Clinically relevant GABARAP deficiency abrogates bortezomib-induced immunogenic cell death in multiple myeloma.

Recently, it was revealed that the high-risk, poor-prognosis downregulation of GABA type A receptor-associated protein (GABARAP) causes a defect in both autophagy and surface exposure of calreticulin (CALR) in multiple myeloma (MM) cells responding to bortezomib. Hence, GABARAP-defective MM cells fail to undergo immunogenic cell death.

Environmental Dyeing and Functionalization of Silk Fabrics with Natural Dye Extracted from Lac.

Most traditional synthetic dyes and functional reagents used in silk fabrics are not biodegradable and lack green environmental protection. Natural dyes have attracted more and more attention because of their coloring, functionalization effects, and environmental benefits. In this study, natural dyes were extracted from lac and used for coloring and functionalization in silk fabrics without any other harmful dyes. The extraction conditions were studied and analyzed by the univariate method. The optimal extraction process was that the volume ratio of ethanol to water was 60:40 with a solid-liquid ratio of 1:10, and reacting under the neutrality condition for 1 h at 70 °C. Silk fabric can be dyed dark owing to the certain lifting property of lac. After being dyed by Al3+ post-medium, the levels of the washing fastness, light fastness, and friction fastness of silk fabric are all above four with excellent fastness. The results show that the dyed silk fabrics have good UV protection, antioxidation, and antibacterial properties. The UV protection coefficient UPF is 42.68, the antioxidant property is 98.57%, and the antibacterial property can reach more than 80%. Therefore, the dyeing and functionalization of silk fabrics by utilizing naturally lac dyes show broad prospects in terms of the application of green sustainable dyeing and functionalization.

PD-L1+ macrophages suppress T cell-mediated anticancer immunity.

Recently, we showed that an autologous DC-based vaccine induces an increase in immunosuppressive PD-L1+ tumor-associated macrophages (TAM) both in the tumor and the tumor draining lymph nodes, thereby blunting the efficacy of therapeutic immunization. Only the combination of the DC vaccine with anti-PD-L1 immune checkpoint inhibition, but not the use of antibodies targeting PD-1 alone, was able to set off CD8+ cytotoxic T lymphocyte (CTL)-mediated tumor suppression in mice. In sum, we delineated a PD-L1 checkpoint blockade-based strategy to avoid TAM-induced T cell exhaustion during DC vaccine therapy.

Fish Scale for Wearable, Self-Powered TENG.

Flexible and wearable devices are attracting more and more attention. Herein, we propose a self-powered triboelectric nanogenerator based on the triboelectric effect of fish scales. As the pressure on the nanogenerator increases, the output voltage of the triboelectric nanogenerator increases. The nanogenerator can output a voltage of 7.4 V and a short-circuit current of 0.18 µA under a pressure of 50 N. The triboelectric effect of fish scales was argued to be related to the lamellar structure composed of collagen fiber bundles. The nanogenerator prepared by fish scales can sensitively perceive human activities such as walking, finger tapping, and elbow bending. Moreover, fish scales are a biomass material with good biocompatibility with the body. The fish-scale nanogenerator is a kind of flexible, wearable, and self-powered triboelectric nanogenerator showing great prospects in healthcare and body information monitoring.

Long non-coding RNA H19 mediates the miR-29b/transforming growth factor-ß1/Drosophila mothers against decapentaplegic 3 signalling pathway to promote bladder fibrosis in diabetic rats.

PURPOSE: Diabetic bladder fibrosis is a common comorbidity. Altered expression of some long non-coding RNAs (LncRNAs) has been associated with bladder fibrosis. LncRNA H19 has been reported to regulate bladder cancer through miR-29b. However, the action mechanism of LncRNA H19 in bladder fibrosis is unclear. METHODS: In vitro, human bladder smooth muscle cells (HBSMCs) were cultured with transforming growth factor-ß1 (TGF-ß1) for 48 h to construct cell model of bladder fibrosis. HBSMCs were then transfected with si-LncRNA H19, si-NC, miR-29b-mimic, mimic-NC, or miR-29b-inhibitor. In vivo, Sprague-Dawley (SD) rats were given a high-sucrose-high-fat (HSHF) diet for 4 weeks and injected with streptozotocin (STZ, 50 mg/kg) to induce bladder fibrosis model in diabetic rats, followed by injection of lentiviral particles knocking down LncRNA H19 expression, empty vector, or miR-29b-inhibitor, respectively. RESULTS: LncRNA H19 was up-regulated in TGF-ß1-induced HBSMC fibrosis and STZ-induced diabetic rat bladder fibrosis, whereas miR-29b was down-regulated. si-LncRNA H19 reduced blood glucose levels and improved histopathological damage of bladder tissue in rats. In addition, si-LncRNA H19 or miR-29b-mimic increased the expression of E-cadherin, but decreased the expression of N-cadherin, vimentin, fibronectin (FN) in bladder tissues, and HBSMCs. si-LncRNA H19 reduced TGF-ß1/p-drosophila mothers against decapentaplegic 3 (Smad3) protein in HBSMCs and in rat bladder tissues, while miR-29b-inhibitor reversed the effect of si-LncRNA H19. CONCLUSION: This study indicated that LncRNA H19 may inhibit bladder fibrosis in diabetic rats by targeting miR-29b via the TGF-ß1/Smad3 signalling pathway.

BCL2 inhibition stimulates dendritic cell function for improved anticancer immunotherapy.

Recently we developed a dendritic cell (DC) genotype-phenotype screening platform that is based on CRISPR/Cas9-mediated gene editing of immortalized DC precursors. Whole genome screening for gain-of-function phenotypes led to the identification of BCL2 as a DC-specific immune checkpoint. Genetic or pharmacological inhibition of BCL2 similarly enhanced the antigen presentation capacity of conventional type-1 dendritic cells (cDC1) and mediated T cell-dependent anticancer immunity. The therapeutic anticancer efficacy of the BCL2 inhibitor venetoclax in mice was further increased when combined with a PD-1-targeted immune checkpoint inhibitor. In sum, we delineated a novel strategy of dual checkpoint blockade for cancer immunotherapy in which improvement of DC antigen presentation and avoidance of T cell exhaustion can be advantageously combined.

Minimally Invasive Surgical Therapies for Ureteral Polyps: A Systematic Review.

Background: Ureteral polyps are rare benign ureteral tumor. No guideline recommends that open or minimally invasive surgery is best for treating ureteral polyps. This article aims to provide a comprehensive review of the minimally invasive techniques currently available for treating ureteral polyps. Materials and Methods: We performed a comprehensive search of articles published in PubMed, using the keywords "ureteral" and "polyp," or "polyps." Results: A total of 275 studies were obtained from the literature search but 96 articles were excluded. Conclusions: Several minimally invasive approaches were developed with the advancement of medical technology, including endoscopic, laparoscopic, and robotic approaches; however, the best surgical technique was yet to be decided. Due to the advantages and disadvantages of these approaches, the best surgical approach should be tailored to each patient's needs and the surgeon's preferences and experience.

Tenecteplase Plus Butyphthalide for Stroke Within 4.5-6 Hours of Onset (EXIT-BT): a Phase 2 Study.

To date, the benefit of intravenous thrombolysis is confined to within 4.5 h of onset for acute ischemic stroke (AIS) without advanced neuroimaging selection. The current trial aimed to investigate the safety and efficacy of intravenous tenecteplase (TNK) plus Dl-3-n-Butylphthalide (NBP) in AIS within 4.5 to 6 h of onset. In this randomized, multicenter trial, eligible AIS patients were randomly assigned to receive intravenous TNK (0.25 mg/kg) plus NBP or NBP within 4.5 to 6 h of onset. The primary endpoint was symptomatic intracranial hemorrhage (sICH). Secondary endpoints included excellent functional outcome defined as a modified Rankin Scale score of 0 to 1 at 90 days. 100 patients diagnosed by non-contrast CT (NCCT) were enrolled, including 50 in TNK group and 50 in control group. sICH occurred in 2.0% (1/50) in TNK group and 0.0% (0/49) in control group with no difference (unadjusted P = 0.998). The proportion of excellent functional outcome was 77.6% (38/49) in TNK group and 69.4% (34/49) in control group with non-significance (absolute difference 8.2%, P = 0.36). A significant decrease in NIHSS score at 24 h (P = 0.004) and more early neurological improvement (20.4% vs 4.1%; P = 0.026) was observed in TNK vs control group, but there was no difference in other secondary outcomes. This phase 2 study suggests that intravenous TNK with adjuvant NBP seems safe, feasible and may improve early neurological function in AIS patients within 4.5 to 6 h of symptom onset selected using NCCT.Clinical Trials Registration: This trial was registered with ClinicalTrials.gov (NCT05189509).

Results of Gensingen Bracing in Patients With Adolescent Idiopathic Scoliosis: Retrospective Cross-Sectional Feasibility Study.

BACKGROUND: Bracing is an essential part of scoliosis treatment. The standard of brace treatment for patients with scoliosis today is still very variable in terms of brace quality and outcome. The Gensingen brace is a further developed Chêneau brace derivative with individual design, which can be adapted through computer-aided design. OBJECTIVE: This study aims to generate a template to obtain a database for prospective multicenter studies study to analyze the results of high-corrective asymmetric Gensingen brace treatment for patients with adolescent idiopathic scoliosis (AIS). METHODS: A template for the database was created, which contains the patients' basic data (age, menarcheal status, Risser Sign, curve pattern, and daily brace wearing time), the Cobb angles of curvature, and the cosmetically relevant angles of trunk rotation (ATR). A retrospective review of medical records of patients with AIS, who met the Scoliosis Research Society's inclusion criteria for brace studies, was performed to test the feasibility of the template. Template items were filled in by the researchers. RESULTS: Out of 115 patients between 2014 and 2018, the complete data of 33 patients followed up at least 3 months after complete Gensingen brace weaning could be analyzed. The mean age was 12 years, the mean Cobb angle was 33.6°, and the mean Risser value was 0.7 at the beginning of the treatment. The mean improvement in the Cobb angle on in-brace x-ray imaging was -26.1० (80% of in-brace correction). The Cobb angle of the major curvature changed as follows: curve stabilization was achieved in 7 (21.2%) cases, and curve improvement was achieved in 26 (78.8%) cases. None of the patients showed a curve progression. The Cobb angle was significantly reduced in the brace at the end of treatment and at follow-up evaluation (P<.001). ATR improved significantly for thoracic (P<.001) and lumbar curves (P<.001). CONCLUSIONS: The database proved to be informative in the assessment of radiological and clinical outcome parameters. The example data set we have generated can be a helpful tool for professionals who work in clinics but do not store regular patient data. Especially with regard to different patient collectives worldwide, different results may be achieved with the same standards of care. In addition, the results of this study suggest that above-average correction effects with a full-time brace application lead to significant improvements in the Cobb angle after brace treatment has been completed.

Lymph node and tumor-associated PD-L1+ macrophages antagonize dendritic cell vaccines by suppressing CD8+ T cells.

Current immunotherapies provide limited benefits against T cell-depleted tumors, calling for therapeutic innovation. Using multi-omics integration of cancer patient data, we predict a type I interferon (IFN) responseHIGH state of dendritic cell (DC) vaccines, with efficacious clinical impact. However, preclinical DC vaccines recapitulating this state by combining immunogenic cancer cell death with induction of type I IFN responses fail to regress mouse tumors lacking T cell infiltrates. Here, in lymph nodes (LNs), instead of activating CD4+/CD8+ T cells, DCs stimulate immunosuppressive programmed death-ligand 1-positive (PD-L1+) LN-associated macrophages (LAMs). Moreover, DC vaccines also stimulate PD-L1+ tumor-associated macrophages (TAMs). This creates two anatomically distinct niches of PD-L1+ macrophages that suppress CD8+ T cells. Accordingly, a combination of PD-L1 blockade with DC vaccines achieves significant tumor regression by depleting PD-L1+ macrophages, suppressing myeloid inflammation, and de-inhibiting effector/stem-like memory T cells. Importantly, clinical DC vaccines also potentiate T cell-suppressive PD-L1+ TAMs in glioblastoma patients. We propose that a multimodal immunotherapy and vaccination regimen is mandatory to overcome T cell-depleted tumors.

Immunogenic cell death (ICD) enhancers-Drugs that enhance the perception of ICD by dendritic cells.

The search for immunostimulatory drugs applicable to cancer immunotherapy may profit from target-agnostic methods in which agents are screened for their functional impact on immune cells cultured in vitro without any preconceived idea on their mode of action. We have built a synthetic mini-immune system in which stressed and dying cancer cells (derived from standardized cell lines) are confronted with dendritic cells (DCs, derived from immortalized precursors) and CD8+ T-cell hybridoma cells expressing a defined T-cell receptor. Using this system, we can identify three types of immunostimulatory drugs: (i) pharmacological agents that stimulate immunogenic cell death (ICD) of malignant cells; (ii) drugs that act on DCs to enhance their response to ICD; and (iii) drugs that act on T cells to increase their effector function. Here, we focus on strategies to develop drugs that enhance the perception of ICD by DCs and to which we refer as "ICD enhancers." We discuss examples of ICD enhancers, including ligands of pattern recognition receptors (exemplified by TLR3 ligands that correct the deficient function of DCs lacking FPR1) and immunometabolic modifiers (exemplified by hexokinase-2 inhibitors), as well as methods for target deconvolution applicable to the mechanistic characterization of ICD enhancers.

Analysis of non-covalent interaction between ß-lactoglobulin and hyaluronic acid under ultrasound-assisted treatment: Conformational structures and interfacial properties.

Hyaluronic acid (HA) used as a food ingredient is gaining acceptance and popularity. However, the studies available for the effect of HA concentrations on the properties of ß-lactoglobulin (ß-LG) were limited. In this study, we investigated that the molecular characterization and functional properties of the complex formed by the non-covalent binding of ß-LG and HA, as well as the ultrasound-assisted treatment at acidic pH. The optimal pH and ratio of ß-LG/HA were set as 7 and 4:1, respectively. The fluorescence spectroscopy, circular dichroism spectroscopy, and molecular docking results revealed that the addition of HA and ultrasound induced a decrease in random coil and α-helix and an increase in ß-sheet contents in ß-LG. By the complexation with HA, the thermal stability, freezing stability, and antioxidant properties of ß-LG were all improved under ultrasound treatment. The results of the present study can be useful for the modulation of HA based biopolymer complexes and the exploitation as encapsulating or structuring agents in food industry.

Immunogenic cell stress and death in the treatment of cancer.

The successful treatment of oncological malignancies which results in long-term disease control or the complete eradication of cancerous cells necessitates the onset of adaptive immune responses targeting tumor-specific antigens. Such desirable anticancer immunity can be triggered via the induction of immunogenic cell death (ICD) of cancer cells, thus converting malignant cells into an in situ vaccine that elicits T cell mediated adaptive immune responses and establishes durable immunological memory. The exploration of ICD for cancer treatment has been subject to extensive research. However, functional heterogeneity among ICD activating therapies in many cases requires specific co-medications to achieve full-blown efficacy. Here, we described the hallmarks of ICD and classify ICD activators into three distinct functional categories namely, according to their mode of action: (i) ICD inducers, which increase the immunogenicity of malignant cells, (ii) ICD sensitizers, which prime cellular circuitries for ICD induction by conventional cytotoxic agents, and (iii) ICD enhancers, which improve the perception of ICD signals by antigen presenting dendritic cells. Altogether, ICD induction, sensitization and enhancement offer the possibility to convert well-established conventional anticancer therapies into immunotherapeutic approaches that activate T cell-mediated anticancer immunity.

Conventional type 1 dendritic cells (cDC1) in cancer immunity.

Cancer immunotherapy, alone or in combination with conventional therapies, has revolutionized the landscape of antineoplastic treatments, with dendritic cells (DC) emerging as key orchestrators of anti-tumor immune responses. Among the distinct DC subsets, conventional type 1 dendritic cells (cDC1) have gained prominence due to their unique ability to cross-present antigens and activate cytotoxic T lymphocytes. This review summarizes the distinctive characteristics of cDC1, their pivotal role in anticancer immunity, and the potential applications of cDC1-based strategies in immunotherapy.

The BCL2 inhibitor venetoclax mediates anticancer effects through dendritic cell activation.

BCL2 is an apoptosis-inhibitory oncoprotein that also possesses apoptosis-unrelated activities. Pharmacological BCL2 inhibitors have been developed with the scope of driving BCL2-dependent cancer cells into apoptosis, and one BCL2 antagonist, venetoclax, has been clinically approved for the treatment of specific leukemias and lymphomas. Nonetheless, it appears that venetoclax, as well as genetic BCL2 inhibition, can mediate anticancer effects through an indirect action. Such an indirect effect relies on the enhancement of the immunostimulatory function of dendritic cells, hence increasing tumor immunosurveillance. Mechanistically, BCL2 inhibition involves improved antigen presentation by conventional type-1 dendritic cells (cDC1s) due to the activation of an interferon response, leading to a T cell-mediated anticancer immune response that can be further enhanced by PD-1 blockade. These findings support the emerging hypothesis that successful antineoplastic drugs generally mediate their effects indirectly, through the immune system, rather via merely cell-autonomous effects on malignant cells.

Monovalent Omicron COVID-19 vaccine triggers superior neutralizing antibody responses against Omicron subvariants than Delta and Omicron bivalent vaccine.

The continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses a challenge to determine the optimal updated composition of the coronavirus disease 2019 (COVID-19) vaccine. The present study aimed to investigate the immunogenicity of the Delta monovalent vaccine, the Omicron monovalent vaccine, and the Delta and Omicron BA.1 bivalent vaccine. Three COVID-19 vaccines were designed using the heterologous DNA prime-protein boost strategy, with each vaccine containing either Delta receptor-binding domain (RBD) of the spike protein, Omicron RBD, or both Delta and Omicron antigens. Temporal serum antibody binding titers and neutralizing antibody titers induced by the three vaccines in New Zealand White rabbits were analyzed. To further dissect the vaccine elicited antibodies (mAb) responses at the molecular level, a panel of rabbit monoclonal antibodies (RmAbs) was generated by a high-throughput single B cell sorting and discovery pipeline and further comprehensively characterized. The Omicron monovalent vaccine induced higher antibody binding titers and neutralization activities than the Delta and Omicron bivalent vaccine. Four RmAbs with robust neutralization capacity were isolated from rabbits immunized with the Omicron or Delta monovalent vaccine. Notably, 9E11 isolated from the Omicron monovalent vaccine group neutralized all the Omicron subvariants with an IC50 value ranging from 1.5 to 503.6 ng/mL; thus, this vaccine could serve as a prophylactic and therapeutic intervention. Given the increasing incidence of COVID-19 cases due to the Omicron variant, RBD from the Omicron strain could serve as a candidate immunogen that can induce higher neutralization activities against the SARS-CoV-2 Omicron sublineages.

Transurethral 1470 nm diode laser vaporization versus plasma kinetic enucleation of the prostate for the treatment of benign prostatic hyperplasia: A retrospective study.

To compare the efficacy, safety, and complications of transurethral 1470 nm diode laser vaporization and plasma kinetic enucleation of prostate (PKEP) in benign prostatic hyperplasia treatment. A retrospective matched-paired comparison of patients treated using transurethral 1470 nm diode laser vaporization (n = 40) or PKEP (n = 40) was conducted. Baseline characteristics, preoperative data, and postoperative outcomes at the 24-month follow-up of the patients were recorded. The present study found no significant preoperative differences between the 2 treatment groups. Compared with PKEP, 1470 nm diode laser vaporization had a significantly shorter operation time and less intraoperative blood loss, but there were no marked differences between the 2 groups in terms of postoperative bladder irrigation time, catheterization time, and hospital stay. Moreover, at the 24-month follow-up postoperatively, there were no marked differences in the International Prostatic Symptomatic Score (IPSS), quality of life (QOL), maximum urinary flow rate (Qmax), and post-void residual urine volume (PVR) between the 2 groups. IPSS, QOL, Qmax, and PVR had improved significantly compared to preoperative assessment at 24-month follow-up in both groups and there was no significant difference in the variation of IPSS, QOL, Qmax and PVR before and after the operation. Furthermore, complications were comparable between the 2 treatment groups. Transurethral 1470 nm diode laser vaporization and PKEP are effective strategies in the treatment of benign prostatic hyperplasia. However, 1470 nm diode laser vaporization offers advantages over PKEP in terms of shortening operation time and reducing intraoperative bleeding. Nonetheless, further research with a larger number of patients and long-term follow-up is necessary to confirm and validate these findings.

Rapid and portable bunyavirus SFTSV RNA testing utilizing catalytic hairpin assembly coupled with lateral flow immunoassay.

Severe fever with thrombocytopenia syndrome (SFTS) is a prevalent, life-threatening, emergent infectious disease. Currently, reverse transcription-polymerase chain reaction is the gold standard for diagnosing SFTS virus (SFTSV) infection, which requires sophisticated equipment and professional personnel that are frequently unavailable in most SFTS endemic rural areas. Here, we reported a simple, rapid nucleic acid amplification system that combined the catalytic hairpin assembly (CHA) with a lateral flow immunoassay (LFIA) strip-based detection method for SFTSV detection. The detection of SFTSV RNA could be realized by generation of H1-H2 hybrid duplexes labeled with biotin and digoxin, which subsequently added to the LFIA test strips containing streptavidin conjugated with Alexa Fluor 647 as well as anti-digoxin antibodies. Our CHA-based LFIA assay offered high amplification efficiency and specificity with a detection limit of 1 aM. Crucially, this method enabled stable detection of 500 copies/mL of SFTSV within 30 min using clinical serum samples. Therefore, our CHA-based LFIA approach provided a potential useful tool to facilitate early and precise diagnosis of SFTS patients in poorly resourced SFTS endemic areas.IMPORTANCESevere fever with thrombocytopenia syndrome (SFTS) is an emerging and potentially fatal infectious disease prevalent in China. Here we report a simple, rapid nucleic acid amplification system, the catalytic hairpin assembly (CHA) in conjunction with a lateral flow immunoassay (LFIA) strip-based detection method for SFTS virus detection, which demonstrated high amplification efficiency and specificity with limit of detection of 1 aM. Most importantly, we also validate our CHA-based LFIA assay using the clinical serum samples, which was fully compatible with reverse transcription-PCR results. Therefore, our strategy provides a potential useful tool to facilitate early and precise diagnosis of SFTS patients especially in poorly resourced SFTS endemic areas.

Clinical value of droplet digital PCR in the diagnosis and dynamic monitoring of suspected bacterial bloodstream infections.

BACKGROUND: Bloodstream infections (BSIs) represent a significant public health challenge due to their high morbidity and mortality. The clinical prognosis of BSIs is closely related to the timely and accurate diagnosis and the rational use of initial antimicrobials. We aimed to evaluate the clinical value of droplet digital PCR (ddPCR) in rapid diagnosis and dynamic monitoring of BSIs. METHODS: In this prospective study, using a ddPCR-based approach which detects 18 common pathogens, we compared the detection results and clinical concordance rates of ddPCR with blood culture (BC) in 211 patients with suspected BSIs. Further, the inflammatory profile of BSIs with Gram-negative bacteria was analyzed by Olink proteomics platform. RESULTS: Our data showed that the positive detection rate of ddPCR was 48.82%, which was higher than that of BC (9.48%). For BC-validated BSIs, ddPCR had a sensitivity of 90.00% and a specificity of 55.50%. When considering clinically-validated BSIs, the diagnostic value of ddPCR improved with a sensitivity of 92.59% and a specificity of 78.46%.The bacterial load detected by ddPCR was correlated with traditional clinical inflammatory indicators such as interleukin-6 (IL-6) and C-reactive protein (CRP). In addition, using Olink proteomics platform, we revealed that serological osteoprotegerin (OPG), interleukin-8 (IL-8), interleukin-18 receptor 1 (IL-18R1), C-C motif chemokine 20 (CCL20) and IL-6 were substantially elevated in Gram-negative bacteria-associated BSIs, which could serve as novel auxiliary diagnostic indicators for Gram-negative bacteria BSIs. CONCLUSION: ddPCR has the potential to provide early pathogen diagnosis, dynamic monitoring, and treatment regimen optimization for patients with BSIs.