ß-glucan combined with Envafolimab and Endostar as immune rechallenge for metastatic non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitor rechallenge has emerged as a prominent study area in non-small cell lung cancer (NSCLC). ß-glucan was reported to reverse resistance to anti-PD-1/PD-L1 inhibitors by regulating the tumor microenvironment. In this self-initiated clinical trial (ChiCTR2100054796), NSCLC participants who have previously failed anti-PD-1 therapy received ß-glucan (500 mg, bid, d1-21), Envafolimab (300 mg, d1) and Endostar (210 mg, civ72h) every 3 weeks until disease progression or unacceptable toxicity. The clinical efficacy and adverse events were observed, while serum samples were collected for proteomic analysis. RESULTS: Twenty Three patients were enrolled from January 2022 to March 2023 (median age, 65 years; male, n = 18 [78.3%]; squamous NSCLC, n = 9 [39.1%]; mutant type, n = 13 [56.5%]). The overall response rate (ORR) was 21.7% and disease control rate (DCR) was 73.9%. Median progression-free survival (mPFS) and median overall survival (mOS) was 4.3 months [95% CI: 2.0-6.6] and 9.8 months [95% CI: 7.2-12.4], respectively. The mPFS between PD-L1 positive and negative subgroup has significant difference (6.3 months vs. 2.3 months, p = 0.002). Treatment-related adverse events (TRAEs) occurred in 52.2% of patients. The most common TRAEs were hypothyroidism (26.1%) and fatigue (26.1%). 2 (8.7%) grade 3 adverse events were reported. No adverse reaction related deaths have been observed. Proteomic analysis revealed that the levels of CASP-8, ARG1, MMP12, CD28 and CXCL5 correlated with resistance to the treatment while the levels of CD40-L and EGF related to the favorable response. CONCLUSION: ß-glucan combined with Envafolimab and Endostar has considerable efficacy and safety for immune rechallenge in metastatic NSCLC patients who failed of anti-PD-1 treatment previously, especially for PD-L1 positive patients.

Comparative Study Between Variable Flip Angle and Modified Look-Locker Inversion Recovery for Evaluating Renal Interstitial Fibrosis.

BACKGROUND: Variable flip angle (VFA) and modified Look-Locker inversion recovery (MOLLI) are frequently used for noninvasive evaluation of renal interstitial fibrosis (IF) in chronic kidney disease (CKD). However, controversy remains over which method is preferred. PURPOSE: To compare the diagnostic efficacy of VFA and MOLLI for T1 mapping in evaluating renal IF. STUDY TYPE: Prospective. SUBJECTS: Fifty-one participants with CKD (CKD stage 1-5, 35 males) and 18 healthy volunteers (eight males). FIELD STRENGTH/SEQUENCE: 3.0 T, three-dimensional gradient echo sequence for B1+ VFA, and two-dimensional gradient echo sequence for MOLLI. ASSESSMENT: Image quality was assessed on a five-point scale. Cortex and medulla T1 values (cT1 and mT1), corticomedullary T1 value difference (ΔT1, medulla - cortex), and corticomedullary T1 value ratio (ratio T1, cortex:medulla) were compared between VFA and MOLLI as well as between IF grade (0-4) based on biopsy. STATISTICAL TESTS: Intraclass correlation coefficient, Bland-Altman analysis, analysis of variance, Kruskal-Wallis test, correlation analysis, and receiver operating characteristics analysis with the area under the curve (AUC). P-value <0.05 was considered significant. RESULTS: MOLLI provided significantly better image quality compared to VFA. cT1 and mT1 values significantly differed between VFA and MOLLI (cT1-VFA: 1771.4 ± 139.4 msec vs. cT1-MOLLI: 1729.9 ± 132.1 msec; mT1-VFA: 2076.0 [interquartile range (IQR): 2045.9-2129.9] msec vs. mT1-MOLLI: 2039.2 [IQR: 1997.8-2071.6] msec). ΔT1 and ratio T1 values were not different between VFA and MOLLI (ΔT1: 300.8 ± 71.4 vs. 306.0 ± 78.4, respectively, P = 0.33 and ratio T1: 0.85 ± 0.038 vs. 0.85 ± 0.041, respectively, P = 0.064). No difference was observed between T1 variables and T1 mapping methods in diagnosing IF. DATA CONCLUSION: ΔT1 and ratio T1 were not different between VFA and MOLLI. Both VFA and MOLLI are effective for noninvasive assessment of renal IF. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

A retrospective analysis of comorbidities in patients with psoriasis at a single centre.

Introduction: Psoriasis is a chronic inflammatory disease occurring worldwide. It is currently considered a multi-system disease, which is associated with several comorbidities. Aim: To deeply understand the clinical characteristics of psoriasis comorbidities and explore the relationship between psoriasis comorbidities, different subtypes and related influencing factors. Material and methods: This retrospective study analysed data from the electronic inpatient medical record system of dermatology and non-dermatology departments at a tertiary hospital in China. We collected relevant demographic data and clinical features of all patients diagnosed with psoriasis from January 2013 to September 2023. Results: This study ultimately included a total of 1097 patients with psoriasis. Psoriasis vulgaris was the most common among the subtypes of psoriasis, with 957 (87.2%) cases. The sample consisted of 65.6% of males and 34.4% of females, with an average age of 53.5 ±15.2 years. Common comorbidities of psoriasis included hypertension (38.2%), hyperlipidaemia (29.4%), type 2 diabetes mellitus (24.6%), fatty liver disease (21.4%), coronary heart disease (21.0%), tumours (15.5%), gastroduodenal disease (14.4%), osteoarthropathy (11.8%), and cerebrovascular disease (10.8%). The incidence of hypertension (p = 0.015), hyperuricemia (p < 0.001), osteoarthropathy (p < 0.001), and autoimmune disease (p = 0.003) among different subtypes of psoriasis showed statistically significant differences. In addition, gender, smoking and alcohol consumption all have significant impacts on the distribution of comorbidities. Conclusions: The distribution of psoriasis comorbidities and complications varies among different subtypes of psoriasis. Lifestyles such as smoking and alcohol abuse, as well as gender, are also associated with the occurrence of psoriasis comorbidities.

Correlation between chemical denaturation and the unfolding energetics of Acanthamoeba actophorin.

The actin filament network is in part remodeled by the action of a family of filament severing proteins that are responsible for modulating the ratio between monomeric and filamentous actin. Recent work on the protein actophorin from the amoeba Acanthamoeba castellani identified a series of site-directed mutations that increase the thermal stability of the protein by 22°C. Here, we expand this observation by showing that the mutant protein is also significantly stable to both equilibrium and kinetic chemical denaturation, and employ computer simulations to account for the increase in thermal or chemical stability through an accounting of atomic-level interactions. Specifically, the potential of mean force (PMF) can be obtained from steered molecular dynamics (SMD) simulations in which a protein is unfolded. However, SMD can be inefficient for large proteins as they require large solvent boxes, and computationally expensive as they require increasingly many SMD trajectories to converge the PMF. Adaptive steered molecular dynamics (ASMD) overcomes the second of these limitations by steering the particle in stages, which allows for convergence of the PMF using fewer trajectories compared with SMD. Use of the telescoping water scheme within ASMD partially overcomes the first of these limitations by reducing the number of waters at each stage to only those needed to solvate the structure within a given stage. In the PMFs obtained from ASMD, the work of unfolding Acto-2 was found to be higher than the Acto-WT by approximately 120 kCal/mol and reflects the increased stability seen in the chemical denaturation experiments. The evolution of the average number of hydrogen bonds and number of salt bridges during the pulling process provides a mechanistic view of the structural changes of the actophorin protein as it is unfolded, and how it is affected by the mutation in concert with the energetics reported through the PMF.

The ribosomal protein P0A is required for embryo development in rice.

BACKGROUND: The P-stalk is a conserved and vital structural element of ribosome. The eukaryotic P-stalk exists as a P0-(P1-P2)2 pentameric complex, in which P0 function as a base structure for incorporating the stalk onto 60S pre-ribosome. Prior studies have suggested that P0 genes are indispensable for survival in yeast and animals. However, the functions of P0 genes in plants remain elusive. RESULTS: In the present study, we show that rice has three P0 genes predicted to encode highly conserved proteins OsP0A, OsP0B and OsP0C. All of these P0 proteins were localized both in cytoplasm and nucleus, and all interacted with OsP1. Intriguingly, the transcripts of OsP0A presented more than 90% of the total P0 transcripts. Moreover, knockout of OsP0A led to embryo lethality, while single or double knockout of OsP0B and OsP0C did not show any visible defects in rice. The genomic DNA of OsP0A could well complement the lethal phenotypes of osp0a mutant. Finally, sequence and syntenic analyses revealed that OsP0C evolved from OsP0A, and that duplication of genomic fragment harboring OsP0C further gave birth to OsP0B, and both of these duplication events might happen prior to the differentiation of indica and japonica subspecies in rice ancestor. CONCLUSION: These data suggested that OsP0A functions as the predominant P0 gene, playing an essential role in embryo development in rice. Our findings highlighted the importance of P0 genes in plant development.

Value of multiparametric magnetic resonance imaging for evaluating chronic kidney disease and renal fibrosis.

OBJECTIVES: To identify optimized MRI markers for evaluating chronic kidney disease (CKD) and renal interstitial fibrosis (IF). MATERIALS AND METHODS: This prospective study included 43 patients with CKD and 20 controls. The CKD group was divided into mild and moderate-to-severe subgroups based on pathological results. Scanned sequences included T1 mapping, R2* mapping, intravoxel incoherent motion imaging, and diffusion-weighted imaging. One-way analyses of variance were used to compare MRI parameters among groups. Correlations of MRI parameters with estimated glomerular filtration rate (eGFR) and renal IF were analyzed using age as covariates. The support vector machine (SVM) model was used to evaluate the diagnostic efficacy of multiparametric MRI. RESULTS: Compared to control values, renal cortical apparent diffusion coefficient (cADC), medullary ADC (mADC), cortical pure diffusion coefficient (cDt), medullary Dt (mDt), cortical shifted apparent diffusion coefficient (csADC), and medullary sADC (msADC) values gradually decreased in the mild and moderate-to-severe groups, while cortical T1 (cT1) and medullary T1 (mT1) values gradually increased. Values of cADC, mADC, cDt, mDt, cT1, mT1, csADC, and msADC were significantly associated with eGFR and IF (p < 0.001). The SVM model indicated that multiparametric MRI combining cT1 and csADC can distinguish patients with CKD from controls with high accuracy (0.84), sensitivity (0.70), and specificity (0.92) (AUC: 0.96). Multiparametric MRI combining cT1 and cADC exhibited high accuracy (0.91), sensitivity (0.95), and specificity (0.81) for evaluating IF severity (AUC: 0.96). CONCLUSION: Multiparametric MRI combining T1 mapping and diffusion imaging may be of clinical utility in non-invasive assessment of CKD and IF. CLINICAL RELEVANCE STATEMENT: This study shows that multiparametric MRI combining T1 mapping and diffusion imaging may be clinically useful in the non-invasive assessment of chronic kidney disease (CKD) and interstitial fibrosis; this could provide information for risk stratification, diagnosis, treatment, and prognosis. KEY POINTS: • Optimized MRI markers for evaluating chronic kidney disease and renal interstitial fibrosis were investigated. • Renal cortex/medullary T1 values increased as interstitial fibrosis increased; cortical shifted apparent diffusion coefficient (csADC) correlated significantly with eGFR and interstitial fibrosis. • Support vector machine (SVM) combining cortical T1 (cT1) and csADC/cADC effectively identifies chronic kidney disease and accurately predicts renal interstitial fibrosis.

Purinergic signaling in myocardial ischemia-reperfusion injury.

Purines and their derivatives, extensively distributed in the body, act as a class of extracellular signaling molecules via a rich array of receptors, also known as purinoceptors (P1, P2X, and P2Y). They mediate multiple intracellular signal transduction pathways and participate in various physiological and pathological cell behaviors. Since the function in myocardial ischemia-reperfusion injury (MIRI), this review summarized the involvement of purinergic signal transduction in diversified pathological processes, including energy metabolism disorder, oxidative stress injury, calcium overload, inflammatory immune response, platelet aggregation, coronary vascular dysfunction, and cell necrosis and apoptosis. Moreover, increasing evidence suggests that purinergic signaling also mediates the prevention and treatment of MIRI, such as ischemic conditioning, pharmacological intervention, and some other therapies. In conclusion, this review exhibited that purinergic signaling mediates the complex processes of MIRI which shows its promising application and prospecting in the future.

Structurally Diverse Sesquiterpenoids from the Genus of Ainsliaea.

The genus of Ainsliaea embraces approximately 70 recognized species, many of which have been used to treat various diseases in folklore medicines. As the main metabolites of Ainsliaea plants, Ainsliaea sesquiterpenoids have drawn considerable attention in related scientific communities due to their intriguing structures and a variety of bioactivities. In this review, we intend to provide a full-aspect coverage of sesquiterpenoids reported from the genus of Ainsliaea, including 145 monomeric sesquiterpenoids and 30 oligomeric ones. Multiple aspects will be summarized, including their classification, distributions, structures, bioactivities, and biomimetic syntheses. In addition, their possible biosynthetic pathway will be discussed in detail.

Effect of bovine lactoferricin on the growth performance, digestive capacity, immune responses and disease resistance in Pacific white shrimp, Penaeus vannamei.

The present study evaluated the growth performance, digestive enzyme activity, non-specific immunity, immunity and growth genes in Penaeus vannamei fed diets supplemented with Bovine lactoferricin (the basal diet without Bovine lactoferricin, the control; 1.0‰ Bovine lactoferricin，LCB1; 1.5‰ Bovine lactoferricin，LCB1.5; 2.0‰ Bovine lactoferricin, LCB2; 2.5‰ Bovine lactoferricin, LCB2.5) for 56 days. The feeding trial showed that the final weight, weight gain rate, and specific growth rate of the shrimp were improved significantly, while the feed conversion ratio was reduced significantly in the LCB1.5 group compared to the control (P < 0.05). The challenge test of Vibrio parahaemolyticus showed that the cumulative mortalities of shrimp in the LCB1.5, LCB2 and LCB2.5 groups were significantly lower than that in the control (P < 0.05). Compared with the control, Lipase and Trypsin activities in the hepatopancreas of LCB1.5 and LCB2 groups were significantly enhanced (P < 0.05). Compared with the control, alkaline phosphatase, acid phosphatase activities in the hepatopancreas and the relative expression levels of Relish, Toll, JAK, STAT, TOR, Raptor, 4E-BP, eIF4E1α, eIF4E2 genes in the hepatopancreas of LCB1.5, LCB2 and LCB2.5 groups were all significantly enhanced (P < 0.05). These results suggested that dietary Bovine lactoferricin could improve the growth performance, digestive capacity and immune responses of shrimp. When resistance against Vibrio parahaemolyticus in shrimp is considered, high dosage of Bovine lactoferricin showed a better effect than low dosage of Bovine lactoferricin. However, high dosage of Bovine lactoferricin can have a negative impact on the growth performance of shrimp. Considering collectively the above, Bovine lactoferricin could improve the growth performance, digestive enzymes activities, immune responses and disease resistance of P. vannamei.

Bovine lactoferricin on non-specific immunity of giant freshwater prawns, Macrobrachium rosenbergii.

This study aimed to investigate the effects of dietary Bovine lactoferricin (LFcinB) on the growth performance and non-specific immunity in Macrobrachium rosenbergii. Five experimental diets were 1.0‰ Bovine lactoferricin (LCB1); 1.5‰ Bovine lactoferricin (LCB1.5); 2.0‰ Bovine lactoferricin (LCB2); 2.5‰ Bovine lactoferricin (LCB2.5); the control group, basal diet without Bovine lactoferricin. A total of 600 prawns were randomly assigned to 5 groups in triplicate in 15 tanks for an 8-week feeding trial. The results showed the final weight, weight gain rate, specific growth rate and survival rate of prawns in the treatment groups were significantly improved versus the control (P < 0.05). The feed conversion ratio was reduced significantly in treatment groups compared to the control (P < 0.05). Compared with the control, alkaline phosphatase (AKP), acid phosphatase (ACP), lysozyme (LZM), catalase (CAT), superoxide dismutase (SOD) activities in the hepatopancreas of the treatment groups were significantly enhanced, and malondialdehyde (MDA) content was reduced significantly (P < 0.05). Compared with the control, the relative expression levels of AKP, ACP, LZM, CAT, SOD, Hsp70, peroxiredoxin-5, Toll, dorsal and relish genes were significantly higher among treatment groups, except for the AKP gene in the LCB1 group and the Hsp70 gene in the LCB1.5 group (P < 0.05). Compared with the control, the relative expression levels of TOR, 4E-BP, eIF4E1α and eIF4E2 genes were significantly enhanced in the LCB1.5 group (P < 0.05). When resistance against Vibrio parahaemolyticus in prawn is considered, higher doses of Bovine lactoferricin show better antibacterial ability. The present study indicated that dietary Bovine lactoferricin could significantly improve the growth performance and improve the antioxidative status of M. rosenbergii. The suitable addition level is 1.5 g/kg. LFcinB has great potential as a new feed additive without the threat of drug resistance.