RETRACTED: Chen et al. A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy. Pharmaceutics 2022, 14, 343.

The Pharmaceutics Editorial Office retracts the article, "A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy" [...].

[Effect of different kinds of gingival retraction agents on the polymerization inhibition of polyvinyl siloxane impression materials].

PURPOSE: To evaluate the effect of different kinds of gingival retraction agents after directly contacted with polyvinyl siloxane impression materials on polymerization inhibition and the inhibition degree. METHODS: Five kinds of gingival retraction agents (0.1% epinephrine hydrochloride, 0.05% oxymetazoline, 15.5% ferric sulfate, 25% aluminum chloride and 5% aluminum chloride) were chosen, normal saline was as control group, and two kinds of polyvinyl siloxane impression materials (ExpressTM, ImprintTM Ⅱ) were combined into 12 groups. There were 12 specimens in each group and 144 specimens in total. Silicone rubber impression materials were mixed by the same operator using a dispensing gun into the acrylic mold, so that they could directly contact the gingival retraction agents on the densely woven cotton fabrics. The samples were removed when the polymerization time arrived according to the manufactures' recommendations and then placed under a stereomicroscope with a magnification of 10 times to observe whether polymerization inhibition occurred, the degree of inhibition was compared afterwards. SPSS 22.0 software package was used for statistical analysis. RESULTS: The polymerization inhibition of two kinds of silicone rubber impression materials occurred in 15.5% ferric sulfate group and 25% aluminum chloride group, and the inhibition occurrence rate was 100%, the difference was statistically significant (P＜0.05) compared with normal saline group. Inhibition was not found in 0.1% epinephrine hydrochloride group, 0.05% oxymetazoline group and 5% aluminum chloride. The effect of 15.5% ferric sulfate and 25% aluminum chloride on polymerization inhibition degree of ImprintTM Ⅱ was greater than ExpressTM, and the difference was statistically significant(P＜0.05). CONCLUSIONS: When silicone rubber impression material is used during impression procedure, attention should be paid to the effect of the gingival retraction agent containing 15.5% ferric sulfate and 25% aluminum chloride on its polymerization. The gingival retraction agent should be washed before impression to avoid the residue directly contacting the silicone rubber to prevent polymerization.

Antifouling Electrochemiluminescence Biosensor Based on Bovine Serum Albumin Hydrogel for the Accurate Detection of p53 Gene in Human Serum.

To detect biomarkers in complex samples, it is fundamental to avoid the nonspecific adsorption of impurities to improve the selectivity of biosensors. In this study, a sensitive antifouling electrochemiluminescence biosensor was proposed based on bovine serum albumin (BSA)- and exonuclease III (Exo III)-mediated nucleic acid cycle signal amplification strategy. Ti3C2Tx-NH4, which has a large surface area and high metal conductivity, was crosslinked with BSA to improve the conductivity of the sensing interface, which shows antifouling performance excellently due to the electrical neutrality and good hydrophilicity of BSA hydrogel. The cyclic amplification strategy based on Exo III and DNA hybridization chain reaction significantly amplified the electrochemiluminescence signal and improved the sensitivity of p53 gene detection. The linear range of the biosensor is 1 fM-1 nM with a detection limit of 0.26 fM. More importantly, the sensor showed excellent selectivity when it was used to detect the p53 gene in real samples, such as serum. Thus, this unique antifouling sensing interface is expected to construct various electrochemical biosensors in clinical diagnosis and biopathological analysis.

Unravelling the pseudocapacitive origin of graphene oxide-based aerogels by comparative insights.

We reveal the intrinsic pseudocapacitive center of graphene-oxide-based aerogels by investigating different modified graphene skeletons from various approaches. A high proportion of carbonyl groups in carbon networks is shown to optimize the construction of rational pseudocapacitive sites by triggering reversible proton-induced surface reactions, leading to satisfactory electrochemical performance.

Characterization of immature ovarian teratomas through single-cell transcriptome.

Introduction: Immature ovarian teratomas are a type of malignant germ cell tumor composed of complicated cell types and are characterized by pathological features of immature neuroectodermal tubules/rosettes. However, there is a lack of understanding of patient-derived immature ovarian teratomas (PDT) at the single cell level. Moreover, whether stem cell lines derived from immature teratomas (CDT) can be used as models for research on PDT remains to be elucidated. Methods: Single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatic analysis was performed on three patient-derived immature ovarian teratomas (PDT) samples to reveal the heterogeneity, evolution trajectory, and cell communication within the tumor microenvironment of PDT. Validations were conducted in additional seven samples through multiplex immunofluorescence. Result: A total of qualified 22,153 cells were obtained and divided into 28 clusters, which can match to the scRNA-seq annotation of CDT as well as human fetal Cell Atlas, but with higher heterogeneity and more prolific cell-cell crosstalk. Radial glia cells (tagged by SOX2) and immature neuron (tagged by DCX) exhibited mutually exclusive expression and differentiated along distinct evolutionary trajectory from cycling neural progenitors. Proportions of these neuroectodermal cell subtypes may play important roles in PDT through contributing to the internal heterogeneity of PDTs. Moreover, the immune cells in PDTs were infiltrated rather than teratoma-derived, with more abundant macrophage in immature neuron than those in radial glia cells, and the infiltrated macrophage subtypes (i.e., M1 and M2) were significantly correlated to clinical grade. Overall, suppressed evolution process and transcriptome regulation in neuroectodermal cells, reduced cell-cell crosstalk, higher M1/M2 proportion ratio, and enhanced T cell effects in tumor microenvironment are enriched in patients with favorable prognosis. Discussion: This study provides a comprehensive profile of PDT at the single cell level, shedding light on the heterogeneity and evolution of neuroectodermal cells within PDTs and the role of immune cells within the tumor microenvironment. Also, our findings highlight the potential usage of CDTs as a model for research on PDT.

Denatured bovine serum albumin hydrogel-based electrochemical biosensors for detection of IgG.

An antifouling sensing surface was constructed by crosslinking two-dimensional nanomaterial MXene with bovine serum albumin (BSA) denatured by urea previously. The immunoglobulin G (IgG) capture peptide was then modified to the surface to construct a highly selective antifouling electrochemical biosensor. Due to the large specific surface area and good electrical conductivity of MXene, the sensitivity of the biosensor is significantly enhanced. The biosensor at a working potential of around - 0.18 V (vs. Ag/AgCl) provides a wide linear detection range (0.1 ng/mL to 10 µg/mL) for IgG with a limit of detection of 23 pg/mL (3σ/k). The result is consistent with that obtained from the commercial enzyme-linked immunosorbent kit. Compared with BSA, which is usually used as a passivator or blocker for biosensing platforms, the hydrogel formed through the peptide chain obtained from BSA with good hydrophilicity can provide a better antifouling sensing surface to resist nonspecific adsorption. The prepared biosensor can quantitatively detect the concentration of IgG in complex human serum with high sensitivity. Thus, the antifouling sensing surface constructed without expensive antifouling materials and complex process is expected to develop as a variety of electrochemical biosensors and used for the clinical testing of biomarkers. Graphical abstract An antifouling sensing surface was constructed by crosslinking two-dimensional nanomaterial MXene with bovine serum albumin (BSA) denatured by urea previously. The immunoglobulin G (IgG) capture peptide was then modified to the surface to construct a highly selective antifouling electrochemical biosensor.

Erythrocyte Membrane-Coated Invisible Acoustic-Sensitive Nanoparticle for Inducing Tumor Thrombotic Infarction by Precisely Damaging Tumor Vascular Endothelium.

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.

Association of anti-TNF-α treatment with gut microbiota of patients with ankylosing spondylitis.

OBJECTIVE: Gut dysbiosis contributes to multiple autoimmune diseases, including ankylosing spondylitis, which is commonly treated with tumor necrosis factor (TNF)-α inhibitors (TNFis). Because host TNF-α levels are considered to interact with gut microbiota, we aimed to systematically investigate the microbiota profile of ankylosing spondylitis patients with anti-TNF-α-based treatment and identify potential key bacteria. METHODS: Fecal samples were collected from 11 healthy controls and 24 ankylosing spondylitis patients before/after anti-TNF-α treatment, the microbiota profiles of which were evaluated by 16S ribosomal DNA amplicon sequencing and subsequent bioinformatic analysis. RESULTS: Significantly different microbial compositions were observed in samples from ankylosing spondylitis patients compared with healthy controls, characterized by a lower abundance of short-chain fatty acid (SCFA)-producing bacteria. All patients exhibited a positive response after anti-TNF-α treatment, accompanied by a trend of restoration in the microbiota compositions and functional profile of ankylosing spondylitis patients to healthy controls. In particular, the abundance of SCFA-producing bacteria (e.g. Megamonsa and Lachnoclostridium ) was not only significantly lower in ankylosing spondylitis patients than in healthy controls and restored after anti-TNF-α treatment but also negatively correlated with disease severity (e.g. cor = -0.52, P = 8 × 10 -5 for Megamonsa ). In contrast, Bacilli and Haemophilus may contribute to ankylosing spondylitis onset and severity. CONCLUSIONS: Microbiota dysbiosis in ankylosing spondylitis patients can be restored after anti-TNF-α treatment, possibly by impacting SCFA-producing bacteria.

Magnetic antifouling material based ratiometric electrochemical biosensor for the accurate detection of CEA in clinical serum.

A novel ratio electrochemical biosensor based on multi-functional nanocomposite was developed. Fe3O4 was synthesized in situ on carboxyl functionalized 2D nanomaterial MXene, and then covalently bonded with [Ru(NH3)6]3+ to obtain nanocomposites MXC-Fe3O4-Ru. Fe3O4 and [Ru(NH3)6]3+ can neutralize the electronegativity of the MXene to make the nanocomposites electrically neutral. Combine with the good hydrophilicity and conductivity of MXene, the nanocomposites can be utilized to construct antifouling electrochemical biosensors without modifying with specific antifouling materials. Moreover, Fe3O4 can endow the nanocomposites with magnetism, and [Ru(NH3)6]3+ is used as an internal standard molecule. The strong magnetic MXC-Fe3O4-Ru can be easily separated and firmly modified on the magnetic gold electrode (MGE). DNA double-stranded (dsDNA) containing an ferrocene (Fc)-modified carcinoembryonic antigen (CEA) aptamer can be specifically captured to the surface of the electrode by amido bond. In the presence of CEA, CEA binds to the aptamer and leaves the electrode surface, the electrochemical signal of Fc decreases, while the electrochemical signal of [Ru(NH3)6]3+ is fixed on the electrode surface remains basically unchanged. The ratio of the electrochemical signals of Fc and [Ru(NH3)6]3+ is proportional to the CEA concentration. The linear range of the sensor is 1 pg/mL to 1 µg/mL with a detection limit of 0.62 pg/mL. With the excellent antifouling performance, good conductivity of the nanocomposite, and the application of the ratiometric strategy, the biosensor can achieve high selectivity, accuracy, and sensitivity for the detection of targets even in complex samples, such as FBS and clinical serum.

A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy.

Venous malformation (VM), which causes severe damage to patients' appearance and organ function, is one of the most common vascular malformations. At present, many drugs in clinical treatment cause various adverse reactions. Herein, we synthesized cationic amphiphilic gelators (TA6, TA8, and TA9) by introducing saturated carbon chains of different lengths to tranexamic acid (TA), which could self-assemble into low-molecular-weight gels (LMWGs) as drug delivery carriers by hydrogen bonds, van der Waals forces, and hydrophobic interactions. The rheological properties, gelation driving force and drug release profiles of TA6, TA8, and TA9 hydrogels were characterized, and the results indicated that the hydrogels prepared in this study possessed the typical characteristics of a gel and could release drugs slowly. More importantly, the TA9 gelator showed significant pharmacological activity, in that it served as both an active drug compound and a drug carrier. The in vitro experiments demonstrated that TA9 induced HUVECs death and hemolysis by destroying cell membranes in a dose-dependent manner, and caused cell death and hemolysis at a concentration of 0.09 µM/mL. Meanwhile, we found TA9 could interact not only with fibrinogen, but also with other endogenous molecules in the blood. After the administration of TA9 hydrogel for 15 days, macroscopic imaging and histological evaluation in mice and rabbits displayed obvious thrombi, inflammatory reactions, and venous embolization, indicating that the mechanism of the TA9 hydrogel in treating VM was involved in two processes. Firstly, the TA9 hydrogel relied on its mechanical strength to physically block veins and continuously release TA9, in situ, for targeted therapy. Then, TA9 destroyed endothelial cells and damaged venous walls critically, causing thrombi. Most excitingly, TA9 was hydrolyzed to TA by enzymes that inhibited the degradation of thrombi by plasmin to prolong the embolization time and to promote venous fibrosis. Compared with other clinically available sclerosants, the degradation of TA9 also empowered a better biocompatibility and biodegradability for the TA9 hydrogel. In conclusion, we synthesized a potentially safe and effective derivative of TA and developed a low-molecular-weight gel as a self-delivery system for TA in treating VM.

Genomic evolution and diverse models of systemic metastases in colorectal cancer.

OBJECTIVE: The systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing. DESIGN: Whole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells. RESULTS: Based on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in ZFP36L2, which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of ZFP36L2 enhances the metastatic potential of CRC cells. CONCLUSION: Our results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis.

Longitudinal Genomic Evolution of Conventional Papillary Thyroid Cancer With Brain Metastasis.

BACKGROUND: Brain metastasis is extremely rare but predicts dismal prognosis in papillary thyroid cancer (PTC). Dynamic evaluation of stepwise metastatic lesions was barely conducted to identify the longitudinal genomic evolution of brain metastasis in PTC. METHOD: Chronologically resected specimen was analyzed by whole exome sequencing, including four metastatic lymph nodes (lyn 1-4) and brain metastasis lesion (BM). Phylogenetic tree was reconstructed to infer the metastatic pattern and the potential functional mutations. RESULTS: Contrasting with lyn1, ipsilateral metastatic lesions (lyn2-4 and BM) with shared biallelic mutations of TSC2 indicated different genetic originations from multifocal tumors. Lyn 3/4, particularly lyn4 exhibited high genetic similarity with BM. Besides the similar mutational compositions and signatures, shared functional mutations (CDK4 R24C , TP53R342*) were observed in lyn3/4 and BM. Frequencies of these mutations gradually increase along with the metastasis progression. Consistently, TP53 knockout and CDK4 R24C introduction in PTC cells significantly decreased radioiodine uptake and increased metastatic ability. CONCLUSION: Genomic mutations in CDK4 and TP53 during the tumor evolution may contribute to the lymph node and brain metastasis of PTC.

Flexible Polypropylene-Supported ZIF-8 Membranes for Highly Efficient Propene/Propane Separation.

Metal-organic framework (MOF) membranes have enormous potential in separation applications. There are several MOF membranes grown on polymer substrates aimed for scale-up, but their brittleness hampers any industrial application. Herein, intergrown continuous polypropylene (PP)-supported ZIF-8 membranes have been successfully synthesized via fast current-driven synthesis (FCDS) within 1 h. The PP-supported ZIF-8 membranes exhibit a promising separation factor of 122 ± 13 for binary C3H6-C3H8 mixtures combined with excellent flexibility behavior. The C3H6/C3H8 separation performance of the PP-supported ZIF-8 membrane was found to be constant after bending the supported ZIF-8 film with a curvature of 92 m-1. This outstanding mechanical property is crucial for practical applications. Moreover, we further synthesized ZIF-8 membranes on various polymer substrates and even polymer hollow fibers to demonstrate the production scalability.

Novel aryltriazole acyclic C-azanucleosides as anticancer candidates.

Nucleoside analogues represent an important class of drug candidates. With the aim of searching for novel bioactive nucleosides, we developed an efficient synthetic way to construct a series of aryl 1,2,3-triazole acyclic C-azanucleosides via Huisgen 1,3-dipolar cycloaddition. The aryl 1,2,3-triazole motifs within these azanucleosides showed coplanar features, suggesting they could act as surrogates for large planar aromatic systems or nucleobases. Moreover, several aryltriazole acyclic C-azanucleosides bearing long alkyl chains exhibited potent antiproliferative activity against various cancer cell lines via induction of apoptosis. Most interestingly, the lead compound significantly down-regulated the key proteins involved in the heat shock response pathway, representing the first anticancer acyclic azanucleoside with such a mode of action. These novel aryl 1,2,3-triazole cyclic C-azanucleosides therefore serve as promising paradigms for further exploring anticancer drug candidates.

The Significance of the CLDN18-ARHGAP Fusion Gene in Gastric Cancer: A Systematic Review and Meta-Analysis.

Objective: The objective of this study was to summarize the clinicopathological characteristics of the CLDN18-ARHGAP fusion gene in gastric cancer patients. Background: The CLDN18-ARHGAP26 fusion gene is one of the most frequent somatic genomic rearrangements in gastric cancer, especially in the genomically stable (GS) subtype. However, the clinical and prognostic meaning of the CLDN18-ARHGAP fusion in gastric cancer patients is unclear. Methods: Studies that investigated CLDN18-ARHGAP fusion gastric cancer patients were identified systematically from the PubMed, Cochrane, and Embase databases through the 28th of February 2020. A systematic review and meta-analysis were performed to estimate the clinical significance of CLDN18-ARHGAP fusion in patients. Results: A total of five eligible studies covering 1908 patients were selected for inclusion in the meta-analysis based on specified inclusion and exclusion criteria. Several fusion patterns were observed linking CLDN18 and ARHGAP26 or ARHGAP6, with the most common type being CLDN18/exon5-ARHGAP26/exon12. The survival outcome meta-analysis of the CLDN18-ARHGAP fusion gene showed that it was associated with overall survival outcomes in gastric cancer (HR, 2.03, 95% CI 1.26-3.26, P < 0.01, random-effects). In addition, diffuse gastric cancer had a greater proportion of CLDN18-ARHGAP fusions than intestinal gastric cancer (13.3%, 151/1,138 vs. 1.8%, 8/442; p < 0.001). Moreover, gastric cancer patients with the CLDN18-ARHGAP fusion gene are more likely to be female or have a younger age, lymph node metastasis and advanced TNM stages. Conclusion: The CLDN18-ARHGAP fusion is one of the molecular characteristics of diffuse gastric cancer and is also an independent prognostic risk factor for gastric cancer. In addition, it is also related to multiple clinical characteristics, including age, sex, lymph node metastasis and tumor stage. However, the mechanism of the CLDN18-ARHGAP fusion gene and potential targeted therapeutic strategies need further exploration.

Balancing the Grain Boundary Structure and the Framework Flexibility through Bimetallic Metal-Organic Framework (MOF) Membranes for Gas Separation.

Separation is one of the most energy-intensive processes in the chemical industry, and membrane-based separation technology helps to reduce the energy consumption dramatically. Supported metal-organic framework (MOF) layers hold great promise as a molecular sieve membrane, yet only a few MOF membranes showed the expected separation performance. The main reasons include e.g. nonselective grain boundary transport or the flexible MOF framework, especially the inevitable linker rotation. Here, we propose a crystal engineering strategy that balances the grain boundary structure and framework flexibility in Co-Zn bimetallic zeolitic imidazolate framework (ZIF) membranes and exploit their contributions to the improvement of membrane quality and separation performance. It reveals that a good balance between the two trade-off factors enabled a "sweet spot" that offers the best C3H6/C3H8 separation factor up to 200.

Rational Discovery of Response Biomarkers: Candidate Prognostic Factors and Biomarkers for Checkpoint Inhibitor-Based Immunotherapy.

Immunotherapy with checkpoint inhibitor has been successfully applied in treatment for multiple cancer types, especially for patients at advanced stage. However, response rate of this promising therapy is low, thus requiring biomarkers for precise medication to reduce the ineffective treatment. With multiple retrospective clinical studies, more and more candidate prognostic factors have been identified with possible mechanic explanation, including the basic clinical characteristics (e.g., age and gender), molecular features (e.g., PD-L1 expression and tumor mutation burden). After validation in independent patient cohorts with large sample size, several markers have been approved as companion biomarkers. However, validation and combinations of all the possible candidate biomarkers are still challenging to predict the treatment outcomes. In this chapter, we will summarize and introduce the prognostic factors and biomarkers for checkpoint inhibitor-based immunotherapy.

Biomimetic Design of Peptide Neutralizer of Ebola Virus with Molecular Simulation.

Ebola virus (EBOV) belongs to the Filoviridae family, which can cause severe hemorrhagic fever in humans and nonprimates. The neutralization of EBOV by monoclonal antibody (mAb) ADI-15946 was reported recently. In the present study, the molecular interactions between the receptor GPcl of EBOV and ADI-15946 were studied by molecular dynamics (MD) simulation and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) analysis. Hydrophobic interaction was identified as the main driving force for the binding of ADI-15946 on EBOV. Moreover, the contribution of each amino acid residue for the binding was evaluated. Then, an affinity binding model (ABM) was constructed using the residues favorable for the binding, including Y107, F108, D109, W110, and R113. The biomimetic design of neutralizer against EBOV according to the ABM of ADI-15946 was then performed, followed by screening using docking, structural similarity. Two neutralizers YFDWHMR and YFDWRYR were obtained, which were proven to be capable of strong binding on GPcl and then neutralizing GPcl. These results would be helpful for the development of neutralizers for Ebola virus.

Programmed cell death factor 4 enhances the chemosensitivity of colorectal cancer cells to Taxol.

Drug resistance and disease relapse are still challenging problems in the chemotherapy of colorectal cancer (CRC). Programmed cell death factor 4 (PDCD4) has previously been reported to act as a tumor suppressor and was implicated in the chemosensitivity of numerous types of human malignancy. In this study, the effect of PDCD4 in the sensitivity of CRC to the chemotherapy drug Taxol was investigated. The results confirmed that lower PDCD4 expression was present in CRC tumor tissues, when compared with in normal adjacent tissues (p) and closely associated with the prognosis of patients with CRC. Upregulation of PDCD4 significantly enhanced the sensitivity of CRC cells to Taxol, by partially contributing to pro-apoptosis and anti-invasion pathways, both through upregulation of the apoptosis-associated protein Bax, and downregulation of the anti-apoptosis protein Bcl-2 and invasion-associated proteins MMP-9. These findings might present a novel strategy for sensitizing tumor cells to apoptosis and, thus, overcoming chemotherapy resistance in CRC.

Identification and application of novel low pH-inducible promoters for lactic acid production in the tolerant yeast Candida glycerinogenes.

Bioproduction of organic acids under low pH condition without adding inducer and neutralizer is an economical craft to decrease downstream cost. Candida glycerinogenes had higher tolerances to low pH and lactic acid than Saccharomyces cerevisiae. QRT-PCR analysis showed that four of fifteen candidates functioned as potentially acid-inducible promoters in C. glycerinogenes. In particular, PCggmt1 showed the strongest induction ability at pH 2.5. Fluorescence analysis indicated that the induction ability of PCggmt1 gradually increased as the pH decreased. In addition, PCggmt1 had the binding sites of Msn2p/4p, Azf1p, and Nrg1p. PCggmt1 was further used to control the expression of lactate dehydrogenase gene from Rhizopus oryzae in C. glycerinogenes. Compared with pH 5.5, the specific activity of lactate dehydrogenase and lactic acid titer at pH 2.5 were increased by 229% and 218%, reaching 13.8 mU/mg and 12.3 g/L, respectively. These results presented here showed a potential to produce organic acid economically at low pH by the stress tolerant C. glycerinogenes and the novel low-pH inducible promoter PCggmt1.