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Abstract Patients with residual nasopharyngeal carcinoma after receiving definitive treatment have poor prognoses. Although immune checkpoint therapies have achieved breakthroughs for treating recurrent and metastatic nasopharyngeal carcinoma, none of these strategies have been assessed for treating residual nasopharyngeal carcinoma. In this single-arm, phase 2 trial, we aimed to evaluate the antitumor efficacy and safety of toripalimab (anti-PD1 antibody) plus capecitabine in patients with residual nasopharyngeal carcinoma after definitive treatment (ChiCTR1900023710). Primary endpoint of this trial was the objective response rate assessed according to RECIST (version 1.1). Secondary endpoints included complete response rate, disease control rate, duration of response, progression-free survival, safety profile, and treatment compliance. Between June 1, 2020, and May 31, 2021, 23 patients were recruited and received six cycles of toripalimab plus capecitabine every 3 weeks. In efficacy analyses, 13 patients (56.5%) had complete response, and 9 patients (39.1%) had partial response, with an objective response rate of 95.7% (95% CI 78.1-99.9). The trial met its prespecified primary endpoint. In safety analyses, 21 of (91.3%) 23 patients had treatment-related adverse events. The most frequently reported adverse event was hand-foot syndrome (11 patients [47.8%]). The most common grade 3 adverse event was hand-foot syndrome (two patients [8.7%]). No grades 4-5 treatment-related adverse events were recorded. This phase 2 trial shows that combining toripalimab with capecitabine has promising antitumour activity and a manageable safety profile for patients with residual nasopharyngeal carcinoma.

Abstract Objectives This study aimed to investigate the incidence, consequences, and predictors of serious chemotherapy‐induced thrombocytopenia (CIT) in nasopharyngeal carcinoma (NPC). Materials and Methods We retrospectively reviewed the clinical records of patients with NPC between 2013 and 2015. Multivariate Cox proportional hazards regression model and propensity score matching were used to estimate the effect of serious CIT on overall survival. Univariate and multivariate logistic regression analyses were applied to identify the predictors of serious CIT. Results and Conclusion The incidence of serious CIT was 5.21% in patients with NPC. Patients who experienced serious thrombocytopenia had a worse long‐term prognosis, while the difference in short‐term survival rate was slight. Chemotherapy regimens of gemcitabine and platinum, 5‐fluorouracil and platinum, taxane and platinum, serum potassium ion concentration, serum lactate dehydrogenase levels, platelet count, red blood cell count, and estimated glomerular filtration rate were predictors of serious CIT.

Abstract Background Dysregulation of lipid metabolism is closely associated with cancer progression. The study aimed to establish a prognostic model to predict distant metastasis-free survival (DMFS) in patients with nasopharyngeal carcinoma (NPC), based on lipidomics. Methods The plasma lipid profiles of 179 patients with locoregionally advanced NPC (LANPC) were measured and quantified using widely targeted quantitative lipidomics. Then, patients were randomly split into the training (125 patients, 69.8%) and validation (54 patients, 30.2%) sets. To identify distant metastasis-associated lipids, univariate Cox regression was applied to the training set (P

Abstract Background To develop and validate a predictive nomogram for tumor residue 3–6 months after treatment based on postradiotherapy plasma Epstein–Barr virus (EBV) deoxyribonucleic acid (DNA), clinical stage, and radiotherapy (RT) dose in patients with stage II–IVA nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). Methods In this retrospective study, 1050 eligible patients with stage II–IVA NPC, who completed curative IMRT and underwent pretreatment and postradiotherapy (-7 to +28 days after IMRT) EBV DNA testing, were enrolled from 2012 to 2017. The prognostic value of the residue was explored using Cox regression analysis in patients (n=1050). A nomogram for predicting tumor residues after 3–6 months was developed using logistic regression analyses in the development cohort (n=736) and validated in an internal cohort (n=314). Results Tumor residue was an independent inferior prognostic factor for 5-year overall survival, progression-free survival, locoregional recurrence-free survival and distant metastasis-free survival (all P

Summary: It is imperative to optimally utilize virtues and obviate defects of fully automated analysis and expert knowledge in new paradigms of healthcare. We present a deep learning-based semiautomated workflow (RAINMAN) with 12,809 follow-up scans among 2,172 patients with treated nasopharyngeal carcinoma from three centers (ChiCTR.org.cn, Chi-CTR2200056595). A boost of diagnostic performance and reduced workload was observed in RAINMAN compared with the original manual interpretations (internal vs. external: sensitivity, 2.5% [p = 0.500] vs. 3.2% [p = 0.031]; specificity, 2.9% [p

Abstract Background To explore the short‐ and long‐term outcomes in patients with nasopharyngeal carcinoma (NPC) with magnetic resonance imaging (MRI)‐detected residual disease at 3 months post‐treatment who received intervention either promptly (0 month) or following observation (after an additional 3 months). Methods A total of 272 patients with residual disease at 3 months post‐treatment (observation [observation for additional 3 months]: 122, intervention [prompt intervention]: 150) were analyzed. Univariate and multivariate analyses were performed to examine the survival. Adverse events were analyzed in all patients. Results Patients in the observation group had a lower 3‐year overall survival (77.1% vs. 85.2%), progression‐free survival (10.2% vs. 18.1%), and locoregional relapse‐free survival (10.2% vs. 20.6%) (all p

In patients with locally advanced resectable oral squamous cell carcinoma (OSCC), the risk of recurrence and metastasis following treatment is high. Here, a phase I clinical trial reports safety and pathological response of neoadjuvant camrelizumab and apatinib in patients with locally advanced resectable OSCC.

Background: Locoregional recurrence of nasopharyngeal carcinoma (NPC) occurs in 10% to 50% of cases following primary treatment. However, the current main prognostic markers for NPC, both stage and plasma Epstein–Barr virus DNA, are not sensitive to locoregional recurrence. Methods: We gathered 385 whole-slide images (WSIs) from haematoxylin and eosin (H&E)-stained NPC sections (n = 367 cases), which were collected from Sun Yat-sen University Cancer Centre. We developed a deep learning algorithm to detect tumour nuclei and lymphocyte nuclei in WSIs, followed by density-based clustering to quantify the tumour-infiltrating lymphocytes (TILs) into 12 scores. The Random Survival Forest model was then trained on the TILs to generate risk score. Results: Based on Kaplan–Meier analysis, the proposed methods were able to stratify low- and high-risk NPC cases in a validation set of locoregional recurrence with a statically significant result (p < 0.001). This finding was also found in distant metastasis-free survival (p < 0.001), progression-free survival (p < 0.001), and regional recurrence-free survival (p < 0.05). Furthermore, in both univariate analysis (HR: 1.58, CI: 1.13–2.19, p < 0.05) and multivariate analysis (HR:1.59, CI: 1.11–2.28, p < 0.05), we also found that our methods demonstrated a strong prognostic value for locoregional recurrence. Conclusion: The proposed novel digital markers could potentially be utilised to assist treatment decisions in cases of NPC.

Excessive cadmium (Cd) accumulation in vegetables due to farmland pollution constitutes a serious threat to human health. Eggplant has a tendency to accumulate Cd. To investigate the mechanism of the differences in Cd accumulation levels between high-Cd (BXGZ) and low-Cd (MYQZ) eggplant cultivar, physiological and biochemical indicators and mRNA expression of eggplant were examined using photosynthetic apparatus, biochemical test kits, Fourier transform infrared (FTIR) spectroscopy and transcriptome sequencing, etc. The results of biochemical test kits and FTIR revealed that MYQZ enhanced pectin methylesterase (PME) activity, and lignin and pectin content in the root cell wall, which was associated with the upregulation of PME, cinnamyl-alcohol dehydrogenase and peroxidase (PODs). Higher levels of cysteine and glutathione (GSH) contents and upregulation of genes associated with sulfur metabolism, as well as higher expression of ATP-binding cassette transporters (ABCs), cation exchangers (CAX) and metal tolerance proteins (MTPs) were observed in MYQZ. In BXGZ, the higher stomatal density and stomatal aperture as well as higher levels of Ca2+ binding protein-1 (PCaP1) and aquaporins and lower levels of A2-type cyclins (CYCA2-1) are consistent with an enhanced transpiration rate in BXGZ. Furthermore, a more developed root system was shown to be associated with higher levels of auxin response factor (ARF19), GATA transcription factors (GATA4, 5 and 11) and auxin efflux carrier component (PIN5) in BXGZ. In conclusion, highly active PME, and higher levels of lignin and pectin in MYQZ are expected to reduce Cd toxicity, while Cd translocation can be inhibited with the help of ABC and other Cd transporters. As for BXGZ, the uptake and translocation of Cd were enhanced by the developed root system and stronger transpiration.

Summary: In nasopharyngeal carcinoma, deep-learning extracted signatures on MR images might be correlated with survival. In this study, we sought to develop an individualizing model using deep-learning MRI signatures and clinical data to predict survival and to estimate the benefit of induction chemotherapy on survivals of patients with nasopharyngeal carcinoma. Two thousand ninety-seven patients from three independent hospitals were identified and randomly assigned. When the deep-learning signatures of the primary tumor and clinically involved gross cervical lymph nodes extracted from MR images were added to the clinical data and TNM staging for the progression-free survival prediction model, the combined model achieved better prediction performance. Its application is among patients deciding on treatment regimens. Under the same conditions, with the increasing MRI signatures, the survival benefits achieved by induction chemotherapy are increased. In nasopharyngeal carcinoma, these prediction models are the first to provide an individualized estimation of survivals and model the benefit of induction chemotherapy on survivals.

To date, Cd contamination of cropland and crops is receiving more and more attention around the world. As a plant hormone, abscisic acid (ABA) plays an important role in Cd stress response, but its effect on plant Cd uptake and translocation varies among plant species. In some species, such as Arabidopsis thaliana, Oryza sativa, Brassica chinensis, Populus euphratica, Lactuca sativa, and Solanum lycopersicum, ABA inhibits Cd uptake and translocation, while in other species, such as Solanum photeinocarpum and Boehmeria nivea, ABA severs the opposite effect. Interestingly, differences in the methods and concentrations of ABA addition also triggered the opposite result of Cd uptake and translocation in Sedum alfredii. The regulatory mechanism of ABA involved in Cd uptake and accumulation in plants is still not well-established. Therefore, we summarized the latest studies on the ABA synthesis pathway and comparatively analyzed the physiological and molecular mechanisms related to ABA uptake, translocation, and detoxification of Cd in plants at different ABA concentrations or among different species. We believe that the control of Cd uptake and accumulation in plant tissues can be achieved by the appropriate ABA application methods and concentrations in plants.

Abstract Background Smart nanoscale drug delivery systems that target acidic tumor microenvironments (TME) could offer controlled release of drugs and modulate the hypoxic TME to enhance cancer therapy. The majority of previously reported MnO2 nanostructures are nanoparticles, nanosheets, or nanocomposites incorporated with other types of nanoparticles, which may not offer the most effective method for drug loading or for the controlled release of therapeutic payloads. Previous studies have designed MnO2 nanoshells that achieve tumor-specific and enhanced combination therapy for localized advanced cancer. However, the therapeutic effect of MnO2 nanoshells on metastatic cancer is still uncertain. Result Here, intelligent “theranostic” platforms were synthesized based on hollow mesoporous MnO2 (H-MnO2) nanoshells that were loaded with chemotherapy agents docetaxel and cisplatin (TP) to form H-MnO2-PEG/TP nanoshells, which were designed to alleviate tumor hypoxia, attenuate angiogenesis, trigger the dissolution of Mn2+, and synergize the efficacy of first-class anticancer chemotherapy. The obtained H-MnO2-PEG/TP nanoshells decomposed in the acidic TME, releasing the loaded drugs (TP) and simultaneously attenuated tumor hypoxia and hypoxia-inducible factor-1α (HIF-1α) expression by inducing endogenous tumor hydrogen peroxide (H2O2) decomposition. In vitro experiments showed that compared with the control group, the proliferation, colony formation and migration ability of CAL27 and SCC7 cells were significantly reduced in H-MnO2-PEG/TP group, while cell apoptosis was enhanced, and the expression of hypoxia-inducible factor-1α(HIF-1α) was down-regulated. In vivo experiments showed that tumor to normal organ uptake ratio (T/N ratio) of mice in H-MnO2-PEG/TP group was significantly higher than that in TP group alone (without the nanoparticle), and tumor growth was partially delayed. In the H-MnO2-PEG/TP treatment group, HE staining showed that most of the tumor cells were severely damaged, and TUNEL assay showed cell apoptosis was up-regulated. He staining of renal and liver sections showed no obvious fibrosis, necrosis or hypertrophy, indicating good biosafety. Fluorescence staining showed that HIF-1α expression was decreased, suggesting that the accumulation of MnO2 in the tumor caused the decomposition of H2O2 into O2 and alleviated the hypoxia of the tumor. Conclusion In conclusion, a remarkable in vivo and in vitro synergistic therapeutic effect is achieved through the combination of TP chemotherapy, which simultaneously triggered a series of antiangiogenic and oxidative antitumor reactions. Graphic abstract

Abstract Background The relationship between spinal sagittal subtypes and lumbar disc degeneration is unclear. Thus, we aimed to investigate the relationship between lumbar intervertebral disc degeneration and age in asymptomatic healthy individuals with different sagittal alignments. Methods In this cross-sectional observational study, we examined 209 asymptomatic young and middle-aged volunteers (123 women and 86 men) who were divided into the following three groups according to age: groups A (20–30 years), B (31–40 years), and C (41–50 years). The volunteers underwent full-spine standing lateral radiography and magnetic resonance imaging (MRI, 3.0 T) of the lumbar spine. Based on panoramic radiography, two observers measured the spinopelvic parameters and classified the spine into Roussouly subtypes. The degree of disc degeneration was assessed based on T2-weighted images according to the Pfirrmann classification. Results There was a statistically significant difference in the degree of degeneration of type I spine between groups B and C at L4-L5 (P

Both cadmium (Cd) contamination and boron (B) deficiency in farmland soils pose a threat to the yield and quality of crops in Southern China. The present study investigated the mechanisms by which B reduces Cd accumulation in rice (Oryza sativa) seedlings. Boron supplementation partially restored the decline in shoot and root biomass caused by Cd treatment (26% and 33%, respectively), with no significant difference between the B+Cd and control groups. We also found that B significantly reduced shoot and root Cd concentrations (by 64% and 25%, respectively) but increased Cd concentration (by 43%) and proportion (from 38% to 55%) in root cell walls. Transcriptome analysis and biochemical tests suggested that B supplementation enhanced lignin and pectin biosynthesis, pectin demethylation, and sulfur and glutathione metabolism. Moreover, B decreased the expression of some Cd-induced transporter-related genes (i.e., HMA2, Nramp1, and several ABC genes). These results indicate that B relieved Cd toxicity and reduced Cd accumulation in rice seedlings by restraining Cd uptake and translocation from root to shoot by improving Cd tolerance and chelation ability. These novel findings would benefit further investigations into how B influences Cd uptake, translocation, detoxification, and accumulation in crops.

Cadmium (Cd) contamination of croplands has become a threat to crop food safety and human health. In this study, we investigated the effect of sulfur on the growth of water spinach under Cd stress and the amount of Cd accumulation by increasing the soil sulfate content. We found that the biomass of water spinach significantly increased after the application of sulfur while the shoot Cd concentration was considerably reduced (by 31%). The results revealed that sulfur could promote the expression of PME and LAC genes, accompanied by an increase in PME activity and lignin content. Also, the cell wall Cd content of water spinach roots was significantly increased under sulfur treatment. This finding suggests that sulfur could enhance the adsorption capacity of Cd by promoting the generation of cell wall components, thereby inhibiting the transportation of Cd via the apoplastic pathway. In addition, the higher expression of Nramp5 under the Cd1S0 (concentration of Cd and sulfur are 2.58 and 101.31 mg/kg respectively) treatment led to increased Cd uptake. The CAX3 and ABC transporters and GST were expressed at higher levels along with a higher cysteine content and GSH/GSSR value under Cd1S1 (concentration of Cd and sulfur are 2.60 and 198.36 mg/kg respectively) treatment, which contribute to the Cd detoxification and promotion of Cd compartmentalization in root vacuoles, thereby reducing the translocation of Cd to the shoot via the symplastic pathway.

Sepsis is a systemic inflammatory reaction caused by various infectious or noninfectious factors, which can lead to shock, multiple organ dysfunction syndrome, and death. It is one of the common complications and a main cause of death in critically ill patients. At present, the treatments of sepsis are mainly focused on the controlling of inflammatory response and reduction of various organ function damage, including anti-infection, hormones, mechanical ventilation, nutritional support, and traditional Chinese medicine (TCM). Among them, Xuebijing injection (XBJI) is an important derivative of TCM, which is widely used in clinical research. However, the molecular mechanism of XBJI on sepsis is still not clear. The mechanism of treatment of “bacteria, poison and inflammation” and the effects of multi-ingredient, multi-target, and multi-pathway have still not been clarified. For solving this issue, we designed a new systems pharmacology strategy which combines target genes of XBJI and the pathogenetic genes of sepsis to construct functional response space (FRS). The key response proteins in the FRS were determined by using a novel node importance calculation method and were condensed by a dynamic programming strategy to conduct the critical functional ingredients group (CFIG). The results showed that enriched pathways of key response proteins selected from FRS could cover 95.83% of the enriched pathways of reference targets, which were defined as the intersections of ingredient targets and pathogenetic genes. The targets of the optimized CFIG with 60 ingredients could be enriched into 182 pathways which covered 81.58% of 152 pathways of 1,606 pathogenetic genes. The prediction of CFIG targets showed that the CFIG of XBJI could affect sepsis synergistically through genes such as TAK1, TNF-α, IL-1β, and MEK1 in the pathways of MAPK, NF-κB, PI3K-AKT, Toll-like receptor, and tumor necrosis factor signaling. Finally, the effects of apigenin, baicalein, and luteolin were evaluated by in vitro experiments and were proved to be effective in reducing the production of intracellular reactive oxygen species in lipopolysaccharide-stimulated RAW264.7 cells, significantly. These results indicate that the novel integrative model can promote reliability and accuracy on depicting the CFIGs in XBJI and figure out a methodological coordinate for simplicity, mechanism analysis, and secondary development of formulas in TCM.

Adipose tissue-derived stromal cells are promising candidates investigating the stem cell-related treatment. However, their proportion and utility in the human body decline with time, rendering stem cells incompetent to complete repair processes in vivo. The involvement of circRNAs in the aging process is poorly understood. Rat subcutaneous adipose tissue from 10-week-old and 27-month-old rats were used for hematoxylin and eosin (H and E) staining, TUNEL staining, and circRNA sequencing. Rat adipose tissue-derived stromal cells were cultured and overexpressed with circ-ATXN2. Proliferation was examined using xCELLigence real-time cell analysis, EdU staining, and cell cycle assay. Apoptosis was induced by CoCl2 and examined using flow cytometry. RT-PCR assay and Oil Red O staining were used to measure adipogenesis at 48 h and 14 days, respectively. H and E staining showed that the diameter of adipocytes increased; however, the number of cells decreased in old rats. TUNEL staining showed that the proportion of apoptotic cells was increased in old rats. A total of 4,860 and 4,952 circRNAs was detected in young and old rats, respectively. Among them, 67 circRNAs exhibited divergent expression between the two groups (fold change ≥2, p ≤ 0.05), of which 33 were upregulated (49.3%) and 34 were downregulated (50.7%). The proliferation of circ-ATXN2-overexpressing cells decreased significantly in vitro, which was further validated by xCELLigence real-time cell analysis, EdU staining, and cell cycle assay. Overexpression of circ-ATXN2 significantly increased the total apoptotic rate from 5.78 ± 0.46% to 11.97 ± 1.61%, early apoptotic rate from 1.76 ± 0.22% to 5.50 ± 0.66%, and late apoptosis rate from 4.02 ± 0.25% to 6.47 ± 1.06% in adipose tissue-derived stromal cells. Furthermore, in circ-ATXN2-overexpressing cells, RT-PCR assay revealed that the expression levels of adipose differentiation-related genes PPARγ and CEBP/α were increased and the Oil Red O staining assay showed more lipid droplets. Our study revealed the expression profile of circRNAs in the adipose tissue of old rats. We found a novel age-related circular RNA—circ-ATXN2—that inhibits proliferation and promotes cell death and adipogenesis in rat adipose tissue-derived stromal cells.

Abstract Drug-resistant urinary tract infections (UTIs) are difficult and sometimes impossible to treat. Many UTIs are caused by uropathogenic Escherichia coli (UPEC). We developed an intact rat model of UTI, by catheterizing female rats and introducing a bioluminescent UPEC strain into the female rat bladder which lasted for up to six days. We recently showed that antimicrobial photodynamic inactivation (aPDI) of a bacterial infection mediated by the well-known phenothiazinium salt, methylene blue (MB) could be strongly potentiated by addition of the non-toxic salt potassium iodide (KI). In the intact rat model we introduced MB into the bladder by catheter, followed by KI solution and delivered intravesicular illumination with a diffusing fiber connected to a 1 W 660 nm laser. Bioluminescent imaging of the bacterial burden was carried out during the procedure and for 6 days afterwards. Light-dose dependent loss of bioluminescence was observed with the combination of MB followed by KI, but recurrence of infection was seen the next day in some cases. aPDT with MB + KI gave a significantly shorter duration of infection compared to untreated controls. aPDT with MB alone was the least effective. No signs of aPDT damage to the bladder lining were detected. This procedure to treat urinary tract infections without antibiotics by using already approved pharmaceutical substances (MB and KI) may have clinical applicability, either initially as a stand-alone therapy, or as an adjunct to antibiotic therapy by a rapid and substantial reduction of the bacterial burden.

Abstract We previously showed that blue (415 nm) and green (540 nm) wavelengths were more effective in stimulating osteoblast differentiation of human adipose-derived stem cells (hASC), compared to red (660 nm) and near-infrared (NIR, 810 nm). Intracellular calcium was higher after blue/green, and could be inhibited by the ion channel blocker, capsazepine. In the present study we asked what was the effect of these four wavelengths on proliferation of the hASC? When cultured in proliferation medium there was a clear difference between blue/green which inhibited proliferation and red/NIR which stimulated proliferation, all at 3 J/cm2. Blue/green reduced cellular ATP, while red/NIR increased ATP in a biphasic manner. Blue/green produced a bigger increase in intracellular calcium and reactive oxygen species (ROS). Blue/green reduced mitochondrial membrane potential (MMP) and lowered intracellular pH, while red/NIR had the opposite effect. Transient receptor potential vanilloid 1 (TRPV1) ion channel was expressed in hADSC, and the TRPV1 ligand capsaicin (5uM) stimulated proliferation, which could be abrogated by capsazepine. The inhibition of proliferation caused by blue/green could also be abrogated by capsazepine, and by the antioxidant, N-acetylcysteine. The data suggest that blue/green light inhibits proliferation by activating TRPV1, and increasing calcium and ROS.

Abstract Infantile haemangiomas (IHs) are the most common congenital vascular tumours of infancy. Propranolol has been demonstrated to be effective for IHs; however, the factors affecting its therapeutic effect remain unknown. We enrolled 169 infants with IHs of the head and neck region treated with oral propranolol at a dose of 2.0 mg/kg/day. We evaluated the therapeutic responses 6 months after treatment and the end of treatment, which were categorized into four grades. The type and location of the lesions and the infant age at treatment initiation were analysed. The clinical response rate (III + IV) was 91.72% at 6 months after treatment and 97.63% at the end of treatment. The average treatment duration was 9.99 (2–24) months. The group aged 4–6 months exhibited a greater therapeutic response rate (98.48%). The treatment duration was shorter (9.52 months) for mixed-type IHs. Better therapeutic responses were observed for IHs located around the parotid, periorbital, cheek, and neck regions and for multiple IH lesions. Our study indicated that propranolol is effective for IHs affecting the head and neck. The age at treatment initiation and the location of the lesions had a significant effect on the therapeutic response, whereas the lesion type might affect the treatment duration.

Biofilm describes a microbially-derived sessile community in which microbial cells are firmly attached to the substratum and embedded in extracellular polymeric matrix. Microbial biofilms account for up to 80% of all bacterial and fungal infections in humans. Biofilm-associated pathogens are particularly resistant to antibiotic treatment, and thus novel antibiofilm approaches needed to be developed. Antimicrobial Photodynamic therapy (aPDT) had been recently proposed to combat clinically relevant biofilms such as dental biofilms, ventilator associated pneumonia, chronic wound infections, oral candidiasis, and chronic rhinosinusitis. aPDT uses non-toxic dyes called photosensitizers (PS), which can be excited by harmless visible light to produce reactive oxygen species (ROS). aPDT is a multi-stage process including topical PS administration, light irradiation, and interaction of the excited state with ambient oxygen. Numerous in vitro and in vivo aPDT studies have demonstrated biofilm-eradication or substantial reduction. ROS are produced upon photo-activation and attack adjacent targets, including proteins, lipids, and nucleic acids present within the biofilm matrix, on the cell surface and inside the microbial cells. Damage to non-specific targets leads to the destruction of both planktonic cells and biofilms. The review aims to summarize the progress of aPDT in destroying biofilms and the mechanisms mediated by ROS. Finally, a brief section provides suggestions for future research.

Antimicrobial photodynamic inactivation (aPDI) employs photosensitizing dyes activated by visible light to produce reactive oxygen species. aPDI is independent of the antibiotic resistance status of the target cells, and is thought unlikely to produce resistance itself. Among many PS that have been investigated, tetracyclines occupy a unique niche. They are potentially dual-action compounds that can both kill bacteria under illumination, and prevent bacterial regrowth by inhibiting ribosomes. Tetracycline antibiotics are regarded as bacteriostatic rather than bactericidal. Doxycycline (DOTC) is excited best by UVA light (365 nm) while demeclocycline (DMCT) can be efficiently activated by blue light (415 nm) as well as UVA. Both compounds were able to eradicate Gram-positive (methicillin-resistant Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria (>6 log(10) steps of killing) at concentrations (10-50μM) and fluences (10-20J/cm2). In contrast to methylene blue, MB plus red light, tetracyclines photoinactivated bacteria in rich growth medium. When ~3 logs of bacteria were killed with DMCT/DOTC+light and the surviving cells were added to growth medium, further bacterial killing was observed, while the same experiment with MB allowed complete regrowth. MIC studies were carried out either in the dark or exposed to 0.5mW/cm2 blue light. Up to three extra steps (8-fold) increased antibiotic activity was found with light compared to dark, with MRSA and tetracycline-resistant strains of E. coli. Tetracyclines can accumulate in bacterial ribosomes, where they could be photoactivated with blue/UVA light producing microbial killing via ROS generation.

Low-level laser (light) therapy (LLLT) has been clinically applied around the world for a spectrum of disorders requiring healing, regeneration and prevention of tissue death. One area that is attracting growing interest in this scope is the use of transcranial LLLT to treat stroke and traumatic brain injury (TBI). We developed a mouse model of severe TBI induced by controlled cortical impact and explored the effect of different treatment schedules. Adult male BALB/c mice were divided into 3 broad groups (a) sham-TBI sham-treatment, (b) real-TBI sham-treatment, and (c) real-TBI active-treatment. Mice received active-treatment (transcranial LLLT by continuous wave 810 nm laser, 25 mW/cm(2), 18 J/cm(2), spot diameter 1 cm) while sham-treatment was immobilization only, delivered either as a single treatment at 4 hours post TBI, as 3 daily treatments commencing at 4 hours post TBI or as 14 daily treatments. Mice were sacrificed at 0, 4, 7, 14 and 28 days post-TBI for histology or histomorphometry, and injected with bromodeoxyuridine (BrdU) at days 21-27 to allow identification of proliferating cells. Mice with severe TBI treated with 1-laser Tx (and to a greater extent 3-laser Tx) had significant improvements in neurological severity score (NSS), and wire-grip and motion test (WGMT). However 14-laser Tx provided no benefit over TBI-sham control. Mice receiving 1- and 3-laser Tx had smaller lesion size at 28-days (although the size increased over 4 weeks in all TBI-groups) and less Fluoro-Jade staining for degenerating neurons (at 14 days) than in TBI control and 14-laser Tx groups. There were more BrdU-positive cells in the lesion in 1- and 3-laser groups suggesting LLLT may increase neurogenesis. Transcranial NIR laser may provide benefit in cases of acute TBI provided the optimum treatment regimen is employed.

Low-level laser (light) therapy (LLLT) has been known since 1967 but still remains controversial due to incomplete understanding of the basic mechanisms and the selection of inappropriate dosimetric parameters that led to negative studies. The biphasic dose-response or Arndt-Schulz curve in LLLT has been shown both in vitro studies and in animal experiments. This review will provide an update to our previous ( Huang et al. 2009 ) coverage of this topic. In vitro mediators of LLLT such as adenosine triphosphate (ATP) and mitochondrial membrane potential show biphasic patterns, while others such as mitochondrial reactive oxygen species show a triphasic dose-response with two distinct peaks. The Janus nature of reactive oxygen species (ROS) that may act as a beneficial signaling molecule at low concentrations and a harmful cytotoxic agent at high concentrations, may partly explain the observed responses in vivo. Transcranial LLLT for traumatic brain injury (TBI) in mice shows a distinct biphasic pattern with peaks in beneficial neurological effects observed when the number of treatments is varied, and when the energy density of an individual treatment is varied. Further understanding of the extent to which biphasic dose responses apply in LLLT will be necessary to optimize clinical treatments.

Despite over forty years of investigation on low-level light therapy (LLLT), the fundamental mechanisms underlying photobiomodulation at a cellular level remain unclear.In this study, we isolated murine embryonic fibroblasts (MEF) from transgenic NF-kB luciferase reporter mice and studied their response to 810 nm laser radiation. Significant activation of NF-kB was observed at fluences higher than 0.003 J/cm(2) and was confirmed by Western blot analysis. NF-kB was activated earlier (1 hour) by LLLT compared to conventional lipopolysaccharide treatment. We also observed that LLLT induced intracellular reactive oxygen species (ROS) production similar to mitochondrial inhibitors, such as antimycin A, rotenone and paraquat. Furthermore, we observed similar NF-kB activation with these mitochondrial inhibitors. These results, together with inhibition of laser induced NF-kB activation by antioxidants, suggests that ROS play an important role in the laser induced NF-kB signaling pathways. However, LLLT, unlike mitochondrial inhibitors, induced increased cellular ATP levels, which indicates that LLLT also upregulates mitochondrial respiration.We conclude that LLLT not only enhances mitochondrial respiration, but also activates the redox-sensitive NFkB signaling via generation of ROS. Expression of anti-apoptosis and pro-survival genes responsive to NFkB could explain many clinical effects of LLLT.

Transcranial low-level laser therapy (LLLT) using near-infrared light can efficiently penetrate through the scalp and skull and could allow non-invasive treatment for traumatic brain injury (TBI). In the present study, we compared the therapeutic effect using 810-nm wavelength laser light in continuous and pulsed wave modes in a mouse model of TBI.TBI was induced by a controlled cortical-impact device and 4-hours post-TBI 1-group received a sham treatment and 3-groups received a single exposure to transcranial LLLT, either continuous wave or pulsed at 10-Hz or 100-Hz with a 50% duty cycle. An 810-nm Ga-Al-As diode laser delivered a spot with diameter of 1-cm onto the injured head with a power density of 50-mW/cm(2) for 12-minutes giving a fluence of 36-J/cm(2). Neurological severity score (NSS) and body weight were measured up to 4 weeks. Mice were sacrificed at 2, 15 and 28 days post-TBI and the lesion size was histologically analyzed. The quantity of ATP production in the brain tissue was determined immediately after laser irradiation. We examined the role of LLLT on the psychological state of the mice at 1 day and 4 weeks after TBI using tail suspension test and forced swim test.The 810-nm laser pulsed at 10-Hz was the most effective judged by improvement in NSS and body weight although the other laser regimens were also effective. The brain lesion volume of mice treated with 10-Hz pulsed-laser irradiation was significantly lower than control group at 15-days and 4-weeks post-TBI. Moreover, we found an antidepressant effect of LLLT at 4-weeks as shown by forced swim and tail suspension tests.The therapeutic effect of LLLT for TBI with an 810-nm laser was more effective at 10-Hz pulse frequency than at CW and 100-Hz. This finding may provide a new insight into biological mechanisms of LLLT.

The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing cell death and tissue damage has been known for over forty years since the invention of lasers. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial in mainstream medicine. The biochemical mechanisms underlying the positive effects are incompletely understood, and the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. A biphasic dose response has been frequently observed where low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. The so-called Arndt-Schulz curve is frequently used to describe this biphasic dose response. This review will cover the molecular and cellular mechanisms in LLLT, and describe some of our recent results in vitro and in vivo that provide scientific explanations for this biphasic dose response.

Novel Fe3O4/maifan stone composite were prepared by a simple solvothermal method. Physicochemical properties of the novel Fe3O4/maifan stone composite were analyzed using energy-dispersive X-ray spectroscopy, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, N2 adsorption, Fourier-transform infrared spectroscopy and X-ray photoelectron spectroscopy. The Fe3O4/maifan stone composite were used for the adsorption of ciprofloxacin (CIP) antibiotic removal. This paper represents an artificial neural network (ANN) based approach for modeling the adsorption process of the adsorption of CIP onto Fe3O4/maifan stone composite in batch adsorption experiments. The ANN model was trained and validated with the adsorption experiments data where pH, adsorbent dosage, and initial CIP concentration were selected as the variables for the batch study, whereas the removal efficiency was considered as the output. The ANN model was first developed using a three-layer back-propagation network with the optimum structure of 3-3-1. The model employed tangent sigmoid transfer function as input in the hidden layer whereas a linear transfer function was used in the output layer. The comparison between modeled data and experimental data provided high degree of correlation (R² = 0.99942) which indicated the applicability of ANN model for describing the adsorption process with reasonable accuracy. The kinetics of the adsorption of CIP onto Fe3O4/maifan stone composite was better fitted with the pseudo-second-order kinetics model, and thermodynamic parameters of the adsorption of CIP onto Fe3O4/maifan stone composite were calculated. This Fe3O4/maifan stone composite adsorbent can be easily separated. [ABSTRACT FROM AUTHOR]