A randomized double-blinded trial to assess recurrence of systemic allergic reactions following COVID-19 mRNA vaccination.

BACKGROUND: Systemic allergic reactions (sARs) following coronavirus disease 2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than after traditional vaccines. OBJECTIVE: We aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions. METHODS: In this randomized, double-blinded, phase 2 trial, participants aged 16 to 69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive a second dose of BNT162b2 (Comirnaty) vaccine and placebo on consecutive days in a blinded, 1:1 crossover fashion at the National Institutes of Health. An open-label BNT162b2 booster was offered 5 months later if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Spikevax) vaccine during the study. The primary end point was recurrence of sAR following second dose and booster vaccination; exploratory end points included biomarker measurements. RESULTS: Of 111 screened participants, 18 were randomly assigned to receive study interventions. Eight received BNT162b2 second dose followed by placebo; 8 received placebo followed by BNT162b2 second dose; 2 withdrew before receiving any study intervention. All 16 participants received the booster dose. Following second dose and booster vaccination, sARs recurred in 2 participants (12.5%; 95% CI, 1.6 to 38.3). No sAR occurred after placebo. An anaphylaxis mimic, immunization stress-related response (ISRR), occurred more commonly than sARs following both vaccine and placebo and was associated with higher predose anxiety scores, paresthesias, and distinct vital sign and biomarker changes. CONCLUSIONS: Our findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs.

An Efficient Electron Ptychography Method for Retrieving the Object Spectrum from Only a Few Iterations.

We present an efficient approach for electron ptychography based on a mathematical relationship that differs from that underlying the established algorithms of the ptychography iterative engine or the noniterative algorithms like the Wigner-distribution-deconvolution or the single-side-band method. Three variables are handled in this method-the transfer function of the objective lens, the object spectrum, and the diffraction wave whose phase is unknown. In the case of an aberration-corrected electron microscope, one is able to obtain a well-estimated transfer function of the lens. After reducing the number of three variables down to two, we construct an iterative loop between the object spectrum and the diffraction wave, which retrieves the object spectrum within a small number of iterations. We tested this object spectrum retrieval method on both a calculated and an experimental 4D-STEM datasets. By applying this method, we explore the influence of sampling, dose, and the size of illumination aperture on the reconstructed phase images.

Spontaneous Redox-Reaction-Driven Growth of Ag Nanoparticles on Co(OH)2 Nanoflower Arrays for Surface-Enhanced Raman Scattering.

A simple and reliable method is developed to fabricate Ag-nanoparticle-decorated Co(OH)2 nanoflowers grafted on polyacrylonitrile (PAN) nanopillar arrays as uniform and sensitive surface-enhanced Raman scattering (SERS) substrates. First, Co(OH)2-nanosheet-assembled nanoflowers are achieved on the highly uniform PAN nanopillar arrays via electrochemical deposition. Then, Ag nanoparticles (Ag-NPs) are decorated onto the Au-nanoparticle-precoated Co(OH)2 nanoflowers based on a spontaneous redox reaction (SRR) between the silver ions and Co(OH)2 nanosheets at room temperature. Ag-NPs can be successfully in situ synthesized on the Co(OH)2 nanoflowers, and Au nanoparticles precoated on the surface of the Co(OH)2 nanosheets can ensure that the Co(OH)2 nanoflower structure does not collapse. Because of the highly uniform PAN nanopillar arrays and the high-density sub-10 nm gaps between the neighboring Ag-NPs on the surface of the Co(OH)2 nanoflowers, the hierarchical three-dimensional Ag@Co(OH)x grown on PAN nanopillar arrays can produce a reproducible and sensitive SERS effect. To verify the SERS performance of the substrate, 4-aminothiophenol (4-ATP) is used as the probe molecule, and the Ag@Co(OH)x grown on PAN nanopillar arrays is employed as the SERS substrate. As a result, 4-ATP concentrations as low as 10-10 M can still be identified, exhibiting high SERS activity. Additionally, the relative standard deviation value of the main characteristic peak of 10-5 M 4-ATP is 9.43%, indicating good uniformity of the SERS signal of the substrate. The SRR between silver ions and Co(OH)2 can provide a simple route to prepare heterostructures as SERS substrates, which has great potential for application in the field of analysis.

Crack Segmentation Extraction and Parameter Calculation of Asphalt Pavement Based on Image Processing.

Crack disease is one of the most serious and common diseases in road detection. Traditional manual methods for measuring crack detection can no longer meet the needs of road crack detection. In previous work, the authors proposed a crack detection method for asphalt pavements based on an improved YOLOv5s model, which is a better model for detecting various types of cracks in asphalt pavements. However, most of the current research on automatic pavement crack detection is still focused on crack identification and location stages, which contributes little to practical engineering applications. Based on the shortcomings of the above work, and in order to improve its contribution to practical engineering applications, this paper proposes a method for segmenting and analyzing asphalt pavement cracks and identifying parameters based on image processing. The first step is to extract the crack profile through image grayscale, histogram equalization, segmented linear transformation, median filtering, Sauvola binarization, and the connected domain threshold method. Then, the magnification between the pixel area and the actual area of the calibration object is calculated. The second step is to extract the skeleton from the crack profile images of asphalt pavement using the Zhang-Suen thinning algorithm, followed by removing the burrs of the crack skeleton image using the connected domain threshold method. The final step is to calculate physical parameters, such as the actual area, width, segments, and length of the crack with images obtained from the crack profile and skeleton. The results show that (1) the method of local thresholding and connected domain thresholding can completely filter noise regions under the premise of retaining detailed crack region information. (2) The Zhang-Suen iterative refinement algorithm is faster in extracting the crack skeleton of asphalt pavement, retaining the foreground features of the image better, while the connected-domain thresholding method is able to eliminate the missed isolated noise. (3) In comparison to the manual calibration method, the crack parameter calculation method proposed in this paper can better complete the calculation of crack length, width, and area within an allowable margin of error. On the basis of this research, a windowing system for asphalt pavement crack detection, WSPCD1.0, was developed. It integrates the research results from this paper, facilitating automated detection and parameter output for asphalt pavement cracks.

RBCK1 is an endogenous inhibitor for triple negative breast cancer via hippo/YAP axis.

BACKGROUND: Triple negative breast cancer (TNBC) is one of the most lethal breast cancer subtypes. Due to a lack of effective therapeutic targets, chemotherapy is still the main medical treatment for TNBC patients. Thus, it is important and necessary to find new therapeutic targets for TNBC. Recent genomic studies implicated the Hippo / Yap signal is over activated in TNBC, manifesting it plays a key role in TNBC carcinogenesis and cancer progression. RBCK1 was firstly identified as an important component for linear ubiquitin assembly complex (LUBAC) and facilitates NFKB signaling in immune response. Further studies showed RBCK1 also facilitated luminal type breast cancer growth and endocrine resistance via trans-activation estrogen receptor alpha. METHODS: RBCK1 and YAP protein expression levels were measured by western blotting, while the mRNA levels of YAP target genes were measured by RT-PCR. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of Hippo signaling activity was accomplished with luciferase assays, RT-PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect YAP protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the YAP protein. RESULTS: In our current study, our data revealed an opposite function for RBCK1 in TNBC progression. RBCK1 over-expression inhibited TNBC cell progression in vitro and in vivo, while RBCK1 depletion promoted TNBC cell invasion. The whole genomic expression profiling showed that RBCK1 depletion activated Hippo/YAP axis. RBCK1 depletion increased YAP protein level and Hippo target gene expression in TNBC. The molecular biology studies confirmed that RBCK1 could bind to YAP protein and enhance the stability of YAP protein by promoting YAP K48-linked poly-ubiquitination at several YAP lysine sites (K76, K204 and K321). CONCLUSION: Our study revealed the multi-faced RBCK1 function in different subtypes of breast cancer patients and a promising therapeutic target for TNBC treatment. Video abstract.

TRIM3 facilitates estrogen signaling and modulates breast cancer cell progression.

BACKGROUND: Breast cancer is the most common cancer in women worldwide. More than 70% of breast cancers are estrogen receptor (ER) alpha positive. Compared with ER alpha-negative breast cancer, which is more aggressive and has a shorter survival time, ER alpha-positive breast cancer could benefit from endocrine therapy. Selective estrogen receptor modulators, such as tamoxifen, are widely used in endocrine therapy. Approximately half of ER alpha-positive breast cancer patients will eventually develop endocrine resistance, making it a major clinical challenge in therapy. Thus, decoding the throughput of estrogen signaling, including the control of ER alpha expression and stability, is critical for the improvement of breast cancer therapeutics. METHODS: TRIM3 and ER alpha protein expression levels were measured by western blotting, while the mRNA levels of ER alpha target genes were measured by RT-PCR. A CCK-8 assay was used to measure cell viability. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling activity was accomplished with luciferase assays, RT-PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect ER alpha protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the ER alpha protein. RESULTS: In our current study, we found that TRIM3, an E3 ligase, can promote ER alpha signaling activity and breast cancer progression. TRIM3 depletion inhibits breast cancer cell proliferation and migration, while unbiased RNA sequencing data indicated that TRIM3 is required for the activity of estrogen signaling on the -genome-wide scale. The immunoprecipitation assays indicated that TRIM3 associates with ER alpha and promotes its stability, possibly by inducing K63-linked polyubiquitination of ER alpha. In conclusion, our data implicate a nongenomic mechanism by which TRIM3 stabilizes the ER alpha protein to control ER alpha target gene expression linked to breast cancer progression. CONCLUSION: Our study provides a novel posttranslational mechanism in estrogen signaling. Modulation of TRIM3 expression or function could be an interesting approach for breast cancer treatment. Video abstract.

Integrated Differential Phase Contrast (IDPC)-STEM Utilizing a Multi-Sector Detector for Imaging Thick Samples.

The integrated differential phase contrast (IDPC) method is useful for generating the potential map of a thin sample. We evaluate theoretically the potential of IDPC imaging for thick samples by varying the focus at different sample thicknesses. Our calculations show that high defocus values result in enhanced anisotropy of the contrast transfer function (CTF) and uninterpretable images, if a quadrant detector is applied. We further show that applying a multi-sector detector can result in an almost isotropic CTF. By sector number-dependent calculations for both Cc/C3-corrected and C3-corrected scanning transmission electron microscopy (STEM), we show that the increase of detector sectors not only removes the anisotropy of the CTF, but also improves image contrast and resolution. For a proof-of-principle IDPC-STEM (uncorrected) experiment, we realize the functionality of a 12-sector detector from a physical quadrant detector and demonstrate the improvement in contrast and resolution on the example of InGaN/GaN quantum well structure.

Computationally Efficient Handling of Partially Coherent Electron Sources in (S)TEM Image Simulations via Matrix Diagonalization.

We introduce a novel method to improve the computational efficiency for (S)TEM image simulation by employing matrix diagonalization of the mixed envelope function (MEF). The MEF is derived by taking the finite size and the energy spread of the effective electron source into account, and is a component of the transmission cross-coefficient that accounts for the correlation between partially coherent waves. Since the MEF is a four-dimensional array and its application in image calculations is time-consuming, we reduce the computation time by using its eigenvectors. By incorporating the aperture function into the matrix diagonalization, only a small number of eigenvectors are required to approximate the original matrix with high accuracy. The diagonalization enables for each eigenvector the calculation of the corresponding image by employing the coherent model. The individual images are weighted by the corresponding eigenvalues and then summed up, resulting in the total partially coherent image.

Urchin-like ZnO-nanorod arrays templated growth of ordered hierarchical Ag/ZnO hybrid arrays for surface-enhanced Raman scattering.

Here, a universal strategy for the controllable synthesis of three dimensional (3D) hierarchical Ag/ZnO hybrid arrays based on the urchin-like ZnO-nanorod array template is presented. The urchin-like ZnO-nanorod arrays are first achieved by electrodepositing a high density of ZnO-nanorods onto the surface of highly hexagonally arranged arrays of polystyrene (PS) microspheres, and then Ag-nanoparticles (Ag-NPs) are assembled onto the surface of each ZnO-nanorod via photochemical reaction, ion sputtering, galvanic cell reaction deposition and electrochemical deposition, forming the ordered hierarchical Ag/ZnO hybrid arrays. The urchin-like Ag/ZnO hybrid arrays with well-ordered hierarchical morphology and high density 'hot spots' located in the sub-10 nm gaps between neighboring Ag-NPs on both the same ZnO-nanorod and neighboring ZnO-nanorods can be directly utilized as hybrid surface-enhanced Raman scattering (SERS) substrates with high SERS activity. This work provides a strategy for the rational assembly of well-ordered hierarchical noble metal/semiconductor hybrid arrays, which may open up many opportunities in areas such as catalysis, SERS, and biosensing.

Molecular characterization of hard tick Haemaphysalis longicornis from China by sequences of the internal transcribed spacers of ribosomal DNA.

In the present study, the entire first and second internal transcribed spacer (ITS-1 and ITS-2) regions of nuclear ribosomal DNA (rDNA) of Haemaphysalis longicornis from China were amplified by polymerase chain reaction. The 45 representative amplicons were sequenced, and sequence variation in the ITS was examined. The ITS sequences of H. longicornis were 3644 bp in size, including the part of 18S rDNA, 28S rDNA sequences and the complete ITS-1, 5.8S rDNA and ITS-2 sequences. Sequence analysis revealed that the ITS-1, 5.8S rDNA and ITS-2 of this hard tick were 1582, 152, and 1610 bp in size, respectively. The intra-specific sequence variations of ITS-1 and ITS-2 within H. longicornis were 0-2 and 0-2.2%; however, the inter-specific sequence differences among members of the genus Haemaphysalis were significantly higher, being 35.1-55.2 and 37-52% for ITS-1 and ITS-2, respectively. The molecular approach employed in this study provides the foundation for further studies of the genetic variation of H. longicornis from different hosts and geographical origins in China.

Genetic variation in mitochondrial genes of the tick Haemaphysalis flava collected from wild hedgehogs in China.

The tick Haemaphysalis flava (Acari: Ixodidae) is an important ectoparasite, which causes direct damage to their hosts and also acts as a vector of various infectious disease agents in China. Despite its significance, the epidemiology, genetics and biology of H. flava has not been studied in detail. In the present study, the genetic variation in three mitochondrial (mt) DNA regions, namely cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 and 4 (nad1 and nad4), was examined in H. flava ticks collected from wild hedgehogs in China. A portion of cox1 (pcox1), nad1 (pnad1) and nad4 (pnad4) genes were PCR amplified from individual H. flava ticks and the amplicons were sequenced. The length of the sequences of pcox1, pnad1 and pnad4 were 849, 285 and 626 bp, respectively. The intra-specific sequence variation within H. flava was 0-0.4% for pcox1, 0-0.4% for pnad1 and 0-0.3% for pnad4. However, the inter-specific variation was significantly higher, 12.5-14.3%, 13.6-24.8% and 14.8-19% for pcox1, pnad1 and pnad4, respectively. Phylogenetic analysis based on Maximum likelihood (ML) method using the combined target mt gene sequences confirmed that all isolates of Haemaphysalis were H. flava. The molecular approach employed in this study provides a tool for further elucidating the molecular diversity of H. flava in China and elsewhere in Asia.

Fabrication of hexagonally patterned flower-like silver particle arrays as surface-enhanced Raman scattering substrates.

Hierarchical assembly of plasmonic nanostructures can induce high surface-enhanced Raman scattering (SERS) activity. However, it is a challenge to uniformly disperse the hierarchical nanostructures onto a planar substrate to achieve SERS signal reproducibility. This report presents a facile route to fabricate a hexagonally patterned flower-like silver particle array as the SERS substrate. First, hexagonally ordered silver hemisphere arrays with smooth surface are molded in the pores of an anodic aluminum oxide template. Ag-nanosheets are then electrodeposited onto the surface of individual silver hemispheres. The numerous nano-edges and nano-gaps between adjacent nanosheets render a large number of hot spots, leading to high SERS activity over a larger area of chip. The silver flower-like array is employed as the SERS substrate, which is able to detect 0.1 nM rhodamine 6 G and 1 µM 3,3',4,4'-tetrachlorobiphenyl (PCB-77, a persistent organic pollutant).

An ordered array of hierarchical spheres for surface-enhanced Raman scattering detection of traces of pesticide.

An ordered array of hierarchically-structured core-nanosphere@space-layer@shell-nanoparticles has been fabricated for surface-enhanced Raman scattering (SERS) detection. To fabricate this hierarchically-structured chip, a long-range ordered array of Au/Ag-nanospheres is first patterned in the nano-bowls on the planar surface of ordered nanoporous anodic titanium oxide template. A ultra-thin alumina middle space-layer is then conformally coated on the Au/Ag-nanospheres, and Ag-nanoparticles are finally deposited on the surface of the alumina space-layer to form an ordered array of Au/Ag-nanosphere@Al2O3-layer@Ag-nanoparticles. Finite-difference time-domain simulation shows that SERS hot spots are created between the neighboring Ag-nanoparticles. The ordered array of hierarchical nanostructures is used as the SERS-substrate for a trial detection of methyl parathion (a pesticide) in water and a limit of detection of 1 nM is reached, indicating its promising potential in rapid monitoring of organic pollutants in aquatic environment.

Ag Nanoparticle-Grafted PAN-Nanohump Array Films with 3D High-Density Hot Spots as Flexible and Reliable SERS Substrates.

A facile fabrication approach of large-scale flexible films is reported, with one surface side consisting of Ag-nanoparticle (Ag-NP) decorated polyacrylonitrile (PAN) nanohump (denoted as Ag-NPs@PAN-nanohump) arrays. This is achieved via molding PAN films with ordered nanohump arrays on one side and then sputtering much smaller Ag-NPs onto each of the PAN-nanohumps. Surface-enhanced Raman scattering (SERS) activity of the Ag-NPs@PAN-nanohump array films can be improved by curving the flexible PAN film with ordered nanohump arrays during the Ag-sputtering process to increase the density of the Ag-NPs on the sidewalls of the PAN-nanohumps. More 3D hot spots are thus achieved on a large-scale. The Ag-NPs@PAN-nanohump array films show high SERS activity with good Raman signal reproducibility for Rhodamine 6G probe molecules. To trial their practical application, the Ag-NPs@PAN-nanohump array films are employed as SERS substrates for trace detection of trinitrotoluene and a congener of polychlorinated biphenyls. A lower detection limit of 10(-12) m and 10(-5) m can be achieved, respectively. Furthermore, the flexible Ag-NPs@PAN-nanohump array films can also be utilized as swabs to probe traces of methyl parathion on the surface of fruits such as apples. The as-fabricated SERS substrates therefore have promising potential for applications in rapid safety inspection and environmental protection.

ZnO-Ag hybrids for ultrasensitive detection of trinitrotoluene by surface-enhanced Raman spectroscopy.

An efficient and green approach was used to fabricate novel and low-cost surface-enhanced Raman scattering (SERS) spectroscopy sensors based on 4-aminothiophenol (4-ATP) functionalized ZnO-Ag hybrid nanoflowers for the detection of explosives. Such SERS sensors exhibited high sensitivity to rhodamine 6G (R6G) at a low concentration of 10(-12) M and an enhancement factor of over 4.12 × 10(6) was achieved. Moreover, the Raman-inactive trinitrotoluene (TNT) initiated the high Raman scattering of non-resonated 4-ATP through the formation of a π-donor-π-acceptor interaction between the π-acceptor, TNT, and the π-donor, the 4-ATP-Ag-ZnO complex, on the flower-like hybrids. Because this π-donor-π-acceptor interaction could effectively induce the "hot spots" for SERS, TNT concentrations as low as 5 × 10(-9) M could be detected. Furthermore, other derivatives of TNT were also explored, and this sensor exhibited better selectivity for TNT than other similarly structured explosives. The low-cost hybrid SERS substrates presented good sensitivity and reproducibility for the analytes employed, demonstrating promising application in forensic science and homeland security.

Efficacy of surgical treatment of perianal infection in patients with hematological malignancy.

The efficacy of surgical intervention for perianal infection in patients with hematologic malignancies is not well established. Therefore, our study aimed to investigate the clinical efficacy and complications of surgical treatment of perianal infection in patients with hematologic malignancies. This retrospective study included patients with hematological malignancies who were diagnosed with perianal infections and treated at the China Aerospace Science & Industry Corporation 731 Hospital between 2018 and 2022. Patient characteristics, hematological data, surgical intervention, and complications, including recurrence and mortality, were analyzed. This study included 156 patients with leukemia aged 2 months to 71 years who were treated surgically for perianal infection, comprising 94 males and 62 females. Perianal infection included 36 cases of abscesses, 91 anal fistulas, and 29 anal fissures accompanied by infection. A total of 36 patients developed severe complications postoperatively, including 4 patients who died, 6 patients with severe incision bleeding, 18 patients with severe pain, 6 patients with sepsis, 12 patients who needed reoperation, 15 patients with hospitalization for more than 2 weeks, and 3 patients with anal stenosis; none of the patients developed anal incontinence. Additionally, risk factors for postoperative complications of perianal infection in patients with hematologic malignancies include leukopenia, agranulocytosis, thrombocytopenia, depth of abscess and not undergone an MRI. Surgical intervention may improve the prognosis of patients with perianal abscess formation, particularly in patients who show no improvement with medical therapy and those who develop perianal sepsis. Granulocytopenia and thrombocytopenia should be improved before surgery, which can significantly reduce postoperative complications. Although these findings are from a case series without a comparator, they may be of value to physicians because to the best of our knowledge, no randomized or prospective studies have been conducted on the management of perianal infections in patients with hematological malignancies.

Nanopillar array-based electrochemical aptamer sensor for STX sensitivity detection.

Saxitoxin (STX) is a cyanotoxin with high toxicity, and therefore, there is an urgent need to develop a facile detection method for STX. In this study, an ordered nanopillar array-based electrochemical aptasensor was fabricated for the high-performance detection of STX. The anti-STX aptamer with methylene blue (MB) incorporated at the 3'-end (MB-Apt) was immobilized at the surface of an Au@PAN nanopillar array electrode and used as the recognition element. The proposed aptasensor demonstrated highly sensitive and selective STX detection because of synergistic catalysis effects of MB and ordered nanopillar arrays along with the selection of MB-Apt. The nanopillar array-based electrochemical aptasensor exhibited high sensitivity over a wide linear concentration range of 1 pM-3 nM with a linear regression equation of ΔI (µA) = 28.0 + 6.9 × log[STX] (R2 = 0.98079) and 3-100 nM with a linear regression equation of ΔI (µA) = 10.7 + 43.4 × log[STX] (R2 = 0.98772), where R is the correlation coefficient. In addition, the limit of detection (LOD) was as low as 1 pM. Furthermore, the designed aptasensor demonstrated excellent selectivity toward STX, preventing interference from neo-STX, okadaic acid, and common metal ions. The presented orderly nanopillar array-based strategy to develop an electrochemical aptasensor for STX detection offers a promising method for developing high-performance electrochemical sensors, and the presented aptasensor should find useful application in the detection of shellfish poison.

Phenotypic switching as a non-genetic mechanism of resistance predicts antibody therapy regimens.

Despite the specificity and effectiveness of antibody therapy, resistance to treatment remains a major barrier for their broad clinical applications. While genetic mutations are known to be critical, the impact of non-genetic mechanisms, such as epigenetic changes and phenotypic adaptations, on resistance to antibody-dependent cellular cytotoxicity (ADCC) is not fully understood. Our study investigated the non-genetic resistance mechanisms that colorectal cancer cells develop against cetuximab and the resulting ADCC pressure. Resistance clones exhibited decreased EGFR/HER2 expressions, enriched interferon-related pathways, and lower NK cell activation. Interestingly, these resistance clones regained sensitivity upon the withdrawal of therapeutic pressure, implying phenotypic plasticity and reversibility. To counter resistance, we developed a mathematical model recapitulating the phenotypic switching dynamics. The model predicted that intermittent dosing strategy outperforms continuous regimen in delaying treatment resistance. Our findings have implications for improving efficacy and circumventing resistance to targeted antibody therapies.

Free PEG Suppresses Anaphylaxis to PEGylated Nanomedicine in Swine.

Covalent conjugation of poly(ethylene glycol) (PEG) is frequently employed to enhance the pharmacokinetics and biodistribution of various protein and nanoparticle therapeutics. Unfortunately, some PEGylated drugs can induce elevated levels of antibodies that can bind PEG, i.e., anti-PEG antibodies (APA), in some patients. APA in turn can reduce the efficacy and increase the risks of allergic reactions, including anaphylaxis. There is currently no intervention available in the clinic that specifically mitigates allergic reactions to PEGylated drugs without the use of broad immunosuppression. We previously showed that infusion of high molecular weight free PEG could safely and effectively suppress the induction of APA in mice and restore prolonged circulation of various PEGylated therapeutics. Here, we explored the effectiveness of free PEG as a prophylaxis against anaphylaxis induced by PEG-specific allergic reactions in swine. Injection of PEG-liposomes (PL) resulted in anaphylactoid shock (pseudoanaphylaxis) within 1-3 min in both naïve and PL-sensitized swine. In contrast, repeated injection of free PEG alone did not result in allergic reactions, and injection of free PEG effectively suppressed allergic reactions to PL, including in previously PL-sensitized swine. These results strongly support the further investigation of free PEG for reducing APA and allergic responses to PEGylated therapeutics.

Genome-wide sequencing identified extrachromosomal circular DNA as a transcription factor-binding motif of the senescence genes that govern replicative senescence in human mesenchymal stem cells.

Introduction: Mesenchymal stem cells (MSCs) have long been postulated as an important source cell in regenerative medicine. During subculture expansion, mesenchymal stem cell (MSC) senescence diminishes their multi-differentiation capabilities, leading to a loss of therapeutic potential. Up to date, the extrachromosomal circular DNAs (eccDNAs) have been demonstrated to be involved in senescence but the roles of eccDNAs during MSC. Methods: Here we explored eccDNA profiles in human bone marrow MSCs (BM-MSCs). EccDNA and mRNA was purified and sequenced, followed by quantification and functional annotation. Moreover, we mapped our datasets with the downloading enhancer and transcription factor-regulated genes to explore the potential role of eccDNAs. Results: Sequentially, gene annotation analysis revealed that the majority of eccDNA were mapped in the intron regions with limited BM-MSC enhancer overlaps. We discovered that these eccDNA motifs in senescent BMSCs acted as motifs for binding transcription factors (TFs) of senescence-related genes. Discussion: These findings are highly significant for identifying biomarkers of senescence and therapeutic targets in mesenchymal stem cells (MSCs) for future clinical applications. The potential of eccDNA as a stable therapeutic target for senescence-related disorders warrants further investigation, particularly exploring chemically synthesized eccDNAs as transcription factor regulatory elements to reverse cellular senescence.