Plausible presence of new state in neutron stars with masses above 0.98MTOV.

We investigate the neutron star (NS) equation of state (EOS) by incorporating multi-messenger data of GW170817, PSR J0030 + 0451, PSR J0740 + 6620, and state-of-the-art theoretical progresses, including the information from chiral effective field theory (χEFT) and perturbative quantum chromodynamics (pQCD) calculation. Taking advantage of the various structures sampling by a single-layer feed-forward neural network model embedded in the Bayesian nonparametric inference, the structure of NS matter's sound speed cs is explored in a model-agnostic way. It is found that a peak structure is common in the cs2 posterior, locating at (2.4-4.8)ρsat (nuclear saturation density) and cs2 exceeds c2/3 at 90% credibility. The non-monotonic behavior suggests evidence of the state deviating from the hadronic matter inside the very massive NSs. Assuming the new/exotic state is featured as it is softer than typical hadronic models or even with hyperons, we find that a sizable (⩾10-3M⊙) exotic core, likely made of quark matter, is plausible for the NS with a gravitational mass above about 0.98MTOV, where MTOV represents the maximum gravitational mass of a non-rotating cold NS. The inferred MTOV=(2.18-0.13+0.27)M⊙ (90% credibility) is well consistent with the value of (2.17-0.12+0.15)M⊙ estimated independently with GW170817/GRB 170817A/AT2017gfo assuming a temporary supramassive NS remnant formed after the merger. PSR J0740 + 6620, the most massive NS detected so far, may host a sizable exotic core with a probability of ≈0.36.

Merger and Postmerger of Binary Neutron Stars with a Quark-Hadron Crossover Equation of State.

Fully general-relativistic binary-neutron-star (BNS) merger simulations with quark-hadron crossover (QHC) equations of state (EOS) are studied for the first time. In contrast to EOS with purely hadronic matter or with a first-order quark-hadron phase transition (1PT), in the transition region QHC EOS show a peak in sound speed and thus a stiffening. We study the effects of such stiffening in the merger and postmerger gravitational (GW) signals. Through simulations in the binary-mass range 2.5

Genetic Characteristics of Resectable Colorectal Cancer with Pulmonary Metastasis.

The lung is the most common extra-abdominal metastasis site of colorectal cancer (CRC). This study aimed to investigate the genetic variation of pulmonary metastases (PM) and primary tumors in resectable CRC. The clinical data of 410 patients with PM after CRC surgery and 33 paraffin-embedded tissue samples from January 2012 to July 2019 in our hospital were collected retrospectively. Next, 450-panel gene detection technologies based on next-generation sequencing (NGS) were used to analyze the changes in the gene map and the overall variation in cancer-related genes in PM and primary tumors. After quality control, 19 samples were included in the final gene analysis. The results showed that APC (89.5%), TP53 (89.5%), and KRAS (53%) were the most common mutations in PM and primary tumors, but the gene amplification variation was enriched in primary tumors (4.6% vs. 11.4%). KRAS G12D was the most common site variation of the KRAS gene in both PM and primary tumors of CRC. There was no hotspot mutation in the TP53 locus in CRC, and the TP53 mutation in the PM was consistent with that in the primary lesion. The microsatellite instability (MSI) levels of 10 patients were MSS. The mean tumor mutation burden (TMB) of the primary tumor (5.3 muts·Mb-1) was slightly higher than that of metastasis (5.0 muts·Mb-1). In our institution, the genetic characteristics of resectable PM from CRC may be highly consistent with those of the primary tumor.

Smart Stimuli-Responsive and Mitochondria Targeting Delivery in Cancer Therapy.

Dysfunction in the mitochondria (Mc) contributes to tumor progression. It is a major challenge to deliver therapeutic agents specifically to the Mc for precise treatment. Smart drug delivery systems are based on stimuli-responsiveness and active targeting. Here, we give a whole list of documented pathways to achieve smart stimuli-responsive (St-) and Mc-targeted DDSs (St-Mc-DDSs) by combining St and Mc targeting strategies. We present the formulations, targeting characteristics of St-Mc-DDSs and clarify their anti-cancer mechanisms as well as improvement in efficacy and safety. St-Mc-DDSs usually not only have Mc-targeting groups, molecules (lipophilic cations, peptides, and aptamers) or materials but also sense the surrounding environment and correspondingly respond to internal biostimulators such as pH, redox changes, enzyme and glucose, and/or externally applied triggers such as light, magnet, temperature and ultrasound. St-Mc-DDSs exquisitely control the action site, increase therapeutic efficacy and decrease side effects of the drug. We summarize the clinical research progress and propose suggestions for follow-up research. St-Mc-DDSs may be an innovative and sensitive precision medicine for cancer treatment.

Cytomembrane-mimicking nanocarriers with a scaffold consisting of a CD44-targeted endogenous component for effective asparaginase supramolecule delivery.

Highly effective and safe delivery of therapeutic enzymes is pivotal to the success of antitumor therapy. Herein, we report on a targeted enzyme delivery system based on cytomembrane-mimicking nanocarriers (CmN) and a supramolecular technique (SmT). Specifically, each CmN had a scaffold that mainly consisted of a CD44-targeted endogenous component conjugated with polyethylene glycol 2000 (HA-g-PEG) that self-assembled with α-cyclodextrin (ACD). The CmN acted as a microbioreactor with an inner hollow space with the capacity to confine the large molecule asparaginase (Asp) in an Asp/ACD-supramolecular complex conjugated to the inner region. The supramolecular Asp loaded into the CmN (A-S-CmN) exhibited superior stability, kinetic properties, catalytic activity and antitumor effects compared to free Asp due to the dual protection of the supramolecular complex and the nanovesicle, the CD44 targeting-homing ability, the prolonged effects of HA-g-PEG, and the favorable inner microenvironment of the constructed supramolecular CmN. The A-S-CmN also showed a decrease in in vivo toxicity and immunogenicity. CmN combined with SmT therapeutics are easy to implement and extend for use in the delivery of various enzymes and for many types of cancer treatment.

Biomimetic Membrane-Structured Nanovesicles Carrying a Supramolecular Enzyme to Cure Lung Cancer.

Platforms for enzyme delivery must simultaneously have plasma stability, high catalytic activity, and low/no immunogenicity of the enzyme. Here, we designed a novel biomimetic membrane-structured nanovesicle (BNV) to efficiently carry supramolecular enzymes to meet the above requirements. We complexed l-asparaginase (Aase) with hydroxypropyl-ß-cyclodextrin (HPCD) to form a supramolecular amphiphile (AS) by self-assembly via noncovalent reversible interactions. We then used the first synthesized polyethylene glycol (PEG 2 kDa)-decorated hyaluronan (12 kDa) and HPCD to self-assemble a semipermeable biomimetic membrane-structured nanovesicle (BNV) together with AS loading. As compared to native Aase, AS@BNV exhibited superior catalytic activity preservation, improved catalytic activity, better pharmacokinetics in rats, enhanced cytotoxic effects, increased antitumor efficacy, and decreased side effects. The underlying mechanisms, such as the autophagy inhibition action against tumor cells, protein-protein docking of the interaction between Aase-serum albumin, and decreased hepatic enzymatic activity, were investigated. This approach paves the way for new types of powerful biomimetic-, supramolecular-, and nanocarrier-based enzymatic therapies.