Anode Materials
In article number 2105228, Ming‐Sheng Wang and co‐workers reveal the encapsulation mechanism and confined growth kinetics of lithium crystals in carbonaceous nanotubes by in situ ...transmission electron microscopy. Unusual Li nanostructures such as 2D membranes and multi‐crystal nanowires are discovered. Importantly, sufficient nitrogen/oxygen doping or pre‐lithiation would be critical for the carbon hosts to reliably encapsulate Li metal in a battery anode.
Induction of broadly neutralizing monoclonal antibodies (bNAbs) that bind to the viral envelope glycoproteins is a major goal of hepatitis C virus (HCV) vaccine research. The study of bNAbs arising ...in natural infection is essential in this endeavor. We generated a human antibody, 8D6, recognizing the E2 protein of HCV isolated from a chronic hepatitis C patient. This antibody shows broadly neutralizing activity, which covers a pan-genotypic panel of cell culture-derived HCV virions (HCVcc). Functional and epitope analyses demonstrated that 8D6 can block the interaction between E2 and CD81 by targeting a highly conserved epitope on E2. We describe how the 8D6 lineage evolved via somatic hypermutation to achieve broad neutralization. We found that the V(D)J recombination-generated junctional and somatic hypermutation-induced disulfide bridge (C-C) motif in the CDRH3 is critical for the broad neutralization and binding activity of 8D6. This motif is conserved among a series of broadly neutralizing HCV antibodies, indicating a common binding model. Next, the 8D6 inferred germline (iGL) was reconstructed and tested for its binding affinity and neutralization activity. Interestingly, 8D6 iGL-mediated relatively strong inhibition of the 1b genotype PR79L9 strain, suggesting that PR79L9 may serve as a potential natural viral strain that provides E2 sequences that induce bNAbs. Overall, our detailed epitope mapping and genetic studies of the HCV E2-specific mAb 8D6 have allowed for further refinement of antigenic sites on E2 and reveal a new mechanism to generate a functional CDRH3, while its iGL can serve as a probe to identify potential HCV vaccine strains.
Purpose
This trial evaluated the addition of cetuximab to a modified FOLFOXIRI (mFOLFOXIRI: 5‐fluorouracil/folinic acid, oxaliplatin, irinotecan) as conversion therapy in a two‐group, nonrandomized, ...multicenter, phase II trial in patients with initially technically unresectable colorectal liver‐limited metastases (CLM) and BRAF/RAS wild‐type.
Patients and Methods
Patients were enrolled to receive cetuximab (500 mg/m2) plus mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, folinic acid 400 mg/m2, 5‐fluorouracil 2,800 mg/m2 46‐hour infusion, every 2 weeks) (the cetuximab group) or the same regimen of mFOLFOXIRI alone (the control group), in a 2:1 ratio allocation. The primary endpoint was the rate of no evidence of disease (NED) achieved. Secondary endpoints included resection rate, objective response rate (ORR), survival, and safety.
Results
Between February 2014 and July 2019, 117 patients were registered for screening at six centers in China, and 101 of these were enrolled (67 cetuximab group, 34 control group). The rate of NED achieved was 70.1% in the cetuximab group and 41.2% in the control group (difference 29.0%; 95% confidence interval CI, 9.1%–48.8%; p = .005). Patients in the cetuximab group had improved ORR (95.5% vs. 76.5%; difference 19.1%; 95% CI, 17.4%–36.4%; p = .010) compared with those in control group. Progression‐free survival and overall survival showed the trend to favor the cetuximab group. The incidence of grade 3 and 4 adverse events was similar in the two groups.
Conclusion
Addition of cetuximab to mFOLFOXIRI improved the rate of NED achieved. This combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable CLM.
Implications for Practice
This trial evaluated the addition of cetuximab to a modified FOLFOXIRI as conversion therapy in a phase II trial in patients with initially technically unresectable colorectal liver‐limited metastases and BRAF/RAS wild‐type. The rate of no evidence of disease achieved was 70.1% in the cetuximab plus modified FOLFOXIRI group and 41.2% in the modified FOLFOXIRI group. Objective response rates, overall survival, and progression‐free survival were improved in the cetuximab group when compared with the modified FOLFOXIRI group. Addition of cetuximab to modified FOLFOXIRI increased the rate of no evidence of disease achieved, and this combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable colorectal liver‐limited metastasis.
The FOCULM study was designed to evaluate whether cetuximab would improve the efficacy of a modified FOLFOXIRI regimen as conversion therapy in patients with RAS/BRAF wild‐type unresectable colorectal liver‐limited metastases. Results are reported here.
Chinese Bama minipigs could be potential donors for the supply of xenografts because they are genetically stable, highly inbred, and inexpensive. However, porcine endogenous retrovirus (PERV) is ...commonly integrated in pig genomes and could cause a cross-species infection by xenotransplantation. For screening out the pigs with low copy numbers of PERV proviruses, we have developed a novel semiquantitative analysis approach based on magnetic nanoparticles (MNPs) and chemiluminescence (CL) for estimating relative copy numbers (RCNs) of PERV proviruses in Chinese Bama minipigs. The CL intensities of PERV proviruses and the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were respectively determined with this method, and the RCNs of PERV proviruses were calculated by the equation: RCN of PERV provirus = CL intensity of PERV provirus/CL intensity of GAPDH. The results showed that PERVs were integrated in the genomes of Bama minipigs at different copy numbers, and the copy numbers of PERV-C subtype were greatly low. Two Bama minipigs with low copy numbers of PERV proviruses were detected out and could be considered as xenograft donor candidates. Although only semiquantitation can be achieved, this approach has potential for screening out safe and suitable pig donors for xenotransplantation.
Porcine endogenous retrovirus (PERV) is commonly integrated in pig genomes, and could cause a cross-species infection by xenotransplantation. In this study, we developed a rapid and ultrasensitive ...approach for detection and subtyping of PERV provirus based on magnetic nanoparticles (MNPs) and chemiluminescence (CL). The carboxylated MNPs (CMNPs) were covalently coupled with aminated probes for capturing biotinylated target fragments of PERV, the product of polymerase chain reaction (PCR). Agarose gel electrophoresis analysis approved the reliability of biotinylated fragments. The MNPs composites were incubated with streptavidin-alkaline phosphatase (SA-ALP) and CL signal intensities were determined by subsequently adding 3-(2'-spiroadamantane)-4-methoxy-4-(3"-phosphoryloxy) phenyl-1,2-dioxetane (AMPPD). The optimal assay conditions of this approach were 1 mM for SA modification, 10 µM for probe modification, 55 (PERV), 54 (PERV-A), 50 (PERV-B), and 56 °C (PERV-C) for hybridization temperatures respectively, and 30 min for hybridization time. This approach was specific and highly sensitive, and the limit of detection (LOD) was 100 amol, which has the potential for screening out safe pig donors for xenotransplantation as well as to examine clinical samples from human patients treated with porcine xenotranplantation.
Herein, the ultimate tensile strength and electrical conductivity of precipitation-strengthened Cu-Ni-Si alloys were simultaneously improved by utilizing a machine learning-based multiobjective ...design strategy. The multiobjective design strategy consists of five main steps: creating the initial dataset, generating alloy features, screening key alloy features, modeling and inversely designing, and experimental iteration. Of particular note is the constraint placed on the initial composition-properties dataset, considering the rules governing the addition of Co. This constraint ensures that the dataset adheres to the required specifications. To evaluate the optimized degree of the inverse design composition, a joint expectation improvement function was employed. This function effectively integrates the ultimate tensile strength and electrical conductivity. Through a process of five mutually reinforcing iterations of machine learning and experimentation, the combined property of the designed alloy surpasses the Pareto frontier initially formed by the collected data. Microstructure analysis further confirmed the significant precipitation strengthening effects achieved in the optimized alloy.
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•Machine learning models for UTS and EC of Cu-Ni-Si alloys with high predictive performance were built.•The combined property of inversely designed alloy through ML method achieved significant improvement.•Our composition design strategy achieved prominent precipitation strengthening effects.
To demonstrate the clinical applicability of 3-dimensional CT angiography (3D-CTA) in evaluating the anatomic variations of inferior mesenteric artery (IMA) and left colic artery (LCA), to help make ...pre-operative strategies of rectal cancer surgery.
188 patients with abdominal and pelvic contrast-enhanced CT scan were retrospectively enrolled and 3D-CTA was reconstructed. The origin and branching patterns of IMA, tracking patterns of LCA, intersectional patterns among IMA, LCA and inferior mesenteric vein (IMV) were examined, and their associations with clinical features were analyzed.
The origin of IMA was located 42.1 ± 7.7 mm above iliac artery bifurcation, 64.4% within the area of the 3rd lumbar vertebra. 47.3% of LCA arose independently from IMA, 27.1% arose at the root of sigmoid artery (SA), 20.7% shared a common trunk with SA while 4.8% of LCA was absent. As for track of LCA before anastomosis with marginal artery, 53.2% went straight upward while medial to the inner border of left kidney (Type A), 27.1% traveled diagonally across left kidney (Type B) and14.9% went infero-laterally to the lower border of left kidney (Type C). Short IMA trunk was independently associated with type A LCA and lower site of IMA origin. At the horizontal level of IMA origin, 29% of the LCA went distant from IMV, while 71% (21% medial, 50% lateral) were mutually close, and the close type was independently associated with type A LCA.
Preoperative understanding of the vascular variations and the mutual relationship among LCA, IMA and IMV could be obtained by 3D-CTA, which would further help surgeons to set detailed plans for laparoscopic rectal cancer surgery.
•Different types of left colic artery anatomy was displayed.•Intersectional patterns among IMA, LCA and IMV were evaluated.•There were specific clinical characteristics for type A LCA.
Subcutaneous microvascular visualization is important for accurate diagnosis and precise treatment of those diseases that are associated with subcutaneous microangiopathy. Pure optical imaging ...technology and ultrasound imaging technology are commonly used to observe subcutaneous blood vessels non-invasively. However, pure optical imaging is limited to visualizing superficial skin features due to the strong scattering of light by biological tissues, while ultrasound imaging which can detect deep tissues has poor resolution and low contrast to reveal microvascular networks. This results in a lack of intuitive understanding of the disease lesion.
A miniaturized photoacoustic (PA) probe, which is capable of imaging subcutaneous microvessels with high resolution and deep penetration, was built in this work. The probe is small enough to be hand-held and takes 16 seconds to obtain a maximum amplitude projection image of 400×400 pixels with the imaging area of 2×2 mm
.
The miniaturized PA probe was measured to have a lateral resolution of about 8.9 µm and an imaging depth of about 2.4 mm. Besides,
animal experiments and human skin imaging have been implemented. The results show that the miniaturized PA probe not only visualizes the subcutaneous microvessels, but also obtains quantitative information such as the diameters and the depths of blood vessels.
The miniaturized PA probe has potential been used into clinic, and providing quantitative blood vessel information for the diagnosis and monitoring of vascular diseases.
Although molecular hydrogen (H
) has potential therapeutic effects in animals, whether or how this gas functions in plant disease resistance has not yet been elucidated. Here, after rice stripe virus ...(RSV) infection, H
production was pronouncedly stimulated in Zhendao 88, a resistant rice variety, compared to that in a susceptible variety (Wuyujing No.3). External H
supply remarkably reduced the disease symptoms and RSV coat protein (CP) levels, especially in Wuyujing No.3. The above responses were abolished by the pharmacological inhibition of H
production. The transgenic
plants overexpressing a hydrogenase gene from Chlamydomonas reinhardtii also improved plant resistance. In the presence of H
, the transcription levels of salicylic acid (SA) synthetic genes were stimulated, and the activity of SA glucosyltransferases was suppressed, thus facilitating SA accumulation. Genetic evidence revealed that two SA synthetic mutants of
(
and
) were more susceptible to RSV than the wild type (WT). The treatments with H
failed to improve the resistance to RSV in two SA synthetic mutants. The above results indicated that H
enhances rice resistance to RSV infection possibly through the SA-dependent pathway. This study might open a new window for applying the H
-based approach to improve plant disease resistance.
Although molecular hydrogen has potential therapeutic effects in animals, whether or how this gas functions in plant disease resistance has not yet been elucidated. RSV was considered the most devastating plant virus in rice, since it could cause severe losses in field production. This disease was thus selected as a classical model to explore the interrelationship between molecular hydrogen and plant pathogen resistance. In this study, we discovered that both exogenous and endogenous H
could enhance plant resistance against
infection by regulating salicylic acid signaling. Compared with some frequently used agrochemicals, H
is almost nontoxic. We hope that the findings presented here will serve as an opportunity for the scientific community to push hydrogen-based agriculture forward.
Although neoadjuvant chemo-radiotherapy (CRT) achieves low local recurrence rates in locally advanced rectal cancer (LARC), it raises a lot of concerns about long-term anal and sexual functions. We ...explored the efficacy of preoperative chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in patients with LARC.
Patients with LARC evaluated by pelvic magnetic resonance imaging (MRI) were enrolled in this trial. All received 4 to 6 cycles of mFOLFOXIRI. MRI was performed to assess clinical response after chemotherapy. Patients with mesorectal fascia-positive or ycT4a/b after re-evaluation would receive radiation before surgery, whereas responders would have immediate total mesorectal excision (TME). Adjuvant chemotherapy with mFOLFOX6 (folinic acid, 5-fluorouracil, and oxaliplatin) was recommended. The primary endpoint was the proportion of tumor downstaging to ypT0-2N0M0. The secondary endpoints were pathologic complete response rate (pCR), 3-year disease-free survival rate, and safety.
Overall, 106 patients were enrolled and received neoadjuvant mFOLFOXIRI chemotherapy. A total of 103 participants underwent TME surgery. Among 103 patients who completed at least 4 cycles of preoperative chemotherapy, 2 received short-term radiation before TME, and 12 underwent long-term CRT after MRI evaluation. The pCR rate was 20.4%, and the tumor downstaging rate was 42.7%. Among patients without preoperative long-term radiotherapy, the pCR rate and tumor downstaging rate were 17.4% and 41.3%, respectively. Among the per-protocol population, the tumor downstaging rate was 48.1%, and the pCR rate was 20.3%. The chemotherapy-related toxicity was well-tolerated.
Neoadjuvant chemotherapy with mFOLFOXIRI and selective radiation does not seem to compromise outcomes in LARC. It could be a reasonable alternative to CRT in previously untreated patients with LARC.
The efficacy of preoperative chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in 106 enrolled patients with locally advanced rectal cancer in a phase II trial was explored. The endpoints included tumor downstaging to ypT0-2N0M0, pathologic complete response rate, disease-free survival rate, and safety. The pathologic complete response and tumor downstaging rates were 20.4% and 42.7%, respectively. Neoadjuvant chemotherapy with mFOLFOXIRI and selective radiation did not compromise outcomes in locally advanced rectal cancer.
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