Effect of combining evolocumab with statin on carotid intraplaque neovascularization in patients with premature coronary artery disease (EPOCH).

BACKGROUND AND AIMS: We aimed to explore the effect of PCSK9 inhibitor based on the background of statin on carotid intraplaque neovascularization (IPN) assessed by serial contrast-enhanced ultrasound (CEUS) analysis in Chinese patients with premature coronary artery disease (PCAD). METHODS: 41 patients were included to receive treatments with biweekly evolocumab (n = 22) or placebo (n = 19) in addition to statin therapy for 52 weeks. All patients were newly diagnosed with PCAD and treatments were initiated at baseline of the observations. Baseline and 52-week CEUS were acquired to measure the max plaque height (MPH) and IPN. The primary outcome was the 52-week IPN changes, the secondary endpoints included the 52-week MPH changes and major adverse cardiovascular events. RESULTS: The mean ± SD age of the participants was 46.76 ± 8.56 years, and 61% (25/41) of patients were on statins before the start of the study. There was no statistically significant difference in the history of statins treatment and the initiated lipid-lowering therapy of atorvastatin and rosuvastatin between groups (p > 0.05). At 52 weeks, the evolocumab group showed a lower LDL level (0.84 ± 0.45 mmol/L vs. 1.58 ± 0.51 mmol/L, p < 0.001) and a greater decrease in percent reduction of LDL-C level (-65% vs. -32%) and a higher percent of achieving lipid-lowering target (95% vs. 53%, p < 0.05) compared with the placebo group. At 52 weeks, IPN (evolocumab group: 0.50 ± 0.60 vs. 1.50 ± 0.80, p < 0.001; placebo group: 0.79 ± 0.54 vs. 1.26 ± 0.65, p < 0.05) and MPH (evolocumab group: 2.01 ± 0.44 mm vs. 2.57 ± 0.90 mm, p < 0.05, placebo group: 2.21 ± 0.58 mm vs. 2.92 ± 0.86 mm, p < 0.05) reduced significantly in both groups from baseline to 52-week follow-up. IPN and MPH were decreased by both treatments. Still, there was no significant difference in delta (52 weeks - baseline) MPH by an ANOVA analysis between the two groups [evolocumab group: -0.56 mm (2.01 mm-2.57 mm); placebo group: -0.71 mm (2.21 mm-2.92 mm), p > 0.05]. In the evolocumab group, the change in the mean reduction of IPN from baseline [-1.00 (0.50-1.50) vs. -0.47 (0.79-1.26), p < 0.05] and the incidence of patients with carotid IPN decrease were significantly greater reduction (90% vs. 58%, p < 0.05). CONCLUSIONS: If compared to placebo, the PCSK9 inhibitor evolocumab combined with statins resulted in a greater decrease in LDL-C and plaque neovascularization in Chinese patients with PCAD.

HLA-class II restricted TCR targeting human papillomavirus type 18 E7 induces solid tumor remission in mice.

T cell receptor (TCR)-engineered T cell therapy is a promising potential treatment for solid tumors, with preliminary efficacy demonstrated in clinical trials. However, obtaining clinically effective TCR molecules remains a major challenge. We have developed a strategy for cloning tumor-specific TCRs from long-term surviving patients who have responded to immunotherapy. Here, we report the identification of a TCR (10F04), which is human leukocyte antigen (HLA)-DRA/DRB1*09:01 restricted and human papillomavirus type 18 (HPV18) E784-98 specific, from a multiple antigens stimulating cellular therapy (MASCT) benefited metastatic cervical cancer patient. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4+ and CD8+ T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity and outstanding safety profiles. As a result, this TCR is currently being investigated in a phase I clinical trial for treating HPV18-positive cancers. This study provides an approach for developing safe and effective TCR-T therapies, while underscoring the potential of HLA class II-restricted TCR-T therapy as a cancer treatment.

Unlocking the power of immunotherapy: Combinatorial delivery of plasmid IL-15 and gemcitabine to synergistically remodeling the tumor microenvironment.

Cancer immunotherapy has emerged as a promising clinical treatment strategy in recent years. Unfortunately, the satisfactory antitumor therapeutic efficacy of immunotherapy is limited by intricate immunosuppressive tumor microenvironment (ITM). To remodel the ITM and alleviate the immune evasion, we constructed FA-PEG-modified liposomes to deliver plasmid IL-15 (pIL-15) and gemcitabine (GEM) (FPCL@pIL-15 + FPGL), respectively. The FPCL@pIL-15 (150 nm) and FPGL (120 nm) exhibited symmetrically spherical structures as well as desirable penetration and accumulation on tumor tissue depending on folic acid (FA) specialized targeting function. The transfected expression of IL-15 efficiently fosters the proliferation and co-activation of Natural killer (NK) cells and CD8+T cells through binding to IL-15R. FPGL upregulated the expression of Natural killer group 2 member D ligands (NKG2DLs) and reinforced recognition by NK cells to alleviate the immune evasion, and simultaneously promoted activation of CD8+T cells through immunogenic cell death (ICD) effects. More importantly, the combinatorial administration achieved intended anti-tumor efficacy in the subcutaneous 4T1 tumor model. In essence, we demonstrated that combining FPCL@pIL-15 with FPGL synergistically stimulates and mobilizes the immune system to reverse the ITM and trigger an anti-tumor immune response, indicating a tremendous potential for application in immunotherapy.

Pharmacokinetic Evaluation of the CYP3A4 and CYP2C9 Drug-Drug Interaction of Avacopan in 2 Open-Label Studies in Healthy Participants.

Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30 mg of avacopan increased the area under the curve (AUC) of midazolam by 1.81-fold and celecoxib by 1.15-fold when administered without food, and twice-daily oral administration of 30 or 60 mg of avacopan increased the AUC of simvastatin by approximately 2.6-3.5-fold and the AUC of the active metabolite ß-hydroxy-simvastatin acid by approximately 1.4-1.7-fold when co-administered with food. Furthermore, the AUC of avacopan increased by approximately 2.19-fold when co-administered with itraconazole and decreased by approximately 13.5-fold when co-administered with rifampin. These findings provide critical insights into the potential drug-drug interactions involving avacopan, which could have significant implications for patient care and treatment planning. (NCT06207682).

Effect of moderate-intensity statin on carotid intraplaque neovascularization of coronary artery disease: a retrospective cohort study.

Background: Statin treatment can reduce atherosclerotic plaque as detected via invasive intracoronary methods. However, few studies have evaluated the effect of moderate-intensity statin therapy on carotid intraplaque neovascularization (IPN) using semiquantitative indices. This study thus aimed to assess the effect of statin on the carotid IPN of coronary artery disease with contrast-enhanced ultrasound (CEUS). Methods: In this noncontrol, retrospective, cohort study, 35 inpatients who underwent coronary angiography, serial CEUS, and laboratory evaluations were consecutively enrolled from June 2020 to December 2022 at the Department of Cardiology, Chinese PLA General Hospital. All patients were administered moderate-intensity statin during serial CEUS, and continuous and categorical assessment of IPN and maximum plaque height (MPH) of carotid plaque was performed. Patients with a target low-density lipoprotein cholesterol (LDL-C) <1.8 mmol/L at 12-month follow-up were compared with those who did not reach the LDL-C 1.8 mmol/L target. Results: From baseline to 12-month follow-up, there were significant differences in the LDL-C levels between patients (2.71±1.29 vs. 1.35±0.83 mmol/L), those with 12-month follow-up LDL-C <1.8 mmol/L (2.58±1.24 vs. 1.08±0.52 mmol/L), and those with 12-month follow-up LDL-C ≥1.8 mmol/L (3.24±1.44 vs. 2.56±0.85 mmol/L) all P values <0.05, with decreases of 41%, 49%, and 11% from baseline, respectively. The mean MPH (12 months to baseline) decreased from 2.47±0.63 to 2.22±0.60 mm (P<0.05), and the IPN also decreased from 1.15±0.62 to 0.58±0.56, representing a reduction of 0.57±0.59 from baseline (P<0.001). In the LDL-C <1.8 mmol/L patients, there were significant differences between baseline and 12 months in MPH (2.37±0.56 vs. 2.03±0.52 mm; P<0.05) and IPN (1.32±0.77 vs. 0.54±0.63; P<0.05) compared with those with a follow-up LDL-C ≥1.8 mmol/L. Patients with a follow-up LDL-C <1.8 mmol/L, compared with those with a follow-up LDL-C ≥1.8 mmol/L, showed a significantly greater reduction in MPH (-0.34±0.46 vs. -0.13±0.39; P<0.05) and IPN (-0.79±0.63 vs. -0.57±0.79; P<0.05). Additionally, patients with carotid IPN regression showed a higher percent change in LDL-C compared with those without carotid IPN regression (-53.31±23.20 vs. -29.55±19.47; P<0.05). Conclusions: Controlling the LDL-C to <1.8 mmol/L under moderate-intensity statin can stabilize and reduce carotid IPN as detected by the semiquantitative noninvasive CEUS.

Revealing the degrading-possibility of methyl red by two azoreductases of Anoxybacillus sp. PDR2 based on molecular docking.

Azo dyes, as the most widely used synthetic dyes, are considered to be one of the culprits of water resources and environmental pollution. Anoxybacillus sp. PDR2 is a thermophilic bacterium with the ability to degrade azo dyes, whose genome contains two genes encoding azoreductases (named AzoPDR2-1 and AzoPDR2-2). In this study, through response surface methodology (RSM), when the initial pH, inoculation volume and Mg2+ addition amount were 7.18, 10.72% and 0.1 g/L respectively, the decolorization rate of methyl red (MR) (200 mg/L) could reach its maximum (98.8%). The metabolites after biodegradation were detected by UV-Vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), and liquid chromatography mass spectrometry (LC-MS/MS), indicating that MR was successfully decomposed into 4-aminobenzoic acid and other small substrates. In homologous modeling, it was found that both azoreductases were flavin-dependent azoreductases, and belonged to the α/ß structure, using the Rossmann fold. In their docking results with the cofactor flavin mononucleotide (FMN), FMN bound to the surface of the protein dimer. Nicotinamide adenine dinucleotide (NADH) was superimposed on the plane of the pyrazine ring between FMN and the activity pocket of protein. Besides, both azoreductase complexes (azoreductase-FMN-NADH) exhibited a substrate preference for MR. Asn104 and Tyr74 played an important role in the combination of the azoreductase AzoPDR2-1 complex and the azoreductase AzoPDR2-2 complex with MR, respectively. This provided assistance for studying the mechanism of azoreductase biodegradation of azo dyes in thermophilic bacteria.

Canine distemper virus (CDV)-neutralizing activities of an anti-CDV canine-derived single-chain variable antibody fragment 4-15 (scFv 4-15) screened by phage display technology.

Canine distemper virus (CDV) is a highly contagious pathogen that causes severe diarrhea, fever and vomiting in domestic dogs, posing a serious threat to the dog breeding industry. Currently, there are no effective therapeutic agents for emergency treatment despite the availability of vaccines against CDV infection. Single-chain fragment variable (scFv) antibody has been demonstrated to effectively inhibit virus infections, suggesting a potential candidate as a therapeutic agent for canine distemper. In this study, a phage-displayed scFv library was constructed from the peripheral blood lymphocytes of dog immunized intramuscularly with live-attenuated CDV vaccine, and was subjected to four rounds of pannings against CDV. Subsequent indirect enzyme-linked immunosorbent assay screening revealed high-affinity scFv antibodies specific to CDV, and indirect immunofluorescence assay screening revealed CDV-neutralizing activity of scFv antibodies. Our results showed that a scFv antibody 4-15 (scFv 4-15) with high-affinity binding to CDV and neutralizing activity against CDV was obtained, which displayed effective therapeutic potential in vivo for dogs challenged with a lethal dose of CDV. Conclusively, the scFv 4-15 with high-affinity binding and neutralizing activity to CDV that was obtained by phage display technology provides a promising candidate for the therapeutic agents against CDV infection.

Comprehensive Analysis Reveals the Potential Roles of CDKN3 in Pancancer and Verification in Endometrial Cancer.

Background: Cyclin-dependent kinase inhibitor 3 (CDKN3) has been studied in many cancers. However, the comprehensive and systematic pancancer analysis of CDKN3 genes is still lacking. Methods: Data were downloaded from online databases. R was used for analysis of the differential expression and gene alteration of CDKN3 and of the associations between CDKN3 expression and survival, signaling pathways, and drug sensitivity. Clinical samples and in vitro experiments were selected for verification. Results: CDKN3 expression was higher in most types of cancers, and this phenotype was significantly correlated with poor survival. CDKN3 showed gene alterations and copy number alterations in many cancers and associated with some immune-related pathways and factors. Drug sensitivity analysis elucidated that CDKN3 could be a useful marker for therapy selection. Clinical samples elucidated CDKN3 expressed high in endometrial cancer tissue. In vitro studies showed that CDKN3 induced pro-tumor effect in immune environment and facilitated endometrial cancer cell proliferation and G1/S phase transition. Conclusion: CDKN3 has been shown to be highly expressed in most types of cancers and promoted cancer cell progression. CDKN3 may serve as a novel marker in clinical diagnosis, treatment, and prognosis prediction in future.

Up-regulated lncRNA CYLD as a ceRNA of miR-2383 facilitates bovine viral diarrhea virus replication by promoting CYLD expression to counteract RIG-I-mediated type-I IFN production.

Bovine viral diarrhea virus (BVDV) is one of the most important pathogens of cattle, causing numerous economic losses to the cattle industry. To date, many potential mechanisms of BVDV evading or subverting innate immunity are still unknown. In this study, an lnc-CYLD/miR-2383/CYLD axis involved in BVDV-host interactions was screened from RNA-seq-based co-expression networks analysis of long noncoding RNAs, microRNAs and mRNAs in BVDV-infected bovine cells, and underlying mechanisms of lnc-CYLD/miR-2383/CYLD axis regulating BVDV replication were explored. Results showed that BVDV-induced up-regulation of the lnc-CYLD competed for binding to the miR-2383, and then promoted CYLD expression, thereby inhibiting RIG-I-mediated type-I interferon (IFN) production, which was subsequently confirmed by treatment with lnc-CYLD overexpression and miR-2383 inhibitor. However, miR-2383 transfection and small interfering RNA-mediated lnc-CYLD knockdown inhibited CYLD expression and enhanced RIG-I-mediated type-I IFN production, inhibiting BVDV replication. In addition, interaction relationship between lnc-CYLD and miR-2383, and colocalization relationship of lnc-CYLD, miR-2383 and CYLD were confirmed by dual-luciferase assay and in situ hybridization assay. Conclusively, up-regulation of the lnc-CYLD as a competing endogenous RNA binds to the miR-2383 to reduce inhibitory effect of the miR-2383 on the CYLD expression, playing an important role in counteracting type-I IFN-dependent antiviral immunity to facilitate BVDV replication.

Sugar metabolism and 14-3-3 protein genes expression induced by arbuscular mycorrhizal fungi and phosphorus addition to response drought stress in Populus cathayana.

Sugar, as a nutrient exchange substance between arbuscular mycorrhizal (AM) fungi and host plants, plays an important role in the abiotic stress response of mycorrhizal plants. This experiment aimed to study the effects of AM fungi and phosphorus (P) addition on the sugar metabolism and 14-3-3 gene expression of Populus cathayana under drought stress. The results showed that drought affects the process of sugar metabolism by increasing the activities of amylase and invertase, resulting in the decrease of starch content in leaves and roots and the accumulation of soluble sugars (including reducing sugar and sucrose) in roots. Under drought stress, the activity or content of sucrose synthetase, sucrose phosphate synthase, acid invertase, alkaline invertase, reducing sugar, soluble sugar, sucrose, and starch in the root showed the best mycorrhizal effect at the 100 mg P level. The expression levels of the 14-3-3 genes (PcGRF10 and PcGRF11) were significantly increased by mycorrhizal induction under drought stress. These levels were positively correlated with SS, SPS, sucrose, and starch phosphorylase in leaves, as well as with almost all sugar metabolism indicators in roots. However, they were negatively correlated with starch content in both leaves and roots. Sugar metabolism and 14-3-3 protein gene expression were induced by AM fungi and P addition in response to drought stress. The 14-3-3 genes induced by AM fungi may be involved in participating in osmotic regulation during drought stress. This study provides a new idea for the mechanism of sugar metabolism of mycorrhizal plants in arid regions.

Expression and clinicopathological characteristics of PDX1, PTF1A, and SALL4 in large and small ducts of ectopic pancreas located in gastro-duodenum and jejunum.

An ectopic pancreas is defined as pancreatic tissue outside its normal location, anatomically separated from the pancreas. The transcription factor pancreas/duodenum homeobox protein 1 (PDX1) is involved in maintaining the pancreas and functions in early pancreatic development, beta cell differentiation, and endocrine non beta cells. Pancreatic transcription factor 1 subunit alpha (PTF1A) affects exocrine cell formation and regulation of acinar cell identity, and is expressed in exocrine cells as a transcription factor. The depletion of SALL4 disrupts self-renewal and induces differentiation. To clarify which of PDX1, PTF1A, or SALL4 determines the difference in Heinrich's classification, we examined the localization and number of positive cells. We analyzed the differential expression of PDX1, PTF1A, and SALL4 in large and small ducts in ectopic pancreas by immunohistochemistry. Results showed that the number of PTF1A-positive cells in large ducts was more widespread in type I than in type II in the gastro-duodenum, and more SALL4-positive cells were noticed in large ducts than in small ducts in the gastro-duodenum of type II. Our results revealed that PTF1A might promote exocrine differentiation in developing the pancreatic tissues, and that those with widespread expression differentiate into exocrine cells.

Cooling vest improves surgeons' thermal comfort without affecting cognitive performance: a randomised cross-over trial.

OBJECTIVES: Surgeons become uncomfortable while performing surgery because heat transfer and evaporative cooling are restricted by insulating surgical gowns. Consequently, perceptions of thermal discomfort during surgery may impair cognitive performance. We, therefore, aimed to evaluate surgeons' thermal comfort, cognitive performance, core and mean skin temperatures, perceptions of sweat-soaked clothing, fatigue and exertion with and without a CoolSource cooling vest (Cardinal Health, Dublin, Ohio, USA). METHODS: Thirty orthopaedic surgeons participated in a randomised cross-over trial, each performing four total-joint arthroplasties with randomisation to one of four treatment sequences. The effects of cooling versus no cooling were measured using a repeated-measures linear model accounting for within-subject correlations. RESULTS: The cooling vest improved thermal comfort by a mean (95% CI) of -2.1 (-2.7 to -1.6) points on a 0-10 scale, p<0.001, with no evidence of treatment-by-period interaction (p=0.94). In contrast, cooling had no perceptible effect on cognition, with an estimated mean difference (95% CI) in Cleveland Clinic Cognitive Battery (C3B) Processing Speed Test score of 0.03 (95% CI -2.44 to 2.51), p=0.98, or in C3B Visual Memory Test score with difference of 0.88 (95% CI -2.25 to 4.01), p=0.57. Core temperature was not lower with the cooling vest, with mean difference (95% CI) of -0.13 (-0.33°C to 0.07°C), p=0.19, while mean skin temperature was lower, with mean difference of -0.23 (95% CI -0.40°C to -0.06°C) lower, p=0.011. The cooling vest significantly reduced surgeons' perceptions of sweat-soaked clothing, fatigue and exertion. CONCLUSIONS: A cooling vest worn during surgery lowered core and skin temperatures, improved thermal comfort, and decreased perceptions of sweating and fatigue, but did not improve cognition. Thermal discomfort during major orthopaedic surgery is thus largely preventable, but cooling does not affect cognition. TRIAL REGISTRATION NUMBER: NCT04511208.

A two-photon iridium(III) complex probe for sensitive detection of SO2 derivatives in living cell mitochondria.

The derivatives of sulfur dioxide (HSO3-) formed in the biological environment play a vital role in the circulation system. Excessive SO2 derivatives will cause serious damage to the living system. Herein, a two-photon phosphorescent probe based on Ir(III) complex (named as Ir-CN) was designed and synthesized. Ir-CN is extremely selective and sensitive to SO2 derivatives with significant phosphorescent enhancement and increased phosphorescent lifetime. The detection limit of Ir-CN for SO2 derivatives reaches 0.17 µM. More importantly, Ir-CN preferentially accumulates in mitochondria, so bisulfite derivatives can be detected at subcellular level, which enriching the application of metal complex probe in biological detection. In addition, both single-photon and two-photon images can clearly show that Ir-CN is targeted to mitochondria. Benefits from its good biocompatibility, Ir-CN may be used as a reliable tool to detect SO2 derivatives in mitochondrion of living cells.

Application effect of perioperative nursing mediated by 3D printing and mind mapping in gynecological tumor laparoscopy.

Probing influence by perioperative nursing mediated by 3D printing and mind mapping in gynecological tumor laparoscopy. 90 subjects divided into three groups: A (n=30), B (n=30) and C (n=30). Each group was given a different type of nursing intervention postoperative recovery (postoperative anal gas exhausting time, eating time, hospital stay, leaving bed-time, and drainage tube extraction time) were compared among the three groups. Hamilton Anxiety Scale (HAMA)/Hamilton Depression Scale (HAMD), strategies Used by People to Promote Health (SUPPH), Generic quality-of-life Inventory (GQOLI-74) scores and complication rates were compared among the three groups. The postoperative recovery of group A and B was better than group C, and group A was better than group B (P<0.05). Post-intervening, HAMA/HAMD scorings within groups A/B reduced compared with group C, with group A＞group B (P<0.05). The complication rate of group A and B was lower than that of group C (P<0.05). Perioperative nursing mediated by 3D printing and mind mapping works well.

Comparative Study on Chemical Constituents of Ginseng Flowers with Four Consecutive Cultivation Age.

The harvest period of cultivated ginseng is generally 4-6 years. Ginseng flowers (GFs), the nonmedicinal parts, are usually removed every autumn, in which components are generally believed to stay unchanged with the increasing cultivation age. Recently, few documents were reported on the variation of volatile organic compounds (VOCs) and other components about ginseng flowers. This study had an insight into the variation of the chemical constituents with the cultivation ages through the comparison of the volatile organic compounds, gross ginsenosides, crude polysaccharide, and gross proteins of ginseng flowers from 3-, 4-, 5-, and 6-yr-old (GF3, GF4, GF5, and GF6) which were conducted by headspace solid-phase microextraction-gas chromatography-triple quadrupole mass spectrometry (HS-SPME-GC-QQQ/MS) and spectroscopic analysis combined with multivariate statistical analysis, including one-way ANOVA analysis and T test. The results indicated that the crude polysaccharide contents raised significantly depending on cultivation age except 6-yr-old, whereas the gross ginsenosides and the gross protein content were indistinctive. According to the peak intensity of determined VOCs, the contents of most differential compounds arranged in an order from high to low are GF3, GF4, GF5, and GF6, such as the compounds 2-15, 17-19, 22, and 25-26, therefore, they can be inferred that they are important markers to identify the age of GFs. 461 common differential compounds were gained and 26 common volatile organic compounds were identified with RSI >800 and RI and RIx no more than 30, including alcohols (such as 11, 12, and 15), sesquiterpenes (such as 2, 3, and 4), esters (such as 1 and 26), naphthalene and naphthol (such as 7 and 20), which had potential effects on curing Alzheimer's disease, inflammatory diseases, and prostate cancer based on network pharmacology analysis. This paper firstly revealed the variation rules of constitutions of GFs, which may provide a reference for the harvest and making rational application.

Integration of proteome and metabolome profiling to reveal heat stress response and tolerance mechanisms of Serratia sp. AXJ-M for the bioremediation of papermaking black liquor.

The use of thermophilic bacteria for treating paper black liquor seems to be an efficient bioremediation strategy. In our previous work, the lignin-degrading bacterium Serratia sp. AXJ-M exhibited excellent heat tolerance ability. However, the molecular mechanism of its response to heat stress is unknown. Therefore, the heat stress response of AXJ-M was investigated using morphological and analytical methods. A comparative genomics analysis revealed interesting insights into the adaptability of the genetic basis of AXJ-M to harsh environments. Moreover, TMT quantitative proteomic analysis and parallel reaction monitoring (PRM) assays revealed that proteins related to both component systems, ABC transporters, carbohydrate, and amino metabolism, energy metabolism, etc., were differentially expressed. The non-targeted metabolome analysis revealed that the metabolic pathways associated with the fatty acid and amino acid biosynthesis and metabolism, together with the TCA cycle were most significantly enriched. Furthermore, integrated omics suggested that AXJ-M made metabolic adaptations to compensate for the increased energy demand caused by adverse environmental stimuli. The dominant heat regulator HspQ mediated heat adaptation of AXJ-M at high temperatures and modulated DyP expression. To summarize, the present study sheds light on the effect of high temperature on the lignin-degrading bacterium and its tolerance and underlying regulatory mechanisms.

Nociception Level Index-Guided Intraoperative Analgesia for Improved Postoperative Recovery: A Randomized Trial.

BACKGROUND: Nociception is the physiological response to nociceptive stimuli, normally experienced as pain. During general anesthesia, patients experience and respond to nociceptive stimuli by increasing blood pressure and heart rate if not controlled by preemptive analgesia. The PMD-200 system from Medasense (Ramat Gan, Israel) evaluates the balance between nociceptive stimuli and analgesia during general anesthesia and generates the nociception level (NOL) index from a single finger probe. NOL is a unitless index ranging from 0 to 100, with values exceeding 25 indicating that nociception exceeds analgesia. We aimed to demonstrate that titrating intraoperative opioid administration to keep NOL <25 optimizes intraoperative opioid dosing. Specifically, we tested the hypothesis that pain scores during the initial 60 minutes of recovery are lower in patients managed with NOL-guided fentanyl than in patients given fentanyl per clinical routine. METHODS: We conducted a randomized, single-center trial of patients having major abdominal open and laparoscopic surgeries. Patients were randomly assigned 1:1 to intraoperative NOL-guided fentanyl administration or fentanyl given per clinical routine. The primary outcome was pain score (0-10 verbal response scale) at 10-minute intervals during the initial 60 minutes of recovery. Our secondary outcome was a measure of adequate analgesia, defined as a pain score <5, assessed separately at each interval. RESULTS: With a planned maximum sample size of 144, the study was stopped for futility after enrolling 72 patients from November 2020 to October 2021. Thirty-five patients were assigned to NOL-guided analgesic dosing and 37 to routine care. Patients in the NOL group spent significantly less time with a NOL index >25 (median reduction [95% confidence interval {CI}] of 14 [4-25] minutes) were given nearly twice as much intraoperative fentanyl (median [quartiles] 500 [330, 780] vs 300 [200, 330] µg), and required about half as much morphine in the recovery period (3.3 [0, 8] vs 7.7 [0, 13] mg). However, in the primary outcome analysis, NOL did not reduce pain scores in the first 60 minutes after awakening, assessed in a linear mixed effects model with mean (standard error [SE]) of 4.12 (0.59) for NOL and 4.04 (0.58) for routine care, and estimated difference in means of 0.08 (-1.43, 1.58), P = .895. CONCLUSIONS: More intraoperative fentanyl was given in NOL-guided patients, but NOL guidance did not reduce initial postoperative pain scores.

Engineering nanoparticles boost TNBC therapy by CD24 blockade and mitochondrial dynamics regulation.

Although cancer immunotherapy has achieved remarkable progress, the clinical treatment of triple-negative breast cancer (TNBC) is still tough to make a breakthrough. The unsatisfactory therapeutic effect may be attributed to the lack of tumor immunogenicity and the strong immunosuppressive tumor microenvironment (ITM). In order to overcome the above shortcomings, engineering nanoparticles (P-aCD24/CEL + P/shMFN1) was designed to deliver anti-CD24 monoclonal antibody (aCD24), celastrol (CEL) and mitofusin 1 shRNA (shMFN1) for synergistic tumor cells-targeted treatment and tumor-associated macrophages (TAMs)-targeted immunomodulation. CD24, highly expressed on tumor cells, interacts with Siglec10 on TAMs to protect tumor cells from phagocytosis by macrophages, and thus has become a novel and dominant immune checkpoint in TNBC. P-aCD24/CEL achieved the release of aCD24 based on the dual response of carrier to pH and MMP2 in tumor microenvironment. Moreover, CEL increased "eat me" signal CRT and induced the immunogenic cell death (ICD) of tumor cells, together with decreased "don't eat me" signal CD24, reactivated macrophage phagocytosis of tumor cells, and ultimately improves the macrophage-based immunotherapy. On the other hand, P/shMFN1 could target TAMs for mitochondrial dynamics regulation via durable MFN1 silencing in TAMs, thereby reversing the phenotype of M2-TAMs. P-aCD24/CEL and P/shMFN1 could synergistically elicit evident antitumor immune responses and long-term immune memory to significantly inhibit tumor progress and postoperative recurrence. Based on remodeling the ITM and increasing antitumor immune response, this combination immunotherapy strategy showed great potential for TNBC treatment.

Recombination and Mutation in a New HP-PRRSV Strain (SD2020) from China.

A new HP-PRRSV strain (SD2020) was isolated from pigs with suspected highly pathogenic porcine reproductive and respiratory syndrome disease in a pig farm in Shandong Province, China, and its genome was sequenced. This pig farm has been using the VR-2332 vaccine strain to immunize pigs for a long time. The phylogenic and single nucleotide polymorphisms (SNPs) analysis of the viruses isolated from dead pigs showed that SD2020 was a natural recombinant virus of the VR-2332 vaccine strain and the JXA1 similar strain, and that two splicing fragments highly homologous to JXA1 in the virus genome were probably derived from the JXA1 wild strain and JXA1-R vaccine strain, respectively. Therefore, the possible recombination events of SD2020 and its mutation site might be related to high pathogenicity.