Effective reversal of tumor immunosuppression is of critical importance in cancer therapy. A multifunctional delivery vector that can effectively deliver CRISPR‐Cas9 plasmid for β‐catenin knockout to ...reverse tumor immunosuppression is constructed. The multi‐functionalized delivery vector is decorated with aptamer‐conjugated hyaluronic acid and peptide‐conjugated hyaluronic acid to combine the tumor cell/nuclear targeting function of AS1411 with the cell penetrating/nuclear translocation function of TAT‐NLS. Due to the significantly enhanced plasmid enrichment in malignant cell nuclei, the genome editing system can induce effective β‐catenin knockout and suppress Wnt/β‐catenin pathway, resulting in notably downregulated proteins involved in tumor progression and immunosuppression. Programmed death‐ligand 1 (PD‐L1) downregulation in edited tumor cells not only releases the PD‐1/PD‐L1 brake to improve the cancer killing capability of CD8+ T cells, but also enhances antitumor immune responses of immune cells. This provides a facile strategy to reverse tumor immunosuppression and to restore immunosurveillance and activate anti‐tumor immunity.
An aptamer/peptide‐functionalized delivery vector is constructed to effectively deliver CRISPR‐Cas9 plasmid to tumor cells for β‐catenin knockout to eliminate tumor immunosuppression. The significantly decreased programmed death‐ligand 1 (PD‐L1) in edited tumor cells not only releases the PD‐1/PD‐L1 brake to improve the cancer‐killing capability of T cells, but also enhances the antitumor immune responses of the immune cells co‐cultured with edited tumor cells.
Summary
Background
Treatment of chronic drug‐induced liver injury (DILI) or herb‐induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications ...for corticosteroids for chronic DILI/HILI.
Aims
To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI.
Methods
This was a randomised open‐label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48‐week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48‐week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety.
Results
Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40 years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p = 0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)‐like DILI and non‐AIH‐like subgroups, showed comparable responses. No severe adverse events were observed during the trial.
Conclusion
This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH‐like features can achieve both biochemical response and histological improvements with good safety. (ClinicalTrials.gov, NCT 02651350).
Berberine is an important traditional medicinal herb, which has been effectively used in the treatment of dysentery, diarrhea, stomatitis, throat infections, and hepatitis in folk medicine. In this ...study, the interaction between Berberine and human serum albumin (HSA) was investigated by fluorescence spectroscopy and UV−vis absorbance spectroscopy. In the mechanism discussion, it was proved that the fluorescence quenching of HSA by berberine is a result of the formation of berberine−HSA complex. Fluorescence quenching constants were determined using the Stern−Volmer equation and Scatchard equation to provide a measure of the binding affinity between berberine and HSA. The results of thermodynamic parameters ΔG, ΔH, and ΔS at different temperatures indicate that the electrostatic interactions play a major role for berberine−HSA association. Site marker competitive experiments indicated that the binding of berberine to HSA primarily took place in subdomain IIA. Furthermore, the distance r between donor (Trp-214) and acceptor (berberine) was obtained according to fluorescence resonance energy transfer (FRET).
Highly stretchable and electrically conductive thermoplastic polyurethane (TPU) nanofibrous composite based on electrospinning for flexible strain sensor and stretchable conductor has been fabricated ...via in situ polymerization of polyaniline (PANI) on TPU nanofibrous membrane. The PANI/TPU membrane-based sensor could detect a strain from 0 to 160% with fast response and excellent stability. Meanwhile, the TPU composite has good stability and durability. Besides, the composite could be adapted to various non-flat working environments and could maintain opportune conductivity at different operating temperatures. This work provides an easy operating and low-cost method to fabricate highly stretchable and electrically conductive nanofibrous membrane, which could be applied to detect quick and tiny human actions.
Background and Aims
To clarify high‐risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI.
Approach and Results
...Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high‐risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3‐fold in patients with significant inflammation compared to none or mild inflammation (p < 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR‐6) with a concordance index of 0.824 (95% CI, 0.798–0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort.
Conclusions
Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR‐6 model provides an easy‐to‐use approach to assess the outcome of chronic DILI.
Background and Aim
Chinese herbal medicine (CHM), as well as Western medicine (WM), is an important cause of drug‐induced liver injury (DILI). However, the differences between CHM and WM as agents ...implicated in liver injury have rarely been reported.
Methods
Overall, 1985 (2.05%) DILI cases were retrospectively collected from the 96 857 patients hospitalized because of liver dysfunction in the 302 Military Hospital between January 2009 and January 2014.
Results
In all the enrolled patients with DILI, CHM was implicated in 563 cases (28.4%), while 870 cases (43.8%) were caused by WM and the remaining patients (27.8%) by the combination of WM and CHM. Polygonum multiflorum was the major implicated CHM. Compared with WM, the cases caused by CHM showed more female (51 vs 71%, P < 0.001) and positive rechallenge (6.1 vs 8.9%, P = 0.046), a much greater proportion of hepatocellular injury (62.2 vs 88.5%, P < 0.001), and a higher mortality (2.8 vs 4.8%, P = 0.042); however, no differences in the rates of chronic DILI and ALF were found (12.9 vs 12.4%, P = 0.807; 7.6 vs 7.6%, P = 0.971). Based on Roussel Uclaf Causality Assessment Method, 75.6% of cases caused by CHM were classified as probable and only 16.6% as highly probable, significantly different from WM (38.4 and 60.3%, all P < 0.001).
Conclusions
The causal relationship between CHM and liver injury is much complex, and the clinical characteristics of DILI caused by CHM differ from those caused by WM.
Motivated by the LHCb observation of exotic states
X
0
,
1
(
2900
)
with four open quark flavors in the
D
-
K
+
invariant mass distribution in the decay channel
B
±
→
D
+
D
-
K
±
, we study the ...spectrum and decay properties of the open charm tetraquarks. Using the two-body chromomagnetic interactions, we find that the two newly observed states can be interpreted as a radial excited tetraquark with
J
P
=
0
+
and an orbitally excited tetraquark with
J
P
=
1
-
, respectively. We then explore the mass and decays of the other flavor-open tetraquarks made of
s
u
d
¯
c
¯
and
d
s
u
¯
c
¯
, which are in the
6
¯
or 15 representation of the flavor SU(3) group. We point that these two states can be found through the decays:
X
d
s
u
¯
c
¯
(
′
)
→
(
D
-
K
-
,
D
s
-
π
-
)
, and
X
s
u
d
¯
c
¯
(
′
)
→
D
s
-
π
+
. We also apply our analysis to open bottom tetraquark
X
b
and predict their masses. The open-flavored
X
b
can be discovered through the following decays:
X
u
d
s
¯
b
¯
→
B
0
K
+
,
X
d
s
u
¯
b
¯
(
′
)
→
(
B
0
K
-
,
B
s
0
π
-
)
, and
X
s
u
d
¯
b
¯
(
′
)
→
B
s
0
π
+
.
In this tutorial review, we will explore recent advances in the construction and application of Förster resonance energy transfer (FRET)-based small-molecule fluorescent probes. The advantages of ...FRET-based fluorescent probes include: a large Stokes shift, ratiometric sensing and dual/multi-analyte responsive systems. We discuss the underlying energy donor-acceptor dye combinations and emphasise their applications for the detection or imaging of cations, anions, small neutral molecules, biomacromolecules, cellular microenvionments and dual/multi-analyte responsive systems.
In this tutorial review, we will explore recent advances in the construction and application of Förster resonance energy transfer (FRET)-based small-molecule fluorescent probes.
Aim
The aim of this study was to use a metabonomics approach to identify potential biomarkers of exhaled breath condensate (EBC) for predicting the prognosis of acute‐on‐chronic liver failure (ACLF).
...Methods
Using liquid chromatography mass spectrometry, EBC metabolites of ACLF patients surviving without liver transplantation (n = 57) and those with worse outcomes (n = 45), and controls (n = 15) were profiled from a specialized liver disease center in Beijing. The metabolites were used to identify candidate biomarkers, and the predicted performance of potential biomarkers was tested.
Results
Forty‐one metabolites, involving glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, and amino acid metabolism, as candidate biomarkers for discriminating the different outcomes of ACLF were selected. A prognostic model was constructed by a panel of four metabolites including phosphatidylinositol 20:4(5Z,8Z,11Z,14Z)/13:0, phosphatidyl ethanolamine (12:0/22:0), L‐metanephrine and ethylbenzene, which could predict the worse prognosis in ACLF patients with sensitivity (84.4%) and specificity (89.5%) (area under the receiver operating characteristic curve AUC = 0.859, 95% confidence interval CI = 0.787–0.931). Compared with Model for End‐Stage Liver Disease (MELD) score (AUC = 0.639, 95% CI = 0.526–0.753) and MELD‐sodium (MELD‐Na) score (AUC = 0.692, 95% CI = 0.582–0.803), EBC‐associated metabolite signature model could better predict worse outcomes in patients with ACLF (p < 0.05). Using the MELD‐Na score and EBC metabolite signatures, a decision tree model was built for predicting the prognosis of ACLF identified on logistic regression analyses (AUC = 0.906, 95% CI = 0.846–0.965).
Conclusion
EBC metabolic signatures show promise as potential biomarkers for predicting worse prognosis of ACLF.
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