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The promoted electrocatalytic hydrogenation of biomass-derived furfural to 2-methylfuran is for the first time identified in a water/oil bi-phasic system, in which the oil phase can quickly separate hydrophobic products from the electrode/electrolyte interfaces, resulting in a beneficial equilibrium toward hydrodeoxygenation. [ABSTRACT FROM AUTHOR]

Various circular RNAs (circRNAs) are novel class of non-coding RNAs, which are pervasively transcribed in the genome. CircRNAs play important roles in human, animals and plants. Up to now, there was no report regarding circRNAs of cleft palate by 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) induce. The present study screened identification and characterization of differential expressed-circRNAs in TCDD-induced cleft palate. 6903 circRNAs candidates came from cleft palates. Among them, 3525 circRNAs are up-regulation, and 3378 circRNAs are down-regulation by TCDD induce. The cluster and GO analysis found that circRNAs involved in biological process, cellular component, and molecular function. Through the analysis of KEGG Pathway, circRNAs made functions via classical signaling pathway in cleft palate, such as TGF-beta signaling pathway, BMP signal pathway, MAPK signaling pathway. In addition, we found down-regulated circRNA224, circRNA3302 and up-regulated circRNA5021 targeted tgfbr3, but up-regulated circRNA4451 targeted tgfbr2. circRNA4451 may make functions through TGF-beta signaling pathway. These results suggested that many different circRNAs may make important role in TCDD-induced cleft palate, which provided a theoretical basis for further research. [ABSTRACT FROM AUTHOR]

The infusion of chimeric antigen receptor (CAR) T cells that target specific tumor-associated antigens is a promising strategy that has exhibited encouraging results in clinical trials. However, few studies have focused on the effectiveness and safety of CD20 CAR T cells in rituximab-refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma (B-NHL) patients, particularly those treated with rituximab for a short time. This prospective study aimed to assess the effectiveness and toxicity of CD20 CAR T cells in R/R B-NHL patients previously treated with rituximab. The authors conducted a prospective, single-center phase I study on the effectiveness and toxicity of CD20 CAR T cells in rituximab-treated R/R B-NHL patients (no. ChiCTR2000036350). A total of 15 patients with R/R B-NHL were enrolled between November 21, 2017, and December 1, 2021. An overall response rate of 100% was shown in enrolled patients, with 12 (80%) achieving complete remission and three (20%) achieving partial remission for the best response. The median follow-up time was 12.4 months. Progression-free survival and overall survival were not yet reached by the data cutoff day. No patient developed grade 4 cytokine release syndrome, and only one patient had immune effector cell-associated neurotoxicity syndrome. All enrolled B-NHL patients who were previously R/R to rituximab achieved different degrees of clinical response with tolerable toxicities. Notably, patients who had received rituximab within 3 months had a poorer prognosis. [ABSTRACT FROM AUTHOR]

Persistence of CAR-T cell function is associated with relapse rate after CAR-T therapy, while co-stimulatory agents are highly concerned with the persistence of CAR-T cells. In this study, we designed and constructed a series of BCMA-targeting second-generation CAR constructs containing CD28, 41BB, and OX40 molecules, respectively, to identify the costimulatory domains most favorable for persistence. The results of routine in vitro studies showed that OX40-CAR-T and 41BB-CAR-T had similar antitumor effects and were superior to CD28-CAR-T in terms of proliferation and cytotoxicity. Although difficult to distinguish by conventional functional assays, OX40-CAR-T cells exhibited greater proliferation and enhanced immune memory than 41BB-CAR-T cells with the repeated stimulation assay by BCMA-expressing target cells. In vivo studies further demonstrated that OX40-CAR-T cells had stronger proliferative activity than 41BB-CAR-T cells, which was highly consistent with the in vitro antitumor activity and proliferation results. Our study provides for the first time a scientific basis for designing OX40-CAR-T cell therapy to improve relapse in patients with MM after CAR-T treatment. [ABSTRACT FROM AUTHOR]

Epidemiological evidence suggests that the metabolic profiles of each individual exposed to arsenic (As) are related to the risk of cancer, coronary heart disease, and diabetes. The arsenite methyltransferase (AS3MT) gene plays a key role in As metabolism. Several single nucleotide polymorphisms in the AS3MT gene may affect both enzyme activity and gene transcription. AS3MT polymorphisms are associated with the proportions of monomethylarsenic acid (MMA) and dimethylarsenic acid (DMA) in urine as well as the incidence of cancer. P21 protein is a cyclin-dependent kinase inhibitor. Mutations of the P21 gene have been found in cancer patients. In our study, we investigate whether polymorphisms of the AS3MT gene alter As methylation capacity and adversely affect the P21 gene in arsenic trioxide plant workers. The DNA damage was examined by the quantitative polymerase chain reaction. Restriction fragment length polymorphism was used to analyze the genotype of the AS3MT gene. The results showed that DNA damage in P21 gene fragments was greater in those individuals exposed to high levels of As. There was a strong positive correlation between the DNA damage to P21 gene fragments and the percentage of MMA in urine. However, DNA damage in P21 gene fragments was negatively associated with the percentage of DMA in urine (%uDMA), primary methylation index (PMI), and secondary methylation index. We found that subjects with the rs7085104 GG or GA allele were associated with higher %uDMA and PMI and less DNA damage. The subjects with the rs11191454 GG+GA or GA allele were also associated with higher %uDMA and PMI and less DNA damage. Our results suggest that rs1191454 and rs7085104 in the AS3MT gene affect the As-induced DNA damage by altering individual metabolic efficiency. [ABSTRACT FROM AUTHOR]

Background: Invasive candidiasis is a growing concern worldwide, especially in immunocompromised patients, including ICU patients. Objectives: As Candida albicans is the leading cause of candidaemia, it is important to investigate the evolution of C. albicans in patients with candidaemia. Methods: We analysed 238 strains of C. albicans isolated from different body sites. Antifungal susceptibility testing, CAI loci genotyping and multilocus sequence typing (MLST) of all isolates were performed. The relationships among the total isolates that differed in sequence at only one of the seven housekeeping gene loci were analysed using eBURST. Results: Multilocus sequence typing analysis in 238 isolates by combining seven housekeeping alleles revealed 175 diploid sequence types, in which 84 were newly identified. eBURST analysis for these data recognised 19 clonal complexes (CCs) and 79 singletons. Besides, seventy‐three CAI genotypes were identified. Blood isolates showed maximum genotypes (49), and the dominant genotypes were CAI 17‐21 and CAI 21‐21. Oral isolates possessed 25 CAI genotypes, and the dominant genotypes were CAI 17‐21 and CAI 21‐21 as well. Since isolates with CAI allele numbers <30 showed easier transmission, CAI 17‐21 and CAI 21‐21 were the most frequently transmitted. Finally, the CAI genotypes were classified into six groups. Conclusions: This work revealed the oral and blood strains isolated from the patients with candidaemia in ICU shared the identical dominant CAI genotypes. Our data expanded the C. albicans MLST database and helped with understanding the evolution and spread of invasive candidiasis. [ABSTRACT FROM AUTHOR]

[Display omitted] Electrocatalytic hydrogenation (ECH) enables the sustainable production of chemicals under ambient condition; however, suffers from serious competition with hydrogen (H 2) evolution and the use of precious metals as electrocatalysts. Herein, molybdenum disulfide is for the first time developed as an efficient and noble-metal-free catalyst for ECH via in situ intercalation of ammonia or alkyl-amine cations. This interlayer engineering regulates phase transition (2H → 1 T), and effectively ameliorates electronic configurations and surface hydrophobicity to promote the ECH of biomass-derived oxygenates, while prohibiting H 2 evolution. The optimal one intercalated by dimethylamine (MoS 2 -DMA) is capable of hydrogenating furfural (FAL) to furfuryl alcohol with high Faradaic efficiency of 86.3%–73.3% and outstanding selectivity of >95.0% at −0.25 to −0.65 V (vs. RHE), outperforming MoS 2 and other conventional metals. Such prominent performance stems from the enhanced chemisorption and surface hydrophobicity. The chemisorption of H intermediate and FAL, synchronously strengthened on the edge-sites of MoS 2 -DMA, accelerates the surface elementary step following Langmuir-Hinshelwood mechanism. Moreover, the improved hydrophobicity benefits FAL affinity to overcome diffusion limitation. Discovering the effective modulation of MoS 2 from a typical H 2 evolution electrocatalyst to a promising candidate for ECH, this study broadens the scope to exploit catalysts used for electrochemical synthesis. [ABSTRACT FROM AUTHOR]

Background: Trichophyton benhamiae is a zoophilic dermatophyte that can cause tinea in humans and animals. Lesions caused by T. benhamiae tend to be highly inflammatory, and patients are often infected by animals or other patients infected with T. benhamiae. In this paper, we report the first case of tinea faciei caused by T. benhamiae in a Chinese girl who might be transmitted from a fox.Case Presentation: A 4-year-old girl from HaiNing city developed an itchy, erythematous, and annular plaque on her right face for the past 2 months. Before the lesion appeared, she was in close contact with the fur of a fox for almost 1 week. Septate hyaline hyphae were detected by direct mycological examination of the scales. Cultures grew on Sabouraud's dextrose agar (SDA) at 26 °C for 2 weeks revealed the presence of T. mentagrophytes. A molecular sequencing test confirmed that the isolate was consistent with reference strains to T. benhamiae. Then, the diagnosis of tinea faciei due to T. benhamiae was made. Treatment with terbinafine (oral 125 mg/d) and sertaconazole nitrate cream (topical, twice daily) for 4 weeks was initiated and achieved significant improvement of the skin lesions.Conclusions: This rare dermatophytosis case highlights the importance of ITS sequencing in helping to recognize rare pathogenic fungi that can be easily misdiagnosed with a conventional morphological diagnosis. [ABSTRACT FROM AUTHOR]

Tinea pedis has been associated with Trichophyton rubrum infection. However, it's not clear whether other microbes were implicated in disease pathogenesis. The composition of microbial communities of patients with tinea pedis and healthy controls were analyzed to identify the characteristics of tinea pedis and differences associated with clinical patterns. We found that microbial community structures were different in patients with tinea pedis compared with healthy controls. Moreover, skin microbiome varied in different forms of tinea pedis. Healthy controls exhibited greater fungal diversity than patients with tinea pedis. In patients with tinea pedis, the dominant bacterial and fungal genera were Staphylococcus and Trichophyton. Compared with healthy controls, Corynebacterium tuberculostearicum was decreased and T. rubrum was increased. C. tuberculostearicum was more abundant in vesicular tinea pedis than in hyperkeratotic and interdigital tinea pedis. Interdigital tinea pedis had a higher detection rate of Corynebacterium minutissimum and T. rubrum than the other forms. These results indicated that bacterial microbes may take part in the development of tinea pedis. [ABSTRACT FROM AUTHOR]

The present study was to determine the in vitro activity of posaconazole (POS) against 385 Candida and 268 Aspergillus clinical isolates from China. We found that POS was active against 85.5% Candida and 94.4% Aspergillus isolates. Non–wild-type (non-WT) phenotype was found in a subset of Candida albicans (15.4%), Candida tropicalis (11.9%), Aspergillus fumigatus (4.1%), and Aspergillus flavus (17.4%) isolates. Cross-resistance to POS and other triazoles was seen. Gene sequencing showed that 4 C. albicans , 1 C. tropicalis , and 9 A. fumigatus isolates with cross-resistance to POS and other triazoles had mutations in ERG11 or CYP51A. In conclusion, POS has potent in vitro activity against most of Candida and Aspergillus isolates from China. Non-WT phenotype and those with cross-resistance to POS and other triazoles exist, frequently driven by mutations of ERG11 in Candida spp. and CYP51A in Aspergillus spp. • The susceptibility to posaconazole in Candida spp. and Aspergillus spp. from China was determined for the first time. • Posaconazole was active against most of Candida and Aspergillus isolates in this study. • Non-WT phenotype for posaconazole and those with cross-resistance to posaconazole and other triazoles exist. • Cross-resistance may be caused by mutations of ERG11 in Candida spp. and CYP51A in Aspergillus spp. [ABSTRACT FROM AUTHOR]

Aim: There is conflicting evidence regarding the safety and effectiveness of warfarin for atrial fibrillation (AF) treatment among older end‐stage renal disease (ESRD) patients, and differences among subgroups are unclear. Methods: Older dialysis patients who were newly diagnosed with AF (7/2007‐12/2011) were identified in the United States Renal Data System. The adjusted hazard ratios (HR) of the outcomes (any stroke, ischaemic stroke, major bleeding, severe gastrointestinal bleeding, and death) by time‐varying warfarin use were estimated using Cox regression accounting for the inverse probability of treatment weight. Results: Among 5765 older dialysis patients with incident AF, warfarin was associated with significantly increased risk of major bleeding (HR = 1.50, 95% CI 1.33–1.68), but was not statistically associated with any stroke (HR = 0.92, 95% CI 0.75–1.12), ischaemic stroke (HR = 0.88, 95%CI 0.70–1.11) or gastrointestinal bleeding (HR = 1.03, 95% CI 0.80–1.32). Warfarin use was associated with a reduced risk of mortality (HR = 0.72, 95%CI 0.65–0.80). The association between warfarin and major bleeding differed by sex (male: HR = 1.29; 95%CI 1.08–1.55; female: HR = 1.67; 95%CI 1.44–1.93; P‐value for interaction = 0.03). Conclusion: Older ESRD patients with AF who were treated with warfarin had a no difference in stroke risk, lower mortality risk, but increased major bleeding risk. The bleeding risk associated with warfarin was greater among women than men. The risk/benefit ratio of warfarin may be less favourable among older women. Summary at a Glance: This is a retrospective analysis based on the USRDS database showing how use of warfarin in elderly ESRD patients with AF showed no benefit in lowering stroke risk or mortality risk but increased bleeding risk. [ABSTRACT FROM AUTHOR]

The regulatory network between arsenic, genes and signaling pathways has been reported in arsenic carcinogenesis. Studies on circRNA represent a growing field, but the extent to circRNA potential mechanisms remains poorly understood. So this study we explore the systematic function of hsa_circ_0005050 in mediating the cell apoptosis and proliferation. We demonstrated that hsa_circ_0005050 was highly expressed in subjects who are long-term exposed to arsenic, and could be induced by NaAs 2 O 3 in A549 and 16HBE. Knockdown of hsa_circ_0005050 promotes A549 cell viability, whereas exerts the opposite effects in 16HBE. Mechanistically, hsa_circ_0005050 regulates the p53 and NF-κB signaling pathway involved in the apoptosis and proliferation. And we found that hsa_circ_0005050 could directly bind to the RNA binding protein ILF3 and mutually influence each other's formation. Upon si-hsa_circ_0005050, ILF3 export to the cytoplasm resulting the formation of a ternary complex ILF3-p65-IκBA, breaks the balance of p53 and NF-κB pathway and induces A549 apoptosis and leads to 16HBE proliferation. As a result of these investigations, suggestions were identified for future research. • Arsenic exposure induced hsa_circ_0005050 expression in vivo and vitro. • Si-hsa_circ_0005050 cause an opposite effect on cell apoptosis and proliferation. • Si-hsa_circ_0005050 leads to the disruption of the balance between p53 and p65. • Si-hsa_circ_0005050 promote ILF3 exporting and forming the complex ILF3-p65-IκBA. [ABSTRACT FROM AUTHOR]

Background: A non-invasive tool for tumor regression grade (TRG) evaluation is urgently needed for gastric cancer (GC) treated with neoadjuvant chemotherapy (NAC). Purpose: To develop and validate a radiomics signature (RS) to evaluate TRG for locally advanced GC after NAC and assess its prognostic value. Material and Methods: A total of 103 patients with GC treated with NAC were retrospectively recruited from April 2018 to December 2019 and were randomly allocated into a training cohort (n = 69) and a validation cohort (n = 34). Delineation was performed on both mixed and iodine-uptake images based on dual-energy computed tomography (DECT). A total of 4094 radiomics features were extracted from the pre-NAC, post-NAC, and delta feature sets. Spearman correlation and the least absolute shrinkage and selection operator were used for dimensionality reduction. Multivariable logistic regression was used for TRG evaluation and generated the optimal RS. Kaplan–Meier survival analysis with the log-rank test was implemented in an independent cohort of 40 patients to validate the prognostic value of the optimal RS. Results: Three, five, and six radiomics features were finally selected for the pre-NAC, post-NAC, and delta feature sets. The delta model demonstrated the best performance in assessing TRG in both the training and the validation cohorts (AUCs=0.91 and 0.76, respectively; P >0.1). The optimal RS from the delta model showed a significant capability to predict survival in the independent cohort (P <0.05). Conclusion: Delta radiomics based on DECT images serves as a potential biomarker for TRG evaluation and shows prognostic value for patients with GC treated with NAC. [ABSTRACT FROM AUTHOR]

Objectives The objectives of this study were to determine species distribution and in vitro antifungal susceptibility of Candida isolates identified in the multicentre China-SCAN study of invasive Candida infection (ICI) in intensive care units (ICUs) across China. Methods Candida isolates from patients in the China-SCAN study with documented ICI were evaluated by a central laboratory. Species were identified using chromogenic culture media or the API 20C AUX kit. Susceptibility to fluconazole, voriconazole, itraconazole, caspofungin and amphotericin B was determined using the CLSI broth microdilution method (M27-A3) and updated clinical breakpoints or epidemiological cut-off values. Results A total of 389 isolates from 244 patients were analysed. Species identified most frequently were Candida albicans (40.1%), Candida parapsilosis (21.3%), Candida tropicalis (17.2%) and Candida glabrata (12.9%). Rarer species such as Lodderomyces elongisporus and Candida ernobii were also identified. Fluconazole susceptibility was evident in 85.9% (134/156) of C. albicans, 62.7% (42/67) of C. tropicalis and 48.2% (40/83) of C. parapsilosis isolates. Susceptibility to voriconazole was ≥90% among all species. All isolates were susceptible to amphotericin B and caspofungin except C. glabrata [86.0% (43/50) susceptible to caspofungin]. Cross-resistance between fluconazole and voriconazole was observed for C. parapsilosis and C. glabrata. Conclusions Although C. albicans was the predominant single species, non-albicans species constituted >50% of isolates. Fluconazole susceptibility was lower in most non-albicans species, indicating that fluconazole resistance should be closely monitored. Susceptibility to voriconazole, amphotericin B and caspofungin is encouraging. Differences between these data and those from other regions emphasize the importance of assessing regional variations. [ABSTRACT FROM PUBLISHER]

Short hairpin RNA (shRNA)-mediated gene silencing is an important technology to achieve RNA interference, in which the design of potent and reliable shRNA molecules plays a crucial role. However, efficient shRNA target selection through biological technology is expensive and time consuming. Hence, it is crucial to develop a more precise and efficient computational method to design potent and reliable shRNA molecules. In this work, we present an interpretable classification model for the shRNA target prediction using the Light Gradient Boosting Machine algorithm called ILGBMSH. Rather than utilizing only the shRNA sequence feature, we extracted 554 biological and deep learning features, which were not considered in previous shRNA prediction research. We evaluated the performance of our model compared with the state-of-the-art shRNA target prediction models. Besides, we investigated the feature explanation from the model's parameters and interpretable method called Shapley Additive Explanations, which provided us with biological insights from the model. We used independent shRNA experiment data from other resources to prove the predictive ability and robustness of our model. Finally, we used our model to design the miR30-shRNA sequences and conducted a gene knockdown experiment. The experimental result was perfectly in correspondence with our expectation with a Pearson's coefficient correlation of 0.985. In summary, the ILGBMSH model can achieve state-of-the-art shRNA prediction performance and give biological insights from the machine learning model parameters. [ABSTRACT FROM AUTHOR]

We experimentally demonstrate the transmission of 20-Gbaud QPSK millimeter-wave signals within a 1.2-km wireless range at 128-GHz using constant-modulus-algorithm (CMA) and the maximum ratio combining (MRC) technology with over 2.2-dB gain in a photonics-assisted millimeter wave (MMW) 1 × 2 Single Input Multi Output (SIMO) communication system. MRC is applied for SIMO signal merging which leads to Signal to Noise Ratio (SNR) enhancement and significant Bit Error Rate (BER) reduction. The comparison which is performed for Single Input Single Output (SISO) and SIMO system, demonstrates the BER improvement. To the best of our knowledge, this is the first experimental demonstration of high gain in a D-band MMW 1 × 2 SIMO system by using these technologies. [ABSTRACT FROM AUTHOR]

Exposure to arsenic, an environmental contaminant, is known to cause arsenicosis and cancer. Although considerable research has been conducted to understand the underlying mechanism responsible for arsenic-induced cancers, the precise molecular mechanisms remain unknown, especially at the epigenetic regulation level. Long non-coding RNAs (LncRNAs) that have been shown to mediate various biological processes, including proliferation, apoptosis, necrosis, and mutagenesis. There are few studies on LncRNAs and biological damage caused by environmental pollutants. The LncRNAs taurine upregulated gene 1 (TUG1) regulates cell growth both in vitro and in vivo, and contributes its oncogenic role. However, the precise roles and related mechanisms of arsenic-induced cell apoptosis are still not fully understood owing to controversial findings in the literature. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed higher expression levels of TUG1 in people occupationally exposed to arsenic than in individuals living away from the source of arsenic exosure (N = 25). In addition, the results suggested that TUG1 was involved in arsenic-induced apoptosis. Furthermore, knockdown experiments showed that silencing of TUG1 markedly inhibited proliferation, whereas depletion of TUG1 led to increased apoptosis. The TUG1-small interfering RNA (siRNA) combination with arsenic (3 μM/L) slightly increased apoptosis compared with the TUG1-siRNA. Additionally, the knockdown experiments showed that the silencing of TUG1 by siRNA inhibited proliferation and promoted apoptosis by inducing p53, p-p53 (ser392), FAS, BCL2, MDM2, cleaved-caspase7 proteins in 16HBE cells. These results indicated that arsenic mediates the upregulation of TUG1 and induces cell apoptosis via activating the p53 signaling pathway. [ABSTRACT FROM AUTHOR]

Ionic liquids (ILs) loading ketoconazole (KCZ) have shown better efficacy on rats with tinea pedis than the marketed Daktarin® but clinical studies are still lacking. In this study, we described the clinical translation of ILs containing KCZ (KCZ‐ILs) from the lab into the clinic and evaluated the efficacy and safety of KCZ‐ILs in patients with tinea pedis. Thirty‐six enrolled participants were randomized to receive either KCZ‐ILs (KCZ, 4.72 mg/g) or Daktarin® (control group; KCZ, 20 mg/g) topically twice daily, making the lesion be covered with a thin layer of medication. The randomized controlled trial lasted for 8 weeks including 4 weeks of intervention and 4 weeks of follow‐up. Primary efficacy outcome was the proportion of treatment success responders, defined as patients achieving negative mycological result and ≥60% relative reduction in total clinical symptom score (TSS) from baseline at week 4. Secondary outcomes mainly for evaluating the relapse of disease included the proportion of treatment success individuals at week 8 and fungal recurrence rate at weeks 2, 3, 4, and 8. After 4 weeks of medication, 47.06% of the KCZ‐ILs subjects were treatment successes compared with only 25.00% of those using Daktarin®. Throughout the trial period, KCZ‐ILs induced a significantly lower recurrence rate (52.94%) than that of control patients (68.75%). Furthermore, KCZ‐ILs were found to be safe and well‐tolerated. In conclusion, ILs loading only 1/4 KCZ dose of Daktarin® showed a better efficacy and safety profile in the management of tinea pedis, creating a new opportunity for the treatment of skin diseases caused by fungal infection and is worthy of clinical application. [ABSTRACT FROM AUTHOR]

This article discusses a case of palisaded neutrophilic granulomatous dermatitis (PNGD) associated with Sjögren's syndrome (SS). The patient, a 66-year-old woman, presented with recurrent edematous erythema on her trunk and limbs. Histopathological examination confirmed the diagnosis of PNGD. The patient also had a history of dry mouth and difficulty swallowing, and further testing revealed positive immune antibody indicators for SS. After treatment with medication, the patient's symptoms improved. The article highlights the rarity of PNGD in patients with SS and suggests a possible link between the two conditions. The study was conducted by a team of researchers and was supported by various funding sources. [Extracted from the article]

Arsenic (As) exposure has been a global public health concern for hundreds of millions worldwide. LncRNA APTR (Alu-mediated p21 transcriptional regulator) plays an essential role in tumor growth and development. However, its function in arsenic-induced toxicological responses is still unknown. In this study, we found that the expressions of all transcripts and the transcript NR 134251.1 of APTR were increased in a dose-dependent manner in 16HBE cells treated with sodium arsenite (NaAsO2). Silencing the transcript NR 134251.1 of APTR inhibited cell proliferation and induced apoptosis. However, silencing all transcripts of APTR had the opposite function to the transcript NR 134251.1. Then we examined the protein level of the proliferation and apoptosis-related genes after silencing the transcript NR 134251.1 of APTR. The results showed that silencing the transcript NR 134251.1 of APTR up-regulated the expression of transcription factor E2F1 and regulated its downstream genes involved in proliferation and apoptosis, including p53, phospho-p53-S392, phospho-p53-T55, p21, Cyclin D1, PUMA, Fas, Bim, BIK, Caspase-3, Caspase-7, and Cyt-c. In conclusion, arsenic induced APTR expression and the transcript NR 134251.1 of APTR have an opposite function to all transcripts, providing a theoretical basis for the prevention and treatment of arsenic exposure. [ABSTRACT FROM AUTHOR]

Chimeric receptor T cells (CAR-T) can effectively cure leukemia; however, there are two limitations: a complicated preparation process ex vivo and cytokine release syndrome (CRS). In this study, we constructed a lipid nanoparticle system modified by CD3 antibody on the surface, loading with the plasmid containing the combination gene of interleukin 6 short hairpin RNA (IL-6 shRNA) and CD19-CAR (AntiCD3-LNP/CAR19 + shIL6). The system targeted T cells by the mediation of CD3 antibody and stably transfected T cells to transform them into CAR-T cells with IL-6 knockdown, thus killing CD19-highly expressed leukemia tumor cells and reducing CRS caused by IL-6. In vivo experiments showed that AntiCD3-LNP/CAR19 + shIL6 could stably transfect T cells and produce CAR-T within 90 days to kill the tumor. This significantly prolonged the survival time of leukemia model mice and demonstrated the prepared LNP exhibited the same anti-tumor effect as the traditional CAR-T cells prepared ex vivo. In this study, CAR-T cells were directly produced in vivo after intravenous injection of the lipid nanoparticles, without the need of using the current complex process ex vivo. Additionally, IL-6 expression was silenced, which would be helpful to reduce the CRS and improve the safety of CAR-T therapy. This method improves the convenience of using CAR-T technology and is helpful in further promoting the clinical application of CAR-T. [Display omitted] • New technology is required for CAR-T cells to avoid its complex preparation process and control CRS. • The LNPs modified by CD3 antibody transfected T cells and produced CAR-T cells in vivo. • The CAR-T cells produced by LNPs showed an anti-tumor effect and reduced the incidence of CRS. [ABSTRACT FROM AUTHOR]

Purpose: Chimeric antigen receptor (CAR) T cell therapy has demonstrated clinical success in treating haematologic malignancies but has not been effective against solid tumours thus far. Trop2 is a tumour-related antigen broadly overexpressed on a variety of tumours and has been reported as a promising target for pancreatic cancers. Our study aimed to determine whether CAR T cells designed with a fully human Trop2-specific single-chain fragment variable (scFv) can be used in the treatment of Trop2-positive pancreatic tumours. Methods: We designed Trop2-targeted chimeric antigen receptor engineered T cells with a novel human anti-Trop2 scFv (2F11) and then investigated the cytotoxicity, degranulation, and cytokine secretion profiles of the anti-Trop2 CAR T cells when they were exposed to Trop2 + cancer cells in vitro. We also studied the antitumour efficacy and toxicity of Trop2-specific CAR T cells in vivo using a BxPC-3 pancreatic xenograft model. Results: Trop2-targeted CAR T cells designed with 2F11 effectively killed Trop2-positive pancreatic cancer cells and produced high levels of cytotoxic cytokines in vitro. In addition, Trop2-targeted CAR T cells, which persistently circulate in vivo and efficiently infiltrate into tumour tissues, significantly blocked and even eliminated BxPC-3 pancreatic xenograft tumour growth without obvious deleterious effects observed after intravenous injection into NSG mice. Moreover, disease-free survival was efficiently prolonged. Conclusion: These results show that Trop2-targeted CAR T cells equipped with a fully human anti-Trop2 scFv could be a potential treatment strategy for pancreatic cancer and could be useful for clinical evaluation. [ABSTRACT FROM AUTHOR]

An efficient Au-catalyzed domino intramolecular cyclization reaction has been developed for the construction of pyrimidine derivatives from ynals and amidines at room temperature for 3 h. This transformation provides a new method for the formation of C–C and C–N bonds via intramolecular cyclization. [ABSTRACT FROM AUTHOR]

Patients with central nervous system (CNS) lymphomas have a poor prognosis. Chimeric antigen receptor-modified (CAR) T cells have shown remarkable efficacy for B-cell non-Hodgkin's lymphoma. However, few studies have reported the effects of CAR T cells in the treatment of CNS lymphoma, and the duration of remission is short. In this study, seven CNS lymphoma patients (six patients with secondary CNS lymphomas and one patient with primary CNS lymphoma) were treated with CD19 or CD20 CAR T cell therapy, and the clinical efficacy and toxicity profiles were evaluated. All patients responded to CAR T cell therapy. Four patients achieved complete remission (CR), while three demonstrated partial remission. We also found that either CD19 or CD20 CAR T cells could be detected in the cerebrospinal fluid of four patients. The median progression-free survival and median overall survival were not assessed. The median duration of CR was 22.4 months. Five patients (5/7) in this cohort received combination therapy (bridging with autologous hematopoietic stem cell transplantation and programmed death-1 inhibitor for maintenance treatment) and three (3/7) received CAR T cell therapy as soon as possible after the relapse of CNS lymphoma. This could help explain why these patients achieved long-term remission. After a median follow-up of 10.4 months, three patients demonstrated disease progression, and the antigen loss of CD20 was confirmed as the reason for relapse in one patient. The results of this study suggest that CD19 or CD20 CAR T cells are effective against CNS lymphoma. This research was registered at http://www.chictr.org.cn (No. ChiCTR2000036350). [ABSTRACT FROM AUTHOR]

Arsenic is a toxic metalloid vastly dispersed all over the occupational environments, manifesting multiple adverse health issues related to apoptosis. PUMA (p53 up-regulated modulator of apoptosis) is a crucial member of the Bcl-2 protein family and plays a key role in pro-apoptosis. The purpose of this work was to determine whether inorganic arsenic (NaAsO 2) and its metabolites influenced the expression of PUMA in vivo and vitro, followed by investigating the mechanisms. RNA was extracted from serum and used to determine the expression of PUMA in vivo. The urine samples performed arsenic speciation analysis. This trial tested three-dose proportions in two cell lines (A549: 20, 40, 60 μM/L; 16HBE: 1.5, 3.0, 4.5 μM/L), respectively. According to the results of qRT-PCR and western blotting, NaAsO 2 caused the overexpression of PUMA, not its metabolites. Furthermore, NaAsO 2 induced phosphorylation of p53 at Ser315, 376, 392, and Thr55, and acetylation of p53 at K370, 382 with a dose-response relationship, suggesting the contribution of PUMA up-regulation to p53 phosphorylation and acetylation. CCK-8, JC-1 (5, 5′, 6, 6′-tetrachloro-1, 1′, 3, 3′-tetramethylbenzimi-dazolylcarbocyanine iodide), Hoechst33342/PI and the caspase3 and PARP1 blots were utilized to reveal apoptosis responding to NaAsO 2 exposure. The co-immunoprecipitation assay showed that the interaction between PUMA and Bcl-X enhanced in intensity responding to NaAsO 2 exposure, disrupting the complexes of Bcl-X with other pro-survival Bcl-2-related proteins. To our knowledge, we first reported that NaAsO 2 activated phosphorylation of p53 at Ser315, 376, and Thr55, as well as acetylation of p53 at K370. • Inorganic arsenic exposure caused the overexpression of PUMA in vivo and vitro. • Apoptosis induced by inorganic arsenic. • Inorganic arsenic exposure increased p53 expression in A549 and 16HBE cells. • P53 phosphorylation and acetylation activated at Ser315/376/392/Thr55, K370/382. • Inorganic arsenic exposure enhanced the interaction between PUMA and Bcl-X. [ABSTRACT FROM AUTHOR]

The tumor burden (TB) is significantly related to the severity of cytokine release syndrome (CRS) caused by CAR-T cells, but its correlation with therapeutic efficacy has not been systematically studied. This study focused on the effects of the TB level on both the safety and efficacy of ssCART-19 as a treatment for r/r B-ALL. Taking the 5% tumor burden as the boundary, the study participants were divided into 2 groups, high and low tumor burden groups. Under this grouping strategy, the impacts of differential r/r B-ALL TBs on the clinical therapeutic efficacy (CR rate and long-term survival) and safety profiles after ssCART-19 cell treatment were analysed. 78 patients were reported in this study. The differential B-ALL TBs significantly affected the complete remission (CR) rates of patients treated with ssCART-19, with rates of 93.94% and 75.56% in the low and high TB groups, respectively (P = 0.0358). The effects of TBs on long-term therapeutic efficacy were further studied based on event-free survival (EFS) and overall survival (OS) profiles; both the OS and EFS of the low TB group were better than those of the high TB group, but the differences were not statistically significant. Importantly, the time points of TB measurement did not significantly affect the OS and EFS profiles regardless of whether the TBs were measured before or after fludarabine-cyclophosphamide (FC) preconditional chemotherapy. On the other hand, the severity of CRS was significantly correlated with the TB level (P = 0.0080), and the incidence of sCRS was significantly related to the TB level (the sCRS incidence increased as the TB level increased, P = 0.0224). Unexpectedly, the ssCART-19 cell expansion peaks were not significantly different (P = 0.2951) between the study groups. Patients with a low r/r B-ALL TB yield more net benefits from CAR-T treatment than those with a high TB in terms of safety and CR rate. These findings are critical and valuable for determining the optimal CAR-T cell treatment window for r/r B-ALL patients and will further the development of comprehensive and reasonable CAR-T cell treatment plans for r/r B-ALL patients with differential TBs. Trial registration: ClinicalTrials.gov identifier, NCT03919240. [ABSTRACT FROM AUTHOR]

RNAi effectors (e.g. siRNA, shRNA and miRNA) can trigger the silencing of specific genes causing alteration of genomic functions becoming a new therapeutic area for the treatment of infectious diseases, neurodegenerative disorders and cancer. In cancer treatment, RNAi effectors showed potential immunomodulatory actions by down-regulating immuno-suppressive proteins, such as PD-1 and CTLA-4, which restrict immune cell function and present challenges in cancer immunotherapy. Therefore, compared with extracellular targeting by antibodies, RNAi-mediated cell-intrinsic disruption of inhibitory pathways in immune cells could promote an increased anti-tumour immune response. Along with non-viral vectors, DNA-based RNAi strategies might be a more promising method for immunomodulation to silence multiple inhibitory pathways in T cells than immune checkpoint blockade antibodies. Thus, in this review, we discuss diverse RNAi implementation strategies, with recent viral and non-viral mediated RNAi synergism to immunotherapy that augments the anti-tumour immunity. Finally, we provide the current progress of RNAi in clinical pipeline. [ABSTRACT FROM AUTHOR]

Purpose: To address the issue of local drug delivery in tumor treatment, a novel nanoparticle-hydrogel superstructure, namely semi-interpenetrating polymer networks (semi-IPNs) hydrogel composed of poly (ethylene glycol) diacrylate (PEGDA) and hyaluronic acid (HA) and incorporated with paclitaxel (PTX) loaded PLGA nanoparticles (PEGDA-HA/PLGA-PTX), was prepared by in situ UV photopolymerization for the use of local drug delivery. Methods: Using the gelation time, swelling rate and degradation rate as indicators, the optimal proportion of Irgacure 2959 initiator and the concentration of HA was screened and obtained for preparing hydrogels. Next, paclitaxel (PTX) loaded PLGA nanoparticles (PLGA-PTX NPs) were prepared by the emulsion solvent evaporation method. Results: The mass ratio of the initiator was 1%, and the best concentration of HA was 5 mg/mL in PEGDA-HA hydrogel. In vitro experiments showed that PLGA-PTX NPs had similar cytotoxicity to free PTX, and the cell uptake ratio on NCI-H460 cells was up to 96% by laser confocal microscopy and flow cytometry. The drug release of the PEGDA-HA/PLGA-PTX hydrogel local drug delivery system could last for 13 days. In vivo experiments proved that PEGDAHA/PLGA-PTX hydrogel could effectively inhibit the tumor growth without causing toxic effects in mice. Conclusions: This study demonstrated that the PEGDA-HA/PLGA-PTX hydrogel is a promising local drug delivery system in future clinical applications for tumor therapy. [ABSTRACT FROM AUTHOR]

• The characters of the polysaccharide was modified by the non-thermal plasma. • The hydrophilicity of the polysaccharide plasma-treated was significantly enhanced. • The degree of cross-linking of surface molecules of the polysaccharide increased. • Polysaccharide plasma-treated significantly improve the immunity ability of RAW264.7. In order to improve the hydrophilicity and immune activity of the polysaccharide from Dendrobium nobile Lindl., non-thermal plasma was used to treat the polysaccharide. It was found that the hydrophilicity of the polysaccharide plasma-treated was significantly enhanced. Infrared spectra showed that the content of OH in the molecule increased significantly, and the monosaccharide ring changed from β-pyran sugar to β-furan sugar. The detection of SEM, AFM and TEM showed that the degree of cross-linking of surface molecules increased, and the arrangement of the polysaccharide was more compact and orderly. In vitro cell tests showed that the polysaccharide plasma-treated significantly improve the phagocytosis ability of RAW264.7, and promote the secretion of cytokines TNF-α, IL-6, IL-1. However, the cell proliferation test indicated that the polysaccharide did not increase the concentration of cytokines by promoting cell proliferation. RT-PCR showed that the polysaccharide plasma-treated could promote the expression of IL-1β at the transcriptional level. These results showed that non-thermal plasma treatment can effectively enhance the hydrophilicity of the polysaccharide and enhance its immune activity in vitro. Therefore, it can be inferred that the non-thermal plasma technology can be applied to the modification of active polysaccharides and will promote active polysaccharides to work better. [ABSTRACT FROM AUTHOR]

Background: T cells expressing a chimeric antigen receptor (CAR) engineered to target CD19 can treat leukemia effectively but also increase the risk of complications such as cytokine release syndrome (CRS) and CAR T cell related encephalopathy (CRES) driven by interleukin-6 (IL-6). Here, we investigated whether IL-6 knockdown in CART-19 cells can reduce IL-6 secretion from monocytes, which may reduce the risk of adverse events. Methods: Supernatants from cocultures of regular CART-19 cells and B lymphoma cells were added to monocytes in vitro, and the IL-6 levels in monocyte supernatants were measured 24 h later. IL-6 expression was knocked down in regular CART-19 cells by adding a short hairpin RNA (shRNA) (termed ssCART-19) expression cassette specific for IL-6 to the conventional CAR vector. Transduction efficiency and cell proliferation were measured by flow cytometry, and cytotoxicity was measured by evaluating the release of lactate dehydrogenase into the medium. Gene expression was assessed by qRT-PCR and RNA sequencing. A xenograft leukemia mouse model was established by injecting NOD/SCID/γc-/- mice with luciferase-expressing B lymphoma cells, and then the animals were treated with regular CART-19 cells or ssCART-19. Tumor growth was assessed by bioluminescence imaging. Results: Both recombinant IL-6 and CART-19 derived IL-6 significantly triggered IL-6 release by monocytes. IL-6 knockdown in ssCART-19 cells dramatically reduced IL-6 release from monocytes in vitro stduy. In vivo study further demonstrated that the mice bearing Raji cells treated with ssCART-19 cells showed significant lower IL-6 levels in serum than those treated with regular CART-19 cells, but comparable anti-tumor efficacy between the animal groups. Conclusion: CAR T-derived IL-6 is one of the most important initiators to amplify release of IL-6 from monocytes that further drive sCRS development. IL-6 knockdown in ssCART-19 cells by shRNA technology provide a promising strategy to improve the safety of CAR T cell therapy. [ABSTRACT FROM AUTHOR]

Objective To incorporate an antibacterial agent derived deep eutectic solvent (DES) into a dental resin composite, and investigate the resulting mechanical properties and antibacterial effects. Method The DES was derived from benzalkonium chloride (BC) and acrylic acid (AA) and was incorporated into the dental resin composite through rapid mixing. A three-point bending test was employed to measure the flexural strength of the composite. An agar diffusion test was used to investigate antibacterial activity. Artificial (accelerated) aging was undertaken by immersing the composites in buffer solutions at an elevated temperature for up to 4 weeks. UV–vis spectrophotometry and NMR analysis were conducted to study BC release from the composite. Finally, the biocompatibility of the composite materials was evaluated using osteoblast cell culture for 7 days. Results were compared to those of a control composite which contained no BC. Result The DES-incorporated composite (DES-C) displayed higher flexural strength than a similar BC-incorporated composite BC (BC-C) for the same level of BC. The inclusion of BC conferred antibacterial activity to both BC-containing composites, although BC-C produced larger inhibition halos than DES-C at the same loading of BC. Control composites which contained no BC showed negligible antibacterial activity. After artificial aging, the DES-C composite showed better maintenance of the mechanical properties of the control compared with BC-C, although a decrease was observed during the three-point bending test, particularly upon storage at elevated temperatures. No BC release was detected in the aged solutions of DES-C, whereas the BC-C showed a linear increase in BC release with storage time. Significantly, cell viability results indicated that DES-C has better biocompatibility than BC-C. Significance The incorporation of a BC-based DES into a dental resin composite provides a new strategy to develop antibacterial dental materials with better biocompatibility and longer effective lifetimes without sacrificing the intrinsic mechanical properties of the composite structure. [ABSTRACT FROM AUTHOR]

An efficient copper-catalyzed oxidative coupling of imidazo[1,2- a]pyridines with methyl ketones to directly generate structurally sophisticated 1,2-dicarbonyl imidazo[1,2- a]pyridine derivatives under oxidative conditions is described. The reaction proceeds in good yields using the environmental friendly molecular oxygen as the oxidant. 18O-Labelling experiments unambiguously established that the oxygen of the dicarbonyl products originated from oxygen rather than from water. [ABSTRACT FROM AUTHOR]

A facile and efficient copper(I)-catalyzed intermolecular direct CH homocoupling of imidazo[1,2- a]pyridines with excellent C-3 regioselectivity in dimethyl sulfoxide (DMSO) has been developed. This transformation provides a straightforward and operationally simple route for the preparation of biimidazo[1,2- a]pyridines which are an important structural motif in natural products and pharmaceuticals. [ABSTRACT FROM AUTHOR]

: Grace Chan and coauthors conducted a systematic review and meta-analysis of studies evaluating the risk of neonatal infection or colonization during the first seven days of life among newborns of mothers with bacterial infection or colonization during the intrapartum period. Please see later in the article for the Editors' Summary [ABSTRACT FROM AUTHOR]

• Inorganic arsenic, not MMA and DMA, inhibited the expression of DICER1-AS1. • DICER1-AS1 silencing could decrease proliferation in the A549 cell. • DICER1-AS1 regulated the expression of p21, Cyclin A2, Cyclin E2, CDK1 and PCNA. Arsenic, an environmental pollution with diverse toxicities, incurs public health problems. Arsenic trioxide could inhibit cell proliferation in vitro experiments, but the underlying mechanisms are not fully known. LncRNAs are also involved in the arsenic-induced toxicological responses. In our study, we found that the expression of lncRNA DICER1-AS1 was significantly inhibited by sodium arsenite in a dose-dependent manner. DICER1-AS1 silencing decreased the A549 cell proliferation and inhibited cell cycle progression. Importantly, DICER1-AS1 silencing induced upregulation of p21 and downregulation of Cyclin A2, Cyclin E2, CDK1 and PCNA. In conclusion, our study provided a new lncRNA-dictated regulatory mechanism participating in arsenic-induced inhibition of cell proliferation. [ABSTRACT FROM AUTHOR]

Using the widely available DMSO as the formylation reagent under oxidative conditions, an efficient Cu-catalyzed C3-formylation reaction of imidazo[1,2-a]pyridine C–H bonds to directly generate structurally sophisticated 3-formyl imidazo[1,2-a]pyridine derivatives has been developed. The reaction proceeded to generate products in good yields, and used the environmentally friendly molecular oxygen as the oxidant. [ABSTRACT FROM AUTHOR]

Background: Fusarium species are the fungal pathogens most commonly responsible for the mycotic keratitis, which are resistant to the majority of currently available antifungal agents. The present study was designed to assess the efficacy of a combination of low doses chlorhexidine with two other commonly used drugs (voriconazole and natamycin) to treat Fusarium infections. Results: We utilized combinations of chlorhexidine and natamycin or voriconazole against 20 clinical Fusarium strains in vitro using a checkerboard-based microdilution strategy. In order to more fully understand the synergistic interactions between voriconazole and chlorhexidine, we utilized a Galleria mellonella model to confirm the combined antifungal efficacy of chlorhexidine and voriconazole in vivo. We found that for voriconazole, natamycin, and chlorhexidine as single agents, the minimum inhibitory concentration (MIC) ranges were 2–8, 4–16, and > 16 μg/ml, respectively. In contrast, the MIC values for voriconazole and chlorhexidine were reduced to 0.25–1 and 1–2 μg/ml, respectively, when these agents were administered in combination, with synergy being observed for 90% of tested Fusarium strains. Combined chlorhexidine and natamycin treatment, in contrast, exhibited synergistic activity for only 10% of tested Fusarium strains. We observed no evidence of antagonism. Our in vivo model results further confirmed the synergistic antifungal activity of chlorhexidine and voriconazole. Conclusions: Our results offer novel evidence that voriconazole and chlorhexidine exhibit synergistic activity when used to suppress the growth of Fusarium spp., and these agents may thus offer value as a combination topical antifungal treatment strategy. [ABSTRACT FROM AUTHOR]

A diagram is presented which shows the selective C3-formylation of imidazo[1,2-a]pyridine C-H bonds using copper (Cu) as catalyst.

The article presents chemical equations related to the article "Regioselective Copper-Catalyzed Oxidative Cross-Coupling of Imidazo[1,2-a]pyridines with Methyl Ketones: An Efficient Route for Synthesis of 1,2-Diketones" by and others, published in the "Advanced Synthesis & Catalysis" in 2016.

An abstract of the study "Regioselective Oxidative Homocoupling Reaction: An Efficient Copper-Catalyzed Synthesis of Biimidazo[1,2-a]pyridines" by S. Lei and colleagues is presented.

Highly functionalized imidazopyridines are efficiently obtained by three-component one-pot reaction of 3-phenylpropiolaldehyde (III), a wide range of pyridin-2-amines (I), and various thiols. [ABSTRACT FROM AUTHOR]

Background: Although neonatal infections cause a significant proportion of deaths in the first week of life, little is known about the burden of neonatal disease originating from maternal infection or colonization globally. This paper describes the prevalence of vertical transmission--the percentage of newborns with neonatal infection among newborns exposed to maternal infection.Methods: We searched Pubmed, Embase, Scopus, Web of Science, Cochrane Library, and WHO Regional Databases for studies of maternal infection, vertical transmission, and neonatal infection. Studies that measured prevalence of bacterial vertical transmission were included. Random effects meta-analyses were used to pool data to calculate prevalence estimates of vertical transmission.Results: 122 studies met the inclusion criteria. Only seven studies (5.7%) were from very high neonatal mortality settings. Considerable heterogeneity existed between studies given the various definitions of infection (lab-confirmed, clinical signs), colonization, and risk factors of infection. The prevalence of early onset neonatal lab-confirmed infection among newborns of mothers with lab-confirmed infection was 17.2% (95%CI 6.5-27.9). The prevalence of neonatal lab-confirmed infection among newborns of colonized mothers was 0% (95% CI 0.0-0.0). The prevalence of neonatal surface colonization among newborns of colonized mothers ranged from 30.9-45.5% depending on the organism. The prevalence of neonatal lab-confirmed infection among newborns of mothers with risk factors (premature rupture of membranes, preterm premature rupture of membranes, prolonged rupture of membranes) ranged from 2.9-19.2% depending on the risk factor.Conclusions: The prevalence of early-onset neonatal infection is high among newborns of mothers with infection or risk factors for infection. More high quality studies are needed particularly in high neonatal mortality settings to accurately estimate the prevalence of early-onset infection among newborns at risk. [ABSTRACT FROM AUTHOR]