A Fluorogenic Molecule for Probing Islet Amyloid Using Flavonoid as a Scaffold Design.

Aggregation of polypeptides and proteins is commonly associated with human and other vertebrate diseases. For example, amyloid plaques consisting of amyloid-ß proteins are frequently identified in Alzheimer's disease and islet amyloid formed by islet amyloid polypeptide (IAPP, amylin) can be found in most patients with type 2 diabetes (T2D). Although many fluorescent dyes have been developed to stain amyloid fibrils, very few examples have been designed for IAPP. In this study, a series of environmentally sensitive fluorescent probes using flavonoid as a scaffold design are rationally designed and synthesized. One of these probes, namely 3-HF-ene-4'-OMe, can bind to IAPP fibrils but not nonfibrillar IAPP by exhibiting a much stronger fluorescent enhancement at 535 nm. In addition, this probe shows better detection sensitivity to IAPP fibrils compared with that of conventionally used thioflavin-T. We demonstrate that 3-HF-ene-4'-OMe can be used to monitor the kinetics of IAPP fibril formation in vitro even in the presence an amyloid inhibitor. To test the specificity of the probe, we attempt to incubate this probe with amyloid fibrils formed from other amyloidogenic proteins. Interestingly, this probe shows different responses when mixed with these fibrils, suggesting the mode of binding of this probe on these fibrils could be different. Moreover, we show that this probe is not toxic to pancreatic mouse ß-cells. Further structural optimization based on the structure of 3-HF-ene-4'-OMe may yield a specific probe for imaging islet amyloid in the pancreas. That would improve our understanding of the relationship between islet amyloid and T2D.

Sideband amplitude modulation absorption spectroscopy of CH4 at 1170 nm.

We report on the method of the sideband amplitude modulation (SAM) to achieve high-sensitivity spectroscopy with a fiber electro-optic modulator (fiber-EOM). This method increases the signal to noise ratio (SNR) by a factor of forty, comparing with conventional absorption spectroscopy. It is a temporal balanced detection to eliminate the intensity noise of the light source, and capable of preserving an undistorted Doppler profile for further quantitative analysis. Taking advantage of the newly developed fiber-EOM, SAM is applicable for various spectroscopies with a simple experimental setup. We performed SAM on CH43ν3 overtone band at 1170 nm using an external cavity Quantum dot laser. We demonstrated that one of the absorption lines buried in the other ten times stronger nearby lines was clearly extracted. SAM shows great potential on the molecular spectroscopy, where the spectrum is complicated and quantitative analysis is required.

Application of two-dimensional fractional-order convolution and bounding box pixel analysis for rapid screening of pleural effusion.

Pleural effusion is a pathologic symptom in which there is accumulation of body fluids around the lungs. A chest radiograph is a rapid examination technique and does not require complex setup for making a preliminary diagnosis of lung and heart diseases. In radiographic visualization, the symptom patterns appear as light or dark areas in the lung cavity. Computer-aided diagnosis is an automatic manner that can rapidly highlight the object region by preanalyzing medical images. It can improve the problems of manual inspection and allow diagnosis in remote medical facilities. Based on the ratios of lung anatomy, the automatic screening manner based on pattern recognition can be viewed as pixel value detection in the bilateral lung cavities. In this study, a fractional-order convolution (FOC) process is used to enhance the original image for an accurate extrapolation of the desired object in an image. The specific object image feature can be improved, and an accurate quantification of the pleural effusion region can be obtained using the suitable ranges of fractional-order parameters. Based on the boundaries of homogeneous regions, the pixel ratios of the lung anatomy between normal and abnormal conditions can be computed. The pleural effusion sizes and volumes can be rapidly estimated through the number of pixel changes. The experimental results reveal that the feature maps are similar and stable on image enhancement and segmentation with two fractional-order enhancement masks, as fractional-order v = 0.05 to 0.20 for mask 1# and v = 0.80 to 0.95 for mask 2#, respectively. The results also demonstrate the feasibility of the study on combining two-dimensional image FOC-process and bounding box pixel analysis to estimate the moderate and large effusion sizes from 500-2,000 mL.

HIF-1α triggers long-lasting glutamate excitotoxicity via system xc- in cerebral ischaemia-reperfusion.

Hypoxia-inducible factor 1α (HIF-1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF-1α might contribute to glutamate-mediated excitotoxicity during cerebral ischaemia-reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF-1α conditional knockout mouse displayed an inhibition in CIR-induced elevation of extracellular glutamate and N-methyl-d-aspartate receptor (NMDAR) activation. By gene screening for glutamate transporters in cortical cells, we found that HIF-1α mainly regulates the cystine-glutamate transporter (system xc- ) subunit xCT by directly binding to its promoter; xCT and its function are up-regulated in the ischaemic brains of rodents and humans, and the effects lasted for several days. Genetic deletion of xCT in cortical cells of mice inhibits either oxygen glucose deprivation/reoxygenation (OGDR) or CIR-mediated glutamate excitotoxicity in vitro and in vivo. Pharmaceutical inhibition of system xc- by a clinically approved anti-cancer drug, sorafenib, improves infarct volume and functional outcome in rodents with CIR and its therapeutic window is at least 3 days. Taken together, these findings reveal that HIF-1α plays a role in CIR-induced glutamate excitotoxicity via the long-lasting activation of system xc- -dependent glutamate outflow and suggest that system xc- is a promising therapeutic target with an extended therapeutic window in stroke. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Clinical ultrasound stimulating angiogenesis following drug-release from polymersomes on the ischemic zone for peripheral arterial occlusive disease.

Peripheral Arterial Occlusive Disease (PAOD) is an aging disease that affects the quality of life of many people by its intermittent claudication and critical limb ischemia presentations. Traditional treatment and management of PAOD are asking patients to make a life change and medication with antiplatelet, statins and cilostazol, which decrease the possibility of clot formation. Our strategy has employed a magnetic Fe3O4-PLGA polymersome to carry the cilostazol into the ischemic area by magnetic attraction following remote-control drug release through low-energy ultrasound exposure. In the animal studies, the cilostazol-loaded Fe3O4-PLGA polymersomes were injected and accumulated at ischemic leg through magnetic attraction. Then, using a clinical-use ultrasound machine the leg was irradiated to forward cilostazol release from the accumulated polymersomes. Dramatically, we found an observable result of bloody flux recovery in the leg after 7 days compared to the non-treated leg that showed no evidence of the blood recovery.

Randomization and resilience of brain functional networks as systems-level endophenotypes of schizophrenia.

Schizophrenia is increasingly conceived as a disorder of brain network organization or dysconnectivity syndrome. Functional MRI (fMRI) networks in schizophrenia have been characterized by abnormally random topology. We tested the hypothesis that network randomization is an endophenotype of schizophrenia and therefore evident also in nonpsychotic relatives of patients. Head movement-corrected, resting-state fMRI data were acquired from 25 patients with schizophrenia, 25 first-degree relatives of patients, and 29 healthy volunteers. Graphs were used to model functional connectivity as a set of edges between regional nodes. We estimated the topological efficiency, clustering, degree distribution, resilience, and connection distance (in millimeters) of each functional network. The schizophrenic group demonstrated significant randomization of global network metrics (reduced clustering, greater efficiency), a shift in the degree distribution to a more homogeneous form (fewer hubs), a shift in the distance distribution (proportionally more long-distance edges), and greater resilience to targeted attack on network hubs. The networks of the relatives also demonstrated abnormal randomization and resilience compared with healthy volunteers, but they were typically less topologically abnormal than the patients' networks and did not have abnormal connection distances. We conclude that schizophrenia is associated with replicable and convergent evidence for functional network randomization, and a similar topological profile was evident also in nonpsychotic relatives, suggesting that this is a systems-level endophenotype or marker of familial risk. We speculate that the greater resilience of brain networks may confer some fitness advantages on nonpsychotic relatives that could explain persistence of this endophenotype in the population.

Wenshen Zhuanggu formula effectively suppresses breast cancer bone metastases in a mouse Xenograft model.

Wenshen Zhuanggu formula (WSZG) is a traditional Chinese medicine used as an adjuvant for the prevention of bone metastases in breast cancer patients. In this study we investigated the efficacy of WSZG in preventing bone metastases and the potential mechanisms in a mouse xenograft model of breast cancer bone metastases. This model was established by injection of human MDA-MB-231BO-Luc breast cancer cells alone or a mixture of the cancer cells with bone marrow-derived mesenchymal stem cells (BMSCs) into left ventricle of the heart in female nude mice. Then the mice were treated with WSZG (3.25, 6.5 or 13.0 mg·kg-1·d-1, ig) for four weeks, whereas zoledronic acid (100 µg/kg per week, ig) was used as a positive control. The occurrence and development of bone metastases were monitored via bioluminescent imaging, and bone lesions were assessed using micro-CT. Intracardiac injection of the mixture of MDA-MB-231BO-Luc breast cancer cells with BMSCs significantly facilitated the bone metastatic capacity of the breast cancer cells, and aggravated bone lesions in the mouse xenograft model of breast cancer bone metastases. Administration of WSZG dose-dependently inhibited the incidence and intensity of bone metastases and protected against bone lesions by suppressing osteoclast formation and tumor cell infiltration. Furthermore, administration of WSZG caused a marked reduction in the expression of CCL5/CCR5 and IL-17B/IL-17BR in bone metastatic tissues. The results demonstrate that WSZG exerts potential therapeutic effects in a mouse xenograft model of breast cancer bone metastases, which are partially mediated by weakening the interaction between BMSCs and breast cancer cells in the tumor microenvironment.

Apparatus for Comparison of Pullout Forces for Various Thoracic Stent Grafts at Varying Neck Angulations and Oversizes.

BACKGROUND: The purpose of this study is to provide an apparatus for comparison of pullout forces for various thoracic stent grafts at varying neck angulations and oversizes. METHODS: An in vitro platform capable of performing pullout tests was used on stent grafts in angulated silicone tubes designed for this study (0°, 45°, 90°, and 135° with a 32-mm inner diameter) in a temperature-controlled chamber (37 ± 2°C). Three commercial stent grafts with sizes commonly used in Taiwan (Valiant: 34, 36, 38, and 40 mm; Zenith TX2: 34, 36, 38, and 40 mm; and TAG: 34, 37, and 40 mm) were used, and each size was tested 8 times for each angulation condition. RESULTS: The mean dislodgement forces (DFs) at 0° angulation within 10-20% oversize were approximately 22.7, 9.6, and 9.0 N for the Valiant, Zenith TX2, and TAG devices, respectively, whereas the mean DFs decreased by 46%, 38%, and 50% to 12.3, 5.9, and 4.5 N when the angulation reached 135°. Regression analysis shows that neck angulation was a significant factor for the Valiant and Zenith TX2 devices (P < 0.0001 and P < 0.0001, respectively) but not for the TAG device (P = 0.483). In addition, oversize and interactions between variables (angulation × oversize) exhibited significant effects on the DFs for all devices (P < 0.0001). CONCLUSIONS: We successfully built up an apparatus for comparison of pullout forces for various thoracic stent grafts at varying neck angulations and oversizes. With the empirical comparative data of different brand stent grafts under various conditions shown and compared, our findings suggest that aortic neck angulation has a negative correlation with stent-graft fixation. To have better stent-graft fixation and seal in the aortic arch for thoracic endovascular aortic repair, a longer landing zone with cautiously selected oversize is a more suitable selection.

Cycling hypoxia induces chemoresistance through the activation of reactive oxygen species-mediated B-cell lymphoma extra-long pathway in glioblastoma multiforme.

BACKGROUND: Cycling hypoxia is a well-recognized phenomenon within animal and human solid tumors. It contributes to the resistance to cytotoxic therapies through anti-apoptotic effects. However, the mechanism underlying cycling hypoxia-mediated anti-apoptosis remains unclear. METHODS: Reactive oxygen species (ROS) production, activation of the hypoxia-inducible factor-1 alpha (HIF-1α) and nuclear factor-κB (NF-κB) signaling pathways, B-cell lymphoma extra-long (Bcl-xL) expression, caspase activation, and apoptosis in in vitro hypoxic stress-treated glioblastoma cells or tumor hypoxic cells derived from human glioblastoma xenografts were determined by in vitro ROS analysis, reporter assay, western blotting analysis, quantitative real-time PCR, caspase-3 activity assay, and annexin V staining assay, respectively. Tempol, a membrane-permeable radical scavenger, Bcl-xL knockdown, and specific inhibitors of HIF-1α and NF-κB were utilized to explore the mechanisms of cycling hypoxia-mediated resistance to temozolomide (TMZ) in vitro and in vivo and to identify potential therapeutic targets. RESULTS: Bcl-xL expression and anti-apoptotic effects were upregulated under cycling hypoxia in glioblastoma cells concomitantly with decreased responses to TMZ through ROS-mediated HIF-1α and NF-κB activation. Tempol, YC-1 (HIF-1 inhibitor), and Bay 11-7082 (NF-κB inhibitor) suppressed the cycling hypoxia-mediated Bcl-xL induction in vitro and in vivo. Bcl-xL knockdown and Tempol treatment inhibited cycling hypoxia-induced chemoresistance. Moreover, Tempol treatment of intracerebral glioblastoma-bearing mice combined with TMZ chemotherapy synergistically suppressed tumor growth and increased survival rate. CONCLUSIONS: Cycling hypoxia-induced Bcl-xL expression via ROS-mediated HIF-1α and NF-κB activation plays an important role in the tumor microenvironment-promoted anti-apoptosis and chemoresistance in glioblastoma. Thus, ROS blockage may be an attractive therapeutic strategy for tumor microenvironment-induced chemoresistance.

Polypyrrole-induced active-edge-S and high-valence-Mo reinforced composites with boosted electrochemical performance for the determination of 2,4,6-trichlorophenol in the aquatic environment.

With the extensive application of halogenated aromatic compounds, including 2,4,6-Trichlorophenol (2,4,6-TCP), improper treatment or discharge contribute to persistently harmful effects on humans and the ecosystem, rendering the identification and monitoring of 2,4,6-TCP in the aquatic environment urgently required. In this study, a highly sensitive electrochemical platform was developed using active-edge-S and high-valence-Mo rich MoS2/polypyrrole composites. MoS2/PPy illustrates superior electrochemical performance and catalytic activity and has not been explored for detecting chlorinated phenols previously. The local environment of polypyrrole induces the richness of active edge S and a high oxidation state of Mo species in the composites, both of which endorse a sensitive anodic current response due to the favored oxidation of 2,4,6-TCP through nucleophilic substitution. Also, the higher complementarity between pyrrole and 2,4,6-TCP with respective electron-rich and electron-poor features through π-π stacking interactions enhances the specific detection capability of 2,4,6-TCP by the MoS2/polypyrrole-modified electrode. The MoS2/polypyrrole-modified electrode achieved a linear range of 0.1-260 µM with an ultralow limit of detection of 0.009 µM. Additionally, the structural stability boosted by the linkage of polypyrrole and MoS2 results in good resistance and satisfactory recovery in real water samples. The compiled results demonstrate that the proposed MoS2/polypyrrole composite opens up a new potential to advance a sensitive, selective, facile fabrication, and low-cost platform for the on-site determination of 2,4,6-TCP in aquatic systems. The sensing of 2,4,6-TCP is important to monitor its occurrence and transport, and can also serve to track the effectiveness and adjust subsequent remediation treatments applied to contaminated sites.

[Research Progress of Next Generation Sequencing in Acute Leukemia --Review].

With the advent of precision medicine, next-generation sequencing (NGS) is playing an increasingly important role in clinical oncology diagnosis and treatment with its advantages of high sensitivity, high accuracy, high efficiency and operability. NGS reveals the genetic characteristics of acute leukemia(AL) patients by screening for specific disease-causing genes to identify occult as well as complex genetic mutations in patients with AL, leading to early diagnosis and targeted drug therapy for AL patients, as well as to predict disease recurrence by detecting mnimal residual disease (MRD) and analyzing mutated genes to determine patient prognosis. NGS plays an increasingly important role in the diagnosis, treatment and prognosis assessment in AL, providing a direction for the pursuit of precision medicine. This paper reviews the research progress of NGS in AL.

Pregnancy Zone Protein as an Emerging Biomarker for Cardiovascular Risk in Pediatric Chronic Kidney Disease.

Cardiovascular disease (CVD) is a significant cause of mortality and morbidity among children with chronic kidney disease (CKD). The causes of pediatric CKD differ from those in adults, as congenital anomalies in the kidney and urinary tract (CAKUT) are the leading causes in childhood. Identifying ideal markers of CVD risk early is crucial for CKD children to improve their care. Previously, we screened differentially expressed proteins in CKD children with or without blood pressure (BP) abnormalities and identified pregnancy zone protein (PZP). In 106 children and adolescents with CKD stages G1-G4, we analyzed plasma PZP concentration. The associations between PZP and ambulatory BP monitoring (ABPM) profile, parameters of cardiac and carotid ultrasounds, indices of arterial stiffness, and nitric oxide (NO) parameters were determined. We observed that PZP positively correlated with arterial stiffness indices, beta index, and pulse wave velocity in CAKUT. CKD children with abnormalities in ABPM and night dipping displayed a higher PZP concentration than those without. Additionally, the PZP level was positively correlated with NO bioavailability. In conclusion, our results suggest PZP has differential influences on cardiovascular risk in CAKUT and non-CAKUT children. Identification of this relationship is novel in the pediatric CKD literature.

Custom-designed sensors embedded 3D-printed wearable device for improving the hemodialysis-related vascular dysfunction detection.

BACKGROUND: The increasing prevalence of end-stage renal disease (ESRD) imposes a substantial economic burden on public health-care systems. Hemodialysis (HD) is a pivotal treatment modality for patients with ESRD. However, prolonged use of HD vessels may result in stenosis, thrombosis, and occlusion due to repeated daily punctures. Thus, early detection and prevention of the dysfunction of dialysis routes are crucial. OBJECTIVE: In this study, we designed a wearable device for the early and accurate detection of arteriovenous access (AVA) stenosis in HD patients. METHODS: A personalized three-dimensional (3D) printed wearable device was designed by combining the phonoangiography (PAG) and photoplethysmography (PPG) techniques. The capability of this device to monitor AVA dysfunction before and after percutaneous transluminal angioplasty (PTA) was evaluated. RESULTS: After PTA, the amplitudes of both PAG and PPG signals increased in patients with arteriovenous fistulas and those with arteriovenous grafts; this might be due to increased blood flow. CONCLUSION: Our designed multi-sensor wearable medical device using PAG, PPG, and 3D printing appears suitable for early and accurate detection of AVA stenosis in HD patients.

Dopamine-dependent functions of hyaluronic acid/dopamine/silk fibroin hydrogels that highly enhance N-acetyl-L-cysteine (NAC) delivered from nasal cavity to brain tissue through a near-infrared photothermal effect on the NAC-loaded hydrogels.

Hyaluronic acid/silk fibroin (HA/SF or HS) hydrogels with remarkable mechanical characteristics have been reported as tissue engineering biomaterials. Herein, the addition of dopamine/polydopamine (DA/PDA) to HS hydrogels to develop multifunctional HA/PDA/SF (or HDS) hydrogels for the delivery of drugs such as N-acetyl-L-cysteine (NAC) from nasal to brain tissue is examined. Herein, DA-dependent functions of HDS hydrogels with highly adhesive forces, photothermal response (PTR) effects generated by near infrared (NIR) irradiation, and anti-oxidative effects were demonstrated. An in-vitro study shows that the HDS/NAC hydrogels could open tight junctions in the RPMI 2650 cell line, a model cell of the nasal mucosa, as demonstrated by the decreased values of transepithelial electrical resistance (TEER) and more discrete ZO-1 staining than those for the control group. This effect was markedly enhanced by NIR irradiation of the HDS/NAC-NIR hydrogels. Compared to the results obtained using NAC solution, an in-vivo imaging study (IVIS) in rats showed an approximately nine-fold increase in the quantity of NAC delivered from the nasal cavity to the brain tissue in the span of 2 h through the PTR effect generated by the NIR irradiation of the nasal tissue and administration of the HDS/NAC hydrogels. Herein, dopamine-dependent multifunctional HDS hydrogels were studied, and the nasal administration of HDS/NAC-NIR hydrogels with PTR effects generated by NIR irradiation was found to have significantly enhanced NAC delivery to brain tissues.

Plasma and Urinary Platelet Factor 4 as Biomarkers for Cardiovascular Risk in Children with Chronic Kidney Disease.

Children suffering from chronic kidney disease (CKD) have a high risk of cardiovascular disease (CVD). The early detection and diagnosis of subclinical CVD in pediatric CKD can reduce mortality later in life. Plasma factor 4 (PF4) is a chemokine released by activated platelets. We examined whether or not PF4 in the plasma and urine, its kidney function normalized ratio, and fractional excretion have differential associations with CVD risk markers in 139 youths aged 3 to 18 years old with CKD stages G1-G4. Significant negative correlations were observed between plasma PF4 and cardiovascular surrogate markers, such as the left ventricular mass index (LVMI), carotid intima-media thickness (cIMT), and pulse wave velocity (PWV). The plasma PF4/creatinine (Cr) ratio was lower in CKD children with a high daytime BP and 24 h BP, high BP load, and nocturnal non-dipping status. After adjusting for confounders, the plasma PF4 and plasma PF4/Cr ratio still independently predicted an abnormal ABPM profile. In addition, both the plasma PF4 and plasma PF4/Cr ratio presented a negative correlation with the L-arginine and asymmetric dimethylarginine ratio. These findings provide convincing evidence supporting the link between PF4 and CVD markers in pediatric CKD. Our study highlights the importance of further research to assess the performance of PF4-related biomarkers in predicting CVD events and CKD progression in children with CKD.

Multifaceted Sulfone-Carbazole-Based D-A-D Materials: A Blue Fluorescent Emitter as a Host for Phosphorescent OLEDs and Triplet-Triplet Annihilation Up-Conversion Electroluminescence.

Electroluminescence (EL) from the singlet-excited (S1) state is the ideal choice for stable, high-performing deep-blue organic light-emitting diodes (OLEDs) owing to the advantages of an adequately short radiative lifetime, improved device durability, and low cost, which are the most important criteria for their commercialization. Herein, we present the design and synthesis of three donor-acceptor-donor (D-A-D)-configured deep-blue fluorescent materials (denoted as TC-1, TC-2, and TC-3) composed of a thioxanthone or diphenyl sulfonyl acceptor and phenyl carbazolyl donor. These systems exhibit strong deep-blue photoluminescence (422-432 nm) in solutions and redshifted emission (472-486 nm) in thin films. The solid-state photoluminescence quantum yield (PLQY) was estimated to be 78 and 94% for TC-2 and TC-3, respectively. TC-2 and TC-3 possess good molecular packing and large molecular cross-sectional areas, which not only improves the PLQY but enhances the triplet-triplet annihilation up-conversion (TTAUC) efficiency of fluorescent emitters. Furthermore, both compounds were applied as an acceptor for confirming their TTAUC property using bis(2-methyldibenzo[f,h]quinoxaline)(acetylacetonate)iridium(III) (Ir(MDQ)2acac) as the sensitizer. Non-doped OLEDs based on TC-2 and TC-3 exhibit blue EL in the 461-476 nm range. In particular, TC-3 exhibits a maximum external quantum efficiency (EQEmax) of 5.1%, and its EL maximum is 476 nm. In addition, the three emitters were employed as hosts in red OLEDs using bis(1-phenylisoquinoline)(acetylacetonate)iridium(III) (Ir(piq)2acac) as the phosphorescent dopant. The red phosphorescent OLEDs based on TC-1, TC-2, and TC-3 achieve excellent EQEmax values of 21.6, 22.9, and 21.9%, respectively, and peak luminance efficiencies of 12.0, 14.0, and 12.3 cd A-1. These results highlight these fluorophores' versatility and promising prospects in practical OLED applications.

Development of a Rare Earth Nanoprobe Enables In Vivo Real-Time Detection of Sentinel Lymph Node Metastasis of Breast Cancer Using NIR-IIb Imaging.

Sentinel lymph node (SLN) biopsy plays a critical role in axillary staging of breast cancer. However, traditional SLN mapping does not accurately discern the presence or absence of metastatic disease. Detection of SLN metastasis largely hinges on examination of frozen sections or paraffin-embedded tissues post-SLN biopsy. To improve detection of SLN metastasis, we developed a second near-infrared (NIR-II) in vivo fluorescence imaging system, pairing erbium-based rare-earth nanoparticles (ErNP) with bright down-conversion fluorescence at 1,556 nm. To visualize SLNs bearing breast cancer, ErNPs were modified by balixafortide (ErNPs@POL6326), a peptide antagonist of the chemokine receptor CXCR4. The ErNPs@POL6326 probes readily drained into SLNs when delivered subcutaneously, entering metastatic breast tumor cells specifically via CXCR4-mediated endocytosis. NIR fluorescence signals increased significantly in tumor-positive versus tumor-negative SLNs, enabling accurate determination of SLN breast cancer metastasis. In a syngeneic mouse mammary tumor model and a human breast cancer xenograft model, sensitivity for SLN metastasis detection was 92.86% and 93.33%, respectively, and specificity was 96.15% and 96.08%, respectively. Of note, the probes accurately detected both macrometastases and micrometastases in SLNs. These results overall underscore the potential of ErNPs@POL6326 for real-time visualization of SLNs and in vivo screening for SLN metastasis. SIGNIFICANCE: NIR-IIb imaging of a rare-earth nanoprobe that is specifically taken up by breast cancer cells can accurately detect breast cancer macrometastases and micrometastases in sentinel lymph nodes.

Correction: The development of surgical risk score and evaluation of necrotizing soft tissue infection in 161 Naja atra envenomed patients.

[This corrects the article DOI: 10.1371/journal.pntd.0010066.].

Novel Self-Assembled Multifunctional Nanoprobes for Second-Near-Infrared-Fluorescence-Image-Guided Breast Cancer Surgery and Enhanced Radiotherapy Efficacy.

Breast-conserving surgery (BCS) is the predominant treatment approach for initial breast cancer. However, due to a lack of effective methods evaluating BCS margins, local recurrence caused by positive margins remains an issue. Accordingly, radiation therapy (RT) is a common modality in patients with advanced breast cancer. However, while RT also protects normal tissue and enhances tumor bed doses to improve therapeutic effects, current radiosensitizers cannot meet these urgent clinical needs. To address this, a novel self-assembled multifunctional nanoprobe (NP) gadolinium (Gd)-diethylenetriaminepentaacetic acid-human serum albumin (HSA)@indocyanine green-Bevacizumab (NPs-Bev) is synthesized to improve the efficacy of fluorescence-image-guided BCS and RT. Fluorescence image guidance of the second near infrared NP improves complete resection in tumor-bearing mice and accurately discriminates between benign and malignant mammary tissue in transgenic mice. Moreover, targeting tumors with NPs induces more reactive oxygen species under X-ray radiation therapy, which not only increases RT sensitivity, but also reduces tumor progression in mice. Interestingly, self-assembled NPs-Bev using HSA, the magnetic resonance contrast agent and Bevacizumab-targeting vascular growth factor A, which are clinically safe reagents, are safe in vitro and in vivo. Therefore, the novel self-assembled NPs provide a solid precision therapy platform to treat breast cancer.

Exploratory study of ultraviolet B (UVB) radiation and age of onset of bipolar disorder.

BACKGROUND: Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. METHODS: Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. RESULTS: The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. CONCLUSION: UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.