Cytotoxic Peptide Conjugates: Anticancer Therapeutic Strategies

ABSTRACT Traditional chemotherapeutic agents exhibit potent anticancer efficacy. However, in clinical applications, they also exhibit severely toxic side effects, and result in multidrug resistance (MDR) of cancer cells. So, receptor-targeted therapy is catching more attention of scientists from both academic and industry and recently is coming to the central stage of drug development. Certain peptides, due to their advantages like, easy synthesis and low cost, less or no immunogenicity, stability and high affinity, have been used as drug delivery vehicles. For example, cell-targeting peptides and cell-penetrating peptides (CPPs) in conjugation with cytotoxic agents have elicited remarkable effects. Luteinizing hormone-releasing hormone, somatostatin, and bombesin/gastrinreleasing peptide are the cell-targeting peptides that interact with their cognate surface receptors aberrantly expressed in many cancer cells, so these hormone peptides can be incorporated into cytotoxic agents for cell-specific targeting in cancer chemotherapy. Due to their cell-penetrating ability, CPPs also serve as cytotoxic drug delivery vehicles to carry drugs across the plasma membrane and overcome MDR of cancer cells. Cytotoxic agents linked to cell-targeting peptides and CPPs have been considered as an effective and reliable method in cancer chemotherapy. In this review, we address the applications of these peptides as drug delivery vehicles in targeted anticancer drug development

Overexpression of long non-coding RNA NORAD promotes invasion and migration in malignant melanoma via regulating the MIR-205-EGLN2 pathway.

Growing evidence suggests that long non-coding RNAs NORAD and miR-205 play a significant role in regulating cancer progression and metastasis. In this study, high expression of NORAD was firstly observed in melanoma tissues and human malignant melanoma cell lines, our aim was to study the interaction of them in the process of invasion and migration of malignant melanoma cells. NORAD, miR-205, and EGLN2 mRNA level in MM cells was detected by qRT-PCR. In situ hybridization (ISH) was performed to detect NORAD expression in MM tissues specimens. Effects of NORAD and miR-205 on Prolyl hydroxylase 2 (EGLN2) expression was explored by western blot in MM cells line. Dual-luciferase reporter assay was performed to verify the interaction relationship between NORAD and miR-205, as well as, miR-205 and EGLN2. Transwell assay was conducted to explore the effects of NORAD and miR-205 in vitro. Xenografts in nude mice experiment were used to confirm the role of NORAD and miR-205 in vivo. In vitro, NORAD knockdown significantly inhibited migration and invasion of malignant melanoma cells and elevated the expression of miR-205, there was an interaction between miR-205 and NORAD in the RNA-induced silencing complex. Upregulation of miR-205 induced significant inhibition of migratory and invasive ability compared with the scrambled control. However, downregulating NORAD largely reversed this effect. Furthermore, the regulatory effects of miR-205 on EGLN2 levels and the induction of endoplasmic reticulum stress were reversed by NORAD. In vivo, deletion of miR-205 induced tumor growth in nude mice. NORAD may play critical roles in tumorigenesis and progression of malignant melanoma by regulating of the miR-205-EGLN2 pathway, and may serve as a new therapeutic target

Secure Computation for G-Module and its Applications

Secure computation enables two or more parties to jointly evaluate a function without revealing to each other their private input. G-module is an abelian group M, where the group G acts compatibly with the abelian group structure on M. In this work, we present several secure computation protocols for G-module operations in the online/offline mode. We then show how to instantiate those protocols to implement many widely used secure computation primitives in privacy-preserving machine learning and data mining, such as oblivious cyclic shift, one-round shared OT, oblivious permutation, oblivious shuffle, secure comparison, oblivious selection, DReLU, and ReLU, etc. All the proposed protocols are constant-round, and they are 2X - 10X more efficient than the-state-of-the-art constant-round protocols in terms of communication complexity

ABCC3 as a marker for multidrug resistance in non-small cell lung cancer

Multidrug resistance (MDR) contributes to the failure of chemotherapy and high mortality in non-small cell lung cancer (NSCLC). We aim to identify MDR genes that predict tumor response to chemotherapy. 199 NSCLC fresh tissue samples were tested for chemosensitivity by MTT assay. cDNA microarray was done with 5 samples with highest resistance and 6 samples with highest sensitivity. Expression of ABCC3 mRNA and protein was detected by real-time PCR and immunohistochemisty, respectively. The association between gene expression and overall survival (OS) was examined using Cox proportional hazard regression. 44 genes were upregulated and 168 downregulated in the chemotherapy-resistant group. ABCC3 was one of the most up-regulated genes in the resistant group. ABCC3-positive expression correlated with lymph node involvement, advanced TNM stage, more malignant histological type, multiple-resistance to anti-cancer drugs, and reduced OS. ABCC3 expression may serve as a marker for MDR and predictor for poor clinical outcome of NSCLC

miRNA-378 reverses chemoresistance to cisplatin in lung adenocarcinoma cells by targeting secreted clusterin

Cisplatin resistance is a major obstacle in the treatment of NSCLC, and its mechanism has not been fully elucidated. The objectives of the study were to determine the role of miR-378 in the sensitivity of lung adenocarcinoma cells to cisplatin (cDDP) and its working mechanism. With TargetScan and luciferase assay, miR-378 was found to directly target sCLU. miR-378 and sCLU were regulated in A549/cDDP and Anip973/cDDP cells to investigate the effect of miR-378 on the sensitivity and apoptotic effects of cDDP. The effect of miR-378 upregulation on tumor growth was analyzed in a nude mouse xenograft model. The correlation between miR-378 and chemoresistance was tested in patient samples. We found that upregulation of miR-378 in A549/cDDP and Anip973/cDDP cells significantly down-regulated sCLU expression, and sensitized these cells to cDDP. miR-378 overexpression inhibited tumor growth and sCLU expression in a xenograft animal model. Analysis of human lung adenocarcinoma tissues revealed that the cDDP sensitive group expressed higher levels of miR-378 and lower levels of sCLU. miR-378 and sCLU were negatively correlated. To conclude, we identified sCLU as a novel miR-378 target, and we showed that targeting sCLU via miR-378 may help disable the chemoresistance against cisplatin in lung adenocarcinoma cells

Baseline Staging Tests Based on Molecular Subtype is Necessary for Newly Diagnosed Breast Cancer

Background: Bone scanning (BS), liver ultrasonography (LUS), and chest radiography (CXR) are commonly recommended for baseline staging in patients with newly diagnosed breast cancer. The purpose of this study is to demonstrate whether these tests are indicated for specific patient subpopulation based on clinical staging and molecular subtype. Methods: A retrospective study on 5406 patients with newly diagnosed breast cancer was conducted to identify differences in occurrence of metastasis based on clinical staging and molecular subtypes. All patients had been evaluated by BS, LUS and CXR at diagnosis. Results: Complete information on clinical staging was available in 5184 patients. For stage I, II, and III, bone metastasis rate was 0%, 0.6% and 2.7%, respectively (P \u3c 0.01); liver metastasis rate was 0%, 0.1%, and 1.0%, respectively (P \u3c 0.01); lung metastasis rate was 0.1%, 0.1%, and 0.7%, respectively (P \u3c 0.01). Complete information on molecular subtype was available in 3411 patients. For Luminal A, Luminal B (HER2−), Luminal BH (HER2+), HER2+ overexpression, and Basal-like, bone metastasis rate was 1.4%, 0.7%, 2.5%, 2.7%, and 0.9%, respectively (P \u3c 0.05); liver metastasis rate was 0.1%, 0.1%, 1.0%, 1.1%, and 0.9%, respectively (P \u3c 0.01); lung metastasis rate was 0.20%, 0%, 0%, 0.27%, and 0.9%, respectively (P \u3c 0.05). cT (tumor size), cN (lymph node), PR (progesterone receptor), and HER2 status predicted bone metastasis (P \u3c 0.05). cT, cN, ER (estrogen receptor), PR, and HER2 status predicted liver metastasis (P \u3c 0.05). cT, cN, and PR status predicted lung metastasis (P \u3c 0.05). Conclusion: These data indicate that based on clinical staging and molecular subtypes, BS, LUS and CXR are necessary for patients with newly diagnosed breast cancer

PSR J1926-0652: A Pulsar with Interesting Emission Properties Discovered at FAST

We describe PSR J1926-0652, a pulsar recently discovered with the Five-hundred-meter Aperture Spherical radio Telescope (FAST). Using sensitive single-pulse detections from FAST and long-term timing observations from the Parkes 64-m radio telescope, we probed phenomena on both long and short time scales. The FAST observations covered a wide frequency range from 270 to 800 MHz, enabling individual pulses to be studied in detail. The pulsar exhibits at least four profile components, short-term nulling lasting from 4 to 450 pulses, complex subpulse drifting behaviours and intermittency on scales of tens of minutes. While the average band spacing P3 is relatively constant across different bursts and components, significant variations in the separation of adjacent bands are seen, especially near the beginning and end of a burst. Band shapes and slopes are quite variable, especially for the trailing components and for the shorter bursts. We show that for each burst the last detectable pulse prior to emission ceasing has different properties compared to other pulses. These complexities pose challenges for the classic carousel-type models.Comment: 13pages with 12 figure