Transdermal cold atmospheric plasma-mediated immune checkpoint blockade therapy.

Despite the promise of immune checkpoint blockade (ICB) therapy against cancer, challenges associated with low objective response rates and severe systemic side effects still remain and limit its clinical applications. Here, we described a cold atmospheric plasma (CAP)-mediated ICB therapy integrated with microneedles (MN) for the transdermal delivery of ICB. We found that a hollow-structured MN (hMN) patch facilitates the transportation of CAP through the skin, causing tumor cell death. The release of tumor-associated antigens then promotes the maturation of dendritic cells in the tumor-draining lymph nodes, subsequently initiating T cell-mediated immune response. Anti-programmed death-ligand 1 antibody (aPDL1), an immune checkpoint inhibitor, released from the MN patch further augments the antitumor immunity. Our findings indicate that the proposed transdermal combined CAP and ICB therapy can inhibit the tumor growth of both primary tumors and distant tumors, prolonging the survival of tumor-bearing mice.

Mechanistic Insight into Permeation of Plasma-Generated Species from Vacuum into Water Bulk.

Due to their potential benefits, cold atmospheric plasmas (CAPs), as biotechnological tools, have been used for various purposes, especially in medical and agricultural applications. The main effect of CAP is associated with reactive oxygen and nitrogen species (RONS). In order to deliver these RONS to the target, direct or indirect treatment approaches have been employed. The indirect method is put into practice via plasma-activated water (PAW). Despite many studies being available in the field, the permeation mechanisms of RONS into water at the molecular level still remain elusive. Here, we performed molecular dynamics simulations to study the permeation of RONS from vacuum into the water interface and bulk. The calculated free energy profiles unravel the most favourable accumulation positions of RONS. Our results, therefore, provide fundamental insights into PAW and RONS chemistry to increase the efficiency of PAW in biological applications.

Detection of a major QTL conditioning trichome length and density on chromosome arm 4BL and development of near isogenic lines targeting this locus in bread wheat.

Trichomes are differentiated epidermal cells and can be found on above ground organs of nearly all land plants. Results from previous studies show that trichomes play important roles against a wide range of both biotic and abiotic stresses. By examining differences between parental genotypes of available populations, we identified a population of recombinant inbred lines showing clear segregation for trichome density and length. Assessing the F8 lines of the population growing in the field detected a major locus on chromosome arm 4BL. This locus was detected based the assessments of either fully expanded third leaves or flag leaves after anthesis. Based on the position of the QTL, an SSR marker was used to identify heterozygous plants at this locus from F5 lines derived from the same cross for the F8 population. Three pairs of near isogenic lines targeting this locus were obtained from these heterozygous plants. Difference in trichome length between the two lines with opposite alleles for each of these NIL pairs were similar to that between the two parental genotypes for the mapping populations, confirming that this single locus is mainly responsible for the trichome characteristics measured in this study. The allele with long and dense trichome is dominant as this characteristic was shown by the heterozygous individuals at this marker locus. Apart from the targeted locus, NIL pairs have highly homogeneous genetic backgrounds. Thus, the NILs could be invaluable in understanding the relationship between trichome density and resistance or tolerance to various biotic and abiotic stresses. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-021-01201-8.

Vapor-liquid equilibrium and critical asymmetry of square well and short square well chain fluids.

The critical behavior of square well fluids with variable interaction ranges and of short square well chain fluids have been investigated by grand canonical ensemble Monte Carlo simulations. The critical temperatures and densities were estimated by a finite-size scaling analysis with the help of histogram reweighting technique. The vapor-liquid coexistence curve in the near-critical region was determined using hyper-parallel tempering Monte Carlo simulations. The simulation results for coexistence diameters show that the contribution of |t|(1-α) to the coexistence diameter dominates the singular behavior in all systems investigated. The contribution of |t|(2ß) to the coexistence diameter is larger for the system with a smaller interaction range λ. While for short square well chain fluids, longer the chain length, larger the contribution of |t|(2ß). The molecular configuration greatly influences the critical asymmetry: a short soft chain fluid shows weaker critical asymmetry than a stiff chain fluid with same chain length.

Trehalose enhanced cold atmospheric plasma-mediated cancer treatment.

Cold atmospheric plasma (CAP) is a unique form of physical plasma that has shown great potential for cancer therapy. CAP uses ionized gas to induce lethal oxidative stress on cancer cells; however, the efficacy of CAP therapy continues to be improved. Here, we report an injectable hydrogel-mediated approach to enhance the anti-tumor efficacy of CAP by regulating the phosphorylation of eIF2α. We discovered that reactive oxygen and nitrogen species (ROS/RNS), two main anti-tumor components in CAP, can lead to lethal oxidative stress on tumor cells. Elevated oxidative stress subsequently induces eIF2α phosphorylation, a pathognomonic marker of immunogenic cell death (ICD). Trehalose, a natural disaccharide sugar, can further enhance CAP-induced ICD by elevating the phosphorylation of eIF2α. Moreover, injectable hydrogel-mediated delivery of CAP/trehalose treatment promoted dendritic cell (DC) maturation, initiating tumor-specific T-cell mediated anti-tumor immune responses. The combination therapy also supported the polarization of tumor-associated macrophages to an M1-like phenotype, reversing the immunosuppressive tumor microenvironment and promoting tumor antigen presentation to T cells. In combination with immune checkpoint inhibitors (i.e., anti-programmed cell death protein 1 antibody, aPD1), CAP/trehalose therapy further inhibited tumor growth. Importantly, our findings also indicated that this hydrogel-mediated local combination therapy engaged the host systemic innate and adaptive immune systems to impair the growth of distant tumors.

KIF5B-mediated internalization of FMDV promotes virus infection.

Foot-and-mouth disease (FMD) is a highly contagious and economically important disease, which is caused by the FMD virus (FMDV). Although the cell receptor for FMDV has been identified, the specific mechanism of FMDV internalization after infection remains unknown. In this study, we found that kinesin family member 5B (KIF5B) plays a vital role during FMDV internalization. Moreover, we confirmed the interaction between KIF5B and FMDV structural protein VP1 by co-immunoprecipitation (Co-IP) and co-localization in FMDV-infected cells. In particular, the stalk [amino acids (aa) 413-678] domain of KIF5B was indispensable for KIF5B-VP1 interaction. Moreover, overexpression of KIF5B dramatically enhanced FMDV replication; consistently, knockdown or knockout of KIF5B suppressed FMDV replication. Furthermore, we also demonstrated that KIF5B promotes the internalization of FMDV via regulating clathrin uncoating. KIF5B also promotes the transmission of viral particles to early and late endosomes during the early stages of infection. In conclusion, our results demonstrate that KIF5B promotes the internalization of FMDV via regulating clathrin uncoating and intracellular transport. This study may provide a new therapeutic target for developing FMDV antiviral drugs.

Methylation in cornea and corneal diseases: a systematic review.

Corneal diseases are among the primary causes of blindness and vision loss worldwide. However, the pathogenesis of corneal diseases remains elusive, and diagnostic and therapeutic tools are limited. Thus, identifying new targets for the diagnosis and treatment of corneal diseases has gained great interest. Methylation, a type of epigenetic modification, modulates various cellular processes at both nucleic acid and protein levels. Growing evidence shows that methylation is a key regulator in the pathogenesis of corneal diseases, including inflammation, fibrosis, and neovascularization, making it an attractive potential therapeutic target. In this review, we discuss the major alterations of methylation and demethylation at the DNA, RNA, and protein levels in corneal diseases and how these dynamics contribute to the pathogenesis of corneal diseases. Also, we provide insights into identifying potential biomarkers of methylation that may improve the diagnosis and treatment of corneal diseases.

Black phosphorus boosts wet-tissue adhesion of composite patches by enhancing water absorption and mechanical properties.

Wet-tissue adhesives have long been attractive materials for realizing complicated biomedical functions. However, the hydration film on wet tissues can generate a boundary, forming hydrogen bonds with the adhesives that weaken adhesive strength. Introducing black phosphorus (BP) is believed to enhance the water absorption capacity of tape-type adhesives and effectively eliminate hydration layers between the tissue and adhesive. This study reports a composite patch integrated with BP nanosheets (CPB) for wet-tissue adhesion. The patch's improved water absorption and mechanical properties ensure its immediate and robust adhesion to wet tissues. Various bioapplications of CPB are demonstrated, such as rapid hemostasis (within ~1-2 seconds), monitoring of physical-activity and prevention of tumour-recurrence, all validated via in vivo studies. Given the good practicability, histocompatibility and biodegradability of CPB, the proposed patches hold significant promise for a wide range of biomedical applications.

Injectable cold atmospheric plasma-activated immunotherapeutic hydrogel for enhanced cancer treatment.

Despite the promise of immune checkpoint blockade (ICB) for cancer treatment, challenges associated with this therapy still exist, including low response rates and severe side effects in patients. Here, we report a hydrogel-mediated combination therapy for enhanced ICB therapy. Specifically, cold atmospheric plasma (CAP), an ionized gas consisting of therapeutically effective reactive oxygen species (ROS) and reactive nitrogen species (RNS), can effectively induce cancer immunogenic cell death, releasing tumor-associated antigens in situ and initiating anti-tumor immune responses, which, therefore, can synergistically augment the efficacy of immune checkpoint inhibitors. To minimize the systemic toxicity of immune checkpoint inhibitors and improve the tissue penetration of CAP, an injectable Pluronic hydrogel was employed as a delivery method. Our results show that major long-lived ROS and RNS in CAP can be effectively persevered in Pluronic hydrogel and remain efficacious in inducing cancer immunogenic cell death after intratumoral injection. Our findings suggest that local hydrogel-mediated combination of CAP and ICB treatment can evoke both strong innate and adaptive, local and systemic anti-tumor immune responses, thereby inhibiting both tumor growth and potential metastatic spread.

Blue light impairs cornea and corneal wound healing by downregulating VCAM1 partly.

This study aimed to investigate the effects of long-term pollution from different wavelengths of light on the corneal epithelium (CE) and identify potential biomarkers. Rabbits were exposed to red, green, blue, white, and environmental light for 6 weeks. The CE was assessed using various techniques such as fluorescein sodium staining, transcriptome sequencing, electron microscopy, and molecular assays. In human corneal epithelial cells (hCECs), the downregulation of vascular cell adhesion molecule 1 (VCAM1) in response to blue light (BL) pollution was observed. This downregulation of VCAM1 inhibited migration, increased reactive oxygen species (ROS) levels, and apoptosis, and inhibited the AKT/p70 S6 kinase cascade in hCECs. Animal experiments confirmed that BL pollution caused similar effects on the rabbit cornea, including increased ROS production, apoptosis, delayed wound healing, and decreased VCAM1 expression. Overall, BL-induced VCAM1 downregulation may impair CE and wound healing and promote ROS and apoptosis in vitro and in vivo.

Cold atmospheric plasma for addressing the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has greatly stressed the global community, exposing vulnerabilities in the supply chains for disinfection materials, personal protective equipment, and medical resources worldwide. Disinfection methods based on cold atmospheric plasma (CAP) technologies offer an intriguing solution to many of these challenges because they are easily deployable and do not require resource-constrained consumables or reagents needed for conventional decontamination practices. CAP technologies have shown great promise for a wide range of medical applications from wound healing and cancer treatment to sterilization methods to mitigate airborne and fomite transfer of viruses. This review engages the broader community of scientists and engineers that wish to help the medical community with the ongoing COVID-19 pandemic by establishing methods to utilize broadly applicable CAP technologies.

COL11A1 as an novel biomarker for breast cancer with machine learning and immunohistochemistry validation.

Machine learning (ML) algorithms were used to identify a novel biological target for breast cancer and explored its relationship with the tumor microenvironment (TME) and patient prognosis. The edgR package identified hub genes associated with overall survival (OS) and prognosis, which were validated using public datasets. Of 149 up-regulated genes identified in tumor tissues, three ML algorithms identified COL11A1 as a hub gene. COL11A1was highly expressed in breast cancer samples and associated with a poor prognosis, and positively correlated with a stromal score (r=0.49, p<0.001) and the ESTIMATE score (r=0.29, p<0.001) in the TME. Furthermore, COL11A1 negatively correlated with B cells, CD4 and CD8 cells, but positively associated with cancer-associated fibroblasts. Forty-three related immune-regulation genes associated with COL11A1 were identified, and a five-gene immune regulation signature was built. Compared with clinical factors, this gene signature was an independent risk factor for prognosis (HR=2.591, 95%CI 1.831-3.668, p=7.7e-08). A nomogram combining the gene signature with clinical variables, showed better predictive performance (C-index=0.776). The model correction prediction curve showed little bias from the ideal curve. COL11A1 is a potential therapeutic target in breast cancer and may be involved in the tumor immune infiltration; its high expression is strongly associated with poor prognosis.

Construction of ceRNA Networks Associated With CD8 T Cells in Breast Cancer.

Background: The infiltration of CD8 T cells is usually linked to a favorable prognosis and may predict the therapeutic response of breast cancer patients to immunotherapy. The purpose of this research is to investigate the competing endogenous RNA (ceRNA) network correlated with the infiltration of CD8 T cells. Methods: Based on expression profiles, CD8 T cell abundances for each breast cancer (BC) patient were inferred using the bioinformatic method by immune markers and expression profiles. We were able to extract the differentially expressed RNAs (DEmRNAs, DEmiRNAs, and DElncRNAs) between low and high CD8 T-cell samples. The ceRNA network was constructed using Cytoscape. Machine learning models were built by lncRNAs to predict CD8 T-cell abundances. The lncRNAs were used to develop a prognostic model that could predict the survival rates of BC patients. The expression of selected lncRNA (XIST) was validated by quantitative real-time PCR (qRT-PCR). Results: A total of 1,599 DElncRNAs, 89 DEmiRNAs, and 1,794 DEmRNAs between high and low CD8 T-cell groups were obtained. Two ceRNA networks that have positive or negative correlations with CD8 T cells were built. Among the two ceRNA networks, nine lncRNAs (MIR29B2CHG, NEAT1, MALAT1, LINC00943, LINC01146, AC092718.4, AC005332.4, NORAD, and XIST) were selected for model construction. Among six prevalent machine learning models, artificial neural networks performed best, with an area under the curve (AUC) of 0.855. Patients from the high-risk category with BC had a lower survival rate compared to those from the low-risk group. The qRT-PCR results revealed significantly reduced XIST expression in normal breast samples, which was consistent with our integrated analysis. Conclusion: These results potentially provide insights into the ceRNA networks linked with T-cell infiltration and provide accurate models for T-cell prediction.

An Innovative Breast-Conserving Oncoplastic Technique for Treating Small to Medium Volume Breasts With a Tumor in the Lower Quadrant: The Folding Flap Technique.

Background: Here, we describe an innovative oncoplastic technique for small to medium volume breasts with a tumor in the lower quadrant and this technique could provide sufficient tissue to avoid visible defects after tumor removal and help reshape the natural shape of the breast. Methods: A detailed procedure for the folding flap technique is described step by step. Then, the results of a retrospective analysis of patients treated using this technique, including complications and disease recurrence rate, between January 2017 and November 2021 are reported. Aesthetic outcomes were evaluated on a 5-point scale proposed by the Paris Breast Center. Results: A total of 52 patients underwent surgery with the folding flap technique, The average operation time was 98.4 min (range, 75-120 min), and the mean bleeding volume was 56.5 mL (range, 20-100 mL). A margin-positive result was confirmed in 1 patient who underwent re-excision. Short-term postoperative complications were observed in 7 patients, including 4 with fat liquefaction, 2 with seroma, and 1 with skin redness and swelling. No flap necrosis was observed. The median follow-up time was 28.6 months (range, 9-58 months), and 2 patients experienced local recurrence. The mean aesthetic score was 4.7 points, with 36 patients scoring 5 points and 26 patients scoring 4 points, respectively. Conclusions: The folding flap technique, as an innovative and favorable oncoplastic technique for treating small- to medium-volume breasts with a tumor in the lower quadrant, could retain sufficient tissue to fill the residual cavity after the operation while improving the aesthetic outcome of the breast.

Effects of physical exercise on working memory in older adults: a systematic and meta-analytic review.

BACKGROUND: This systematic and meta-analytic review aimed to investigate the effects of physical exercise on the working memory of older adults, and to identify the moderators of these effects. METHODS: We searched six electronic databases for randomized controlled trials on the effects of physical exercise on working memory that were published before or on May 15, 2020. The PEDro scale was used to evaluate the methodological quality of the included studies. Stata 14.0 software was used to perform the meta-analysis, subgroup analysis, and publication bias testing. RESULTS: A total of 28 studies and 2156 participants were included. The methodological quality of the included studies was fair to excellent, and there was no publication bias. Overall, we found that physical exercise had a significant effect on working memory in older adults (standardized mean difference = 0.30, p < 0.0001). The effects of physical exercise on working memory were moderated by exercise frequency, intensity, type, duration, cognitive status, and control subgroup (active/passive), but not by intervention period or age of participant. CONCLUSION: Physical exercise can effectively improve the working memory of older adults. The recommended physical exercise is multi-component exercise or mind-body exercise of moderate intensity for 45-60 min 3 times a week, for more than 6 months.

In situ microscopy for plasma erosion of complex surfaces.

A novel method for the in situ visualization and profilometry of a plasma-facing surface is demonstrated using a long-distance microscope. The technique provides valuable in situ monitoring of the microscopic temporal and morphological evolution of a material surface subject to plasma-surface interactions, such as ion-induced sputter erosion. Focus variation of image stacks enables height surface profilometry, which allows a depth of field beyond the limits associated with high magnification. As a demonstration of this capability, the erosion of a volumetrically featured aluminum foam is quantified during ion-bombardment in a low-temperature argon plasma where the electron temperature is ∼7 eV and the plasma is biased relative to the target surface such that ions impinge at ∼300 eV. Three-dimensional height maps are reconstructed from the images captured with a long-distance microscope with an x-y resolution of 3 × 3 µm2 and a focus-variation resolution based on the motor step-size of 20 µm. The time-resolved height maps show a total surface recession of 730 µm and significant ligament thinning over the course of 330 min of plasma exposure. This technique can be used for developing plasma-facing components for a wide range of plasma devices for applications such as propulsion, manufacturing, hypersonics, and fusion.

Portable air-fed cold atmospheric plasma device for postsurgical cancer treatment.

Surgery represents the major option for treating most solid tumors. Despite continuous improvements in surgical techniques, cancer recurrence after surgical resection remains the most common cause of treatment failure. Here, we report cold atmospheric plasma (CAP)­mediated postsurgical cancer treatment, using a portable air-fed CAP (aCAP) device. The aCAP device we developed uses the local ambient air as the source gas to generate cold plasma discharge with only joule energy level electrical input, thus providing a device that is simple and highly tunable for a wide range of biomedical applications. We demonstrate that local aCAP treatment on residual tumor cells at the surgical cavities effectively induces cancer immunogenic cell death in situ and evokes strong T cell­mediated immune responses to combat the residual tumor cells. In both 4T1 breast tumor and B16F10 melanoma models, aCAP treatment after incomplete tumor resection contributes to inhibiting tumor growth and prolonging survival.

Coordination of a Dual-Channel Pharmaceutical Supply Chain Based on the Susceptible-Infected-Susceptible Epidemic Model.

With the continuous development of Internet, online pharmaceutical channels in many countries have seen rapid expansion. As a result, pharmaceutical supply chain participants can adopt dual channels, namely, both online channels and offline channels. As online channels compete with traditional offline channels, it is of great relevance to study the potential conflicts and coordination between them, which is the focus of this paper. Specifically, this article develops a susceptible-infected-susceptible epidemic model of the dual channels for a pharmaceutical supply chain. Our main findings are that in a competitive situation, there is a positive stable equilibrium. Furthermore, increasing the rate of influence of offline transmission, online transmission, and cross transmission will improve sales. Moreover, improving the transmission influence rate will turn more potential customers into purchasers, increase channel sales, and achieve dual channel coordination. We then conduct numerical analysis to illustrate and complement the findings from the model. Finally, we provide managerial insights for implementing successful dual-channel pharmaceutical supply chains.

Cold atmospheric plasma for SARS-CoV-2 inactivation.

Syndrome coronavirus 2 (SARS-CoV-2) infectious virions are viable on various surfaces (e.g., plastic, metals, and cardboard) for several hours. This presents a transmission cycle for human infection that can be broken by developing new inactivation approaches. We employed an efficient cold atmospheric plasma (CAP) with argon feed gas to inactivate SARS-CoV-2 on various surfaces including plastic, metal, cardboard, basketball composite leather, football leather, and baseball leather. These results demonstrate the great potential of CAP as a safe and effective means to prevent virus transmission and infections for a wide range of surfaces that experience frequent human contact. Since this is the first-ever demonstration of cold plasma inactivation of SARS-CoV-2, it is a significant milestone in the prevention and treatment of coronavirus disease 2019 (COVID-19) and presents a new opportunity for the scientific, engineering, and medical communities.

Effects of Tai Chi Chuan on Cognitive Function in Older Adults with Cognitive Impairment: A Systematic and Meta-Analytic Review.

This systematic and meta-analytic review aimed to investigate the effects of Tai Chi Chuan (TCC) on the cognitive function of the elderly with cognitive impairment and to analyze the moderators of these effects. We searched eight electronic databases for randomized controlled trials on the effects of TCC on cognitive function, published up to June 14, 2020. The PEDro scale was used to evaluate the methodological quality of the included literature. Stata14.0 software was used for meta-analysis, subgroup analysis, and publication bias testing. A total of 19 studies and 1,970 samples were included. The methodological quality of the included literature was fair to good, and there was no publication bias. Overall, the research shows that the effect of TCC on the elderly with cognitive impairment is statistically significant (SMD = 0.31, p < 0.0001). Five of the cognitive function subdomains were significant moderators [Q (5) = 15.66, p=0.008], and the effect size (ES) was the largest for global cognitive function (SMD = 0.41), followed by executive function (SMD = 0.33), memory (SMD = 0.31), and verbal fluency (SMD = 0.27). Regarding the exercise prescription variables, results were significantly moderated by the length of exercise training [Q (2) = 6.00, p=0.05], with ESs largest for moderate length (SMD = 0.41), followed by short length (SMD = 0.40) and long length (SMD = 0.29). However, the results were not moderated by session time or frequency. TCC can improve multiple cognitive functions of the elderly with cognitive impairment. The intervention effects are moderated by exercise length, but not by exercise session time and frequency.