Tumor Microenvironment-Activatable Nanosystem Capable of Overcoming Multiple Therapeutic Obstacles for Augmenting Immuno/Metal-Ion Therapy.

Abnormal tumor microenvironment (TME) imposes barriers to nanomedicine penetration into tumors and evolves tumor-supportive nature to provide tumor cell protection, seriously weakening the action of antitumor nanomedicines and posing significant challenges to their development. Here, we engineer a TME-activatable size-switchable core-satellite nanosystem (Mn-TI-Ag@HA) capable of increasing the effective dose of therapeutic agents in deep-seated tumors while reversing tumor-supportive microenvironment for augmenting immuno/metal-ion therapy. When activated by TME, the nanosystem disintegrates, allowing ultrasmall-sized Ag nanoparticles to become unbound and penetrate deep into solid tumors. Simultaneously, the nanosystem produces O2 and releases TGF-ß inhibitors in situ to drive macrophage M2-to-M1 polarization, increasing intratumoral H2O2 concentration, and ultimately augmenting metal-ion therapy by accelerating hypertoxic Ag+ production. The nanosystem can overcome multiple obstacles that aid in tumor resistance to nanomedicine, demonstrating effective tumor penetration, TME regulation, and tumor inhibition effects. It can provoke long-term immunological memory effects against tumor rechallenge when combined with immune checkpoint inhibitor anti-PD-1. This work provides a paradigm for designing efficient antitumor nanomedicines.

Synthesis of amorphous-MnO2/Clinoptilolite and its utilization for NH4+-N oxidation in an anoxic environment.

Mediating the anoxic ammonia oxidation with manganese oxide (MnOx) can reduce the requirements of dissolved oxygen (DO) concentrations in constructed wetlands (CWs) and improve the removal of ammonium nitrogen (NH4+-N). Recent studies that employed natural manganese ore and/or mine waste as substrates in CWs may develop potentially negative environmental effects due to leachates. However, removing NH4+-N by anoxic ammonia oxidation is influenced by the crystal form of MnOx. In this study, a novel clinoptilolite-based amorphous-MnO2 (amorphous-MnO2/clinoptilolite) was synthesized by the sol-gel method as an alternative substrate to improve the efficiency of anoxic ammonia oxidation and reduce the impact of Mn ion leaching. According to the anoxic ammonia oxidation experiment of clinoptilolite, amorphous-MnO2/clinoptilolite, and manganese ore on NH4+-N, the amounts of NH4+-N removed were 24.55 mg/L/d, 44.55 mg/L/d, and 11.04 mg/L/d, respectively, and the initial NH4+-N concentration was 49.53 mg/L. These results indicated that the amorphous-MnO2/clinoptilolite had both the adsorption and the anoxic ammonia oxidation performance. The recycling experiment demonstrated that the effect of anoxic ammonia oxygen mediated by amorphous-MnO2 would not diminish with the gradual saturation of clinoptilolite for NH4+-N. Furthermore, the anoxic ammonia oxidation consumed NH4+-N in the clinoptilolite, which restored the adsorption capacity of the clinoptilolite and simultaneously decreased the leakage of manganese ions in the process, making it environmentally friendly. Therefore, the amorphous-MnO2/clinoptilolite provided an excellent substrate material for the constructed wetland under an anoxic environment, which greatly improved the nitrogen removal capacity compared to existing substrate materials.

Acquired Symmastia: Classification, Causes, and Repair Strategy.

BACKGROUND: Acquired symmastia is a rare complication after breast augmentation that is difficult to fix. METHODS: The medical records of 18 female patients with symmastia treated by our team were reviewed. Data collected included preoperative medical history, implant size, and breast base width. Surgical techniques were systematically reviewed and analyzed based on postoperative follow-up results. RESULTS: Of the 18 patients, 15 patients had undergone implanted breast augmentation and 3 had injected breast augmentation. All 18 patients underwent comprehensive repair with various surgical techniques. Three patients showed recurrence after operation. Four patients were dissatisfied with postoperative breast size and underwent 2-stage replacement surgery. CONCLUSIONS: Symmastia is an intractable surgical complication. Surgical classification can help assess the difficulty of surgery in advance, and the surgical strategy plan can help the surgeon to control the quality of the repair surgery.

Aromatic Amides: A Smart Backbone toward Isolated Ultralong Bright Blue-Phosphorescence in Confined Polymeric Films.

We describe an aromatic amide skeleton for manipulation of triplet excited states toward bright long-lived blue phosphorescence. Spectroscopic studies and theoretical calculations demonstrated that the aromatic amides can promote strong spin-orbit coupling between (π,π*) and the bridged (n,π*) states, and enable multiple channels to populate the emissive 3 (π,π*), as well as facilitate robust hydrogen bonding with polyvinyl alcohol to suppress non-radiative relaxations. Isolated inherent deep-blue (0.155, 0.056) to sky-blue (0.175, 0.232) phosphorescence with high quantum yields (up to 34.7 %) in confined films are achieved. The blue afterglow of the films can last for several seconds and are showcased in information display, anti-counterfeiting, and white light afterglow. Owing to the high population of 3 (π,π*) states, the smart aromatic amide skeleton provides an important molecular design prototype to manipulate triplet excited states for ultralong phosphorescence with various colors.

Rapid, label-free histopathological diagnosis of liver cancer based on Raman spectroscopy and deep learning.

Biopsy is the recommended standard for pathological diagnosis of liver carcinoma. However, this method usually requires sectioning and staining, and well-trained pathologists to interpret tissue images. Here, we utilize Raman spectroscopy to study human hepatic tissue samples, developing and validating a workflow for in vitro and intraoperative pathological diagnosis of liver cancer. We distinguish carcinoma tissues from adjacent non-tumour tissues in a rapid, non-disruptive, and label-free manner by using Raman spectroscopy combined with deep learning, which is validated by tissue metabolomics. This technique allows for detailed pathological identification of the cancer tissues, including subtype, differentiation grade, and tumour stage. 2D/3D Raman images of unprocessed human tissue slices with submicrometric resolution are also acquired based on visualization of molecular composition, which could assist in tumour boundary recognition and clinicopathologic diagnosis. Lastly, the potential for a portable handheld Raman system is illustrated during surgery for real-time intraoperative human liver cancer diagnosis.

Improved functional recovery of rat transected spinal cord by peptide-grafted PNIPAM based hydrogel.

Facilitating angiogenesis, reducing the formation of glial scar tissue, and the occurrence of a strong inflammatory response are of great importance for the repair of central nerve damage. In our previous study, a temperature-sensitive hydrogel grafted with bioactive isoleucine-lysine-valine-alanine-valine (IKVAV) peptide was prepared and it showed regular three-dimensional porous structure, rapid (de)swelling performance and good biological activity. Therefore, in this study, we used this hydrogel scaffold to treat for SCI to study the effect of it to facilitate angiogenesis, inhibit the differentiation and adhesion of keratinocytes, and further reduce the formation of glial scar tissue. The results reveal that the peptide hydrogel scaffold achieved excellent performance and can also promote the expression of angiogenic factors and reduce the secretion of pro-inflammatory factors to a certain extent. Particularly, it can also inhibit the formation of glial scar tissue and repair damaged tissue. The proposed strategy for developing this hydrogel scaffold provides a new insight into designing biomaterials for a broad range of applications in the tissue engineering of the central nervous system (CNS).

Precision Redox: The Key for Antioxidant Pharmacology.

Significance: The redox balance of cells provides a stable microenvironment for biological macromolecules to perform their physiological functions. As redox imbalance is closely related to the occurrence and development of a variety of diseases, antioxidant therapies are an attractive option. However, redox-based therapeutic strategies have not yet shown satisfactory results. To find the key reason is of great significance. Recent Advances: We emphasize the precise nature of redox regulation and elucidate the importance and necessity of precision redox strategies from three aspects: differences in redox status, differences in redox function, and differences in the effects of redox therapy. We then propose the "5R" principle of precision redox in antioxidant pharmacology: "Right species, Right place, Right time, Right level, and Right target." Critical Issues: Redox status must be considered in the context of species, time, place, level, and target. The function of a biomacromolecule and its cellular signaling role are closely dependent on redox status. Accurate evaluation of redox status and specific interventions are critical for the success of redox treatments. Precision redox is the key for antioxidant pharmacology. The precise application of antioxidants as nutritional supplements is also key to the general health of the population. Future Directions: Future studies to develop more accurate methods for detecting redox status and accurately evaluating the redox state of different physiological and pathological processes are needed. Antioxidant pharmacology should consider the "5R" principle rather than continuing to apply global nonspecific antioxidant treatments. Antioxid. Redox Signal. 34, 1069-1082.

Monochromophore-Based Phosphorescence and Fluorescence from Pure Organic Assemblies for Ratiometric Hypoxia Detection.

Hypoxia is a parameter related to many diseases. Ratiometric hypoxia probes often rely on a combination of an O2 -insensitive fluorophore and an O2 -sensitive phosphor in a polymer matrix, which require high cost and multi-step synthesis of transition metal complexes. The two-chromophore hypoxia probes encounter unfavorable energy transfer processes and different stabilities of the chromophores. Reported herein is a pure organic ratiometric hypoxia nanoprobe, assembled by a monochromophore, naphthalimide ureidopyrimidinone (BrNpA-UPy), bridged by a bis-UPy-functionalized benzyl skeleton. The joint factors of quadruple hydrogen bonding, the rigid backbone of UPy, and bromine substitution of the naphthalimide derivative facilitate bright phosphorescence (ΦP =7.7 %, τP =3.2 ms) and fluorescence of the resultant nanoparticles (SNPs) at room temperature, which enable accurate, ratiometric, sensitive oxygen detection (Ksv =189.6 kPa-1 ) in aqueous solution as well as in living HeLa cells.

Enhanced proliferation and differentiation of neural stem cells by peptide-containing temperature-sensitive hydrogel scaffold.

Hydrogel has attracted great attention in the past few years as a widely used material for repairing central nerve damage. However, conventional hydrogel bio-scaffold, such as chitosan, gelatin, and sodium alginate, lack sufficient biological activity and have limited nerve repair capabilities. Therefore, to explore biologically active and intelligent hydrogel materials is particularly important and necessary for central nerve repair. Herein, we developed a temperature-sensitive hydrogel grafted with a bioactive peptide IKVAV (Ile-Lys-Val-Ala-Val, IKVAV). The hydrogel was prepared by copolymerization of N-propan-2-ylprop-2-enamide (NIPAM) and AC-PEG-IKVAV copolymers via reversible addition-fracture chain transfer (RAFT) polymerization, using polyethylene glycol (PEGDA) and N, N'-Methylenebisacrylamide (BISAM) as cross-linking agents. The prepared hydrogel scaffold demonstrates a series of excellent properties such as rapid (de)swelling performance, good biocompatibility, regular three-dimensional porous structure, and in particular good biological activity, which can guide cell fate and mediate neuron's differentiation. Therefore, the developed peptide hydrogel scaffold provides a new strategy for designing biomaterials that are widely used in tissue engineering for central nervous system injury.

Nitrosative stress inhibits aminoacylation and editing activities of mitochondrial threonyl-tRNA synthetase by S-nitrosation.

Structure and/or function of proteins are frequently affected by oxidative/nitrosative stress via posttranslational modifications. Aminoacyl-tRNA synthetases (aaRSs) constitute a class of ubiquitously expressed enzymes that control cellular protein homeostasis. Here, we found the activity of human mitochondrial (mt) threonyl-tRNA synthetase (hmtThrRS) is resistant to oxidative stress (H2O2) but profoundly sensitive to nitrosative stress (S-nitrosoglutathione, GSNO). Further study showed four Cys residues in hmtThrRS were modified by S-nitrosation upon GSNO treatment, and one residue was one of synthetic active sites. We analyzed the effect of modification at individual Cys residue on aminoacylation and editing activities of hmtThrRS in vitro and found that both activities were decreased. We further confirmed that S-nitrosation of mtThrRS could be readily detected in vivo in both human cells and various mouse tissues, and we systematically identified dozens of S-nitrosation-modified sites in most aaRSs, thus establishing both mitochondrial and cytoplasmic aaRS species with S-nitrosation ex vivo and in vivo, respectively. Interestingly, a decrease in the S-nitrosation modification level of mtThrRS was observed in a Huntington disease mouse model. Overall, our results establish, for the first time, a comprehensive S-nitrosation-modified aaRS network and a previously unknown mechanism on the basis of the inhibitory effect of S-nitrosation on hmtThrRS.

Long-term outcomes and prognostic factors of young patients with mucinous and signet-ring cell colorectal cancer.

INTRODUCTION: The aim of the study was to assess the clinico-pathological features and prognosis of mucinous adenocarcinoma (MAC) and signet-ring cell carcinoma (SRC) in young colorectal cancer (CRC) patients. MATERIAL AND METHODS: We retrospectively evaluated the patient records of young patients with MAC and SRC (aged ≤ 40 years) treated at the Cancer Hospital of China Medical University from January 2006 to December 2013. Kaplan-Meier analysis and log-rank testing were performed to estimate overall survival (OS). Subsequently a Cox proportional hazard model was used to calculate hazard ratios for the risk of death. RESULTS: A total of 90 young CRC patients (MAC = 69 and SRC = 21) were included in the analysis during the study period. The overall cumulative 5-year OS rate was 56.6 ±6%. Estimated 5-year OS was 58.1 ±7.7% for MAC and 31.3 ±12.9% for SRC (p = 0.018). On univariate analysis, metastatic disease, AJCC stage, adjuvant chemotherapy (CT), cycles of adjuvant CT, surgery type, lymphovascular invasion, perineural invasion, preoperative carcinoembryonic antigen (CEA) levels, and histologic type were significant prognostic factors for OS. In multivariate analysis, preoperative CEA levels and cycles of adjuvant CT were found to be independent prognostic factors for overall survival (hazard ratio = 2.47; 95% CI: 1.06-5.78, p = 0.037; hazard ratio = 0.18; 95% CI: 0.05-0.62, p = 0.007, respectively). CONCLUSIONS: A greater proportion of young patients with MAC and SRC present with advanced disease. Young patients with SRC have poorer prognosis than MAC. Preoperative CEA levels and cycles of adjuvant CT are two independent predictors of overall survival for young CRC patients with MAC and SRC.

Phase Separation and Cytotoxicity of Tau are Modulated by Protein Disulfide Isomerase and S-nitrosylation of this Molecular Chaperone.

Cells have evolved molecular chaperones that modulate phase separation and misfolding of amyloidogenic proteins to prevent neurodegenerative diseases. Protein disulfide isomerase (PDI), mainly located at the endoplasmic reticulum and also present in the cytosol, acts as both an enzyme and a molecular chaperone. PDI is observed to be S-nitrosylated in the brain of Alzheimer's disease patients, but the mechanism has remained elusive. We herein report that both wild-type PDI and its quadruple cysteine mutant only having chaperone activity, significantly inhibit pathological phosphorylation and abnormal aggregation of Tau in cells, and significantly decrease the mitochondrial damage and Tau cytotoxicity resulting from Tau aberrant aggregation, highlighting the chaperone property of PDI. More importantly, we show that wild-type PDI is selectively recruited by liquid droplets of Tau, which significantly inhibits phase separation and stress granule formation of Tau, whereas S-nitrosylation of PDI abrogates the recruitment and inhibition. These findings demonstrate how phase separation of Tau is physiologically regulated by PDI and how S-nitrosylation of PDI, a perturbation in this regulation, leads to disease.

Multiple-State Emissions from Neat, Single-Component Molecular Solids: Suppression of Kasha's Rule.

Three rigid and structurally simple heterocyclic stilbene derivatives, (E)-3H,3'H-[1,1'-biisobenzofuranylidene]-3,3'-dione, (E)-3-(3-oxobenzo[c] thiophen-1(3H)-ylidene)isobenzofuran-1(3H)-one, and (E)-3H,3'H-[1,1'-bibenzo[c] thiophenylidene]-3,3'-dione, are found to fluoresce in their neat solid phases, from upper (S2 ) and lowest (S1 ) singlet excited states, even at room temperature in air. Photophysical studies, single-crystal structures, and theoretical calculations indicate that large energy gaps between S2 and S1 states (T2 and T1 states) as well as an abundance of intra and intermolecular hydrogen bonds suppress internal conversions of the upper excited states in the solids and make possible the fluorescence from S2 excited states (phosphorescence from T2 excited states). These results, including unprecedented fluorescence quantum yields (2.3-9.6 %) from the S2 states in the neat solids, establish a unique molecular skeleton for achieving multi-colored emissions from upper excited states by "suppressing" Kasha's rule.

Transaxillary Endoscopic Approach to Capsular Contracture Following Previous Breast Augmentation: Operative Technique and Clinical Outcome.

BACKGROUND: Capsular contracture (CC) is a complication of breast augmentation that frequently requires revision surgery. The axillary approach reduces the visibility of the postoperative scar. It is unclear whether the previous incision can be used to repair the deformity caused by CC. METHODS: This study analyzed 21 patients (42 breasts) with grade III-IV CC during 2012-2017. The mean age of the patients was 32 years (range 23-48). Previous axillary scars were used to expose, and CCs were taken out completely or partially. Breast implants were removed. The dissection was performed with endoscopic assistance, using electrocautery under direct visualization. RESULTS: The mean follow-up period was 13 months (range 6-24 months). The dissection plane was changed to dual plane. Thirty-five CCs were taken out completely. Thirty-eight breast implants taken out remained intact. None of the patients required additional surgery. CONCLUSION: Endoscopic-assisted treatment may be an effective technique for treating CC and avoiding the additional scar. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Ratiometric O2 sensing based on selective self-sensitized photooxidation of donor-acceptor fluorophores.

We report a series of organic fluorophores that undergo selective self-sensitized photooxidation upon light irradiation in air accompanied by a change of fluorescence from yellow to blue on the seconds timescale. The distinct emission changes allow the ratiometric quantitation of O2 concentration.

Pure Organic Room Temperature Phosphorescence from Excited Dimers in Self-Assembled Nanoparticles under Visible and Near-Infrared Irradiation in Water.

Pure organic room temperature phosphorescence (RTP) has unique advantages and various potential applications. However, it is challengeable to achieve organic RTP under visible and near-infrared (NIR)-light excitation, especially in aqueous solution. Herein we assemble difluoroboron ß-diketonate compounds to form organic nanoparticles (NPs) in water. The resulting NPs are able to show efficient RTP, effective uptake, and bright imaging of HeLa cells under both visible- and NIR-light excitation. More strikingly, spectroscopic study, single-crystal X-ray diffraction, and DFT calculation reveal that the efficient RTP in organic NPs is originated from dimers in their excited states. The multiple interactions and intermolecular charge transfer in the dimer structures are of significance in promoting the production of dimer triplet excited states and suppressing the nonradiative decays to boost the RTP under visible- and NIR-light irradiation in water.

Promotion of Para-Chlorophenol Reduction and Extracellular Electron Transfer in an Anaerobic System at the Presence of Iron-Oxides.

Anaerobic dechlorination of chlorophenols often subjects to their toxicity and recalcitrance, presenting low loading rate and poor degradation efficiency. In this study, in order to accelerate p-chlorophenol (p-CP) reduction and extracellular electron transfer in an anaerobic system, three iron-oxide nanoparticles, namely hematite, magnetite and ferrihydrite, were coupled into an anaerobic system, with the performance and underlying role of iron-oxide nanoparticles elucidated. The reductive dechlorination of p-CP was notably improved in the anaerobic systems coupled by hematite and magnetite, although ferrihydrite did not plays a positive role. Enhanced dechlorination of p-CP in hematite or magnetite coupled anaerobic system was linked to the obvious accumulation of acetate, lower oxidation-reduction potential and pH, which were beneficial for reductive dechlorination. Electron transfer could be enhanced by Fe2+/Fe3+ redox couple on the iron oxides surface formed through dissimilatory iron-reduction. This study demonstrated that the coupling of iron-oxide nanoparticles such as hematite and magnetite could be a promising alternative to the conventional anaerobic reduction process for the removal of CPs from wastewater.

Identification of compound D2923 as a novel anti-tumor agent targeting CSF1R.

Colony-stimulating factor 1 receptor (CSF1R) plays a critical role in promoting tumor progression in various types of tumors. Here, we identified D2923 as a novel and selective inhibitor of CSF1R and explored its antitumor activity both in vitro and in vivo. D2923 potently inhibited CSF1R in vitro kinase activity with an IC50 value of 0.3 nM. It exhibited 10- to 300-fold less potency against a panel of kinases tested. D2923 markedly blocked CSF-1-induced activation of CSF1R and its downstream signaling transduction in THP-1 and RAW264.7 macrophages and thus inhibited the in vitro growth of macrophages. Moreover, D2923 dose-dependently attenuated the proliferation of a small panel of myeloid leukemia cells, mainly by arresting the cells at G1 phase as well as inducing apoptosis in the cells. The results of the in vivo experiments further demonstrated that D2923 displayed potent antitumor activity against M-NFS-60 xenografts, with tumor growth inhibition rates of 50% and 88% at doses of 40 and 80 mg/kg, respectively. Additionally, D2923 was well tolerated with no significant body-weight loss observed in the treatment groups compared with the control. Furthermore, a western blot analysis and the immunohistochemistry results confirmed that the phosphorylation of CSF1R in tumor tissue was dramatically reduced after D2923 treatment, and this was accompanied by the depletion of macrophages in the tumor. Meanwhile, the expression of the proliferation marker Ki67 was also markedly decreased in the D2923 treatment group compared with the control group. Taken together, we identified D2923 as a novel and effective CSF1R inhibitor, which deserves further investigation.

A light-driven molecular machine based on stiff stilbene.

We report a new molecular design for optically triggered nm-scale translation of a submolecular component relative to another. We used a rotaxane-like molecule terminated at one end with stiff stilbene that served both as a chromophore to trigger the translation of the pillar[5]arene "wheel" and as a stopper to prevent its dethreading.

Supramolecular Polymer-Based Fluorescent Microfibers for Switchable Optical Waveguides.

We report the switchable optical waveguide microfibers based on fluorescent supramolecular polymer for the first time. The pillar[5]arene-based supramolecular polymeric microfibers were prepared easily from the viscous solution of bispillar[5]arene host (bisP5A) and diphenylanthracene-derived guest (GD). The resulting microfibers  act as an active optical waveguide material with long propagation distance (400 µm) and low optical propagation loss (0.01 dB/µm). When photoresponsive dithienylethene-derived guest (GDTE) was added, the resulting ternary microfibers show switchable optical waveguide by the noninvasive control of UV/vis light with negligible fatigue over four cycles. This convenient preparation method is also applied for the quadruple-hydrogen-bonded fluorescent supramolecular polymeric microfibers which imply good light propagation property with an optical loss coefficient of 0.02 dB/µm.