Establishment and assessment of a nomogram for predicting prognosis in bone-metastatic prostate cancer.

OBJECTIVE: For the purposes of patients' consultation, condition assessments, and guidance for clinicians' choices, we developed a prognostic predictive model to evaluate the 1-, 3-, and 5-year overall survival (OS) rates of bone-metastatic prostate cancer (PCa) patients. METHODS: We gathered data from 5522 patients with bone metastatic PCa registered in the Surveillance, Epidemiology, and End Results (SEER) database to develop a nomogram. A total of 359 bone metastatic PCas were collected from 2 hospitals to validate the nomogram and assess its discriminatory ability. In addition, we plotted the actual survival against the predicted risk to assess the calibration accuracy. Moreover, we designed a web calculator to quickly obtain accurate survival probability outcomes. RESULTS: Univariate and multivariate Cox hazard regression analyses suggested that age, marital status, prostate-specific antigen (PSA) level, Gleason score, clinical T stage, N stage, surgery, and chemotherapy were closely associated with OS rates. The calibration charts of the training and validation groups showed a high accuracy and reliability. The decision curve analysis (DCA) suggested a favorable clinical net benefit. CONCLUSION: Based on demography and clinical pathology, we developed a reliable nomogram to help clinicians more accurately predict the 1-, 3-, and 5-year OS rates of patients with bone metastatic PCa to guide evaluation and treatment.

Nonfluent Variant Primary Progressive Aphasia on FDG, 11 C-PIB, and 18 F-APN-1607 PET Imaging.

ABSTRACT: A 61-year-old right-handed man presented with decreased cognitive function, short-term memory, fluent speech disorders, and grammatical errors for 1 year. The patient underwent PET imaging with 11 C-PIB, 18 F-FDG, and 18 F-APN-1607. The 11 C-PIB PET showed no amyloid accumulation; the 18 F-FDG PET showed hypometabolism in the bilateral frontal lobe, temporal lobe, and midbrain; and the 18 F-APN-1607 PET showed tau accumulation in the brainstem, basal ganglia, and left inferior frontal gyrus. These findings suggested a diagnosis of nonfluent variant primary progressive aphasia. This case emphasizes the value of combined imaging of glucose metabolism, Aß, and tau PET in the diagnosis of nonfluent variant primary progressive aphasia.

A Co(II) compound: photocatalytic activity and application value in trigeminal neuralgia with minimally invasive interventional therapy guided by CT.

A new thermostable Co(II)-based compound, namely [Co3(L)2(HTEA)2]n (1, HL = isonicotinic acid, H3TEA = triethanolamine), has been successfully synthesized by the isomicotinic acid ligand and HTEA anion. The photocatalytic property of 1 was also investigated, indicating that it shows excellent photocatalytic activity for the degradation of Rhodamine B (MB) solution under the UV light irradiation. For the treatment of trigeminal neuralgia, the content of the inflammatory cytokines released into the trigeminal ganglion tissue fluid was measured with enzyme-linked immunosorbent assay (ELISA) assay. Then, the real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was conducted and the activation of the nuclear factor kappa-B (NF-κB) inflammatory signaling pathway was measured.

Comparison of lidocaine and ropivacaine stellate ganglion blockade in treating upper limb postherpetic neuralgia.

ABSTRACT: To provide a basis for treating postherpetic neuralgia (PHN), we compared the efficacy of lidocaine and ropivacaine stellate ganglion block (SGB) in PHN treatment in the upper limbs.Data from 252 patients with upper-limb PHN were retrospectively analyzed. The lidocaine group (n = 118) was treated with oral pregabalin capsules 75 mg twice a day, tramadol hydrochloride sustained release tablets 100 mg twice a day, and amitriptyline 25 mg once at night combined with ultrasound-guided lidocaine SGB; the ropivacaine group (n = 134) was orally administered the same medicines combined with ultrasound-guided ropivacaine SGB. The visual analog scale (VAS), self-rating anxiety scale (SAS), and adverse reactions were compared between the groups before treatment and at 1 week, 1 month, and 3 months after treatment.There were no significant differences between the lidocaine and ropivacaine groups in terms of sex, age, height, weight, and pain duration (P > .05). There was no significant difference between the groups in VAS and SAS scores before treatment (P > .05). At 1 week, 1 month, and 3 months after ultrasound-guided SGB treatment, the VAS and SAS scores were significantly lower in the ropivacaine group than in the lidocaine group (P < .05). There were no significant differences between the groups in terms of adverse reactions (P > .05).For ultrasound-guided SGB treatment of upper limb PHN, ropivacaine is superior to lidocaine. Ultrasound-guided ropivacaine SGB is safe and effective for the treatment of upper limb PHN.

Has China's New Round of Collective Forest Reforms Reduced Forest Fragmentation? A Case Study of the Beijing-Tianjin-Hebei Region.

The new wave of reform of collective forestland tenure (NRCFT) in China is considered an important policy for achieving sustainable management of forest resources. The purpose of this study is to investigate the influence of NRCFT on forest fragmentation in the Beijing-Tianjin-Hebei region of China based on a fixed-effects model. The forest fragmentation was analyzed based on the remote sensing images of Landsat and landscape pattern indices in the Beijing-Tianjin-Hebei region from 2000 to 2018. The results showed that (1) The NRCFT has significantly contributed to reducing forest fragmentation. (2) The effect of economic growth on forest fragmentation showed an inverted U-shape. (3) The implementation of the Grain for Green Program (GGP) and the transformation of rural energy consumption significantly reduce the degree of forest fragmentation. This study has crucial implications for formulating policies, achieving good forest governance, and reducing forest fragmentation.

Redox-sensitive hyaluronic acid-cholesterol nanovehicles potentiate efficient transmembrane internalization and controlled release for penetrated "full-line" inhibition of pre-metastatic initiation.

Metastatic breast cancer is a major cause of cancer-related mortality worldwide. The tumor-specific penetration and triggered drug release for "full-line" inhibition of pre-metastatic initiation are of essential importance in improving mortality rates. Here, a crosslinked, redox-sensitive amphiphilic conjugate (cHLC) was constructed with a combination of features, including hyaluronic acid (HA)-mediated tumor active targeting, lipoic acid (LA) core-crosslinking based bio-stability and reducibility, and lipid raft anchoring-promoted HA-mediated endocytosis through cholesterol (CHO) modification for the penetrated co-delivery of paclitaxel (PTX) and the multi-targeted anti-metastatic agent, silibinin (SB). Resultantly, the nanodrug (cHLC/(PTX + SB)) demonstrated enhanced tumor cytoplasm-selective rapid drug delivery in a 4T1 model both in vitro and in vivo. The released SB efficiently sensitized cells to PTX treatment and inhibited the whole process of pre-metastatic initiation including epithelial-to-mesenchymal transition (EMT), local and blood vessel invasion. The exquisite design of this delivery system provides a deep insight into enhancing focus accessibility of multi-targeted drugs for an efficient inhibition of tumor metastasis.

Tumor microenvironment remodeling-based penetration strategies to amplify nanodrug accessibility to tumor parenchyma.

Remarkable advances in nano delivery systems have provided new hope for tumor prevention, diagnosis and treatment. However, only limited clinical therapeutic effects against solid tumors were achieved. One of the main reasons is the presence of abundant physiological and pathological barriers in vivo that impair tumoral penetration and distribution of the nanodrugs. These barriers are related to the components of tumor microenvironment (TME) including abnormal tumor vasculature, rich composition of the extracellular matrix (ECM), and abundant stroma cells. Herein, we review the advanced strategies of TME remodeling to overcome these biological obstacles against nanodrug delivery. This review aims to offer a perspective guideline for the implementation of promising approaches to facilitate intratumoral permeation of nanodrugs through alleviation of biological barriers. At the same time, we analyze the advantages and disadvantages of the corresponding methods and put forward possible directions for the future researches.

Biomineralization-inspired dasatinib nanodrug with sequential infiltration for effective solid tumor treatment.

The complex blood environment, heterogenic enhanced permeability and retention (EPR) effect, and dense matrix comprise the primary "leakage obstacles" impeding specific accumulation and penetration of nanodrugs against solid tumors, thus forming a key bottleneck for their clinical application. Herein, we present a biomineralization-inspired dasatinib (DAS) nanodrug (CIPHD/DAS) that sequentially permeates all of the abovementioned hindrances for efficient treatment of solid tumors. CIPHD/DAS exhibited a robust hybrid structure constructed from an iRGD-modified hyaluronic acid-deoxycholic acid organic core and a calcium phosphate mineral shell. In vitro and in vivo data demonstrated the mechanism of sequential tumoral infiltration was based on mineral-stiffened blood circulation with decreased premature drug leakage, iRGD-endowed tumor-specific transendothelial transport for "first-order promotion of accumulation" and DAS-mediated restoration of fibrotic stromal homeostasis for "second-order promotion of penetration". Resultantly, CIPHD/DAS showed remarkable distal drug availability in desmoplastic 4T1/CAFs orthotropic mouse models and significantly suppressed tumor growth and metastasis. This optimized strategy with sequential permeabilization of the capital "leakage obstacles" validates a promising paradigm to conquer the "impaired delivery and penetration" associated bottleneck of nanodrugs in the clinical treatment of solid tumors.

Co-delivery of silybin and paclitaxel by dextran-based nanoparticles for effective anti-tumor treatment through chemotherapy sensitization and microenvironment modulation.

Modulation of tumor microenvironment (TME) has been indicated as an approach to improve efficacy of cancer therapy. Here, we proposed a nano co-delivery based combination therapy of paclitaxel (PTX) and silybin (SB) which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. A dextran-based amphiphilic polymer (Dex-DOCA) was successfully developed for in vivo co-delivery and thus "synchronizing" the biodistribution, transport and release of PTX and SB. Resultantly, Dex-DOCA exhibited an excellent encapsulating efficiency for both PTX and SB with adjustable loading ratio for an optimal synergistic antitumor activity. Moreover, the co-loaded nanoparticles efficiently discharged the two drugs at the prospective dosage ratio specifically in acid endo/lysosome mimic environments. The results of in vitro cytotoxicity and cell apoptosis assays further confirmed the SB sensitized PTX potency. Finally, in vivo investigation demonstrated that the co-loaded nanoparticles could effectively accumulate in tumor sites by passive targeting, and inhibit tumor growth through an enhanced intratumoral penetration (resulted from stromal components eradication and tumor vessels normalization associated TME modulation), as well as a sensitization effect of SB on PTX cytotoxic chemotherapy.

Double-passage ground-state cooling induced by quantum interference in the hybrid optomechanical system.

We propose a quantum interference cooling scheme for a nano-mechanical resonator (NAMR) in a hybrid optomechanical system. In our scheme, atoms are trapped in an optomechanical cavity, and this optomechanical cavity interacts both atoms and an optical cavity. Therefore, the absorption of the optomechanical resonator can be modified by quantum interference effects induced by the atom-cavity and cavity-cavity couplings. With the modification of the quantum interference, the desired transition for cooling is enhanced, while the undesired transition for heating can be suppressed. As a result, the NAMR vibration can be cooled down to its ground state. Particularly, with the assistance of the atoms, the experimental difficulty can be reduced since the effective decay rate of the cavity can be decreased via the quantum interference for the atom-cavity coupling.

Multifunctional Hyaluronic Acid-Decorated Redox-Responsive Magnetic Complex Micelle for Targeted Drug Delivery with Enhanced Antitumor Efficiency and Anti-Cell-Migration Activity.

A novel multifunctional hyaluronic acid-decorated redox-responsive magnetic complex micelle (HA/CSO-SS-Hex/Fe3O4/PTX) based on a reducible hexadecanol-modified chitosan oligosaccharide polymer micelle (CSO-SS-Hex) coated with hyaluronic acid (HA) and loaded with paclitaxel (PTX) Fe3O4 nanoparticles is developed. HA is coated onto the surface of micelles via electrostatic absorption and acts as a targeting ligand for CD44 over expression in many tumor cells. A CSO-SS-Hex polymer micelle was used for PTX incorporation and GSH-triggered intracellular release. The PTX in micelles was used to provide chemotherapy. Fe3O4 nanoparticles were used for magnetic targeting. The complex micelle showed enhanced antitumor efficiency and anti-cell-migration activity. The HA/CSO-SS-Hex/Fe3O4/PTX micelle was stable under physiological conditions, while it was sensitive to release the loaded drug in the presence of 10 mM glutathione (GSH). The complex micelle showed enhanced cellular uptake and fast drug release due to the combined effect of magnet targeting, CD44 receptor-mediated internalization and redox-response drug release in tumor cells. Cell viability tests revealed that HA/CSO-SS-Hex/Fe3O4/PTX micelle displayed enhanced cytotoxicity against A549, B16F10 and HepG2 cell lines compared to non-targeted formulations of PTX. An anti-cell migration assay was also performed. The result showed that although there was no significant difference in the anti-cell migration activities between the HA/CSO-SS-Hex/Fe3O4/PTX micelle and free PTX, the activities of HA/CSO-SS-Hex/Fe3O4/PTX were stronger than non-targeted CSO-SS-Hex/Fe3O4/PTX micelles. Thus, the novel HA/CSO-SS-Hex/Fe3O4/PTX micelle is highly effective for targeted drug delivery and might have potential implications for the chemotherapy of primary tumors and their metastases.

N-mercapto acetyl-N'-octyl-O, N″-glycol chitosan as an efficiency oral delivery system of paclitaxel.

Herein, thioglycolic acid modified N-octyl-O, N'-glycol chitosan (N-mercapto acetyl-N'-octyl-O, N″-glycol chitosan, abbreviated as SH-OGC) was synthesized to improve the oral bioavailability of paclitaxel (PTX). PTX was readily solubilized into the hydrophobic inner core of SH-OGC. Pharmacokinetic studies demonstrated that the bioavailability of PTX was greatly enhanced when delivered by SH-OGC compared to Taxol® or non-sulfhydrylated OGC micelles. Caco-2 cell experiments confirmed PTX or rhodamine-123-loaded SH-OGC demonstrated effective cellular accumulation via caveola-mediated endocytosis along with the inhibition of P-gp efflux. Furthermore, Caco-2 transport studies demonstrated that the mechanistic basis of SH-OGC efficacy was attributed to P-gp inhibition, enhanced permeability of tight junctions and clathrin-mediated transcytosis across the endothelium. In addition, SH-OGC exhibited increased intestinal retention through thiol-mediated mucoadhesion compared with OGC according to results of mucoadhesion evaluation on freshly excised rat intestine. In summary, SH-OGC micelles may present as a promising delivery vehicle for enhancing the oral bioavailability of P-gp substrates.

Success with neurotropin in treating pediatric lower extremity pain induced by spinal cord injury after epidural anesthesia.

Spinal cord injury (SCI) complicated by epidural anesthesia, though rare, can result in neuropathic pain. However, the treatment for this kind of life-altering injury remains a challenge. A 7-year-old girl was referred with dyskinesia and severe pain in her right lower extremity due to an accidental SCI following lumbar puncture. After treatment with analgesics such as gabapentin, mecobalamin, and dexamethasone/methylprednisolone for 1 week, the myodynamia had improved, but progressive pain persisted. After treatment with neurotropin, a gradual decrease in visual analog scale score from 7 to 0 was observed. We herein first describe that neurotropin produced sustained relief of pain induced by SCI. This case suggests that neurotropin might be a promising drug in treating pediatric neuropathic pain caused by SCI.

Noise squeezing of fields that bichromatically excite atoms in a cavity.

It is well known that bichromatic excitation on one common transition can tune the emission or absorption spectra of atoms due to the modulation frequency dependent non-linearities. However little attention has been focused on the quantum dynamics of fields under bichromatic excitation. Here we present dissipative effects on noise correlations of fields in bichromatic interactions with atoms in cavities. We first consider an ensemble of two-level atoms that interacts with the two cavity fields of different frequencies and considerable amplitudes. By transferring the atom-field nonlinearities to the dressed atoms we separate out the dissipative interactions of Bogoliubov modes with the dressed atoms. The Bogoliubov mode dissipation establishes stable two-photon processes of two involved fields and therefore leads to two-mode squeezing. As a generalization, we then consider an ensemble of three-level Λ atoms for cascade bichromatic interactions. We extract the Bogoliubov-like four-mode interactions, which establish a quadrilateral of the two-photon processes of four involved fields and thus result in four-mode squeezing.

Quantum-beat based dissipation for spin squeezing and light entanglement.

We show an engineered dissipation for the spin squeezing and the light entanglement in a quantum beat system, in which two bright fields interact with an ensemble of three-level atoms in V configuration. The dissipation is based on the atom-field nonlinear interaction that is controlled by the atomic coherence between the excited states off two-photon resonance. Physical analysis and numerical verification are presented for the symmetrical parameters by using the dressed atomic states. It is shown that for particular parameters, the engineered dissipation induces almost perfect two-mode squeezing and entanglement both for the bright fields and for the dressed spins. The excited-state spin has squeezing of near 40% below the standard quantum limit although there remains the spontaneous emission from the involved excited states.

[Rebound depolarization of substantia gelatinosa neurons and its modulatory mechanisms in rat spinal dorsal horn].

OBJECTIVE: To investigate the rebound depolarization of substantia gelatinosa (SG) neurons in rat spinal dorsal horn and explore its modulatory mechanisms to provide better insights into rebound depolarization-related diseases. METHODS: Parasagittal slices of the spinal cord were prepared from 3- to 5-week-old Sprague-Dawley rats. The electrophysiologic characteristics and responses to hyperpolarization stimulation were recorded using whole-cell patch-clamp technique. The effects of hyperpolarization-activated cyclic nucleotide gated cation (HCN) channel blockers and T-type calcium channel blockers on rebound depolarization of the neurons were studied. RESULTS: A total of 63 SG neurons were recorded. Among them, 23 neurons showed no rebound depolarization, 19 neurons showed rebound depolarization without spikes, and 21 neurons showed rebound depolarization with spikes. The action potential thresholds of the neurons without rebound depolarization were significantly higher than those of the neurons with rebound depolarization and spikes (-28.7∓1.6 mV vs -36.0∓2.0 mV, P<0.05). The two HCN channel blockers CsCl and ZD7288 significantly delayed the latency of rebound depolarization with spike from 45.9∓11.6 ms to 121.6∓51.3 ms (P<0.05) and from 36.2∓10.3 ms to 73.6∓13.6 ms (P<0.05), respectively. ZD7288 also significantly prolonged the latency of rebound depolarization without spike from 71.9∓35.1 ms to 267.0∓68.8 ms (P<0.05). The T-type calcium channel blockers NiCl2 and mibefradil strongly decreased the amplitude of rebound depolarization with spike from 19.9∓6.3 mV to 9.5∓4.5 mV (P<0.05) and from 26.1∓9.4 mV to 15.5∓5.0 mV (P<0.05), respectively. Mibefradil also significantly decreased the amplitude of rebound depolarization without spike from 14.3∓3.0 mV to 7.9∓2.0 mV (P<0.05). CONCLUSION: Nearly two-thirds of the SG neurons have rebound depolarizations modulated by HCN channel and T-type calcium channel.

[Minocycline reduces hyperpolarization-activated current in rat substantia gelatinosa neurons].

OBJECTIVE: To investigate the effect of minocycline on hyperpolarization-activated current (Ih) in the substantia gelatinosa (SG) neurons in rat spinal dorsal horn. METHODS: In vitro spinal cord transverse slices were prepared from 3-5-week-old male Sprague-Dawley rats. Using whole-cell patch clamp technique, Ih currents were recorded before and after bath application of minocycline (1-300 µmol/L) to the SG neurons. RESULTS: Ih currents were observed in nearly 50% of the recorded neurons, and were blocked by Ih blocker CsCl and ZD7288. Minocycline rapidly and reversibly reduced the amplitude of Ih and decreased the current density in a concentration-dependent manner with an IC50 of 34 µmol/L. CONCLUSION: Minocycline suppresses the excitability of SG neurons through inhibiting the amplitude and current density of Ih and thereby contributes to pain modulation.

Benzoxaborole antimalarial agents. Part 2: Discovery of fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles.

A series of new boron-containing benzoxaborole compounds was designed and synthesized for a continuing structure-activity relationship (SAR) investigation to assess the antimalarial activity changes derived from side-chain structural variation, substituent modification on the benzene ring and removal of boron from five-membered oxaborole ring. This SAR study demonstrated that boron is required for the antimalarial activity, and discovered that three fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 14 and 20) have excellent potencies (IC(50) 0.026-0.209 µM) against Plasmodium falciparum.

Synthesis and structure-activity relationships of novel benzoxaboroles as a new class of antimalarial agents.

A series of boron-containing benzoxaborole compounds was designed and synthesized for a structure-activity relationship investigation surrounding 7-(HOOCCH(2)CH(2))-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1) with the goal of discovering a new antimalarial treatment. Compound 1 demonstrates the best potency (IC(50)=26nM) against Plasmodium falciparum and has good drug-like properties, with low molecular weight (206.00), low ClogP (0.86) and high water solubility (750µg/mL at pH 7).