CI, 1.6-20.4) and 80.0% (95% CI, 64.4-90.9), respectively. The median DoR was 12.1 months (95% CI, 10.3-not reached). The median PFS was 5.4 months (95% CI, 4.1-7.5), and the median OS was 12.1 months (95% CI, 9.1-16.7). The estimated 12-month OS rate was 51.5% (95% CI, 34.9-65.9). The most frequent grade 3 or higher treatment-related adverse events occurring in more than 5% of patients included hypertension (27.5%), palmar-plantar erythrodysesthesia syndrome (10%), decreased neutrophil count (10%), and proteinuria (7.5%). CONCLUSION: Camrelizumab plus famitinib demonstrated favorable benefits in PFS and OS, along with manageable safety profiles, in patients with advanced NSCLC who progressed after platinum-doublet chemotherapy and immunotherapy. This finding warrants further exploration.

Retracted: Expression of TP53, BCL-2, and VEGFA Genes in Esophagus Carcinoma and its Biological Significance.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Wei Wei, Yanqin Wang, Xiaoming Yu, Lan Ye, Yuhua Jiang, Yufeng Cheng. Expression of TP53, BCL-2, and VEGFA Genes in Esophagus Carcinoma and its Biological Significance. Med Sci Monit, 2015; 21: 3016-3022. DOI: 10.12659/MSM.894640.

Helicobacter pylori infection and Parkinson's Disease: etiology, pathogenesis and levodopa bioavailability.

Parkinson's disease (PD), a neurodegenerative disorder with an unknown etiology, is primarily characterized by the degeneration of dopamine (DA) neurons. The prevalence of PD has experienced a significant surge in recent years. The unidentified etiology poses limitations to the development of effective therapeutic interventions for this condition. Helicobacter pylori (H. pylori) infection has affected approximately half of the global population. Mounting evidences suggest that H. pylori infection plays an important role in PD through various mechanisms. The autotoxin produced by H. pylori induces pro-inflammatory cytokines release, thereby facilitating the occurrence of central inflammation that leads to neuronal damage. Simultaneously, H. pylori disrupts the equilibrium of gastrointestinal microbiota with an overgrowth of bacteria in the small intestinal known as small intestinal bacterial overgrowth (SIBO). This dysbiosis of the gut flora influences the central nervous system (CNS) through microbiome-gut-brain axis. Moreover, SIBO hampers levodopa absorption and affects its therapeutic efficacy in the treatment of PD. Also, H. pylori promotes the production of defensins to regulate the permeability of the blood-brain barrier, facilitating the entry of harmful factors into the CNS. In addition, H. pylori has been found to induce gastroparesis, resulting in a prolonged transit time for levodopa to reach the small intestine. H. pylori may exploit levodopa to facilitate its own growth and proliferation, or it can inflict damage to the gastrointestinal mucosa, leading to gastrointestinal ulcers and impeding levodopa absorption. Here, this review focused on the role of H. pylori infection in PD from etiology, pathogenesis to levodopa bioavailability.

Efficacy of anti-programmed cell death protein 1 monoclonal antibody combined with bevacizumab and/or Pseudomonas aeruginosa injection in transplanted tumor of mouse forestomach carcinoma cell gastric cancer in mice and its mechanism in regulating tumor immune microenvironment.

Tumor immunotherapy represented by programmed cell death protein 1 (PD-1) inhibitors is considered as the most promising cancer treatment method and has been widely used in the treatment of advanced gastric cancer (GC). However, the effective rate of PD-1 inhibitor monotherapy is low. In this study, we constructed a transplanted tumor model in GC mice by inoculating mouse forestomach carcinoma cell (MFC) GC cells into 615 mice. Interventions were conducted with normal saline, anti-PD-1 monoclonal antibody (mAb), bevacizumab, Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA), anti-PD-1 mAb combined with bevacizumab, anti-PD-1 mAb combined with PA-MSHA, bevacizumab combined with PA-MSHA, anti-PD-1 mAb combined with bevacizumab and PA-MSHA, respectively. The tumor growth curves were drawn. TUNEL assay, western blotting, and immunohistochemistry were used to detect tumor proliferation and apoptosis. Flow cytometry and ELISA were used to detect the expression of tumor infiltrating lymphocytes and cytokines. This study found that anti-PD-1 mAb alone could not significantly inhibit the growth of transplanted tumors in mice. Anti-PD-1 mAb combined with bevacizumab, anti-PD-1 mAb combined with PA-MSHA, anti-PD-1 mAb combined with bevacizumab and PA-MSHA could all significantly inhibit tumor growth in mice, and the combination of three drugs presented the highest tumor inhibition rate. Anti-PD-1 mAb combined with bevacizumab and PA-MSHA could significantly upregulate the number of Th1-type cells, CD8 + T cells, and Type I tumor-associated macrophages (TAMs), while downregulate the number of Th2-type cells, myeloid-derived suppressor cells, regulatory T cells, and Type II TAMs. Therefore, we conclude that anti-PD-1 mAb combined with bevacizumab and/or PA-MSHA has a synergistic effect. Bevacizumab and PA-MSHA can transform the tumor immunosuppressive microenvironment into a supportive immune microenvironment, thus maximizing the antitumor effect of anti-PD-1 mAb.

Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: A substantial proportion of patients with unresectable stage III non-small-cell lung cancer (NSCLC) cannot either tolerate or access concurrent chemoradiotherapy, so sequential chemoradiotherapy is commonly used. We assessed the efficacy and safety of sugemalimab, an anti-PD-L1 antibody, in patients with stage III NSCLC whose disease had not progressed after concurrent or sequential chemoradiotherapy. METHODS: GEMSTONE-301 is a randomised, double-blind, placebo-controlled, phase 3 trial in patients with locally advanced, unresectable, stage III NSCLC, done at 50 hospitals or academic research centres in China. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had not progressed after concurrent or sequential chemoradiotherapy. We randomly assigned patients (2:1, using an interactive voice-web response system) to receive sugemalimab 1200 mg or matching placebo, intravenously every 3 weeks for up to 24 months. Stratification factors were ECOG performance status, previous chemoradiotherapy, and total radiotherapy dose. The investigators, trial coordination staff, patients, and study sponsor were masked to treatment allocation. The primary endpoint was progression-free survival as assessed by blinded independent central review (BICR) in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of assigned study treatment. The study has completed enrolment and the results of a preplanned analysis of the primary endpoint are reported here. The trial is registered with ClinicalTrials.gov, NCT03728556. FINDINGS: Between Aug 30, 2018 and Dec 30, 2020, we screened 564 patients of whom 381 were eligible. Study treatment was received by all patients randomly assigned to sugemalimab (n=255) and to placebo (n=126). At data cutoff (March 8, 2021), median follow-up was 14·3 months (IQR 6·4-19·4) for patients in the sugemalimab group and 13·7 months (7·1-18·4) for patients in the placebo group. Progression-free survival assessed by BICR was significantly longer with sugemalimab than with placebo (median 9·0 months [95% CI 8·1-14·1] vs 5·8 months [95% CI 4·2-6·6]; stratified hazard ratio 0·64 [95% CI 0·48-0·85], p=0·0026). Grade 3 or 4 treatment-related adverse events occurred in 22 (9%) of 255 patients in the sugemalimab group versus seven (6%) of 126 patients in the placebo group, the most common being pneumonitis or immune-mediated pneumonitis (seven [3%] of 255 patients in the sugemalimab group vs one [<1%] of 126 in the placebo group). Treatment-related serious adverse events occurred in 38 (15%) patients in the sugemalimab group and 12 (10%) in the placebo group. Treatment-related deaths were reported in four (2%) of 255 patients (pneumonia in two patients, pneumonia with immune-mediated pneumonitis in one patient, and acute hepatic failure in one patient) in the sugemalimab group and none in the placebo group. INTERPRETATION: Sugemalimab after definitive concurrent or sequential chemoradiotherapy could be an effective consolidation therapy for patients with stage III NSCLC whose disease has not progressed after sequential or concurrent chemoradiotherapy. Longer follow-up is needed to confirm this conclusion. FUNDING: CStone Pharmaceuticals and the National Key Research and Development Program of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Pyroptosis predicts immunotherapy outcomes across multiple cancer types.

Pyroptosis is a programmed cell death characterized by inflammation and may coordinate with cancer immunotherapy, but assessments of pyroptosis in patients with immunotherapy are lacking. We evaluated the pyroptosis potentials in 71 cohorts with 24,388 cancer patients. They were elevated in tumors compared to normal tissues but had a weak relationship with prognosis. High pyroptosis potentials indicated "hot tumors" characteristics and high objective response rates to PD1/PDL1 inhibitors derived from clinical trials. In 15 cohorts with patients treated with immunotherapy, a pyroptosis score showed predictive values in objective response rate, progression-free survival, and overall survival. Systematic treatments, such as chemotherapy or endocrine therapy, enhanced pyroptosis in drug-resistant tumors. These results were further validated in three independent clinical cohorts and our two institutional cohorts by immunohistochemistry. Our findings uncover a value of pyroptosis potentials to predict immunotherapy responses and a theoretical rationale for combining pyroptosis inducers and immunotherapy in cancer treatment.

A multi-center, single-arm, phase II study of anlotinib plus paclitaxel and cisplatin as the first-line therapy of recurrent/advanced esophageal squamous cell carcinoma.

BACKGROUND: Anlotinib, a tyrosine kinase inhibitor, has shown encouraging anti-tumor activity in esophageal squamous cell carcinoma (ESCC). This study was designed to assess the efficacy and safety of anlotinib plus paclitaxel and cisplatin (TP) as first-line therapy for advanced ESCC. METHODS: In a multi-center, single-arm, phase II clinical trial, patients (aged > 18 years) with ESCC, which was judged to be locally advanced, recurrent, or metastatic, received 10 mg oral anlotinib once daily on days 1-14, 135 mg/m2 intravenous paclitaxel on day 1, and 60-75 mg/m2 intravenous cisplatin on days 1-3 every 3 weeks for a maximum of 4-6 cycles as the initial therapy in five centers in China. Subsequently, patients received anlotinib monotherapy (10 mg) as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-seven patients were enrolled in this study between October 2019 and March 2021. The median follow-up was 14.04 months (IQR, 9.30-19.38). Of 46 with assessable efficacy, the median PFS and median overall survival were 8.38 months (95% CI, 6.59-10.17) and 18.53 months (95% CI, 13.11-23.95), respectively. The objective response rate was 76.1% (95% CI, 61.2-87.4%), with 4 (8.7%) complete responses and 31 (67.4%) partial responses. The disease control rate was 91.3% (95% CI, 79.2-97.6%). The median duration of response was 6.80 months (95% CI, 4.52-9.08), and 1 patient had an ongoing response for 23 months. Subgroup analysis revealed no association between clinical factors and survival or response. Of the 47 patients with assessable safety, the main grade ≥ 3 treatment-emergent adverse events (TEAEs) were neutropenia (17.0%), bone marrow suppression (12.8%), and vomiting (10.6%). No treatment-related deaths or serious TEAEs were observed. Notably, higher c-Kit levels were an independent factor for superior PFS (HR = 0.032; 95% CI, 0.002-0.606; P = 0.022). CONCLUSIONS: The study demonstrated a manageable safety profile and durable clinical response of anlotinib plus TP as first-line therapy in advanced ESCC, which suggested a potential therapeutic option for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04063683. Registered 21 August 2019.

The measurement of NRF2 and TP53 in blood expects radiotherapeutic sensitivity in patients with esophageal cancer.

OBJECTIVE: This study investigates the relationship between the mRNA expression of nuclear factor erythroid 2-related factor 2 (NRF2) and Tumor protein p53 (TP53) in circulating tumor cells (CTC) and sensitivity to radiotherapy in patients with esophageal cancer. To investigate the relationship between cytokines IL-6, CD8+, and NRF2 during patient treatment and their predictive role for treatment. METHODS: Radiosensitivity was assessed by measuring a morphological or functional change in the tumor in response to ionizing radiation. Fasting venous anticoagulated blood (EDTA anticoagulation) was drawn from patients, and the Trizol-chloroform two-step method was used for RNA extraction. Data were collected from 45 patients admitted with radiotherapy alone from January 2018 to December 2021. The expression levels of NRF2mRNA (Messenger Ribose Nucleic Acid) and TP53mRNA in CTCs were detected by reverse transcription-polymerase chain reaction (RT-PCR). Pre- and post-treatment changes in IL-6 and CD8+ were recorded. The correlation between their expression level and the clinical stage, radiotherapy sensitivity, and efficacy of patients was analyzed. RESULTS: Twenty-six cases were sensitive to radiotherapy, and 19 were resistant, for a radiotherapy sensitivity rate of 58.8%. NRF2mRNA and TP53mRNA values increased in 19 radiotherapy-resistant patients and decreased in 26 radiotherapy-sensitive patients compared with those before radiotherapy (P = 0.001, P＜0.05). The ΔCT values of NRF2mRNA and TP53mRNA before treatment were moderately correlated with prognosis (P < 0.002). Inflammatory cytokine IL-6 was elevated in 22 of 45 patients after radiation, P = 0.04. NRF2 mRNA level was consistently elevated with CD8+ in 10 patients, P = 0.02. CONCLUSIONS: The expression of NRF2mRNA and TP53mRNA in the CTCs found in the peripheral blood of patients with esophageal squamous carcinoma was significantly associated with the sensitivity to radiotherapy. NRF2 mRNA level was consistently elevated with CD8+ and IL-6 in patients.

RAD001 targeted HUVECs reverses 12-lipoxygenase-induced angiogenesis in oesophageal squamous cell carcinoma.

12-LOX plays an important role in the progression of various malignancies. However, the underlying mechanisms of the action of 12-LOX and tumour treatment strategies remain not fully defined. In this study, we investigated the possible roles of 12-LOX in ESCC and explored the new therapeutic target. Approximately 73% of ESCC tissues showed marked up-regulation of 12-LOX, which was associated with poor prognosis. 12-LOX overexpression was positively correlated with the malignant progression of ESCC as demonstrated both in vitro and in vivo. Up-regulation of 12-LOX significantly increased the proliferation of ESCC cells and the xenograft volume. Moreover, 12-LOX up-regulation promoted tube formation of HUVECs and tumour angiogenesis in xenografts. Mechanism investigation indicated that 12-LOX overexpression led to activation of the PI3K/AKT/mTOR pathway and the up-regulation of VEGF in ESCC cells. Subsequent analysis indicated that the RAD001 could reverse the 12-LOX-induced promoting effect on ESCC. Specifically, the application of RAD001 inhibited the proliferation of ESCC cells and the tube-forming ability of HUVECs. In the drug group, the xenografts exhibited significant volume reduction and angiogenesis inhibition. We demonstrated that RAD001 could inhibit HUVEC migration. These findings presented the evidence that RAD001 had distinct roles on HUVECs and could exert anti-tumour effects by targeting not only the PI3K/AKT/mTOR pathway but the angiogenesis in ESCC.

Screening of tumor grade-related mRNAs and lncRNAs for Esophagus Squamous Cell Carcinoma.

BACKGROUND: The goal of our study was to screen tumor grade-related lncRNAs and mRNAs to reveal the underlying molecular mechanism of esophagus squamous cell carcinoma (ESCC). METHODS: The lncRNA and mRNA sequencing data were obtained from The Cancer Genome Atlas (TCGA). Tumor grade correlation analysis of lncRNAs and mRNAs was executed, followed by the functional enrichment analysis of all tumor grade-related mRNAs. The differentially expression mRNAs (DEmRNAs) and differentially expressed lncRNAs (DElncRNAs) were obtained. PPI network and DEmRNA-DElncRNA interaction analysis were constructed. The functional annotation of the DEmRNAs co-expressed with DElncRNAs was performed. The expression levels of the candidate genes were validated using qRT-PCR. RESULTS: A total of 1864 tumor grade-related mRNAs (846 positively related and 1018 negatively related) and 552 tumor grade-related lncRNAs (331 positively related and 221 negatively related) were obtained. The top 10 significantly grade-related mRNAs and lncRNAs included CA12, FABP4, DECR1, BAIAP2, IL1RAPL2, PPARD, LAD1, TSPAN10, LDOC1, ZNF853, RP11-25G10.2, RP11-557H15.3, RP11-521D12.5, CHKB-AS1, RP11-219B4.3, CH17-335B8.4, RP11-99 J16-A.2, CTB-111H14.1, ADNP-AS1, and JHDM1D-AS1. SFN, IL1RAPL2, and RP11-25G10.2 were overlapped from grade 1, grade 2, and grade 3. PPI network showed that top 10 proteins with higher degrees, including GNAI1, RAP2B, GNAZ, SHH, ADCY1, PRKAR2B, SH3GL1, GNA15, and ARRB1. A DElncRNAs-nearby DEmRNAs network was constructed to obtain hub lncRNAs including ADAMTS9-AS2, RP11-210 M15.2, RP11-13 K12.1, ZBED3-AS1, and RP11-25G10.2. Except for RP11-25G10.2, ADAMTS9-AS1, ZBED3-AS1, SFN, ATP1A2, and GNA15 were consistent with our TCGA analysis. CONCLUSIONS: Alterations of DEmRNAs and DElncRNAs may provide key insights into the molecular mechanisms of ESCC.

Thymine DNA glycosylase-regulated TAZ promotes radioresistance by targeting nonhomologous end joining and tumor progression in esophageal cancer.

Radiation resistance is a major cause of esophageal cancer relapse or metastasis. Transcriptional coactivator with PDZ binding domain (TAZ) is a final effector of the Hippo signaling pathway and plays critical roles in several types of cancer, but how it participates in the progression and radiation resistance of esophageal cancer remains unclear. Here, we revealed that TAZ was the strongest prognostic factor among Hippo pathway members. Overexpression of TAZ predicted poor outcome and adverse pathological features. In cell and animal models, TAZ facilitated cell proliferation, motility, and radiation resistance. Additionally, TAZ promoted expression of nonhomologous end joining (NHEJ)-related genes, which are the main contributors to repair irradiation-induced DNA breaks and result in radiation resistance. Amplification of the TAZ gene occurred in 2.5%-3.2% of esophageal cancers. In addition, the CpG islands of the TAZ gene were demethylated in esophageal cancer under thymine DNA glycosylase (TDG) regulation. Knockdown of TDG inhibited cell growth, motility, and radiation resistance, which were overridden by TAZ overexpression. Collectively, these findings suggest that the TDG/TAZ/NHEJ axis is a critical player in esophageal cancer progression and radiation resistance, as well as a potential target for radiotherapy.

Isocitrate dehydrogenase 2 contributes to radiation resistance of oesophageal squamous cell carcinoma via regulating mitochondrial function and ROS/pAKT signalling.

BACKGROUND: Antioxidase alleviates the accumulation of radiation-induced reactive oxygen species (ROS) and therefore has strong connections with radioresistance. Isocitrate dehydrogenase 2 (IDH2) facilitates the turnover of antioxidase, but its role in radiotherapeutic efficiency in oesophageal squamous cell carcinoma (ESCC) still remains elusive. METHODS: The involvement of IDH2 in radiotherapeutic efficacy in ESCC was investigated in vitro and vivo by IDH2 knockdown. IDH2 expression in biopsy specimens of 141 patients was identified to evaluate its clinical significance. RESULTS: We found that Kyse510 and Kyse140 cells were more radioresistant and had higher IDH2 expression. In these two cell lines, IDH2 knockdown intensified the radiation-induced ROS overload and oxidative damage on lipid, protein, and nucleic acids. In addition, IDH2 silencing aggravated the radiation-induced mitochondrial dysfunction and cell apoptosis and ultimately promoted radiosensitisation via inhibiting AKT phosphorylation in a ROS-dependent manner. Furthermore, IDH2 depletion facilitated the radiation-induced growth inhibition and cell apoptosis in murine xenografts. Finally, IDH2 expression was correlated with definite chemoradiotherapy (dCRT) efficacy and served as an independent prognostic factor for survival of ESCC patients. CONCLUSIONS: IDH2 plays a key role in the radioresistance of ESCC. Targeting IDH2 could be a promising regimen to improve radiotherapeutic efficiency in ESCC patients.

Reversal of P-glycoprotein-mediated multidrug resistance by novel curcumin analogues in paclitaxel-resistant human breast cancer cells.

Multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy, and the main cause of MDR has been attributed to overexpression of P-glycoprotein (P-gp). In this present study, four P-gp modulators (E,E)-4,6-bis(styryl)-2-(substituted amino)-pyrimidines were evaluated for their activity in a breast cancer cell line overexpressing P-gp (LCC6MDR). The four modulators displayed significantly better P-gp modulating activity compared with the positive control verapamil (RF = 5.4), with a relative fold (RF) increase in activity ranging from 33.3 to 86.0. In contrast to compounds a and c that exhibited lower cytotoxicity, compounds b and d were nontoxic towards both cancer cells and normal cells, with IC50 values greater than 100 µmol/L. The qRT-PCR results demonstrated that after exposure to 2 µmol/L of compounds a, b, c, and d, the mRNA expression level of MDR1 in LCC6MDR cells decreased to 45%, 50%, 38%, and 51%, respectively. However, the Western-blot results indicated that compound c could reverse P-gp mediated MDR, but not via decreases in protein expression. DOX and Rh123 accumulation and efflux results further confirmed that the reversal of MDR activity happens via inhibition of P-gp efflux and increases in intracellular drug accumulation. These results demonstrated that compound c has low toxicity and is an efficient P-gp modulator, highlighting its potential as a promising candidate for P-gp-mediated reversal of MDR.

Attitude computation algorithm for star camera based on combining calibration and attitude determination processes.

In this paper, a new approach for calculating star camera attitudes, which can calculate calibration parameters and attitude information simultaneously, in situations where precise camera calibration results are unknown, is proposed. This algorithm combines the calibration and attitude determination processes, achieving significantly improved performance as a result. Experiments using 1500 star images from different sky regions show that, compared with the traditional method that separates calibration and attitude determination, the proposed algorithm not only exhibits more precise and stable results, but also shows improved tolerance for the star mismatching which is inevitable in star sensor data process technology.

miR-146a-5p mediates epithelial-mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2.

This corrects the article DOI: 10.1038/bjc.2016.367.

The miRNA-kallikrein interaction: a mosaic of epigenetic regulation in cancer.

The kallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases with trypsin- and chymotrypsin-like activities. Dysregulated expression and/or aberrant activation of KLKs has been linked to various pathophysiological processes, including cancer. Many KLKs have been identified as potential cancer biomarkers. microRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression by pairing to the 3' untranslated region (UTR) of complimentary mRNA targets. miRNAs are dysregulated in many cancers, including prostate, kidney and ovarian cancers. Several studies have shown that miRNAs are involved in the post-transcriptional regulation of KLKs. However, recent evidence suggests that miRNAs can also act as downstream effectors of KLKs. In this review, we provide an update on the epigenetic regulation of KLKs by miRNAs. We also present recent experimental evidence that supports the regulatory role of KLKs on miRNA networks. The potential diagnostic and therapeutic applications of miRNA-kallikrein interactions are also discussed.

New on-orbit geometric interior parameters self-calibration approach based on three-view stereoscopic images from high-resolution multi-TDI-CCD optical satellites.

To increase the field of view (FOV), combining multiple time-delayed and integrated charge-coupled devices (TDI-CCD) into the camera and the pushbroom imaging modality are traditionally used with high-resolution optical satellites. It is becoming increasingly labor- and cost-intensive to build and maintain a calibration field with high resolution and broad coverage. This paper introduces a simple and feasible on-orbit geometric self-calibration approach for high-resolution multi-TDI-CCD optical satellites based on three-view stereoscopic images. With the aid of the a priori geometric constraint of tie points in the triple-overlap regions of stereoscopic images, as well as tie points between adjacent single TDI-CCD images (STIs), high accuracy calibration of all TDI-CCD detectors can be achieved using a small number of absolute ground control points (GCPs) covering the selected primary STI. This method greatly reduces the demand on the calibration field and thus is more time-, effort- and cost-effective. Experimental results indicated that the proposed self-calibration approach is effective for increasing the relative internal accuracy without the limitations associated with using a traditional reference calibration field, which could have great significance for future super-high-resolution optical satellites.

Effects of MiR-210 on proliferation, apoptosis and invasion abilities of esophageal cancer cells.

PURPOSE: To investigate the effects of microRNA-210 (miRNA- 210) on the biological behaviors (proliferation and invasion) of EC109 cells of highly metastatic human esophageal cancer (EC). METHODS: The EC109 genomic DNA of human EC was used as a template to amplify the precursor sequence of miRNA-210 by polymerase chain reaction (PCR). The precursor sequence of miRNA-210 was sub-cloned into the eukaryotic expression vector pcDNA3.1(-) via double digestion by BamH I and Hind III restriction enzymes. Then the pcDNA3.1 (-)-pri-miRNA-210 vector (named as p-miRNA-210) that was constructed successfully was transiently transfected into EC109 cells of human EC in vitro. Quantitative real-time PCR (qRT-PCR) was used to detect the expression level of mature miR-210. 3-(4,5-dimethyl-2-thiazolyl)-2,5- diphenyl-2-H-tetrazolium bromide (MTT) assay and scratch method were adopted to detect the proliferation and in vitro migration of EC109 cells, and flow cytometry was performed to detect the degree of cell apoptosis. RESULTS: The eukaryotic expression vector carrying miRNA- 210 was constructed successfully. Compared with that in the blank group (Mock) and the control group (P-Blank), miRNA-210 was overexpressed in the transfected EC109 cells. The cell apoptosis was significantly increased compared with that in the control group (p<0.05); the inhibition of proliferation of EC109 cells in the p-miRNA-210 vector transfected group was remarkably elevated (p<0.05), and wound healing ability was also significantly increased (p<0.05). CONCLUSION: The overexpression of miRNA-210 can significantly inhibit the proliferation of EC109 cells of human EC and accelerate the migration ability and the rate of apoptosis, providing a potential strategy for the treatment of EC.

Liquid biopsy: a step forward towards precision medicine in urologic malignancies.

There is a growing trend towards exploring the use of a minimally invasive "liquid biopsy" to identify biomarkers in a number of cancers, including urologic malignancies. Multiple aspects can be assessed in circulating cell-free DNA, including cell-free DNA levels, integrity, methylation and mutations. Other prospective liquid biopsy markers include circulating tumor cells, circulating RNAs (miRNA, lncRNAs and mRNAs), cell-free proteins, peptides and exosomes have also emerged as non-invasive cancer biomarkers. These circulating molecules can be detected in various biological fluids, including blood, urine, saliva and seminal plasma. Liquid biopsies hold great promise for personalized medicine due to their ability to provide multiple non-invasive global snapshots of the primary and metastatic tumors. Molecular profiling of circulating molecules has been a stepping-stone to the successful introduction of several non-invasive multi-marker tests into the clinic. In this review, we provide an overview of the current state of cell-free DNA-based kidney, prostate and bladder cancer biomarker research and discuss the potential utility other circulating molecules. We will also discuss the challenges and limitations facing non-invasive cancer biomarker discovery and the benefits of this growing area of translational research.

RACK1 promotes radiation resistance in esophageal cancer via regulating AKT pathway and Bcl-2 expression.

RACK1 is a seven Trp-Asp 40 repeat protein, which interacts with a wide range of kinases and proteins. RACK1 plays an important role in the proliferation and progression of various cancers. The aim of this study is to detect the role of RACK1 in the radioresistance in esophageal cancer. The results indicated that downregulation of RACK1 reduced the colony formation ability, proliferation ability and resistance of cells to radiation effection through regulating the radiation-related proteins including pAKT, Bcl-2 and Bim; whereas upregulation of RACK1 promoted the ability and radioresistance of ESCC cells. Our findings suggest that RACK1 promotes proliferation and radioresistance in ESCC cells by activating the AKT pathway, upregulating Bcl-2 expression and downregulating protein levels of Bim. Our study fills in gaps in the field of RACK1 and radiation resistance and may provide new possibilities for improving strategies of radiotherapy in esophageal cancer.