One important goal of the current electrocatalysis is to develop integrated electrodes from the atomic level design to multilevel structural engineering in simple ways and low prices. Here, a series ...of oxygen micro‐alloyed high‐entropy alloys (O‐HEAs) is developed via a metallurgy approach. A (CrFeCoNi)97O3 bulk O‐HEA shows exceptional electrocatalytic performance for the oxygen evolution reaction (OER), reaching an overpotential as low as 196 mV and a Tafel slope of 29 mV dec−1, and with stability longer than 120 h in 1 m KOH solution at a current density of 10 mA cm−2. It is shown that the enhanced OER performance can be attributed to the formation of island‐like Cr2O3 microdomains, the leaching of Cr3+ ions, and structural amorphization at the interfaces of the domains. These findings offer a technological‐orientated strategy to integrated electrodes.
A new class of bulk electrodes is designed by incorporating oxide microdomains into the so‐called high‐entropy alloys (HEAs). From these, unprecedented oxygen evolution reaction (OER) activity is achieved, with an ultralow overpotential of 196 mV and a Tafel slope of 29 mV dec−1, and with stability longer than 120 h in 1 m KOH solution at current density of 10 mA cm−2.
Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully ...understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3–13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4
+
and/or CD8
+
T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4
+
and CD8
+
T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients.
Trial registration
ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016).
The effects of HLA-identical sibling donor (ISD) hematopoietic stem cell transplantation (HSCT) on adults with intermediate- or high-risk acute myeloid leukemia (AML) in the first complete remission ...(CR1) are well established. Previous single-center studies have demonstrated similar survival after unmanipulated haploidentical donor (HID) vs ISD HSCT for hematologic malignancies. To test the hypothesis that haploidentical HSCT would be a valid option as postremission therapy for AML patients in CR1 lacking a matched donor, we designed a disease-specific, prospective, multicenter study. Between July 2010 and November 2013, 450 patients were assigned to undergo HID (231 patients) or ISD HSCT (219 patients) according to donor availability. Among HID and ISD recipients, the 3-year disease-free survival rate was 74% and 78% (P = .34), respectively; the overall survival rate was 79% and 82% (P = .36), respectively; cumulative incidences of relapse were 15% and 15% (P = .98); and those of the nonrelapse-mortality were 13% and 8% (P = .13), respectively. In conclusion, unmanipulated haploidentical HSCT achieves outcomes similar to those of ISD HSCT for AML patients in CR1. Such transplantation was demonstrated to be a valid alternative as postremission treatment of intermediate- or high-risk AML patients in CR1 lacking an identical donor. This trial was registered at www.chictr.org as #ChiCTR-OCH-10000940.
•Haploidentical transplant achieves outcomes similar to those of identical-sibling transplant for AML patients in first remission.•Haploidentical transplant is a valid postremission treatment of intermediate- or high-risk AML patients lacking an identical donor.
This study evaluated the effects of pretransplantation minimal residual disease (pre‐MRD) on outcomes of patients with acute lymphoblastic leukemia (ALL) who underwent unmanipulated haploidentical ...stem cell transplantation (haplo‐SCT). A retrospective study including 543 patients with ALL was performed. MRD was determined using multiparametric flow cytometry. Both in the entire cohort of patients and in subgroup cases with T‐ALL or B‐ALL, patients with positive pre‐MRD had a higher incidence of relapse (CIR) than those with negative pre‐MRD in MSDT settings (P < 0.01 for all). Landmark analysis at 6 months showed that MRD positivity was significantly and independently associated with inferior rates of relapse (HR, 1.908; P = 0.007), leukemia‐free survival (LFS) (HR, 1.559; P = 0.038), and OS (HR, 1.545; P = 0.049). The levels of pre‐MRD according to a logarithmic scale were also associated with leukemia relapse, LFS, and OS, except that cases with MRD <0.01% experienced comparable CIR and LFS to those with negative pre‐MRD. A risk score for CIR was developed using the variables pre‐MRD, disease status, and immunophenotype of ALL. The CIR was 14%, 26%, and 59% for subjects with scores of 0, 1, and 2‐3, respectively (P < 0.001). Three‐year LFS was 75%, 64%, and 42%, respectively (P < 0.001). Multivariate analysis confirmed the association of the risk score with CIR and LFS. The results indicate that positive pre‐MRD, except for low level one (MRD < 0.01%), is associated with poor outcomes in patients with ALL who underwent unmanipulated haplo‐SCT.
Objective
This randomized double-blinded clinical study is to investigate the clinical efficacy of per-paravertebral disk ozone injection combined with steroids in the treatment of patients with ...chronic discogenic low back pain (CDLBP).
Methods
Group A (
N
= 60) received a per-paravertebral injection of a steroid mixture of 10 mL with pure oxygen 20 mL, while group B (
N
= 60) received a per-paravertebral injection of a steroid mixture of 10 mL combined with ozone 20 mL (30 μg/mL). Injections were administered once a week for 3 weeks, with a follow-up of 6 months. Clinical outcomes were assessed at week 1, month 3, and month 6 with the help of Visual Analog Scale (VAS) scores and Macnab efficacy evaluation.
Results
The VAS score of both group A (1.65 vs. 6.87,
p
= 0.000) and group B (1.25 vs. 6.85,
p
= 0.000) at week 1 was significantly reduced compared to baseline. The effect was sustained at the 3- and 6-month follow-up periods (
p
< 0.05). Group B had significantly lower VAS scores at month 3 (1.53 vs. 3.82,
p
= 0.000) and month 6 (2.80 vs. 5.05,
p
= 0.000) compared to group A, respectively. Based on Macnab criteria, 95 and 96.7% of patients in groups A and B had good rates “excellent plus good” at week 1, respectively. Good rates were significantly higher in group B at month 3 (91.7 vs. 78.3%,
p
= 0.041) and month 6 (85.0 vs. 68.3%,
p
= 0.031) compared to group A, respectively. No serious adverse events were noted in both groups.
Conclusion
Per-paravertebral injection of steroid and ozone combination resulted in better relief of CDLBP compared to pure oxygen plus steroid.
Clinical Trial Registration
ChiCTR2100044434
https://www.chictr.org.cn/showproj.html?proj=121571
.
BackgroundThe advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed ...to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.MethodsWhole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.ResultsThe HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.ConclusionsThe combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.
Conjugated microporous polymers (CMP) as porous functional materials have received considerable attention due to their unique structures and fascinating properties for the adsorption and degradation ...of dyes. Herein, a triazine-conjugated microporous polymer material with rich N-donors at the skeleton itself was successfully synthesized via the Sonogashira-Hagihara coupling by a one-pot reaction. These two polymers had Brunauer-Emmett-Teller (BET) surface areas of 322 and 435 m
g
for triazine-conjugated microporous polymers (T-CMP) and T-CMP-Me, respectively. Due to the porous effects and the rich N-donor at the framework, it displayed a higher removal efficiency and adsorption performance compared to cationic-type dyes and selectivity properties for (methylene blue) MB
from a mixture solution of cationic-type dyes. Furthermore, the T-CMP-Me could quickly and drastically separate MB
and (methyl orange) MO
from the mixed solution within a short time. Their intriguing absorption behaviors are supported by
C NMR, UV-vis absorption spectroscopy, scanning electron microscopy, and X-ray powder diffraction studies. This work will not only improve the development of porous material varieties, but also demonstrate the adsorption or selectivity of porous materials for dyes from wastewater.
Investigation of proteins in their native state is the core of proteomics towards better understanding of their structures and functions. Surface-enhanced Raman spectroscopy (SERS) has shown its ...unique advantages in protein characterization with fingerprint information and high sensitivity, which makes it a promising tool for proteomics. It is still challenging to obtain SERS spectra of proteins in the native state and evaluate the native degree. Here, we constructed 3D physiological hotspots for a label-free dynamic SERS characterization of a native protein with iodide-modified 140 nm Au nanoparticles. We further introduced the correlation coefficient to quantitatively evaluate the variation of the native degree, whose quantitative nature allows us to explicitly investigate the Hofmeister effect on the protein structure. We realized the classification of a protein of SARS-CoV-2 variants in 15 min, which has not been achieved before. This study offers an effective tool for tracking the dynamic structure of proteins and biomedical research.
Iodide modified Au nanoparticles combined with correlation coefficient allows label-free SERS characterization of proteins in native state and analysis of Hofmeister effect on protein structure, further enabling identification of protein variants.
We have proved fecal microbiota transplantation (FMT) is an efficacious remedy to mitigate acute radiation syndrome (ARS); however, the mechanisms remain incompletely characterized. Here, we aimed to ...tease apart the gut microbiota-produced metabolites, underpin the therapeutic effects of FMT to radiation injuries, and elucidate the underlying molecular mechanisms.
FMT elevated the level of microbial-derived indole 3-propionic acid (IPA) in fecal pellets from irradiated mice. IPA replenishment via oral route attenuated hematopoietic system and gastrointestinal (GI) tract injuries intertwined with radiation exposure without precipitating tumor growth in male and female mice. Specifically, IPA-treated mice represented a lower system inflammatory level, recuperative hematogenic organs, catabatic myelosuppression, improved GI function, and epithelial integrity following irradiation. 16S rRNA gene sequencing and subsequent analyses showed that irradiated mice harbored a disordered enteric bacterial pattern, which was preserved after IPA administration. Notably, iTRAQ analysis presented that IPA replenishment retained radiation-reprogrammed protein expression profile in the small intestine. Importantly, shRNA interference and hydrodynamic-based gene delivery assays further validated that pregnane X receptor (PXR)/acyl-CoA-binding protein (ACBP) signaling played pivotal roles in IPA-favored radioprotection in vitro and in vivo.
These evidences highlight that IPA is a key intestinal microbiota metabolite corroborating the therapeutic effects of FMT to radiation toxicity. Owing to the potential pitfalls of FMT, IPA might be employed as a safe and effective succedaneum to fight against accidental or iatrogenic ionizing ARS in clinical settings. Our findings also provide a novel insight into microbiome-based remedies toward radioactive diseases. Video abstract.
Collective excitations including plasmons, magnons, and layer‐breathing vibration modes emerge at an ultralow frequency (<1 THz) and are crucial for understanding van der Waals materials. Strain at ...the nanoscale can drastically change the property of van der Waals materials and create localized states like quantum emitters. However, it remains unclear how nanoscale strain changes collective excitations. Herein, ultralow‐frequency tip‐enhanced Raman spectroscopy (TERS) with sub‐10 nm resolution under ambient conditions is developed to explore the localized collective excitation on monolayer semiconductors with nanoscale strains. A new vibrational mode is discovered at around 12 cm−1 (0.36 THz) on monolayer MoSe2 nanobubbles and it is identified as the radial breathing mode (RBM) of the curved monolayer. The correlation is determined between the RBM frequency and the strain by simultaneously performing deterministic nanoindentation and TERS measurement on monolayer MoSe2. The generality of the RBM in nanoscale curved monolayer WSe2 and bilayer MoSe2 is demonstrated. Using the RBM frequency, the strain of the monolayer MoSe2 on the nanoscale can be mapped. Such an ultralow‐frequency vibration from curved van der Waals materials provides a new approach to study nanoscale strains and points to more localized collective excitations to be discovered at the nanoscale.
Ultralow‐frequency tip‐enhanced Raman scattering discovers a new breathing mode on 2D semiconductors with strain at nanoscale. This new vibrational mode is a radial breathing mode from nanoscale curvature and can be utilized to image the nanostrain of 2D materials.
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