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There is increasing evidence indicating the significant role of DDX5 (also called p68), acting as a master regulator and a potential biomarker and target, in tumorigenesis, proliferation, metastasis and treatment resistance for cancer therapy. However, DDX5 has also been reported to act as an oncosuppressor. These seemingly contradictory observations can be reconciled by DDX5's role in DNA repair. This is because cancer cell apoptosis and malignant transformation can represent the two possible outcomes of a single process regulated by DDX5, reflecting different intensity of DNA damage. Thus, targeting DDX5 could potentially shift cancer cells from a growth-arrested state (necessary for DNA repair) to apoptosis and cell killing. In addition to the increasingly recognized role of DDX5 in global genome stability surveillance and DNA damage repair, DDX5 has been implicated in multiple oncogenic signaling pathways. DDX5 appears to utilize distinct signaling cascades via interactions with unique proteins in different types of tissues/cells to elicit opposing roles (e.g., smooth muscle cells versus cancer cells). Such unique features make DDX5 an intriguing therapeutic target for the treatment of human cancers, with limited low toxicity to normal tissues. In this review, we discuss the multifaceted functions of DDX5 in DNA repair in cancer, immune suppression, oncogenic metabolic rewiring, virus infection promotion, and negative impact on the human microbiome (microbiota). We also provide new data showing that FL118, a molecular glue DDX5 degrader, selectively works against current treatment-resistant prostate cancer organoids/cells. Altogether, current studies demonstrate that DDX5 may represent a unique oncotarget for effectively conquering cancer with minimal toxicity to normal tissues. [ABSTRACT FROM AUTHOR]

There is increasing evidence indicating the significant role of DDX5 (also called p68), acting as a master regulator and a potential biomarker and target, in tumorigenesis, proliferation, metastasis and treatment resistance for cancer therapy. However, DDX5 has also been reported to act as an oncosuppressor. These seemingly contradictory observations can be reconciled by DDX5's role in DNA repair. This is because cancer cell apoptosis and malignant transformation can represent the two possible outcomes of a single process regulated by DDX5, reflecting different intensity of DNA damage. Thus, targeting DDX5 could potentially shift cancer cells from a growth-arrested state (necessary for DNA repair) to apoptosis and cell killing. In addition to the increasingly recognized role of DDX5 in global genome stability surveillance and DNA damage repair, DDX5 has been implicated in multiple oncogenic signaling pathways. DDX5 appears to utilize distinct signaling cascades via interactions with unique proteins in different types of tissues/cells to elicit opposing roles (e.g., smooth muscle cells versus cancer cells). Such unique features make DDX5 an intriguing therapeutic target for the treatment of human cancers, with limited low toxicity to normal tissues. In this review, we discuss the multifaceted functions of DDX5 in DNA repair in cancer, immune suppression, oncogenic metabolic rewiring, virus infection promotion, and negative impact on the human microbiome (microbiota). We also provide new data showing that FL118, a molecular glue DDX5 degrader, selectively works against current treatment-resistant prostate cancer organoids/cells. Altogether, current studies demonstrate that DDX5 may represent a unique oncotarget for effectively conquering cancer with minimal toxicity to normal tissues. [ABSTRACT FROM AUTHOR]

The utilization of the spiral tube heat exchanger (SHE) has become increasingly prevalent in large-scale liquefaction processes. However, the flow pattern and frictional pressure drop of two-phase flow in the spiral tube have been scarcely studied, particularly under offshore sloshing conditions. An experimental system had been developed to explore the flow pattern and frictional pressure drop characteristics of mixed hydrocarbon fluid in a spiral tube. Moreover, these have been developed in order to examine the effects of sloshing style (roll, pitch, heave), sloshing period (5–15 s), sloshing amplitude (5–15° or 50–150 mm), mass flux (200–800 kg/(m2·s)), vapor quality (0–1), and saturation pressure (2–4 MPa) on the frictional pressure drop of methane/ethane mixture in the spiral tube. The results indicated that sloshing conditions reduce the frictional pressure drop, thereby enhancing fluid flow. A correlation was established to predict the sloshing factor of frictional pressure drop, and the MARD under verification conditions was 6.04%. Furthermore, three flow pattern boundaries were proposed based on We* as an indicator. [ABSTRACT FROM AUTHOR]

Spiral wound tube heat exchanger (SWHE) was confirmed as the core equipment of natural gas liquefaction (LNG). However, there was rare experimental research on large-scale SWHE for LNG, and the theory of heat transfer is not perfect. To investigate the tube-side flow and heat transfer characteristics in spiral tubes, an experimental system was proposed. To ensure the accuracy of the experimental data, the heat transfer coefficients of liquid propane under different conditions were measured, and the data acquired through the experiment were compared with two classical heat transfer correlation (Dittus–Boelter and Geielinski) under the identical working conditions. The applicability of the existing correlation was analyzed using the experimental data, and a novel heat transfer correlation was developed. As indicated by the results, the deviation between the experimental system and the classical correlation under the identical working condition was lower than ±10%. Furthermore, the error comparison between the novel correlation prediction value and the experimental data was less than ±15%. [ABSTRACT FROM AUTHOR]

Pig hair (PH), a keratinous waste, was modified by ammonium thioglycolate in a ball milling to promote its performance of Hg(II) sequestration. The ball milling broke the hydrophobic cuticle sheath and enhanced the reduction of disulfide bond, which increased the sulfydryl content of the modified PH (BTPH) from 0.07 to 11.05 μmol/g. BTPH exhibited a significantly higher capture capacity of Hg(II) (415.4 mg/g) than PH (3.1 mg/g), as well as the commercial activated carbon (219.7 mg/g), and persisted its performance over a wide range of solution pH. Meanwhile, BTPH with a distribution coefficient of 5.703 × 105 mL/g could selectively capture Hg(II) from the water with the coexisting metal ions such as Mg(II), Cd(II) and Pb(II). Moreover, the low-cost BTPH could reduce the Hg(II) from 1.0 mg/L to well below the limit of drinkable water (2 μg/L) in real-world samples. Density functional theory (DFT) calculations and state-of-the-art characterizations illustrated that the binding of Hg(II) to sulfydryl groups was the main adsorption mechanism. Notably, BTPH decreased the mercury content of water spinaches from 24.1 to 0.50 mg/kg and thereby significantly reduced the phytotoxicity of Hg(II). This work therefore provides a sustainable way to utilize keratinous wastes for the remediation of aqueous Hg(II). [Display omitted] • Ball milling promoted the reduction of pig hair to increase its density of –SH. • The modified pig hair (BTPH) revealed a high adsorption capacity of Hg(II). • BTPH with a low cost of ~0.11 $/g showed high selectivity for Hg(II) uptake. • The −SH played the key role in the capture of Hg(II). • BTPH decreased the phytotoxicity of Hg(II) toward the aquatic plants. [ABSTRACT FROM AUTHOR]

Molecular glue (MG) compounds are a type of unique small molecule that can change the protein–protein interactions (PPIs) and interactomes by degrading, stabilizing, or activating the target protein after their binging. These small-molecule MGs are gradually being recognized for their potential application in treating human diseases, including cancer. Evidence suggests that small-molecule MG compounds could essentially target any proteins, which play critical roles in human disease etiology, where many of these protein targets were previously considered undruggable. Intriguingly, most MG compounds with high efficacy for cancer treatment can glue on and control multiple key protein targets. On the other hand, a single key protein target can also be glued by multiple MG compounds with distinct chemical structures. The high flexibility of MG–protein interaction profiles provides rich soil for the growth and development of small-molecule MG compounds that can be used as molecular tools to assist in unraveling disease mechanisms, and they can also facilitate drug development for the treatment of human disease, especially human cancer. In this review, we elucidate this concept by using various types of small-molecule MG compounds and their corresponding protein targets that have been documented in the literature. [ABSTRACT FROM AUTHOR]

We propose a scheme to generate the case of macroscopic entanglement in the optomechanical system, which consist of Fabry-Perot cavity and a mechanical oscillator by applying a homodyne-mediated quantum feedback. We explore the effect of feedback on the entanglement in vacuum and coherent state, respectively. The results show that the introduction of quantum feedback can increase the entanglement effectively between the cavity mode and the oscillator mode. [ABSTRACT FROM AUTHOR]

A technique to evaluate the temperature field is developed by extending the scaled boundary finite element method (SBFEM). Firstly, the method for the steady state problem with prescribed side-face uniform temperature is developed, so only the partial boundary of the problem domain is discretized. Secondly, the effect of the heat capacity on the element interior temperature field is taken into account for the transient heat conduction problem. Thirdly, an improved time domain precise integration method is developed for computing the boundary temperature of the SBFE, meanwhile, a finite-difference scheme is adopted to obtain the element interior temperature at different time. Finally, three examples are presented to illustrate feasibility and good accuracy of the proposed methods. [ABSTRACT FROM AUTHOR]

RNA-dependent protein kinase (PKR) is crucial for the innate immune response, cell growth, proliferation, signal transduction and apoptosis. The activation process of PKR has been studied for many years and is still under debate. To obtain new insight into the mechanism of PKR activation, we solved the crystal structure of a latent mutant of the PKR kinase domain (PKR-KD) in the apo form at a resolution of 2.9 Å. The overall structure of PKR-KD is similar to previously reported structures. Structural analysis revealed a classical back-to-back dimer and a newly defined face-to-face dimer. Analytical ultracentrifugation experiments, electrostatic surface maps and the model of PKR-KD in complex with the eIF2α substrate all support that the face-to-face dimer is more reflective of PKR in solution. Our results provide new information on PKR dimerization and its activation mechanism. [ABSTRACT FROM AUTHOR]

The scaled boundary finite element method is used to determine the seepage free surface of a dam with unbounded base. Two models for the bounded and the unbounded domains are established by using the mentioned method, and the numerical solutions are compared with the analytical results. Also, the free surface seepage of a dam with unbounded base is solved by combining the substructure and scaled boundary finite-element methods. The method has satisfactory accuracy and is quite efficient. [ABSTRACT FROM AUTHOR]

In recent years, the use of phase change materials (PCM) to improve heat and moisture transfer properties of clothing has gained considerable attention. The PCM distribution in the clothing impacts heat and moisture transfer properties of the clothing significantly. For describing the mechanisms of heat and moisture transfer in clothing with PCM and investigating the effect of the PCM distribution, a new dynamic model of coupled heat and moisture transfer in porous textiles with PCM was developed. The effect of water content on physical parameters of textiles and heat transfer with phase change in the PCM microcapsules were considered in the model. Meanwhile, the numerical predictions were compared with experimental data, and good agreement was observed between the two, indicating that the model was satisfactory. Also the effects of the PCM distribution on heat transfer in the textiles-PCM microcapsule composites were investigated by using the model. [ABSTRACT FROM AUTHOR]

To describe the heat and moisture transfer in porous textiles with phase change material (PCM) microcapsules, a dynamic model was developed. In the model the moisture sorption of fibres and the effects of the phase transition temperature range and the heating/cooling rate on the phase change processes of the PCM were considered. Meanwhile, the theoretical predictions were validated by experimental data. Then, the processes of moisture transfer in the inter-fibre void spaces and in the fibres and their interaction with heat transfer and regulation of PCM microcapsules during ambient transient conditions were illustrated by a series of 3D diagrams. The results show that fibre hygroscopicity impacts the effect of PCM microcapsules in delaying fabric temperature variations very significantly. [ABSTRACT FROM AUTHOR]

A model of simultaneous transport in hygroscopic porous materials was developed. Water in fabrics is considered to be present in three forms: liquid water in the void space between fibers, bound water in the fibers, and vapor. It is assumed that the heat and mass transport mechanisms include movement of liquid water due to the capillarity and atmospheric pressure gradient, diffusion of vapor within interfibers due to the partial pressure gradient of vapor and total gas pressure gradient, diffusion of vapor into fiber, evaporation, and condensation of water. The moisture diffusion process into hygroscopic porous materials such as wool fabrics was simulated. At normal atmospheric pressure, the results were compared with experimental data on the temperature and water content changes reported in the literature. The distribution of temperature, moisture concentration, liquid water saturation, and atmospheric pressure in the void space between fibers at different boundary conditions are numerically computed and compared. The conclusion is that atmospheric pressure gradient has significant impact on heat and mass transport processes in hygroscopic porous materials. [ABSTRACT FROM AUTHOR]

Here we investigate the role of the control of apoptosis in normal cell division. We show that interference with the expression or function of the apoptosis inhibitor survivin causes caspase-dependent cell death in the G2/M phase of the cell cycle, and a cell-division defect characterized by centrosome dysregulation, multipolar mitotic spindles and multinucleated, polyploid cells. Use of a dominant-negative survivin mutant or antisense survivin complementary DNA disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21[sup Waf1/Cip1] within centrosomes, and results in caspase-dependent cleavage of p21. Polyploidy induced by survivin antagonists is accentuated in p21-deficient cells, and corrected by exogenous expression of p21. These findings show that control of apoptosis and preservation of p21 integrity within centrosomes by survivin are required for normal mitotic progression. [ABSTRACT FROM AUTHOR]

Reports on an inhibitor of apoptosis, called survivin, that is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. Background about survivin distribution; Interaction between survivin and tubulin; Methods used in the study.

Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin's functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: The alkaloid camptothecin analog SN38 is a potent antineoplastic agent, but cannot be used directly for clinical application due to its poor water solubility. Currently, the prodrug approach on SN38 has resulted in 3 FDA-approved cancer therapeutics, irinotecan, ONIVYDE, and Trodelvy. However, only 2–8% of irinotecan can be transformed enzymatically in vivo into the active metabolite SN38, which severely limits the drug's efficacy. While numerous drug delivery systems have been attempted to achieve effective SN38 delivery, none have produced drug products with antitumor efficacy better than irinotecan in clinical trials. Therefore, novel approaches are urgently needed for effectively delivering SN38 to cancer cells with better efficacy and lower toxicity. Methods: Based on the unique properties of human serum albumin (HSA), we have developed a novel single protein encapsulation (SPE) technology to formulate cancer therapeutics for improving their pharmacokinetics (PK) and antitumor efficacy and reducing their side effects. Previous application of SPE technology to doxorubicin (DOX) formulation has led to a promising drug candidate SPEDOX-6 (FDA IND #, 152154), which will undergo a human phase I clinical trial. Using the same SPE platform on SN38, we have now produced two SPESN38 complexes, SPESN38-5 and SPESN38-8. We conducted their pharmacological evaluations with respect to maximum tolerated dose, PK, and in vivo efficacy against colorectal cancer (CRC) and soft tissue sarcoma (STS) in mouse models. Results: The lyophilized SPESN38 complexes can dissolve in aqueous media to form clear and stable solutions. Maximum tolerated dose (MTD) of SPESN38-5 is 250 mg/kg by oral route (PO) and 55 mg/kg by intravenous route (IV) in CD-1 mice. SPESN38-8 has the MTD of 45 mg/kg by IV in the same mouse model. PK of SPESN38-5 by PO at 250 mg/kg gave mouse plasma AUC0-∞ of 0.05 and 4.5 nmol × h/mL for SN38 and SN38 glucuronidate (SN38G), respectively, with a surprisingly high molar ratio of SN38G:SN38 = 90:1. However, PK of SPESN38-5 by IV at 55 mg/kg yielded much higher mouse plasma AUC0-∞ of 19 and 28 nmol × h/mL for SN38 and SN38G, producing a much lower molar ratio of SN38G:SN38 = 1.5:1. Antitumor efficacy of SPESN38-5 and irinotecan (control) was evaluated against HCT-116 CRC xenograft tumors. The data indicates that SPESN38-5 by IV at 55 mg/kg is more effective in suppressing HCT-116 tumor growth with lower systemic toxicity compared to irinotecan at 50 mg/kg. Additionally, SPESN38-8 and DOX (control) by IV were evaluated in the SK-LMS-1 STS mouse model. The results show that SPESN38-8 at 33 mg/kg is highly effective for inhibiting SK-LMS-1 tumor growth with low toxicity, in contrast to DOX's insensitivity to SK-LMS-1 with high toxicity. Conclusion: SPESN38 complexes provide a water soluble SN38 formulation. SPESN38-5 and SPESN38-8 demonstrate better PK values, lower toxicity, and superior antitumor efficacy in mouse models, compared with irinotecan and DOX. [ABSTRACT FROM AUTHOR]

Astrocytes respond to all forms of central nervous system (CNS) insults by a process referred to as reactive astrogliosis. Inhibition of astrocyte growth and activation is an important strategy for promoting injured CNS repair. STAT3 (signal transducer and activator of transcription 3) is reported to be a critical regulator of astrogliosis, and resveratrol (RES, a dietary polyphenol) is considered to be a natural inhibitor of STAT3 expression and phosphorylation. In this study, we investigated the effects of RES on STAT3 expression and phosphorylation, and then on the proliferation and activation of astrocytes, a critical process in reactive astrogliosis, in rat primary cultured astrocytes and an in vitro scratch-wound model. RES downregulated the expression levels of STAT3, P-STAT3 and GFAP (glial fibrillary acidic protein) in cultured astrocytes. The positive index of Ki67 was apparently reduced in cultured astrocytes after RES treatment. Meanwhile, cultured astrocyte proliferation and activation were attenuated by RES. Moreover, in the established in vitro scratch-wound model the increased expression levels of STAT3, P-STAT3 and GFAP induced by scratching injury were also clearly inhibited by RES. In addition, the inhibitory effect of RES on cell proliferation was similar to that of AG490 (a selective inhibitor of STAT3 phosphorylation) and abrogated by Colivelin (a STAT3 activator) stimuli. Taken together, our data suggest that RES is able to inhibit reactive astrocyte proliferation and activation mainly via deactivating STAT3 pathway. So RES may have a therapeutic benefit for the treatment of the injured CNS. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCMs) and spinal cord cavernous malformations (SCCMs) are common vascular abnormalities of the CNS that can lead to seizure, haemorrhage and other neurological deficits. Approximately 85% of patients present with sporadic (versus congenital) CCMs. Somatic mutations in MAP3K3 and PIK3CA were recently reported in patients with sporadic CCM, yet it remains unknown whether MAP3K3 mutation is sufficient to induce CCMs. Here we analysed whole-exome sequencing data for patients with CCM and found that ∼40% of them have a single, specific MAP3K3 mutation [c.1323C>G (p.Ile441Met)] but not any other known mutations in CCM-related genes. We developed a mouse model of CCM with MAP3K3 I441M uniquely expressed in the endothelium of the CNS. We detected pathological phenotypes similar to those found in patients with MAP3K3 I441M. The combination of in vivo imaging and genetic labelling revealed that CCMs were initiated with endothelial expansion followed by disruption of the blood–brain barrier. Experiments with our MAP3K3 I441M mouse model demonstrated that CCM can be alleviated by treatment with rapamycin, the mTOR inhibitor. CCM pathogenesis has usually been attributed to acquisition of two or three distinct genetic mutations involving the genes CCM1 / 2 / 3 and/or PIK3CA. However, our results demonstrate that a single genetic hit is sufficient to cause CCMs. [ABSTRACT FROM AUTHOR]

We present the result of our research on the tumorigenic ability of single cell clones isolated from an aggressive murine breast cancer cell line in a matched allografting mouse model. Tumor formation is basically dependent on the cell numbers injected per location. We argue that in vivo tumor formation from single cell clones, isolated in vivo from cancer cell lines, may not provide conclusive evidence to disprove the cancer stem cell (CSC) theory without additional data. [ABSTRACT FROM AUTHOR]

It is known that tRNAs play an essential role in genetic information transfer from DNA to protein. The maturation of tRNA precursors is performed by the endoribonuclease RNase P, which classically consists of a main RNA segment and accessory proteins. However, the newly identified human mitochondrial RNase P-like protein (MRPP123) complex is unique in that it is composed of three proteins without RNA. Here, we determined the crystal structure of MRPP123 complex subunit 3 (MRPP3), which is thought to carry out the catalytic reaction. A detailed structural analysis in combination with biochemical assays suggests that MRPP3 is in an auto-inhibitory conformation in which metal ions that are essential for catalysis are excluded from the active site. Our results indicate that further regulation is necessary to rearrange the conformation of the active site of MRPP3 and trigger it, thus providing important information to understand the activation of MRPP123. [ABSTRACT FROM AUTHOR]

We propose a theoretical method to enhance the entanglement between two mechanical resonators in two optomechanical cavities, which are coupled by the photon-hopping process, and each opto-mechanical cavity are consisted of a Fabry-Perot cavity and a mechanical oscillator by applying N atomic medium. We explore the effect of the entanglement between two mechanical oscillators with two atomic mediums and without them, respectively. The results show that the introduction of atoms can effectively increase the entanglement between the two oscillator modes. [ABSTRACT FROM AUTHOR]

Irinotecan and Topotecan are two Camptothecin derivatives (CPTs) whose resistance is associated with the high expression of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). To reverse this resistance, two novel CPTs, FL77-28 (7-(3-Fluoro-4-methylphenyl)-10,11-methylenedioxy-20(S)-CPT) and FL77-29 (7-(4-Fluoro-3-methylphenyl)-10,11-methylenedioxy-20(S)-CPT), were synthesized by our group. In this study, the anti-tumor activities of FL77-28, FL77-29, and their parent, FL118 (10,11-methylenedioxy-20(S)-CPT), were evaluated and the results showed that FL77-28 and FL77-29 had stronger anti-tumor activities than FL118. The transport and uptake of FL118, FL77-28, and FL77-29 were investigated in Caco-2 cells for the preliminary prediction of intestinal absorption. The apparent permeability coefficient from apical to basolateral (Papp AP-BL) values of FL77-28 and FL77-29 were (2.32 ± 0.04) × 10−6 cm/s and (2.48 ± 0.18) × 10−6 cm/s, respectively, suggesting that the compounds had moderate absorption. Since the transport property of FL77-28 was passive diffusion and the efflux ratio (ER) was less than 2, two chemical inhibitors were added to further confirm the involvement of efflux proteins. The results showed that FL77-28 was not a substrate of P-gp or BCRP, but FL77-29 was mediated by P-gp. In conclusion, FL77-28 might be a promising candidate to overcome drug resistance induced by multiple efflux proteins. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC), a difficult‐to‐treat cancer, is expected to become the second‐largest cause of cancer‐related deaths by 2030, while colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer deaths. Currently, there is no effective treatment for PDAC patients. The development of novel agents to effectively treat these cancers remains an unmet clinical need. FL118, a novel anticancer small molecule, exhibits high efficacy against cancers; however, the direct biochemical target of FL118 is unknown. Methods: FL118 affinity purification, mass spectrometry, Nanosep centrifugal device and isothermal titration calorimetry were used for identifying and confirming FL118 binding to DDX5/p68 and its binding affinity. Immunoprecipitation (IP), western blots, real‐time reverse transcription PCR, gene silencing, overexpression (OE) and knockout (KO) were used for analysing gene/protein function and expression. Chromatin IP was used for analysing protein‐DNA interactions. The 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromid assay and human PDAC/CRC cell/tumour models were used for determining PDAC/CRC cell/tumour in vitro and in vivo growth. Results: We discovered that FL118 strongly binds to dephosphorylates and degrades the DDX5 oncoprotein via the proteasome degradation pathway without decreasing DDX5 mRNA. Silencing and OE of DDX5 indicated that DDX5 is a master regulator for controlling the expression of multiple oncogenic proteins, including survivin, Mcl‐1, XIAP, cIAP2, c‐Myc and mutant Kras. Genetic manipulation of DDX5 in PDAC cells affects tumour growth. PDAC cells with DDX5 KO are resistant to FL118 treatment. Our human tumour animal model studies further indicated that FL118 exhibits high efficacy to eliminate human PDAC and CRC tumours that have a high expression of DDX5, while FL118 exhibits less effectiveness in PDAC and CRC tumours with low DDX5 expression. Conclusion: DDX5 is a bona fide FL118 direct target and can act as a biomarker for predicting PDAC and CRC tumour sensitivity to FL118. This would greatly impact FL118 precision medicine for patients with advanced PDAC or advanced CRC in the clinic. FL118 may act as a 'molecular glue degrader' to directly glue DDX5 and ubiquitination regulators together to degrade DDX5. [ABSTRACT FROM AUTHOR]

We have previously shown that the clinically relevant polyamine analog N1,N11-diethylnorspermine (DENSPM) causes rapid apoptosis in human melanoma SK-MEL-28 cells via a series of events that include mitochondrial release of cytochrome c and activation of the caspase cascade. Upstream to these events, DENSPM downregulates polyamine biosynthesis and potently upregulates polyamine catabolism at the level of spermidine/spermine N1-acetyltransferase (SSAT). In searching for downstream effectors that either contribute to or abrogate the apoptotic response, we observed that DENSPM treatment of SK-MEL-28 cells for 30?h led to cytosolic release of Smac/Diablo, a mitochondrial protein known to bind and inhibit the function of inhibitor of apoptosis proteins (IAPs). Subsequently, we found that DENSPM markedly lowered survivin and ML-IAP protein (but not XIAP) levels by 18?h via an apparently Smac/Diablo-independent pathway. Proteasome inhibitors fully prevented survivin and ML-IAP protein loss as well as apoptosis, suggesting that the proteasome-mediated degradation of survivin and ML-IAP is causally linked to the cellular outcome. We also observed that structural analogs of DENSPM which differentially induced SSAT and apoptosis lowered survivin and ML-IAP levels in a manner that correlated with enzyme activity. The linkage between IAPs and SSAT was more directly established by the finding that selective prevention of SSAT induction by small interfering RNA prevented survivin and ML-IAP loss as well as apoptosis during DENSPM treatment. Among the melanoma cell lines (SK-MEL-28, MALME-3M, A375 and LOX), survivin degradation correlated temporally with the onset of DENSPM induced apoptosis or growth inhibition. By contrast, ML-IAP degradation occurred only during rapid apoptosis seen in SK-MEL-28 cells. These data suggest a sequence of events whereby DENSPM induction of SSAT leads to loss of IAP proteins and a more fulminate apoptotic response. The findings implicate survivin and ML-IAP as important determinants of polyamine analog drug action in melanoma cells.Oncogene (2003) 22, 4964-4972. doi:10.1038/sj.onc.1206725 [ABSTRACT FROM AUTHOR]

Activation of the human protease-activated receptor-1 (PAR-1) by thrombin leads to myriad functions essential for maintaining vascular integrity. Upregulation of PAR-1 expression is considered important in atherosclerosis, angiogenesis and tumor metastasis. In vitro analysis of the human PAR-1 promoter function revealed a positive regulatory element between −4.2 and −3.2 kb of the transcription start site. This element was examined in transgenic mice containing either 4.1 or 2.9 kb of the 5′ flanking sequence driving a LacZ reporter gene. Only the 4.1 kb PAR-1 transgene was expressed in vivo and only during embryonic development. The transgene expression was observed only in developing arteries and not in veins. Further examination of this putative regulatory sequence identified a novel noncoding RNA (ncR-uPAR:noncoding RNA upstream of the PAR-1) gene at −3.4 kb. The ncR-uPAR upregulated PAR-1-core promoter-driven luciferase activity and mRNA expression in vitro in a Pol II-dependent manner. This noncoding RNA appears to act in trans, albeit locally at the adjacent PAR-1 promoter. These data suggest that an untranslated RNA plays a role in PAR-1 gene expression during embryonic growth. [Copyright &y& Elsevier]

Summary The newly described apoptosis inhibitor survivin is expressed in many human cancers and appears to play a critical part in both apoptosis regulation and cell cycle progression. Its potential role in malignant melanoma is unknown. In a panel of 30 malignant melanomas, survivin was strongly expressed in all cases (15 of 15) of metastatic malignant melanomas and 13 of 15 cases of invasive malignant melanomas by immunohistochemistry. In invasive malignant melanomas, survivin was also expressed in the in-situ component of the lesion. Survivin expression was found in all cases (11 of 11) of nevi, but not in melanocytes in sections of normal skin. The apoptosis inhibitor bcl-2 was expressed in 26 of 30 cases, but generally at lower levels than that of infiltrating lymphocytes. The mitotic index, as assessed by MIB-1 staining, was consistently higher in metastatic than invasive malignant melanomas. Assessment of apoptotic index by in situ end-labeling revealed extremely low rates of apoptosis in most malignant melanomas. Survivin expression by western blotting was detected in four human metastatic malignant melanoma cell lines but not in cultured normal human melanocytes. Transfection of both YUSAC-2 and LOX malignant melanoma cells with green fluorescence protein-conjugated survivin anti-sense or green fluorescence protein-conjugated survivin dominant negative mutant (Cys85Ala) resulted in increased apoptosis in the absence of other genotoxic stimuli. Two-color flow cytometry confirmed that YUSAC-2 cells transfected with survivin anti-sense expressed less endogenous survivin and exhibited an increased fraction of cells with sub-G1 DNA content. These data demonstrate that apoptosis inhibition by survivin may participate in the onset and progression of malignant melanomas, and suggest that therapeutic targeting of survivin may be beneficial in patients with recurrent or metastatic disease. [ABSTRACT FROM AUTHOR]

The maldistribution of working medium restricts the heat transfer performance of the spiral-wound heat exchangers (SWHEs), especially when the heat exchangers are applied in floating production storage and offloading platform. Therefore, the maldistribution in the SWHEs needs to be studied under sloshing conditions. In the investigation, a novel distributor named "disc distributor" is designed and its distribution characteristic is analysed under sloshing conditions experimentally. The impacts of sloshing amplitude, sloshing periods, mass flow rate and structural parameters on flow uniformity are discussed. The results show that based on steady condition the augmentation of the sloshing amplitude makes the liquid uniformity deteriorate by 14.2–56.0%, and the enlargement of the sloshing period improves the liquid flow uniformity by 12.8–28.3%. The elevation of the mass flow rate promotes the flow uniformity by 23.8–27.0% and 13.9–32.4% under steady and sloshing conditions, respectively. The variation of hole diameter exacerbates distribution performance of the distributor by 5.3–18.4% and 2.5–22.3% under steady and sloshing conditions separately. Heave condition always has less influence on the flow uniformity of the distributor than other sloshing conditions. [ABSTRACT FROM AUTHOR]

Porous ceramics with lightweight, high strength, thermal insulation, and decoration integration were prepared using red mud, construction waste, polished tile waste, and kaolin as raw materials. The influences of the content of red mud, sintering temperature, and blowing agent on the microstructure, mechanical, and thermal properties of porous ceramic were investigated. According to bulk density, pore morphology, compressive strength, and thermal conductivity, the optimum preparation condition of porous ceramic was determined after selecting the raw materials formulations and process parameters. Multi-functional wall insulation materials have been prepared when the content of red mud was 40%, blowing agent was 3%, and sintering temperature was 1080 °C. The bulk density, porosity, compressive strength, thermal conductivity, and softening temperature of porous ceramics were 0.25 g/cm3, 72.15%, 7.26 MPa, 0.058 W/(m K), and 1160 °C respectively. Their corresponding influence mechanisms of pore structure on mechanical and thermal properties were discussed in detail. It was found from the section images of pore morphology that pore distribution and size were significantly uniform in porous ceramic. [ABSTRACT FROM AUTHOR]

Purpose: Recent researches are attempting to verify that the 3D cell models can provide a gap bridge between in vitro and in vivo for anticancer drug evaluations. The aim of this study was to continue the development of novel in vitro 3D cell models and the investigation of the cellular uptake mechanism of camptothecin (CPT) and its derivatives [FL118 (10,11-methylenedioxy-20(S)-camptothecin), 9-Q20 (9-p-trifluoromethylphenyl-10,11-methylenedioxy-20(S)-camptothecin)] in 2D and 3D cell models.Methods: The 3D cell models were established using ultralow attachment 96-well plates. The cytotoxicity of CPT, FL118, and 9-Q20 was evaluated by MTT method. The effects of compound concentration, incubation time, temperature, and transporter inhibitors on the cellular uptake of CPT, FL118, and 9-Q20 were examined in 2D and 3D cell models.Results: The cytotoxicity of CPT, FL118, and 9-Q20 was lower in 3D cell models than 2D cell models. In 2D Caco-2 cell model, the uptake rate of CPT, FL118, and 9-Q20 was faster during the early time of incubation. In 3D Caco-2 cell model, the uptake capacity of CPT, FL118, and 9-Q20 was significantly improved over time. In 3D Caco-2 cell model, Verapamil (P-gp inhibitor) and Gefitinib (BCRP inhibitor) more significantly increased the uptake of CPT and 9-Q20. In contrast, P-gp and BCRP did not affect the accumulation of FL118 in 2D and 3D Caco-2 cell models. The accumulation of CPT, FL118, and 9-Q20 was greater in HepG2 cells than HCT116 cells.Conclusion: The 3D cell models provided more potency information on the process of cellular uptake of CPT, FL118, and 9-Q20, which more objectively reflected the drug sensitivity and drug resistance in vivo compared with the 2D cell models. [ABSTRACT FROM AUTHOR]

Allyl-isothiocyanate (AITC) is a common Isothiocyanates (ITC) and its chemo-preventive and anti-tumor effects are believed to be related to the activation of NF-E2 p45-related Factor 2 (Nrf2). However, its anti-tumor effects on colorectal cancer (CRC) are not well elucidated. Here, we investigated the therapeutic in vitro and/or in vivo effects and mechanisms of action (MOA) for AITC on CRC cell line HCT116 (human) and MC38 (mouse). AITC treatment in a low concentration range (1 mg/kg in vivo) significantly inhibited the tumor cell growth and increased the expression of p21 and Nrf2. The AITC-mediated induction of p21 was dependent on Nrf2 but independent on p53 in vitro and in vivo at low dose. In contrast, the high dose of AITC (5 mg/kg in vivo) failed to increase substantial levels of p21/MdmX, and impaired the total antioxidant capacity of tumors and subsequent anti-tumor effect in vivo. These results suggest that an optimal dose of AITC is important and required for the proper Nrf2 activation and its anti-CRC effects and thus, providing insights into the potential applications of AITC for the prevention and treatment of CRC. [ABSTRACT FROM AUTHOR]

• Hydrocarbon mixtures condensation flow was investigated at heaving condition. • The simulation results coincided to experimental ones with ±15% error. • The impacts of various parameters on pressure drop and heat transfer were discussed. • Methane/ethane mixture had the best heat transfer and the smallest pressure drop. • It showed better performance at heaving condition than static one. A model based on ASNYS CFX was established to explore the pressure drop and heat transfer characteristics of condensation flow with hydrocarbon mixtures in a spiral pipe under static and heaving conditions, whose deviations are within ±15% compared to experimental ones. It considered the effects of motion parameters, operating parameters and structural parameters on frictional pressure drop and heat transfer coefficient for three hydrocarbon mixtures. The ranges of mass flux, vapor quality, heat flux, saturation pressure, hydraulic diameter, curvature diameter and inclination angle were 200–800 kg/(m2·s), 0.3–0.9, 10–20 kW/m2, 2–4 MPa, 6–14 mm, 1.6–2.4 m and 6–14°, respectively. The results demonstrate that methane/ethane mixture has the best heat transfer and the smallest pressure drop among three mixtures. At static condition, as the vapor quality and mass flux increase and the saturation pressure and hydraulic diameter decrease, there are evident increases in heat transfer and pressure drop, whereas the impacts of curvature diameter, inclination angle and heat flux on them are insignificant. Meanwhile, the heaving motion affects pressure drop and heat transfer and makes it show better overall heat transfer performances, where the comprehensive heat transfer factors (CHFs) of 83.33% data points are more than 1. Further, the heaving effects increase with the increasing heaving amplitude and the decreasing heaving cycle. [ABSTRACT FROM AUTHOR]

Highlights • A model was established to investigate condensation flow under sloshing condition. • The influence of different parameters on pressure drop and heat transfer was studied. • The comprehensive effects of sloshing conditions were analyzed. • Sloshing conditions little affect pressure drop, but obviously affect heat transfer. • The heaving condition has the maximum effects on flow and heat transfer among others. Abstract In order to explore condensation flow and heat transfer characteristics in the tube side of spiral wound heat exchange (SWHE) used in floating liquefied natural gas (FLNG) field, a model was established to simulate methane condensation upward flow in a spiral pipe at different sloshing conditions, such as heave, roll and pitch conditions. The simulated results coincide with experiment ones, and the deviations are within ±15%. The effects of various parameters on frictional pressure drop and heat transfer coefficient were discussed in pipes with curvature ratio of 0.003–0.007. The ranges of Reynolds numbers in vapor and liquid flows are respectively 154,944–697,251 and 18,190–127,331. It was found that at static conditions, both frictional pressure drop and heat transfer coefficient increase with the increase of mass flux and the decrease of saturation pressure and hydraulic diameter; with the increase of vapor quality, the heat transfer coefficient first increases and then decreases whereas the frictional pressure drop continuously increases; the effects of curvature diameter are slight. Meanwhile, in most cases, the sloshing motions can cause a remarkable heat transfer enhancement as well as a small decrease of frictional pressure drop. Further, the effects of heaving motion on flow and heat transfer are more obvious than the others, with the average drag reduction and heat transfer augmentation of 1.51% and 15.70%, respectively. These results are helpful for the understanding condensation characteristics in the spiral pipe at sloshing conditions, and for the design of SWHE used in FLNG field. [ABSTRACT FROM AUTHOR]

In this paper, the condensation heat transfer of hydrocarbon mixtures refrigerant (methane/propane) flowing in a helical tube with 10 mm hydraulic diameter was investigated by experiments and numerical simulations. The experiments were conducted at mass flux of 200–400 kg/(m 2 ·s), saturation pressure of 0–4Mpa and heat flux of 4.8–5 kW/m 2 . Also, the effects of mass flux, vapor quality, and saturation pressure on heat transfer coefficient were studied. It was observed that the heat transfer coefficients increased with the increase of mass flux and vapor quality, while the heat transfer coefficients generally decreased as the saturation pressure increased. Meanwhile, annular flow(half-annular flow, annular flow) and Non-annular flow patterns (slug flow, stratified flow, wavy flow, transition flow) were observed during the condensation of methane/propane mixtures refrigerant. And a new flow pattern transition line for hydrocarbon refrigerants condensation process was proposed. The condensation heat transfer coefficient data were compared with several existing correlations, and a modified heat transfer correlation for different flow patterns was proposed, which predicted the results well with a mean absolute error of 10.03%. [ABSTRACT FROM AUTHOR]

Helical tube has been widely used in liquefied natural gas (LNG) liquefying applications. However, studies on the heat transfer performance of hydrocarbon mixture refrigerant in a helical tube have rarely been conducted. In this paper, condensation heat transfer characteristics of hydrocarbon mixture refrigerant in a helical tube were investigated numerically. The tests were conducted at saturation pressure of 2–4 MPa, mass flux of 100–400 kg/(m 2 ·s) and vapor quality 0–1. The numerical model was well verified by experimental data. And the effects of different structural parameters (tube diameter, helix angle and curvature diameter) and operating parameters (mass flux, heat flux and saturation pressure) on the heat transfer of hydrocarbons refrigeration were considered. The results showed that the tube diameter and mass flux had significant effect on condensation heat transfer coefficient. Meanwhile, stratified flow, half-annular flow and annular flow were observed during the condensation of methane/propane mixtures refrigerant by simulations, and a new flow pattern transition line for hydrocarbon refrigerants condensation process was proposed. Finally, the simulation results were compared with several well-known condensation heat transfer correlations. The research results will provide some constructive instructions for more effective design of LNG heat exchanger. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mechanical activation increased the –SH density of human hair in the reduction. • The modified human hair (MTHH) showed > 99 % removal with 476.7 mg/g Hg(II) uptake capacity. • MTHH with a high selectivity for the Hg(II) capture could promote the biosafety of aquatic plant in the medium of Hg(II). • This work exemplified a low-cost strategy of waste control by waste for the Hg(II) capture. The hydrophobic cuticle seal and the low affinity of disulfide bonds inhibit the performance of human hair (HH), a renewable keratin waste with high sulfur content, toward the remediation of aqueous Hg(II). Herein, the mechanical activation (MA) was used to crack the cuticle seal and expose the disulfide bonds for the reduction by ammonium thioglycolate, preparing a modified HH (MTHH) with high density of thiol groups. With a high distribution coefficient (2.6 × 106 mL/g), such MTHH revealed an uptake capacity over 470 mg/g, capable of decreasing the Hg(II) concentration from 1.0 mg/L to well below 2 μg/L in the real-world samples. Moreover, MTHH with the added benefits of high selectivity and low cost could significantly reduce the phytotoxicity of Hg(II) toward aquatic crops. MTHH diminished the mercury intake of water spinaches from 24.64 to about 0.06 mg/kg when cultivating in the water with a Hg(II) concentration of 4.0 mg/L. Density functional theory (DFT) calculations and characterizations such as X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FT-IR) demonstrated that the bonding of Hg(II) to thiol groups was responsible for the Hg(II)-selective and efficient capture. This work exemplifies a sustainable, inexpensive and user-friendly platform of keratin waste for the efficient decontamination of aqueous Hg(II). [ABSTRACT FROM AUTHOR]

Ubiquitin-binding domains (UBDs) are modular elements that bind non-covalently to the ubiquitin and ubiquitin chains. The preferences of UBDs for ubiquitin chains of specific length and linkage are central to their functions. We demonstrated that an artificial t andem h ybrid UBD (ThUBD) exhibits an unbiased high affinity to all ubiquitin chains and is a promising tool for global ubiquitination profiling research. In this study, we labeled fluorescein on the four cysteine residues in the N-terminal glutathione S-transferase (GST) tag of ThUBD, generating a fluorescein-labeled ThUBD (ThUBD-Flu) probe for direct polyubiquitination signal imaging and visualization. Compared to the canonical ubiquitin antibody method, the ThUBD-Flu is hyper-sensitive and accurate to detect ubiquitination signal. More importantly, the ThUBD-Flu probe provided, for the first time, a widely applicable, super-sensitive and unbiased technique for in situ detection of intracellular polyubiquitination signal through immunofluorescence staining, which was only achievable with recombinant fluorescence tag fused ubiquitin gene previously. We propose that ThUBD-Flu, combined with evolving microscopy technology, could serve as prototypes to track and trace cellular polyubiquitination signal in vivo. The ThUBD-Flu probe can temporally and spatially detect the in-situ poly-ubiquitination signal in a hyper-sensitive and unbiased way. [Display omitted] • The developed ThUBD-Flu probe could be used for direct polyubiquitination signal imaging and visualization. • The ThUBD-Flu showed high-performance for polyubiquitination signal detection with super-sensitivity and high accuracy. • The newly developed approach can temporally and spatially distinguish polyubiquitination signal imaging in situ cells. [ABSTRACT FROM AUTHOR]

An ultra-performance liquid chromatography with tandem mass spectrometric detection method was developed for the detection of berberine and its derivatives (A4, B4) in rat plasma and other organs. This validated method was successfully applied to our pharmacokinetic study of BBR derivatives in rats. At the same dose of administration, the C max of B4 was about eight times higher than BBR, and its half-life was approximately two times longer than BBR, according to the bigger areas under plasma concentration curves. Inversely, the pharmacokinetic parameter levels of A4 were all inferior to BBR, suggesting a tight structure-activity relationship of these compounds. Small dose of parenteral administration was used for the study of absolute oral bioavailability of A4, B4, and BBR, and the results calculated were 0.12%, 3.4% and 0.7%, respectively. The accumulations of B4 among all organs were intestine > liver > heart > kidney > lung > spleen > plasma, proving a deeply targeting property of B4, which met our experimental assumption. Together, the experimental results proved that compared with BBR and A4, the derivative B4 had higher absolute oral bioavailability and the ability of deeply targeting so that can be likely used in some organ-targeted diseases. [ABSTRACT FROM AUTHOR]

• FL118 coupled with non-steroidal anti-inflammatory drugs (NSAIDs) were synthesized. • The water-insoluble FL118-NSAIDs(6a - 6d)) could not release FL118 as prodrugs. • 6c could not release FL118, but showed strong inhibition of Topo1 in vitro. • The water-soluble FL118-AA (9a - 9j) could release the FL118 as prodrugs. • The antitumor activity in vivo of FL118-AA were consistent with Topo I activity. Fourteen 20(S)-substituted FL118 hybrids coupled with non-steroidal anti-inflammatory drugs (NSAIDs) or amino acids (AA) were synthesized and characterized. Most of them exhibited excellent antitumor activity against the four types of human cancer cell lines (A549, HepG2, HeLa and HCT116). FL118-NSAID derivatives(6a - 6d) showed insoluble and lactone increased stability, and could not release FL118 as esterase-triggered prodrugs. FL118-AA (9a - 9j) showed better water-soluble and could release the parental compound FL118 as prodrugs in both PBS and human plasma. The antitumor activity in vivo of the FL118-AA 9c, 9i and 9j were consistent with their Topo I inhibitory activity in vitro. The FL118-NSAID 6c could not release FL118, but showed strong inhibition of Topo1 in vitro and low CDOCKER energy with Topo1, the varous formulation of 6c should be try to address the insoluble problem and the drug delivery in the future. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights: [•] YY1 overexpression resulted in survivin promoter repression in a luciferase system. [•] YY1 knockdown using siRNA releases the survivin repression. [•] Using a YY1 tet-off system, YY1 expression represses survivin expression. [•] YY1 is capable of directly binding to the survivin promoter. [ABSTRACT FROM AUTHOR]

Abstract: Growing evidence suggests a role for the antiapoptotic protein survivin in promotion of cancer cell G1/S transition and proliferation. However, the underlying mechanism is unclear. Further, although upregulation of p21WAF1/CIP1 by p53 plays an important role in p53-mediated cell G1 arrests in response to various distresses, it is unknown whether survivin plays a role in the regulation of p21WAF1/CIP1 expression. Here, we report that exogenous expression of survivin in p53-wild type MCF-7 breast cancer cells inhibits the expression of p21WAF1/CIP1 protein, mRNA and promoter activity, while the survivin C84A mutant and antisense failed to do so. Cotransfection experiments in the p53 mutant H1650 lung cancer cell line showed that survivin neutralizes p53-induced p21WAF1/CIP1 expression and promoter activity. Importantly, genetically silencing of endogenous survivin using lentiviral survivin shRNA also enhances endogenous p21 in p53 wild type cancer cells, suggesting the physiological relevance of the fining. We further demonstrated that both p53 and survivin interacts on the two p53-binding sites in the p21WAF1/CIP1 promoter (−2313 to −2212; −1452 to −1310), and survivin physically interacts with p53 in cancer cells. Together, we propose that survivin may act as a transcription factor or cofactor to interact with p53 on the p21WAF1/CIP1 promoter leading to the inhibition of p21WAF1/CIP1 expression at least in part by neutralizing p53-mediated transcriptional activation of the p21 gene. [Copyright &y& Elsevier]

Summary: Although it was observed that inhibition of the antiapoptotic protein survivin expression in lung cancer cells induces apoptosis, the expression and role of survivin variants (survivin-2B and survivin-ΔEx3) in lung cancer have not yet been characterized. We analyzed 24 non-small-cell lung cancer (NSCLC) samples by semi-quantitative RT-PCR. Surprisingly, our results revealed that high-level expression of survivin-2B is significantly associated with the patient category of “no relapse and alive” (p-value<0.0001). In contrast, high-level expression of survivin-ΔEx3 is highly associated with the patient category of “relapse and dead” (p-value<0.0001). Consistent with this observation, exogenous expression of survivin-2B in A549 lung cancer cells inhibited cell growth, disrupted the mitochondria potential, and induced apoptotic cell death, while expression of survivin-ΔEx3 protected the mitochondria potential and facilitated cell survival. These findings provide evidence that survivin-2B and survivin-ΔEx3 play opposite roles in disease relapse and NSCLC cell survival, which is likely through the differential modulation of mitochondrial potential. Thus, controlling the differential expression of survivin-2B and survivin-ΔEx3 may represent novel approaches for cancer therapeutics in NSCLC. [Copyright &y& Elsevier]

Survivin is a unique member of the inhibitor of apoptosis protein family, and its expression is regulated by p53. Recent identification of several functionally divergent survivin variants augments the complexity of survivin action as well as its regulation. Here we report that survivin-2B (retaining a part of intron 2 as a cryptic exon) is positively regulated by p53, and its overexpression plays a role in sensitizing leukemia cells to chemotherapeutic drug doxorubicin. Doxorubicin treatment activated p53, downregulated survivin and survivin-?Ex3 but upregulated survivin-2B in EU-3, an acute lymphocytic leukemia (ALL) cell line with wild-type (wt)-p53 phenotype. In contrast, doxorubicin treatment failed to induce these alterations in EU-6 cells, a mutant-p53 ALL cell line. To specify the role of wt-p53 in regulating survivin and its variants, a temperature-sensitive p53 mutant plasmid p53-143 was transfected into EU-4, a p53-null ALL cell line, to establish a subline EU-4/p53-143. When EU-4/p53-143 cell culture was shifted from 37.5°C to the wt-p53-permissive temperature (32.5°C), the expression of survivin and survivin-?Ex3 was decreased whereas survivin-2B expression was increased, confirming the distinct regulatory effect of p53 on survivin and its variants. To clarify the role of survivin-2B in the process of apoptosis, survivin-2B cDNA was cloned into pcDNA3HA vector and transfected into EU-4 cells. Enforced expression of survivin-2B in EU-4 cells inhibited cell growth and sensitized these cells to doxorubicin-induced apoptosis. These results suggest that survivin-2B variant is a proapoptotic factor and its expression is upregulated by p53.Oncogene (2004) 23, 7545-7551. doi:10.1038/sj.onc.1208038 Published online 30 August 2004 [ABSTRACT FROM AUTHOR]

Survivin is a novel anti-apoptotic protein that is highly expressed in cancer but is undetectable in most normal adult tissues. It was reported that taxol-mediated mitotic arrest of cancer cells is associated with survivin induction, which preserves a survival pathway and results in resistance to taxol. In this study, we provide new evidence that induction of survivin by taxol is an early event and is independent of taxol-mediated G2/M arrest. Taxol treatment of MCF-7 cells rapidly up-regulated survivin expression (3.5-15-fold) within 4 h without G2/M arrest. Lengthening the treatment of cells (48 h) with taxol resulted in decreased survivin expression in comparison with early times following taxol treatment, although G2/M cells were significantly increased at later times. Interestingly, 3 nM taxol induces survivin as effectively as 300 nM and more effectively than 3000 nM. As a result, 3 nM taxol is ineffective at inducing cell death. However, inhibition of taxolmediated survivin induction by small interfering RNA significantly increased taxol-mediated cell death. Taxol rapidly activated the phosphatidylinositol 3-kinase/Akt and MAPK pathways. Inhibition of these pathways diminished survivin induction and sensitized cells to taxol-mediated cell death. A cis-acting DNA element upstream of -1480 in the survivin pLuc-2840 construct is at least partially responsible for taxol-mediated survivin induction. Together, these data show, for the first time, that taxolmediated induction of survivin is an early event and independent of taxol-mediated G2/M arrest. This appears to be a new mechanism for cancer cells to evade taxol-induced apoptosis. Targeting this survival pathway may result in novel approaches for cancer therapeutics. [ABSTRACT FROM AUTHOR]

It has been demonstrated that survivin, a novel member of the inhibitor of apoptosis (IAP) protein family, is expressed in human cancers but is undetectable in normal differentiated tissues. We employed a recombinant adenoviral vector (reAdGL3BSurvivin) in which a tumor-specific survivin promoter and a luciferase reporter gene were inserted into the E1-deleted region of adenovirus vector. Luciferase activity was measured in both multiple tumor cell lines and two primary melanoma cells infected with reAdGL3BSurvivin. Human fibroblast and mammary epithelial cell lines were used as negative controls. A reAdGL3CMV, containing the CMV promoter and luciferase gene, was used as a positive control to normalize the luciferase activity generated by the survivin promoter. Our data revealed that the survivin promoter showed high activity in both established tumor cell lines and the primary melanoma cells. In contrast, the in vivo studies indicated that the activities of survivin promoter were extremely low in the major mouse organs. The survivin promoter appears to be a promising tumor-specific promoter exhibiting a “tumor on” and “liver off” profile, and therefore, it may prove to be a good candidate for transcriptional targeting of cancer gene therapy in a wide variety of tumors.Cancer Gene Therapy (2004) 11, 256-262. doi:10.1038/sj.cgt.7700679 Published online 12 March 2004 [ABSTRACT FROM AUTHOR]

• A numerical model of liquid injected seal is built and validated. • Gas velocity has stronger effect on flow uniformity than liquid velocity. • Liquid pressure drop is always larger than that of gas under the same condition. • An empirical correlation of flow uniformity in liquid injected seal is obtained. • The empirical correlations for pressure drop in liquid injected seal are obtained. For two-phase refrigerant flow, the maldistribution at the entrance of plate-fin heat exchangers (PFHEs) is a severe issue which tends to make the thermal performance of heat exchangers worse. Especially when PFHEs are applied in the field of liquefied natural gas (LNG), the non-uniformity restricts the natural gas liquefaction efficiency of PFHEs. To improve the thermal performance and liquefaction efficiency, a distributor named liquid injected seal is added at the entrance of PFHEs and its maldistribution is analyzed numerically by ANSYS FLUENT. Firstly, a numerical model of liquid injected seal is built and verified by the experimental data. Then, the effects of gas and liquid velocity of refrigerant on the flow uniformity are analyzed. It indicates that the velocity of gas phase is more effective on the distribution characteristic of the distributor than that of liquid phase. In addition, the pressure drop of the distributor is also studied under varied gas and liquid velocities. It is found that the liquid pressure drop is larger than gas pressure drop under the same condition. Further, an empirical correlation for maldistribution is obtained to predict the maldistribution of gas-liquid refrigerants, and empirical correlations for pressure drop in liquid injected seal in PFHEs are proposed. This investigation provides support for the improvement of efficiency of LNG. [ABSTRACT FROM AUTHOR]

Simple Summary: FL118 is a novel orally available small molecule anticancer drug. We found that bladder cancer cells with a mutant Kras is highly sensitive to FL118-induced cell growth inhibition and cell death induction through inhibiting the anti-cancer cell death and drug resistance factors (survivin, Mcl-1, XIAP). In the Kras-mutation bladder cancer cells, FL118 can stimulate the reactive oxygen species (ROS) over-production for killing bladder cancer cells and inhibiting bladder cancer cell-established tumor growth. Elimination of mutant Kras by Kras-specific shRNA technology in mutant Kras-containing bladder cancer cell-established tumor decreased FL118 effectiveness to inhibit bladder cancer tumor growth. In this regard, mutant Kras is a potential favorable biomarker for FL118. This finding is significant because mutant Kras is known to be a formidable challenge treatment resistant factor in various types of cancer. Thus, FL118 could use mutant Kras as favorable biomarker for patient selection to carry out precision medicine. Tumor heterogeneity in key gene mutations in bladder cancer (BC) is a major hurdle for the development of effective treatments. Using molecular, cellular, proteomics and animal models, we demonstrated that FL118, an innovative small molecule, is highly effective at killing T24 and UMUC3 high-grade BC cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 BC cells with wild-type Ras are insensitive to FL118. This concept was further demonstrated in additional BC and colorectal cancer cells with mutant Kras versus those with wild-type Kras. FL118 strongly induced PARP cleavage (apoptosis hallmark) and inhibited survivin, XIAP and/or Mcl-1 in both T24 and UMUC3 cells, but not in the HT1376 cells. Silencing mutant Kras reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC3 cells, suggesting mutant Kras is required for FL118 to exhibit higher anticancer efficacy. FL118 increased reactive oxygen species (ROS) production in T24 and UMUC3 cells, but not in HT1376 cells. Silencing mutant Kras in UMUC3 cells reduced FL118-mediated ROS generation. Proteomics analysis revealed that a profound and opposing Kras-relevant signaling protein is changed in UMUC3 cells and not in HT1376 cells. Consistently, in vivo studies indicated that UMUC3 tumors are highly sensitive to FL118 treatment, while HT1376 tumors are highly resistant to this agent. Silencing mutant Kras in UMUC3 cell-derived tumors decreases UMUC3 tumor sensitivity to FL118 treatment. Together, our studies revealed that mutant Kras is a favorable biomarker for FL118 targeted treatment. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer is a deadly disease with a very low 5-year patient survival rate of 6–8%. The major challenges of eliminating pancreatic cancer are treatment resistance and stromal barriers to optimal drug access within the tumor. Therefore, effective molecular targeting drugs with high intra-tumor access and retention are urgently needed for managing this devastating disease in the clinic. Methods: This study has used the following in vitro and in vivo techniques for the investigation of exceptional anticancer drug FL118's efficacy in treatment of resistant pancreatic cancer: cell culture; immunoblotting analysis to test protein expression; DNA sub-G1 flow cytometry analyses to test cell death; MTT assay to test cell viability; pancreatic cancer stem cell assays (fluorescence microscopy tracing; matrigel assay; CD44-positive cell colony formation assay); human luciferase-labeled pancreatic tumor orthotopic animal model in vivo imaging; pancreatic cancer patient-derived xenograft (PDX) animal models; and toxicology studies with immune-competent BALB/cj mice and beagle dogs. Results: Our studies found that FL118 alone preferentially killed cisplatin-resistant cancer cells, while a combination of FL118 with cisplatin synergistically killed resistant pancreatic cancer cells and reduced spheroid formation of treatment-resistant pancreatic cancer stem-like cells. Furthermore, using in vivo-imaging, we found that FL118 in combination with cisplatin strongly inhibited both drug-resistant pancreatic xenograft tumor growth and metastasis. In PDX model, we demonstrated that FL118 alone effectively eliminated PDX tumors, while FL118 in combination with gemcitabine eliminated PDX tumors that showed relative resistance (less sensitivity) to treatment with FL118. These FL118 efficacy results are consistent with our molecular-targeting data showing that FL118 inhibited the expression of multiple antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and ERCC6, a critical regulator of DNA repair, in treatment-resistant pancreatic stem-like cancer cells. Furthermore, FL118 toxicity studies in BALB/cj mice and beagle dogs indicated that FL118 exhibits favorable hematopoietic and biochemical toxicities. Conclusion: Together, our studies suggest that FL118 is a promising anticancer drug for further clinical development to effectively treat drug-resistant pancreatic cancer alone or in combination with other pancreatic cancer chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]