Cationic Polythiophene as Gene Carrier and Sonosensitizer for Sonodynamic Synergic Gene Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal and highly malignant tumors. Sonodynamic therapy (SDT) is a new cancer treatment method. One of its unique advantages lies in the treatment of deep tumors due to its excellent tissue penetration ability caused by ultrasound (US). However, most sonosensitizers suffer from weak sonodynamic activity and poor tumor-targeting ability. In addition, small interfering RNA (siRNA) is a promising anticancer drug, and the efficacy of siRNA-based gene therapy largely depends on the cell impermeability of the gene carrier. Here, we designed and synthesized a cationic polythiophene derivative (PT2) that can be used as a siRNA carrier for gene therapy. Moreover, PT2 could generate singlet oxygen (1O2) and hydroxyl radicals (O2•-) under US irradiation, which suggests that PT2 could be used for SDT. Our study discovered that NUDT1 promoted HCC proliferation and inhibited intracellular ROS production. Therefore, si-NUDT1 was designed and synthesized. NUDT1 silencing can inhibit the proliferation of tumor cells and increase the production of intracellular ROS to further improve the efficacy of SDT. Then, si-NUDT1 assembled with PT2 and DSPE-PEG-FA to prepare a novel tumor-targeting nanodrug (PT2-siRNA@PEG-FA) for synergic SDT and gene therapy of HCC.

Sorafenib and tetrakis (4-carboxyphenyl) porphyrin assembled nanoparticles for synergistic targeted chemotherapy and sonodynamic therapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is characterized by a high degree of malignancy and mortality. Sorafenib (SOR), a multi-kinase inhibitor, is clinically used in the treatment of HCC. However, SOR suffers from serious side effects and drug resistance. The development of novel therapeutic strategies for HCC therapy is urgently needed. Sonodynamic therapy (SDT) has unique advantages in treating deep tumors due to the merits of deep tissue penetration, low side effects, and the absence of drug resistance. Here, we developed multifunctional nanoparticles (NPs) termed SOR-TCPP@PEG-FA by assembling SOR, tetrakis (4-carboxyphenyl) porphyrin (TCPP), and folic acid (FA)-modified DSPE-PEG. The FA group enhances the tumor targeting capability of these NPs, while TCPP generates ROS under ultrasound (US) irradiation, which are toxic to tumor cells, and SOR with chemotherapeutic effects is released, thus realizing the synergistic SDT and chemotherapy of tumors.

Calcium-enriched carbon nanoparticles loaded with indocyanine green for near-infrared fluorescence imaging-guided synergistic calcium overload, photothermal therapy, and glutathione-depletion-enhanced photodynamic therapy.

Combining phototherapy with other treatments has significantly advanced cancer therapy. Here, we designed and fabricated calcium-enriched carbon nanoparticles (Ca-CNPs) that could effectively deplete glutathione (GSH) and release calcium ions in tumors, thereby enhancing the efficacy of photodynamic therapy (PDT) and the calcium overload effect that leads to mitochondrial dysfunction. Due to the electrostatic interaction, π-π stacking interaction, multiple hydrogen bonds, and microporous structures, indocyanine green (ICG) was loaded onto the surface of Ca-CNPs with a high loading efficiency of 44.7 wt%. The obtained Ca-CNPs@ICG can effectively improve the photostability of ICG while retaining its ability to generate singlet oxygen (1O2) and undergo photothermal conversion (Ca-CNPs@ICG vs. ICG, 45.1% vs. 39.5%). In vitro and in vivo experiments demonstrated that Ca-CNPs@ICG could be used for near-infrared fluorescence imaging-guided synergistic calcium overload, photothermal therapy, and GSH depletion-enhanced PDT. This study sheds light on the improvement of 1O2 utilization efficiency and calcium overload-induced mitochondrial membrane potential imbalance in tumor cells.

Use of immobilisation bra for daily setup of patients with pendulous breasts undergoing radiotherapy.

PURPOSE: A feasibility study to evaluate the Chabner XRT® Radiation Bra (CIVCO Radiotherapy & Qfix, Coralville, IA, USA) as a customised immobilisation device for patients with pendulous breasts undergoing radiotherapy was conducted. METHODS: A total of 34 patients with large pendulous breasts were fitted with the Chabner XRT® Radiation Bra during RT. A mixed-method questionnaire was administered to both radiation therapists (RTTs) and patients. RTTs evaluated the effectiveness of the bra in setup. Patients appraised its comfort level and ease of wearing. Setup reproducibility was evaluated based on a departmental imaging protocol. Acute skin side effects were documented with photos and assessed using the Radiation Therapy Oncology Group (RTOG) classification. RESULTS: Of the patients, 27 (79.4%) completed the questionnaire. 23 patients felt comfortable wearing the bra while 20 felt less exposed during treatment. Reproducibility was acceptable, with a median (range) setup error (isocentre) of 0.0 cm (-0.6 to 0.7 cm; left/right), -0.1 cm (-0.5 to 1.2 cm; posterior) and 0.2 cm (-0.5 to 0.9 cm; inferior) achieved based on matched field borders on skin. However, repeated setups and imaging were required for 3 patients due to large breast size (cups D-G; size 4-5). Minimal skin toxicity (grade 0-1) was observed. No grade ≥ 2 was reported. 10 RTTs completed the survey. Male RTTs (n = 4) were not confident in assisting patients with bra fitting. 8 RTTs agreed that although it was difficult to reproduce the breast tissue for treatment, it helped patients to maintain the treatment position. CONCLUSION: Our study demonstrated the feasibility of using a customised bra which provided optimal setup reproducibility while maintaining minimal skin toxicity and patient comfort, especially the value-added modesty felt among Asian women during their breast cancer radiotherapy.

Catalase-like pleated niobium carbide MXene loaded with polythiophene for oxygenated sonodynamic therapy in solid tumor.

Sonodynamic therapy (SDT), an emerging treatment for solid tumors, has the advantages of deep tissue penetration, non-invasiveness, low side effects, and negligible drug resistance. However, the hypoxic environment of deep solid tumors can discount the efficacy of oxygenated dependent SDT. Here, we synthesized a polythiophene-based sonosensitizer (PT2) and a two-dimensional pleated niobium carbide (Nb2C) Mxene. PT2 was loaded onto the surface of poly(vinylpyrrolidone) (PVP)-coated Nb2C MXene through electrostatic interaction to obtain Nb2C-PVP-PT2 nanosheets (NSs) with a high loading efficiency of 153.7%. Nb2C MXene exhibited catalase-like activity, which could catalyze hydrogen peroxide (H2O2) to produce O2, in turn alleviating tumor hypoxia and enhancing the efficacy of SDT. The depletion of H2O2 further results in abnormal cellular H2O2 levels and reduced tumor cell activity. Moreover, the decomposed NSs led to the release of the sonosensitizer PT2 that can efficiently generate both singlet oxygen and superoxide anions under ultrasound irradiation. These events led to the inhibition of DNA replication of tumor cells, causing tumor cell death, allowing for enhanced SDT efficacy.

Vascular disruption agent and phototherapeutic assembled nanoparticles for enhanced tumor inhibition.

Vascular disruption agent (combretastatin A-4 phosphate) and phototherapeutic (IEICO-4F) assembled nanoparticles (IFC NPs) were prepared for the first time. The IFC NPs have a high photo energy utilization efficiency of up to 96.1%, and could significantly inhibit tumor growth by photodynamic and photothermal therapy enhanced tumor vascular disruption.

Lysosome- and plasma membrane-accumulative and tumor-targetable polythiophene nanoparticles for enhanced sonodynamic therapy.

Sonodynamic therapy (SDT) has emerged as a promising treatment approach of solid tumors given its deep tissue penetration, non-invasiveness, few side effects, and negligible drug resistance. Herein, we report the first polythiophene derivative-based sonosensitizer (PT2) containing a quaternary ammonium salt and dodecyl chains with better ultrasound stability than that of traditional sonosensitizers, such as Rose Bengal and chlorin e6. PT2 was encapsulated by folic acid-containing polyethylene glycol. The obtained nanoparticles (PDPF NPs) exhibited excellent biocompatibility, cancer cell-targeting capacity, and accumulated mainly in the lysosomes and plasma membranes of cells. These NPs could generate singlet oxygen and superoxide anions simultaneously under ultrasound irradiation. In vitro and in vivo experimental results demonstrated that PDPF NPs could induce cancer-cell death through apoptosis and necrosis, inhibit DNA replication, and ultimately achieve tumor depletion upon US irradiation. These findings revealed that polythiophene could serve as an efficacious sonosensitizer for enhanced US treatment of deep-seated tumors.

Regulating photochemical properties of carbon dots for theranostic applications.

As a new zero-dimensional carbon-based material, carbon dots (CDs) have attracted extensive attention owing to their advantages such as easy preparation and surface modification, good biocompatibility and water solubility, and tunable photochemical properties. CDs have become one of the most promising nanomaterials in the field of fluorescent sensing, bioimaging, and cancer therapy. How to precisely regulate the photochemical properties, especially the absorption, fluorescence, phosphorescence, reactive oxygen species generation, and photothermal conversion of the CDs, is the key to developing highly efficient phototheranostics for cancer treatment. Although many studies on cancer therapy using CDs have been published, no review has focused on the regulation of photochemical properties of CDs for phototheranostic applications. In this review, we summarized the strategies such as the selection of suitable carbon source, heteroatomic doping, optimum reaction conditions, surface modification, and assembly strategy to efficiently regulate the photochemical properties of the CDs to meet the requirements of different practical applications. This review might provide some valuable insight and new ideas for the development of CDs with excellent phototheranostic performance. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

A water-soluble thiophene-croconaine dye with a high molar extinction coefficient for NIR fluorescence imaging-guided synergistic photothermal/photodynamic therapy of cancer.

Phototherapeutic agents with near-infrared (NIR) fluorescence, strong reactive oxygen species generation and photothermal conversion capabilities are highly desirable for use in cancer therapy. Herein, a water-soluble NIR croconaine dye (TCR) with a thiophene-croconaine rigid core and two symmetric alkyl chains was designed and synthesized. TCR exhibits intense NIR absorption and fluorescence that peaked at 780 and 815 nm, respectively, with a high molar extinction coefficient of 1.19 × 105 M-1 cm-1. Moreover, TCR has a high photothermal conversion efficiency of 77% and is capable of generating hydroxyl radicals (OH˙) under 735 nm laser irradiation. Based on these outstanding properties, TCR has proven its application in NIR fluorescence imaging-guided synergistic photothermal/photodynamic therapy of cancer.

Boron Dipyrromethene-Based Phototheranostics for Near Infrared Fluorescent and Photoacoustic Imaging-Guided Synchronous Photodynamic and Photothermal Therapy of Cancer.

The regulation of photochemical properties of phototheranostics, especially the absorption, fluorescence, singlet oxygen (1O2) generation, and photothermal conversion efficiency, is a hot research topic. Here, we designed and synthesized four boron dipyrromethene (BODIPY) derivatives with high absorption coefficients and intense fluorescence in the near-infrared (NIR) region. The substituted electron-donating group significantly improved 1O2 generation and fluorescence of BODIPYs, whereas the electron-withdrawing group boosts photothermal conversion. These hydrophobic BODIPYs were further coated with DSPE-PEG-2000 to form water dispersible nanoparticles (NPs). Among these BODIPY NPs, the B-OMe-NPs with methoxyl substituted at the meso-position showed the highest 1O2 generation, a photothermal conversion efficiency of 66.5%, and an NIR fluorescence peak at 809 nm. In vitro and in vivo experiments demonstrated that B-OMe-NPs might be used for NIR fluorescent and photoacoustic imaging-guided photodynamic and photothermal therapy of cancer.

Retraction Note: MALAT2-activated long noncoding RNA indicates a biomarker of poor prognosis in gastric cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

SLEEP-GOAL: A multicenter success criteria outcome study on 302 obstructive sleep apnoea (OSA) patients.

OBJECTIVE: To demonstrate SLEEP-GOAL as a more holistic and comprehensive success criterion for Obstructive Sleep Apnoea (OSA) treatment. METHODS: A prospective 7-country clinical trial of 302 OSA patients, who met the selection criteria, and underwent nose, palate and/or tongue surgery. Pre- and post-operative data were recorded and analysed based on both the Sher criteria (apnoea hypopnea index, AHI reduction 50% and <20) and the SLEEP-GOAL. RESULTS: There were 229 males and 73 females, mean age of 42.4±17.3 years, mean BMI 27.9±4.2. The mean VAS score improved from 7.7±1.4 to 2.5±1.7 (p<0.05), mean Epworth score (ESS) improved from 12.2±4.6 to 4.9±2.8 (p<0.05), mean body mass index (BMI) decreased from 27.9±4.2 to 26.1±3.7 (p>0.05), gross weight decreased from 81.9±14.3kg to 76.6±13.3kg. The mean AHI decreased 33.4±18.9 to 14.6±11.0 (p<0.05), mean lowest oxygen saturation (LSAT) improved 79.4±9.2% to 86.9±5.9% (p<0.05), and mean duration of oxygen <90% decreased from 32.6±8.9 minutes to 7.3±2.1 minutes (p<0.05). The overall success rate (302 patients) based on the Sher criteria was 66.2%. Crosstabulation of respective major/minor criteria fulfilment, based on fulfilment of two major and two minor or better, the success rate (based on SLEEP-GOAL) was 69.8%. Based solely on the Sher criteria, 63 patients who had significant blood pressure reduction, 29 patients who had BMI reduction and 66 patients who had clinically significant decrease in duration of oxygen <90% would have been misclassified as "failures". CONCLUSION: AHI as a single parameter is unreliable. Assessing true success outcomes of OSA treatment, requires comprehensive and holistic parameters, reflecting true end-organ injury/function; the SLEEP-GOAL meets these requirements.

Predictors of difficulty in intubation in patients with obstructive sleep apnoea.

OBJECTIVE: To evaluate predictors of difficult intubation in patients with obstructive sleep apnoea (OSA). METHODOLOGY: Prospective series of 405 OSA patients (350 males/55 females) who had upper airway surgery. Procedures included functional endoscopic sinus surgery, septoplasty, turbinate reduction, palate/tonsil surgery, and/or tongue base surgery. Intubation difficulty (ID) was assessed using Mallampati grade, Laryngoscopic grade (Cormack and Lehane), and clinical parameters including BMI, neck circumference, thyromental distance, jaw adequacy, neck movements and glidescope grading. RESULTS: Mean age was 41.6 years old; mean BMI 26.6; mean neck circumference 44.5cm; mean Apnea Hypopnea Index (AHI) was 25.0; and mean LSAT 82%. The various laryngeal grades (based on Cormack and Lehane), grade 1 - 53 patients (12.9%), grade 2A - 127 patients (31.0%), grade 2B - 125 patients (30.5%), grade 3 - 93 patients (22.7%) and grade 4 - seven patients (1.7%); hence, 24.4% had difficulties in intubation. Parameters that adversely affected intubation were, age of the patient, opening of mouth, retrognathia, overbite, overjet, limited neck extension, thyromental distance, Mallampati grade, and macroglossia (p<0.001). Body mass index (BMI) (p=0.087), neck circumference (p=0.645), neck aches (p=0.728), jaw aches (p=0.417), tonsil size (p=0.048), and AHI (p=0.047) had poor correlation with intubation. BMI-adjusted for Asians and Caucasians, showed that Asians were more likely to have difficulties in intubation (adjusted OR = 4.6 (95%Confidence Interval: 1.05 to 20.06) (p=0.043), compared to the Caucasian group. CONCLUSION: This study illustrates that difficult intubation can be predicted pre-surgery in order to avert any anaesthetic morbidity.

Anterior palatoplasty in the treatment of obstructive sleep apnoea - a systemic review.

This study seeks to determine the objective and subjective success rates of anterior palatoplasty and its variants for the treatment of obstructive sleep apnoea (OSA). A systematic review with two independent searches of Medline, PubMed, Cochrane Library and Evidence Based Medicine Reviews was performed to identify publications relevant to OSA and anterior palatoplasty. All relevant studies published before 30 June 2015 were included. Six studies were included in the systematic review. The numbers of patients in each paper ranged from 13 to 77 (total = 240), and mean age ranged from 21 to 51 years. Substantial and consistent improvement in polysomnography (PSG) outcomes were observed in patients after the anterior palatoplasty, with or without multilevel surgery. The results showed that the anterior palatoplasty technique provides significantly improvement in the post-operative Apnoea-Hypopnea Index. The mean pre-operative AHI (in the 6 papers) improved from 16.3 to 7.1, the snore visual analogue scale improved from 7.5 to 3.1 and the Epworth score reduced from 11.3 to 7.3 post-operatively. The overall pro-rated pooled success rate for all the patients was 72.5%, with a mean follow-up of 17.3 months. Anterior palatoplasty is an effective option in the management of patients with mild to moderate OSA.

A case of ear canal black pigment foreign body mimicking a melanoma.

Melanoma of the ear canal is extremely rare; due to its hidden area, most would present late in their history. We present the first case reported, of a black pigment foreign body mimicking a melanoma in the external auditory canal. A 14 year old Chinese male presented with right sided otalgia and itch. Otoscopic examination revealed an irregular black naevus in the right auditory canal. An intraoperative excision showed a black pigment foreign body giant cell reaction. Clinicians should be aware of the possibility of a foreign body granuloma of the ear canal that might mimic a melanoma.

MALAT2-activated long noncoding RNA indicates a biomarker of poor prognosis in gastric cancer.

The purpose of this study is to investigate the role of the long noncoding RNA metastasis associated lung adenocarcinoma transcript 2 (MALAT2) in the prognosis of stage II/III gastric cancer (GC) patients. The expression of MALAT2 was evaluated in cancer tissues from 146 stage II/III GC patients undergoing radical resection and 60 paired normal samples using quantitative real-time reverse transcriptase PCR. Differences in the expression of MALAT2 between 23 GC and paired normal colonic mucosa samples were analysed with the Wilcoxon test. Relationships between the expression level of MALAT2, patient clinico-pathological parameters and disease-free survival and overall survival were analysed using the uni-variate Kaplan-Meier method and the multivariate COX regression model. The quantitative polymerase chain reaction results showed that MALAT2 was frequently over-expressed in cancer tissues and this over-expression was found to significantly correlate with lymph node metastasis and tumor stage. The ectopic expression of MALAT2 contributed to the migration of human GC SGC-7901 cells, whereas knockdown of MALAT2 inhibited the migration of the SGC-7901 cells in vitro. Further investigation into the underlying mechanisms responsible for the migratory effects revealed that MALAT2 induced the epithelial-mesenchymal transition (EMT) through an MEK/extracellular signal-regulated kinase-dependent mechanism as treatment with the MEK inhibitor, U0126, decreased migration and reversed the EMT in the MALAT2 over-expressed SGC-7901 cells. The expression of MALAT2 is upregulated in GC tissues, and a higher expression level of MALAT2 might serve as a negative prognostic marker in stage II/III GC patients which implies the potential application of MALAT2 in the therapeutic treatment of GC.Cancer Gene Therapy advance online publication, 27 February 2015; doi:10.1038/cgt.2015.6.

Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing.

Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC(50) of 0.04 µM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design.

Magnetoencephalographic spike sources associated with auditory auras in paediatric localisation-related epilepsy.

OBJECTIVE: To characterise magnetoencephalographic spike sources in paediatric patients with auditory auras and recurrent localisation-related epilepsy. METHODS: Six patients (four boys and two girls (ages 7-14 years) were retrospectively studied. All patients had auditory auras as part of their initial seizure manifestation, including four patients who underwent previous brain surgery. Scalp video electroencephalography and magnetoencephalography (MEG) were carried out in six patients, intraoperative electrocorticography in three patients and extraoperative intracranial video electroencephalography in one patient. MEG auditory-evoked fields (AEFs) were studied in four patients. RESULTS: Three patients had elementary auditory auras, one had complex auditory aura and two had both complex and elementary auras. All six patients had clustered MEG spike sources with coexisting scattered spike sources. MEG clusters were localised in the superior temporal gyrus with surrounding scatters in four patients (two left and two right); two patients had scattered spikes in the superior temporal gyrus in addition to clustered MEG spike sources in the left inferior and middle frontal gyri or parieto-occipital region. AEFs were located within an MEG cluster in one patient and within 3 cm of a cluster in two patients. Surgical resection, including the regions of MEG clusters, was carried out in four patients. Three of four patients who had previous surgeries were seizure free at 2 years after excision of the MEG cluster region. CONCLUSIONS: MEG spike sources clustered in the superior temporal gyrus in six patients with auditory auras. These spike sources were in close proximity or seemed to engulf the magnetic AEF. Areas with MEG spike sources contained the residual or recurrent epileptogenic zone after incomplete cortical excision for lesional epilepsy.

Evidence for an oncogenic role of AHI-1 in Sezary syndrome, a leukemic variant of human cutaneous T-cell lymphomas.

Ahi-1 (Abelson helper integration site 1) is a novel gene frequently activated by provirus insertional mutagenesis in murine leukemias and lymphomas. Its involvement in human leukemogenesis is demonstrated by gross perturbations in its expression in human leukemia cells, particularly in cutaneous T-cell lymphoma cell lines where increases in AHI-1 transcripts of 40-fold are seen. To test directly whether deregulated expression of AHI-1 contributes to their transformed properties, knockdown of AHI-1 expression in Hut78 cells, a cell line derived from a patient with Sezary syndrome (SS), was performed using retroviral-mediated RNA interference. Retroviral-mediated suppression specifically inhibited expression of AHI-1 and its isoforms in transduced cells by 80% and also reduced autocrine production of interleukin (IL)-2, IL-4 and tumor necrosis factor-alpha (TNFalpha) by up to 85%. It further significantly reduced their growth factor independence in vitro and the ability to produce tumors in immunodeficient mice. Interestingly, aberrant expression of AHI-1, particularly truncated isoforms, was present in CD4+CD7- Sezary cells from some patients with SS. Elevated expression of IL-2 and TNFalpha was also found in these cells. These findings provide strong evidence of the oncogenic activity of AHI-1 in human leukemogenesis and demonstrate that its deregulation may contribute to the development of SS.