Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer.

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

Long non-coding RNA MAGEA4-AS1 binding to p53 enhances MK2 signaling pathway and promotes the proliferation and metastasis of oral squamous cell carcinoma.

Long non-coding RNAs (lncRNAs) regulate the occurrence, development and progression of oral squamous cell carcinoma (OSCC). We elucidated the expression features of MAGEA4-AS1 in patients with OSCC and its activity as an OSCC biomarker. Furthermore, the impact of up-regulation of MAGEA4-AS1 on the cellular behaviors (proliferation, migration and invasion) of OSCC cells and intrinsic signal mechanisms were evaluated. Firstly, we analyzed MAGEA4-AS1 expression data in The Cancer Genome Atlas (TCGA) OSCC using a bioinformatics approach and in 45 pairs of OSCC tissues using qPCR. Then CCK-8, ethynyl deoxyuridine, colony formation, transwell and wound healing assays were conducted to assess changes in the cell proliferation, migration and invasion protential of shMAGEA4-AS1 HSC3 and CAL27 cells. The RNA sequence of MAGEA4-AS1 was identified using the rapid amplification of cDNA ends (RACE) assay. And whole-transcriptome sequencing was used to identify MAGEA4-AS1 affected genes. Additionally, dual-luciferase reporter system, RNA-binding protein immunoprecipitation (RIP), and rescue experiments were performed to clarify the role of the MAGEA4-AS1-p53-MK2 signaling pathway. As results, we found MAGEA4-AS1 was up-regulated in OSCC tissues. We identified a 418 nucleotides length of the MAGEA4-AS1 transcript and it primarily located in the cell nucleus. MAGEA4-AS1 stable knockdown weakened the proliferation, migration and invasion abilities of OSCC cells. Mechanistically, p53 protein was capable to activate MK2 gene transcription. RIP assay revealed an interaction between p53 and MAGEA4-AS1. MK2 up-regulation in MAGEA4-AS1 down-regulated OSCC cells restored MK2 and epithelial-to-mesenchymal transition related proteins' expression levels. In conclusion, MAGEA4-AS1-p53 complexes bind to MK2 promoter, enhancing the transcription of MK2 and activating the downstream signaling pathways, consequently promoting the proliferation and metastasis of OSCC cells. MAGEA4-AS1 may serve as a diagnostic marker and therapeutic target for OSCC patients.

Influence of Steric Effects on the Emission Behavior of Pyrene-Based Blue Luminogens.

Pyrene-based derivatives have been widely deployed in organic luminescent materials because of their bright fluorescence, high charge carrier mobility, and facile modification. Nevertheless, the fluorescence output of conventional pyrenes is prone to quenching upon aggregation due to extensive intermolecular π-π stacking interactions. To address this issue, a set of new Y-shaped pyrene-containing luminogens are synthesized from a new bromopyrene chemical precursor, 2-hydroxyl-7-tert-butyl-1,3-bromopyrene, where the bromo and hydroxyl groups at the pyrene core can be readily modified to obtain the target products and provide great flexibility in tuning the photophysical performances. When the hydroxy group at the 2-position of pyrene was replaced by a benzyl group, the steric hindrance of the benzyl group not only efficiently inhibits the detrimental intermolecular π-π stacking interactions but also rigidifies the molecular conformation, resulting in a narrow-band blue emission. Moreover, the TPE-containing compounds 2c and 3c possessed characteristic aggregation-induced emission (AIE) properties with fluorescence quantum yields of up to 66% and 38% in the solid state, respectively. Thus, this article has methodically investigated the factors influencing the optical behavior, such as intermolecular interactions, and the steric effects of the substituent group, thereby opening up the potential to develop narrow-band pyrene-based blue emitters for OLED device applications.

Pyrene-Based Deep-Blue Fluorophores with Narrow-Band Emission.

High-efficiency narrow-band luminescent materials have attracted intense interest, resulting in their great colorimetric purity. This has led to a variety of high-tech applications in high-definition displays, spectral analysis, and biomedicine. In this study, a rigid pyrene core was employed as the molecular backbone, and four narrow-band pyrene-based blue emitters were synthesized using various synthetic methods (such as Lewis-acid catalyzed cyclization domino reactions, Pd-catalyzed coupling reactions like Suzuki-Miyaura and Sonogashira). Due to the steric effect of the hydroxy group at the 2-position, the target compounds exhibit deep blue emission (<429 nm, CIEy < 0.08) with full width at half-maximum (FWHM) less than 33 nm both in solution and when solidified. The experimental and theoretical results indicated that the substituents at the 1- and 3-positions afford a large dihedral angle with the pyrene core, and the molecular motion is almost fixed by multiple intra- and intermolecular hydrogen bonding interactions in the crystallized state, leading to a suppression of the vibrational relaxation of the molecular structure. Moreover, we observed that the suppression of the vibrational relaxation in the molecular structures and the construction of rigid conjugated structures can help develop narrow-band organic light-emitting materials.

DRAMP 3.0: an enhanced comprehensive data repository of antimicrobial peptides.

Stapled antimicrobial peptides are an emerging class of artificial cyclic peptide molecules which have antimicrobial activity and potent structure stability. We previously published the Data Repository of Antimicrobial Peptides (DRAMP) as a manually annotated and open-access database of antimicrobial peptides (AMPs). In the update of version 3.0, special emphasis was placed on the new development of stapled AMPs, and a subclass of specific AMPs was added to store information on these special chemically modified AMPs. To help design low toxicity AMPs, we also added the cytotoxicity property of AMPs, as well as the expansion of newly discovered AMP data. At present, DRAMP has been expanded and contains 22259 entries (2360 newly added), consisting of 5891 general entries, 16110 patent entries, 77 clinical entries and 181 stapled AMPs. A total of 263 entries have predicted structures, and more than 300 general entries have links to experimentally determined structures in the Protein Data Bank. The update also covers new annotations, statistics, categories, functions and download links. DRAMP is available online at http://dramp.cpu-bioinfor.org/.

What influences the implementation of clinical guidelines related to enteral nutrition in the intensive care unit: A mixed-methods systematic review.

AIMS: To systematically evaluate and analyse literature concerning the factors influencing the implementation of clinical practice guidelines related to enteral nutrition in the adult intensive care unit. BACKGROUND: Guidelines serve as crucial tools for guiding clinical practice. However, a significant gap persists between current clinical practice and guidelines pertaining to enteral nutrition. It is essential to identify the reasons behind this disparity to foster clinical transformation. METHODS: A mixed-methods systematic review. DATA SOURCES: A systematic search was conducted across PubMed, Embase, Medline, Cochrane, PsycINFO and CNKI databases to identify impediments and facilitators to the implementation of ICU clinical practice guidelines related to enteral nutrition. The types of studies included quantitative, qualitative and mixed-methods studies. The search spanned from January 2003 to January 2024 and was updated in May 2024. The quality assessment of the included literature was conducted using the Mixed-Methods Study Evaluation Tool (MMAT). Data analysis was performed using a data-based convergent integration approach. The protocol for this study was prospectively registered (PROSPERO2023, CRD42023483287). RESULTS: Twenty papers were finally included, and 65 findings were extracted, integrating a total of three categories, Category 1: healthcare provider factors, including three sub-themes: knowledge of guideline-related knowledge and awareness of guideline application; social/professional roles and identity domains; beliefs, attitudes and self-efficacy; collaboration, Category 2: practice environments, including two sub-themes: environmental factors and resource areas; systems and behavioural norms, Category 3: patient values and nutritional support preferences including two sub-themes: patient disease status and value orientation. CONCLUSION: Healthcare professionals should analyse obstacles and facilitators to guideline implementation from multiple perspectives, strengthen healthcare collaboration, improve education and training systems, correct misperceptions and increase awareness of evidence-based practice.

Downregulation of interleukin 11 regulates the transforming growth factor-ß/ERK1/2 signaling pathway to inhibit articular capsule fibrosis and alleviate post-traumatic articular capsule contracture.

BACKGROUND: Post-traumatic capsular contracture is a common complication of joint injury and surgery. Post-traumatic capsular contracture is associated with fibrosis characterized by excessive differentiation and proliferation of myofibroblasts and abnormal secretion and accumulation of extracellular matrix. Previous studies have suggested that interleukin 11 (IL11) plays a role in myocardial fibrosis. We thus hypothesized that IL11 may play a fibrotic role during capsular contracture, in order to discover new targets for preventing joint capsule contracture. METHODS: We constructed a post-traumatic contracture model by excessively extending the knee joint and fixing the joint in the flexion position, and a post-traumatic joint capsule contracture model was constructed in the wild-type, IL11-/-, IL11 R -/-, α-SMA-cre-IL11fl/fl, α-SMA-cre-IL11Rfl/fl mouse strain, with wild-type mice without any treatment of the knee joint as the control group. Fibrotic markers and the expression of IL11 and IL11 R in knee joint tissue were detected in each group of mice. The NIH3T3 cell line was used for in vitro analyses. The expression of fibrosis markers, IL11, transforming growth factor-ß, and ERK1/2 were detected by western blot, enzyme-linked immunosorbent assay, and real time quantitative polymerase chain reaction. RESULTS: Inhibition of IL11 inhibited ERK1/2 phosphorylation, reduced the secretion of collagen in the joint capsule, and inhibited the excessive differentiation and proliferation of myofibroblasts in the post-traumatic joint capsule contracture, thus alleviating the joint capsule contracture and obtaining better joint mobility. CONCLUSION: Downregulation of IL11 in traumatic joint capsule contracture inhibits ERK1/2 phosphorylation, thus significantly relieving joint capsule contracture. Our findings indicate the transforming growth factor-ß/IL11/ERK1/2 axis is an important pathway for the differentiation of fibroblasts into myofibroblasts. Anti-IL11 treatment is an effective means to prevent traumatic joint capsule contracture.

The fluorescence and colorimetric dual-readout probe for clinical rapid detection of mycophenolic acid by the poly(ethylenimine)/silica-coated CdTe quantum dots.

It is particularly meaningful to therapeutic drug monitoring (TDM) of mycophenolic acid (MPA) for transplant patients to maximize the drug efficacy and minimize the adverse effect. In this study, a novel fluorescence and colorimetric dual-readout probe was put forward to fast and reliable detect MPA. The blue fluorescence of MPA was largely enhanced in the presence of poly (ethylenimine) (PEI), while the red fluorescence of CdTe@SiO2 (silica-coated CdTe quantum dots) provided a reliable reference signal. Hence, combining PEI70,000 and CdTe@SiO2, a fluorescence and colorimetric dual-readout probe could be constructed. For fluorescence measurement of MPA, the linearity was obtained in the MPA concentration range of 0.5-50 µg/mL, with a limit of detection (LOD) of 33 ng/mL. For the visual detection, the fluorescent colorimetric card was established in the MPA concentration from 0.5 to 50 µg/mL corresponding to the fluorescence color from red to violet and then to blue, which could be used for semi-quantification. Furthermore, in the light of the ColorCollect APP by the smartphone, the ratio of blue and red brightness values was linear with the MPA concentration from 1 to 50 µg/mL; thus, quantification of MPA could be realized by APP with the LOD of 83 ng/mL. The developed method was successfully applied to the analysis of MPA in the plasma samples of three patients after oral administration of mycophenolate mofetil, which was the prodrug of MPA. The result was comparable to those obtained by the clinically widely-used enzyme multiplied immunoassay technique. The developed probe was fast, cost-effective and operational convenience, and possessed high potential for TDM of MPA.

Rational design of stapled antimicrobial peptides.

The global increase in antimicrobial drug resistance has dramatically reduced the effectiveness of traditional antibiotics. Structurally diverse antibiotics are urgently needed to combat multiple-resistant bacterial infections. As part of innate immunity, antimicrobial peptides have been recognized as the most promising candidates because they comprise diverse sequences and mechanisms of action and have a relatively low induction rate of resistance. However, because of their low chemical stability, susceptibility to proteases, and high hemolytic effect, their usage is subject to many restrictions. Chemical modifications such as D-amino acid substitution, cyclization, and unnatural amino acid modification have been used to improve the stability of antimicrobial peptides for decades. Among them, a side-chain covalent bridge modification, the so-called stapled peptide, has attracted much attention. The stapled side-chain bridge stabilizes the secondary structure, induces protease resistance, and increases cell penetration and biological activity. Recent progress in computer-aided drug design and artificial intelligence methods has also been used in the design of stapled antimicrobial peptides and has led to the successful discovery of many prospective peptides. This article reviews the possible structure-activity relationships of stapled antimicrobial peptides, the physicochemical properties that influence their activity (such as net charge, hydrophobicity, helicity, and dipole moment), and computer-aided methods of stapled peptide design. Antimicrobial peptides under clinical trial: Pexiganan (NCT01594762, 2012-05-07). Omiganan (NCT02576847, 2015-10-13).

Microwave-assisted solid-phase synthesis of nitrogen-doping carbon dot with good solvent compatibility and its sensing of sunitinib.

Microwave-assisted solid-phase synthesis method was simple, convenient, and fast, and herein adopted to produce nitrogen-doping carbon dots (N-CDs) in only 3 min. The N-CDs possessed high fluorescence quantum yield up to 15.9% with satisfactory stability to the environmental pH, ionic strength, and ultraviolet radiation. Particularly, the N-CDs had excellent dispersibility in both water and water-compatible organic solvents with similar fluorescence properties. Sunitinib, a small-molecule tyrosine inhibitor effective for some solid tumors, was found to quench the fluorescence of N-CDs in these media via the inner-filter effect. Hence, it was convenient to combine the proper sample pretreatment with the N-CD probe for sensing sunitinib avoiding the medium incompatibility problem. For rat plasma sample, salting-out liquid-liquid extraction was employed to minimize the sample matrix and concentrate the target sunitinib from aqueous to acetonitrile. The fluorescence detection of sunitinib was then achieved in acetonitrile by the addition of the proper amount of N-CDs. The method provided a good linearity of 0.1 µg/mL to 7 µg/mL with a limit of detection of 30 ng/mL, which met the requirement of the therapeutic drug monitoring of sunitinib. The developed method was potential for on-site detection of sunitinib.

MiR-375-3p alleviates the severity of inflammation through targeting YAP1/LEKTI pathway in HaCaT cells.

Atopic dermatitis (AD) is a relapsing inflammatory skin disease with a complicated pathogenesis. This study aimed to investigate whether miR-375-3p could regulate AD through the Yes-associated protein 1 (YAP1) pathway. In this study, inflammatory response was induced by TNF-α and IFN-γ administration in HaCaT cells. We found that viability and inflammatory factor release, including interleukin-1ß (IL-1ß) and IL-6, were negatively related to miR-375-3p expression in HaCaT cells. We also found that YAP1 overexpression down-regulated lympho-epithelial Kazal type inhibitor (LEKTI) levels and aggravated viability and inflammation in TNF-α and IFN-γ-treated HaCaT cells. Dual-luciferase reporter assay proved the targeted binding of miR-375-3p and YAP1 3'-UTR. Additionally, the protective effect of miR-375-3p on inflammatory response in TNF-α and IFN-γ-treated HaCaT cells could be impeded by YAP1 overexpression. Collectively, our results suggested that miR-375-3p could modulate HaCaT cell viability and inflammation through the YAP1/LEKTI pathway.

Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas.

PARP inhibitors (PARPis) have remarkable antitumor activity in BRCA mutant ovarian carcinoma. Emerging evidence has shown that responses to PARPis are not limited to BRCA mutant tumors, but could expand to other homologous recombination deficiency (HRD) carcinomas. However, relatively little is known about the efficacy of PARPis in patients with HRD when compared to non-HRD carriers. In this systematic review, 13 clinical trials were included and analyzed for the treatment effect of PARPis on progression free survival (PFS) and overall survival (OS) for HRD (BRCA mutant HRD, n = 697; BRCA wild-type HRD, n = 478) vs. non-HRD (n = 1,417) patients. Pooled analyses of the effect of PARPis in both ovarian and nonovarian carcinoma groups showed significantly higher PFS rates at 6 months and 12 months (PFS6 and PFS12) in the HRD subgroup, as compared to the non-HRD subgroup. Within the HRD subgroup, the BRCA-mutant population achieved significantly higher PFS6 (OR: 2.29, 95% CI: 1.03-5.08) and PFS12 (OR: 1.95, 95% CI: 1.26-3.01) when compared to BRCA wild-type patients. Furthermore, within BRCA wild-type carcinomas, mutations in other HRD-related genes also led to increased PFS6 (OR: 1.72, 95% CI: 1.27-2.43) and PFS12 (OR: 1.85, 95% CI: 1.31-2.62), as compared to non-HRD counterparts. Therefore, patients with HRD carcinomas exhibited pronounced PFS advantages upon treatment with PARPis, as compared to non-HRD carcinomas. In addition to BRCA mutations, other non-BRCA HRD-related aberrations may serve as novel biomarkers for the prediction of PARPi efficacy.

Discovery of Baicalin as NDM-1 inhibitor: Virtual screening, biological evaluation and molecular simulation.

The emergence and worldwide spreads of carbapenemase producing bacteria, especially New Delhi metallo-ß-lactamase (NDM-1), has made a great challenge to treat antibiotics-resistant bacterial infections. It can hydrolyse almost all ß-lactam antibacterials. Unfortunately, there are no clinically useful inhibitors of NDM-1. In this study, structure-based virtual screening method led to the identification of Baicalin as a novel NDM-1 inhibitor. Inhibitory assays showed that Baicalin possessed a good inhibition of NDM-1 with IC50 values of 3.89 ±â€¯1.1 µM and restored the susceptibility of E.coli BL21(DE3)/pET28a-NDM-1 to clinically used ß-lactam antibiotics. Molecular docking and molecular dynamics simulations obtained a complex structure between the relatively stable inhibitor molecule Baicalin and NDM-1 enzyme. The results showed that the carboxyl group in Baicalin directly interacted with the Zn2+ in the active center of the enzyme, and the residues such as Glu152, Gln123, Met67, Trp93 and Phe70 in the enzyme formed hydrogen bonds with Baicalin to further stabilize the complex structure.

Population pharmacokinetics of arginine glutamate in healthy Chinese volunteers.

1. The present study developed population pharmacokinetic models of arginine and glutamate in healthy Chinese volunteers. Two nonlinear mixed-effect models were developed using NONMEM® software (ICON Development Solutions, Ellicott City, MD) to describe the pharmacokinetic properties and to assess the relevant parameters as well as the inter-individual variability. The potential covariates were screened using stepwise approach and the stability and predictive capability of the models were performed using bootstrap and visual predictive check. 2. The concentration time curves of arginine and glutamate were best described by a first-order elimination two-compartment model and a nonlinear elimination one-compartment model, respectively. The final parameter estimation of arginine for CL was 44.1 L/h. Q, V1 and V2 were 23 L/h, 20.3 L and 46 L, respectively. The final parameter estimation of glutamate for Vmax and Km were 18.8 mg/h and 77.2 mg/L, respectively. V for low dose and high dose was 23.1 L and 36.3 L, respectively. 3. For arginine, weight was significant covariate on the apparent distribution volume of peripheral compartment. The gain in weight remarkably increases V2. For glutamate, dose as a significant covariate on the apparent distribution volume was included, subjects received high dose (20 g) have remarkably higher V compared to subjects received low dose (10 g).

A cell-internalizing peptide endows tumstatin7 with enhanced antitumor properties.

Tumstatin7 (CNYYSNS) is an antitumor peptide derived from the NC1 domain of Type IV collagen that has been associated with tumor angiogenesis. In this work, we generated a peptide composed of tumstatin7 fused to TAT, a cell-internalizing peptide consisting of 11 amino acids. Tumstatin7-TAT was internalized by cells and triggered cell death. The new peptide was more potent in inducing B16F10 melanoma cell apoptosis in vitro than the shorter tumstatin7. Whereas tumstatin7-TAT significantly reduced tumor cell viability, tumstatin7 showed only weak effects even at the highest treatment concentration applied. Both tumstatin7-TAT and tumstatin7 inhibited cell migration in an in vitro wound healing model, and the former was more effective than the latter in inhibiting tumor growth in vivo. Combining the cell-internalizing property of TAT with the tumor-specific property of tumstatin7 may provide a useful adjunct to tumor therapy.

Safety and efficacy of nivolumab in the treatment of cancers: A meta-analysis of 27 prospective clinical trials.

Immune checkpoint inhibition therapy has benefited people and shown powerful anti-tumor activity during the past several years. Nivolumab, a fully human IgG4 monoclonal antibody against PD-1, is a widely studied immune checkpoint inhibitor for the treatment of cancers. To assess the safety and efficacy of nivolumab, 27 clinical trials on nivolumab were analyzed. Results showed that the summary risks of all grade adverse effects (AEs) and grade ≥3 AEs were 0.65 and 0.12. The rate of nivolumab-related death was 0.25%. The most common any grade AEs were fatigue (25.1%), rush (13.0%), pruritus (12.5%), diarrhea (12.1%), nausea (11.8%) and asthenia (10.4%). The most common grade ≥3 AEs were hypophosphatemia (only 2.3%) and lymphopenia (only 2.1%). The pooled objective response rate (ORR), 6-month progression-free survival (PFS) rate and 1-year overall survival (OS) rate were 0.26, 0.40 and 0.52, respectively. The odds ratio of ORR between PD-L1 positive and negative was 2.34 (95% CI 1.77-3.10, p < 0.0001). The odds ratios of ORR, 6-month PFS rate and 1-year OS rate between nivolumab and chemotherapeutics were 2.77 (95% CI 1.69-4.56, p < 0.0001), 1.97 (95% CI 1.02-3.81, p = 0.04) and 1.87 (95% CI 1.46-2.40, p <0.0001), respectively. In conclusion, nivolumab has durable outcomes with tolerable AEs and drug-related deaths in cancer patients. Nivolumab monotherapy has better treatment response compared with chemotherapy, whereas chemotherapeutics have significantly higher risk of adverse effects than nivolumab.

Computational resources and tools for antimicrobial peptides.

Antimicrobial peptides (AMPs), as evolutionarily conserved components of innate immune system, protect against pathogens including bacteria, fungi, viruses, and parasites. In general, AMPs are relatively small peptides (<10 kDa) with cationic nature and amphipathic structure and have modes of action different from traditional antibiotics. Up to now, there are more than 19 000 AMPs that have been reported, including those isolated from nature sources or by synthesis. They have been considered to be promising substitutes of conventional antibiotics in the quest to address the increasing occurrence of antibiotic resistance. However, most AMPs have modest direct antimicrobial activity, and their mechanisms of action, as well as their structure-activity relationships, are still poorly understood. Computational strategies are invaluable assets to provide insight into the activity of AMPs and thus exploit their potential as a new generation of antimicrobials. This article reviews the advances of AMP databases and computational tools for the prediction and design of new active AMPs. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

A modified thymosin alpha 1 inhibits the growth of breast cancer both in vitro and in vivo: suppressment of cell proliferation, inducible cell apoptosis and enhancement of targeted anticancer effects.

Thymosin alpha 1 (Tα1) is commonly used for treating several diseases; however its usage has been limited because of poor penetration of the target tissue, such as tumor cells. In the present study, Tα1-iRGD, a peptide by conjugating Tα1 with the iRGD fragment, was evaluated its performance in MCF-7 and MDA-MB-231 human breast cancer cells. Compared with the wild-type peptide, Tα1-iRGD was more selective in binding tumor cells in the cell attachment assay. Furthermore, the MTT assay confirmed that Tα1-iRGD proved more effective in significantly inhibiting the growth of MCF-7 cells in contrast to the general inhibition displayed by Tα1. Further, conjugation of Tα1 with iRGD preserved the immunomodulatory activity of the drug by increasing the proliferation of mouse spleen lymphocytes. Further, compared with Tα1 treatment, Tα1-iRGD treatment of MCF-7 cells considerably increased the number of cells undergoing apoptosis, resulting in a dose-dependent inhibition of cancer cell growth, which was associated with a much better effect on up-regulation of the expression of BCL2-associated X protein (Bax), caspase 9, etc. More importantly, treatment with Ta1-iRGD was more efficacious than treatment with Ta1 in vivo. This study highlights the importance of iRGD on enhancement of cell penetration and tumor accumulation. In summary, our findings demonstrate that the novel modified Tα1 developed in this study has the potential to be used for treating breast cancer.

Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing.

PURPOSE: Various forms of hearing loss have genetic causes, but many of the responsible genes have not yet been identified. Here, we describe a large seven-generation Chinese family with autosomal dominant nonsyndromic hearing loss that has been excluded as being caused by known deafness gene mutations associated with autosomal dominant nonsyndromic hearing loss with the aim of identifying a novel causative gene involved in deafness. METHODS: Whole-exome sequencing was conducted in three affected family members, and cosegregation analysis was performed on other members of the family. RESULTS: Whole-exome sequencing and subsequent segregation analysis identified a heterozygous frameshift mutation (c.153_154delCT, p.Gln53Argfs*100) in the oxysterol binding protein-like 2 (OSBPL2) gene in 25 affected family members. The deletion mutation is predicted to lead to premature truncation of the OSBPL2 protein. Modeling and structure-based analysis support the theory that this gene deletion is functionally deleterious. Our finding was further confirmed by the detection of another missense mutation, a c.583C>A transversion (p.Leu195Met) in exon 7 of OSBPL2, in an additional sporadic case of deafness. CONCLUSION: Based on this study, OSBPL2 was identified as an excellent novel candidate gene for autosomal dominant nonsyndromic hearing loss; this study is the first to implicate OSBPL2 mutations in autosomal dominant nonsyndromic hearing loss.