A Novel Multi-Effect Photosensitizer for Tumor Destruction via Multimodal Imaging Guided Synergistic Cancer Phototherapy.

Background: How to ingeniously design multi-effect photosensitizers (PSs), including multimodal imaging and multi-channel therapy, is of great significance for highly spatiotemporal controllable precise phototherapy of malignant tumors. Methods: Herein, a novel multifunctional zinc(II) phthalocyanine-based planar micromolecule amphiphile (ZnPc 1) was successfully designed and synthesized, in which N atom with photoinduced electron transfer effect was introduced to enhance the near-infrared absorbance and nonradiative heat generation. After simple self-assembling into nanoparticles (NPs), ZnPc 1 NPs would exhibit enhanced multimodal imaging properties including fluorescence (FL) imaging (FLI) /photoacoustic (PA) imaging (PAI) /infrared (IR) thermal imaging, which was further used to guide the combined photodynamic therapy (PDT) and photothermal therapy (PTT). Results: It was that under the self-guidance of the multimodal imaging, ZnPc 1 NPs could precisely pinpoint the tumor from the vertical and horizontal boundaries achieving highly efficient and accurate treatment of cancer. Conclusion: Accordingly, the integration of FL/PA/IR multimodal imaging and PDT/PTT synergistic therapy pathway into one ZnPc 1 could provide a blueprint for the next generation of phototherapy, which offered a new paradigm for the integration of diagnosis and treatment in tumor and a promising prospect for precise cancer therapy.

Amyloid-like aggregates of short self-assembly peptide selectively induce melanoma cell apoptosis.

With the rising global incidence of melanoma, new anti-melanoma drugs with low-inducing drug resistance and high selectivity are in urgent need. Inspired by the physiological events in which fibrillar aggregates formed by amyloid proteins are toxic to normal tissues, we here rationally design a tyrosinase responsive peptide, I4K2Y* (Ac-IIIIKKDopa-NH2). Such peptide self-assembled into long nanofibers outside the cells, while it was catalyzed into amyloid-like aggregates by tyrosinase which was rich in melanoma cells. The newly formed aggregates concentrated around the nucleus of melanoma cells, blocking the exchange of biomolecules between the nucleus and cytoplasm and finally leading to cell apoptosis via the S phase arrest in cell cycle distribution and dysfunction of mitochondria. Furthermore, I4K2Y* effectively inhibited B16 melanoma growth in a mouse model but with minimal side effects. We believe that the strategy of combining the usage of toxic amyloid-like aggregates and in-situ enzymatic reactions by specific enzymes in tumor cells will bring profound implications for designing new anti-tumor drugs with high selectivity.

Identification of Molecular Targets and Potential Mechanisms of Yinchen Wuling San Against Head and Neck Squamous Cell Carcinoma by Network Pharmacology and Molecular Docking.

Head and neck squamous cell carcinoma (HNSCC) represents one of the most malignant and heterogeneous tumors, and the patients have low 5-year survival. Traditional Chinese medicine (TCM) has been demonstrated as an effective complementary and/or alternative therapy for advanced malignancies including HNSCC. It has been noted that several herbs that are used for preparing Yinchen Wuling San (YWLS) have anti-tumor activities, whereas their mechanisms of action remain elusive. In this study, network pharmacology and molecular docking studies were employed to explore the underlying mechanisms of action of YWLS against HNSCC. The 58 active ingredients from six herbs used for YWLS and their 506 potential targets were screened from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction database. A total of 2,173 targets associated with HNSCC were mainly identified from the DisGeNET and GeneCards databases. An active components-targets-disease network was constructed in the Cytoscape. Top 20 hub targets, such as AKT1, EGFR, TNF, ESR1, SRC, HSP90AA1, MAPK3, ERBB2, and CCND1, were identified by a degree in the protein-protein interaction (PPI) network. Gene functional enrichment analysis showed that PI3K-AKT, MAPK, Ras, TNF, and EGFR were the main signaling pathways of YWLS in treating HNSCC. There were 48 intersected targets such as EGFR, AKT1, and TNF that were associated with patients' outcomes by the univariate Cox analysis, and most of them had increased expression in the tumor as compared to normal tissues. The area under curves of receiver operating characteristic indicated their diagnostic potential. Inhibition of these survival-related targets and/or combination with EGFR or AKT inhibitors were promising therapeutic options in HNSCC. The partial active components of YWLS exhibited good binding with the hub targets, and ADME analysis further evaluated the drug-likeness of the active components. These compounds and targets identified in this study might provide novel treatment strategies for HNSCC patients, and the subsequent work is essential to verify the underlying mechanisms of YWLS against HNSCC.

Uniportal video-assisted thoracoscopic surgery for complex mediastinal mature teratoma: A case report.

BACKGROUND: Mediastinal mature teratoma is the most common histological type of primary extragonadal germ cell tumor. In this report, we describe a rare case of giant mature teratoma located primarily in the anterior mediastinum and causing partial atelectasis of the upper and middle lobes of the right lung, as well as extrinsic compression of the right atrium. CASE SUMMARY: A 31-year-old male with a giant mediastinal mature teratoma presented with progressive exertional dyspnea and chest pain for 1 mo. Computed tomography of the chest indicated the diagnosis of anterior mediastinal teratoma. The patient underwent right uniportal anterior approach video-assisted thoracoscopic surgery (VATS). En bloc resection of the giant teratoma, wedge resection of the upper and middle lobes of the right lung, resection of the thymus and partial excision of the pericardium were successfully performed. The pathological diagnosis revealed a mature cystic teratoma with foreign-body reaction that was closely related to the right lung, atrium dextrum, superior vena cava and ascending aorta. An atrophic thymic tissue was also discovered at the external teratoma surface. The patient was discharged on postoperative day 7. CONCLUSION: This is the first report of the use of uniportal VATS for complete resection of a teratoma in combination with wedge resection of the right upper and middle lung lobes and partial resection of the pericardium.

Case Report: Pink Urine Syndrome Following Exposure to Propofol: A Rare, Impressive but Benign Complication.

Drug-induced changes in urine color induced by drugs may have clinical significance. Pink urine syndrome (PUS), which has been associated with urinary uric acid (UA) disorders, is most frequently reported in patients with morbid obesity undergoing gastric bypass surgery and/or from propofol anesthesia use in those who potentially have preexisting UA metabolism disorders. However, PUS has rarely occurred following exposure to propofol in non-obese patients, and literature on long-term follow-up after PUS is scarce. We report a case of PUS induced by propofol in a previously healthy non-obese woman after undergoing thoracoscopic wedge resection of pulmonary nodules under general anesthesia using propofol. The patient suddenly developed pink urine 4 h after surgery. A pink sediment rapidly precipitated at the bottom of the test tube following centrifugation of the urine. Amorphous, colorless UA-like crystals were identified under a polarizing microscope. The diagnosis of PUS was confirmed by examining the urinary UA concentration. The patient recovered and as followed-up for 1 month, during which she did not experience any urinary complications. To our knowledge, this is the first report to describe in detail a case of PUS caused by propofol in a non-obese patient with follow-up. PUS is usually benign and can resolve by rapidly on administering lactated Ringer's solution; however, the potential risk of urinary complications, particularly UA lithiasis, should be fully realized.

Detoxification and recovery after cadmium exposure in the freshwater crab Sinopotamon henanense.

Cadmium (Cd) is a common pollutant in the aquatic environment, which puts the health and safety of aquatic organisms and humans at risk. In the present study, the freshwater crab Sinopotamon henanense was exposed to Cd (0, 50, 100, and 500 µg·L-1) for 14 d (0-14th d), followed by 21 d (14-35th d) of depuration. The changes in Cd bioaccumulation, microstructure, biomacromolecules (polysaccharides, neutral lipids, DNA and total proteins), and biochemical parameters (SOD, CAT, GR, TrxR, MDA and AChE) in the gills and hepatopancreas were tested. The injured microstructure, activated antioxidant system, increased MDA, and inhibited AChE of the gills and hepatopancreas responded with progressive bioaccumulation of Cd. Meanwhile, the polysaccharides and neutral lipids in the hepatopancreas reduced and DNA synthesis enhanced. During depuration, more than 58.80 ± 8.53% and 13.84 ± 12.11% of Cd was excreted from the gills and hepatopancreas, respectively. Recovery of microstructure and biomacromolecules as well as alleviated oxidative damage and neurotoxicity were also found in these two organs. Additionally, based on PCA, Ihis, GR and MDA were identified as the optimal biomarkers indicating the health status of crabs. In conclusion, S. henanense could resist Cd stress through antioxidant defence and self-detoxification.

Gut Microbiota in Decapod Shrimps: Evidence of Phylosymbiosis.

Gut microbiota have long attracted the interest of scientists due to their profound impact on the well-being of animals. A non-random pattern of microbial assembly that results in a parallelism between host phylogeny and microbial similarity is described as phylosymbiosis. Phylosymbiosis has been consistently observed in different clades of animal hosts, but there have been no studies on crustaceans. In this study, we investigated whether host phylogeny has an impact on the gut microbiota assemblages in decapod shrimps. We examined the gut microbial communities in 20 shrimp species from three families inhabiting distinct environments, using metabarcoding analyses of the V1-V3 hypervariable region of the 16S rRNA gene. Gut microbial communities varied within each shrimp group but were generally dominated by Proteobacteria. A prevalent phylosymbiotic pattern in shrimps was evidenced for the first time by the observations of (1) the distinguishability of microbial communities among species within each group, (2) a significantly lower intraspecific than interspecific gut microbial beta diversity across shrimp groups, (3) topological congruence between host phylogenetic trees and gut microbiota dendrograms, and (4) a correlation between host genetic distances and microbial dissimilarities. Consistent signals of phylosymbiosis were observed across all groups in dendrograms based on the unweighted UniFrac distances at 99% operational taxonomic units (OTUs) level and in Mantel tests based on the weighted UniFrac distances based on 97% OTUs and amplicon sequence variants. Penaeids exhibited phylosymbiosis in most tests, while phylosymbiotic signals in atyids and pandalids were only detected in fewer than half of the tests. A weak phylogenetic signal was detected in the predicted functions of the penaeid gut microbiota. However, the functional diversities of the two caridean groups were not significantly related to host phylogeny. Our observations of a parallelism in the taxonomy of the gut microbiota with host phylogeny for all shrimp groups examined and in the predicted functions for the penaeid shrimps indicate a tight host-microbial relationship during evolution.

Duration of opioid use and association with socioeconomic status, daily dose and formulation: a two-decade population study in Queensland, Australia.

Background There is an association between the duration of prescription opioids use and an increased risk of serious harm, often unintentional. Objective (1) Describe the trends in duration of prescription opioids dispensing and, (2) determine the risk of long-term use (≥4 months) based on patients' socioeconomic status, daily dose in oral daily morphine milligram equivalent, and opioid formulation. Setting Residents of Queensland (2,827,727), Australia from the age 18 years and who were dispensed pharmaceutical opioids from 1 January 1997 to 31 December 2018. Method Retrospective, longitudinal population-based analysis using data obtained from the Monitoring of Drugs of Dependence system of the Monitored Medicines Unit of Queensland Health. Main outcome measure Contribution of socioeconomic status, and daily dose and opioid formulation (modified-release or immediate-release) to the risk of long-term opioid use. Results There was little difference between the number of patients dispensed opioids for ≥4 months and ≤3 months between 1997 and 2011. Thereafter, the number for those using opioids long-term increased. The highest risk of having opioids dispensed for ≥4 months were for patients in the lowest level of socioeconomic status (adjusted odds ratio 1.36; 95% CI, 1.34, 1.38), compared to people in the highest socioeconomic status areas, followed by the low-socioeconomic status areas, mid-socioeconomic status areas, and high-socioeconomic status areas respectively. The risk of being dispensed prescription opioids for ≥4 months significantly increased as the dose increased: adjusted odds ratio 1.73; 95% CI, 1.71, 1.75, adjusted odds ratio 1.89; 95% CI, 1.87, 1.92, and adjusted odds ratio 3.63; 95% CI, 3.58, 3.69 for the ≥20 to <50 oral daily morphine milligram equivalent, ≥50 to <100 oral daily morphine milligram equivalent and ≥100 oral daily morphine milligram equivalent dose categories, respectively. Conclusion Higher doses and living in a low socioeconomic status areas were associated with increased risk of long-term dispensing of opioid prescriptions.

Pharmaceutical opioids utilisation by dose, formulation, and socioeconomic status in Queensland, Australia: a population study over 22 years.

Background Prescription opioids are a central aspect of pain management and as the prevalence of pain is increasing so is the rate of use of prescription opioids. Increased opioid prescriptions increases the risk of deaths and morbidity. Objective To (a) describe the 22-year trend of prescription opioid dispensing in Queensland, (b) examine the effect of opioid dose, formulation and socioeconomic status on the number of prescriptions dispensed. Design/setting Retrospective analysis of data from the Monitoring of Drugs of Dependence system of the Monitored Medicines Unit of Queensland Health, Australia. Participants Queensland residents (3.3 million) from 18 years old dispensed 18.8 million opioid prescriptions from January 1997 to December 2018. Results Opioid prescriptions dispensed annually increased to over two million in 2018 from about 150,000 prescriptions in 1997. The number of prescriptions for modified-release formulations dispensed annually was three times higher compared to the immediate-release formulations. Oxycodone accounted for over 60% of prescriptions for pharmaceutical opioids since 2013. There was an increase in the number of prescriptions dispensed as socioeconomic status decreased and modified-release opioid formulations positively affects the pattern of dispensing. The highest increase in number of prescriptions dispensed (for all opioids) was observed among the high socioeconomic status (IRR = 1.25, 95% CI 1.25, 1.26). The disparities in the annual number of prescriptions across dose categories are wider in the modified-release than the immediate-release formulations. Conclusion The dispensing of opioids increased significantly in Queensland. There was a positive relationship between the increased dispensing of opioids and locations of lower socioeconomic status.

Evaluating the eighth edition TNM staging system for esophageal cancer among patients receiving neoadjuvant therapy: A SEER study.

BACKGROUND: The evaluation of the eighth edition of ypTNM staging system for patients with esophageal cancer was limited in the setting of neoadjuvant therapy. METHODS: A total of 2324 patients with esophageal cancer receiving radio(chemo)therapy prior to surgery from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2013 were eligible for the analysis. Kaplan-Meier method and Cox proportional hazards models were used to estimate overall survivals. RESULTS: Among patients with preoperative therapy, both the seventh edition TNM grouping and the eighth edition ypTNM grouping could significantly stratify the overall survival (both log-rank P < .001). There was not significant difference in the C-index of the seventh edition TNM grouping (0.575; 95%CI, 0.558-0.593) and the eighth edition ypTNM grouping (0.569; 95%CI, 0.551-0.587) (P = .098). In multivariable Cox analysis, ypN category was the strongest predictor of overall survival (P < .001), followed by tumor grade (HR, 1.33; 95%CI, 1.12-1.56; P = .001). The combination of ypT, ypN, and ypG categories yielded significantly higher C-index (0.591; 95%CI, 0.573-0.609) than that of the seventh edition TNM staging (P = .024). CONCLUSION: Tumor grade remained an independent predictor of overall survival in the setting of neoadjuvant therapy, and could improve the performance of ypTNM staging system.

Multiple opioid prescribers: A genuine quest for treatment rather than aberrant behaviour. A two-decade population-based study.

BACKGROUND: Accessing multiple prescribers for opioid prescription, referred to as doctor-shopping, is associated with an increased risk of opioid overdose and fatalities. AIM: The primary aim of this study was to assess the probability of accessing multiple prescribers among patients dispensed prescription opioids. METHOD: A retrospective population-based study using the Monitoring of Drugs of Dependence system of the Medicines Monitoring Unit (MMU) of Queensland Health, Australia. We assessed the odds of accessing multiple prescribers across both -short-term (≤1 month, 2-3 months) and longer-term (4-6 months and ≥7 months). We examined the relationship between multiple doctor visits, the dispensed dose of opioid and patient's residential socioeconomic status (SES). RESULT: Compared to those dispensed opioid prescriptions for ≥7-12 months, those dispensed opioids for ≤1 month were more likely to have visited ≥3 prescribers (adjusted odds ratio (aOR)) 4.06, 95% CI 4.01, 4.10, while for 2-3 months and 4-6 months the odds were aOR 2.36, 95% CI 2.33, 2.39 and aOR 1.79, 95% CI 1.74, 1.79 respectively. Patients dispensed opioid doses of ≥100 oral morphine milligram equivalent per day (MME/day) were more likely to obtain prescriptions from ≥3 prescribers compare to those receiving a dose of <20MME/day (aOR 1.90; 95% CI 1.87, 1.94). The probability of obtaining opioid prescriptions from multiple prescribers increased as the socioeconomic status decreased: aOR 1.41; 95% CI 1.38, 1.44 for lowest SES compared to the highest SES. CONCLUSION: Patients were more than four time likely to be dispensed opioid prescriptions from multiple prescribers within the first 30 days of initiating opioid treatment, possibly as part of multidisciplinary referral post-hospital discharge. High dose opioid and low SES was associated with higher probability of accessing multiple prescribers.

Network Analysis and Visualisation of Opioid Prescribing Data.

In many countries around the world (including Australia), the prescribing of opioid analgesic drugs is an increasing trend associated with significant increases in drug-related patient harm such as abuse, overdose, and death. In Australia, the Medicines Regulation and Quality Unit within Queensland Health maintains a database recording opioid analgesic drug prescriptions dispensed across the State (population 4.703 million). In this work, we propose the use of network visualisation and analysis as a tool for improved understanding of these data. Prescribing data for Fentanyl patches, a strong opioid with high potential for misuse and subsequent harm, across Queensland, Australia from 2011 to 2018 is analysed as an example of using network analysis, where prescribing patterns are viewed as a dynamic, bipartite graph of the interactions between patients and prescribers over time. The technique provides a global view of a large state-wide prescribing dataset, including the distribution of subgraph structures present. Local analysis is also carried out to demonstrate the clinical utility of the technique, including the dynamics of the graph structure over time. A variety of network statistics that measure network structural and dynamic properties are presented to reveal the characteristics and trends of drug seeking and prescribing behaviours. This approach has been recognised by healthcare professionals at Queensland Health as leading to new and useful insights on the relationship between patients and prescribers and supporting their advisory role to reduce patient harm from inappropriate use of prescription drugs.

Laser-echo reduction method based on a multifocal lens array.

A combination of an image plane tilt method and usage of a multifocal lens array is proposed to reduce the intensity of the laser echo in surveillance and tracking imaging optical systems. The tilt of the image plane was used to reduce the energy of the laser echo, while the aberration due to the tilt of the image plane was effectively corrected by the multifocal lens array. To verify the feasibility and performance of the proposed method, an experimental setup was used, which consisted of a 2×2 lens array with a dual focal length. The experimental results showed that the measured variation law of the energy of the laser echo was consistent with the derived equation of the echo. It was demonstrated that the sharpness of the image edge increased for a tilt angle of 3° when the lens array was added. Thus, the multifocal lens array could effectively reduce the image edge blur caused by the tilted image plane.

Anti-cancer effect of marchantin C via inducing lung cancer cellular senescence associated with less secretory phenotype.

BACKGROUND: Lung cancer is the leading cause of global cancer deaths. Current chemotherapeutic agents for lung cancer treatment are generally accompanied with severe side effects. Here, we report that marchantin C (Mar-C), a potential natural compound with little chemotherapeutic toxicity, exerts a well anti-tumor effect against lung cancer via inducing cellular senescence. METHODS: The antitumor activity of Mar-C was evaluated by MTT and colony formation in vitro cytotoxicity assays, and xenograft and homograft in vivo model. Antitumor mechanisms of Mar-C were investigated through SA-ß-gal staining, Q-PCR, immunoblotting, immunofluorescence, protein array and siRNA knocking-down analysis. RESULTS: Mar-C selectively induces senescence of lung cancer cells with limited cytotoxicity on normal or non-neoplastic cells. Mar-C-induced senescence was associated with the elevation of ROS and activation of DNA-damage, and largely dependent of prolonged p21CIP1 accumulation. The senescence-associated secretory phenotype (SASP) induced by Mar-C was distinct from doxorubicin-induced. Furthermore, Mar-C exhibited an inhibitory activity on tumor growth with little toxicity in animal studies, and significantly prolonged the survival time of tumor-bearing mice than that of doxorubicin or vehicle treatments. CONCLUSION: Mar-C selectively inhibited tumor growth via the induction of cancer cell senescence and had little chemotherapeutic toxicity, suggesting the potential of Mar-C as a promising anticancer agent. GENERAL SIGNIFICANCE: This study provided evidence to identify a novelty of Mar-C that exerted antitumor activity on lung cancer through induction of senescence with limited toxicity.

Hyper-acetylation contributes to the sensitivity of chemo-resistant prostate cancer cells to histone deacetylase inhibitor Trichostatin A.

Therapeutic agents are urgently needed for treating metastatic castration-refractory prostate cancer (mCRPC) that is unresponsive to androgen deprivation and chemotherapy. Our screening assays demonstrated that chemotherapy-resistant prostate cancer (PCa) cells are more sensitive to HDAC inhibitors than paired sensitive PCa cells, as demonstrated by cell proliferation and apoptosis in vitro and in vivo. Kinetic study revealed that TSA-induced apoptosis was significantly dependent on enhanced transcription and protein synthesis in an early stage, which subsequently caused ER stress and apoptosis. ChIP analysis indicated that TSA increased H4K16 acetylation, promoting ER stress gene transcription. The changes in Ac-H4K16, ATF3 and ATF4 were also validated in TSA-treated animals. Further study revealed the higher enzyme activity of HDACs and an increase in acetylated proteins in resistant cells. The higher nucleocytoplasmic acetyl-CoA in resistant cells was responsible for elevated acetylation status of protein and a more vigorous growth state. These results strongly support the pre-clinical application of HDAC inhibitors for treating chemotherapy-resistant mCRPC.

Instance Annotation via Optimal BoW for Weakly Supervised Object Localization.

In this paper, we aim at irregular-shape object localization under weak supervision. With over-segmentation, this task can be transformed into multiple-instance context. However, most multiple-instance learning methods only emphasize single most positive instance in a positive bag to optimize bag-level classification, and leads to imprecise or incomplete localization. To address this issue, we propose a scheme for instance annotation, where all of the positive instances are detected by labeling each instance in each positive bag. Inspired by the successful application of bag-of-words (BoW) to feature representation, we leverage it at instance-level to model the distributions of the positive class and negative class, and then incorporate the BoW learning and instance labeling in a single optimization formulation. We also demonstrate that the scheme is well suited to weakly supervised object localization of irregular-shape. Experimental results validate the effectiveness both for the problem of generic instance annotation and for the application of weakly supervised object localization compared to some existing methods.

Sublethal toxic effects of nonylphenol ethoxylate and nonylphenol to Moina macrocopa.

The aim of this paper was to examine the sublethal toxic effects of nonylphenol ethoxylate (NP10EO), its primary degradation product nonylphenol (NP), and their mixture on Moina macrocopa. Chronic toxicity tests were carried out by using sublethal chemical concentrations. Results showed that all treatments reduced the survivorship, body length, and reproduction of M. macrocopa with NP being 10 %-20 % more toxic to M. macrocopa than NP10EO. Results also indicated that the toxic effects of NP10EO and NP mixture on M. macrocopa were more severe than that of any single chemical alone. At the highest concentration in this experiment, 0.337 mg L(-1) NP10EO plus 0.0154 mg L(-1) NP treatment caused the survivorship of M. macrocopa to zero, neonates number of reproductions to zero, 45.5 % reduction in the body length, and 88 % reduction in the total neonates number.