Effectiveness and Safety of Pyrotinib-Based Therapy in the Treatment of HER2-Positive Breast Cancer Patients with Brain Metastases: A Multicenter Real-World Study.

BACKGROUND: Approximately 30% to 50% of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer develop brain metastasis (BMs). Pyrotinib has shown promising efficacy in these patients. However, real-world evidence supporting its use is scarce. Therefore, we evaluate the efficacy and safety of pyrotinib-based regimens in the real world. MATERIALS AND METHODS: We enrolled patients with BMs from various healthcare facilities in China's Shandong region and used an updated breast-graded prognostic assessment (breast-GPA) to predict survival outcomes. RESULTS: Efficacy and toxicity were assessed in 101 patients. Overall, the median progression-free survival (PFS) was 11.0 months (95% CI, 7.6-14.4 months). PFS was shorter in patients with a breast-GPA of 0 to 2.0 (P< .001). Previous treatment with pertuzumab plus trastuzumab (P = .039) and varying numbers of BMs (P = .028) had a significant positive correlation with PFS. Additionally, radiotherapy (P = .033) for BMs, especially pyrotinib concurrent with radiotherapy (P = .013), significantly prolonged the PFS. In patients with a breast-GPA of 0 to 2.0, a significant difference in PFS was observed depending on whether the brain was the first metastatic site (P< .001). Furthermore, a breast-GPA (0-2.0 vs. 2.5-4.0), and radiotherapy for BMs were found to be independent predictors of PFS. Overall, the objective response rate was 42.6%, while the disease control rate was 88.1%. Diarrhea emerged as the most common adverse event. CONCLUSION: Pyrotinib-based therapy is effective and tolerable in human epidermal growth factor receptor 2-positive metastatic breast cancer with BMs. Patients who underwent radiotherapy for BMs, particularly those who received pyrotinib concurrently with radiotherapy, exhibited a more favorable prognosis.

Efficacy and safety of pyrotinib combined with albumin-bound paclitaxel as first-line treatment for HER2-positive metastatic breast cancer in patients previously treated with adjuvant and/or neoadjuvant trastuzumab therapy: The stage 1 results of a single-arm, phase 2 prospective clinical trial.

OBJECTIVE: It has been observed that the prognosis of patients with HER2-positive metastatic breast cancer has improved significantly with HER2-targeted agents. However, there is still a lack of evidence regarding first-line anti-HER2 treatment options for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, there are no reliable markers that can predict the efficacy of anti-HER2 treatment in these patients. METHODS: Patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer were enrolled. Pyrotinib plus albumin-bound paclitaxel were used as first-line treatment. The primary endpoint was the objective response rate (ORR). The safety profile was also assessed. In order to explore predictive biomarkers using Olink technology, blood samples were collected dynamically. RESULTS: From December 2019 to August 2023, the first stage of the study involved 27 eligible patients. It has not yet reached the median PFS despite the median follow-up being 17.8 months. Efficacy evaluation showed that the ORR was 92.6%, and the DCR was 100%. Adverse events of grade 3 or higher included diarrhoea (29.6%), leukopenia (11.1%), neutropenia (25.9%), oral mucositis (3.7%), and hand-foot syndrome (3.7%). Toll-like receptor 3 (TLR3) and Proto-oncogene tyrosine-protein kinase receptor (RET) were proteins with significant relevance to PFS in these patients. CONCLUSIONS: This study demonstrates that pyrotinib plus albumin-bound paclitaxel as a first-line treatment regimen shows good efficacy and manageable safety for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, a significant association was identified between the expression levels of TLR3 and RET and the PFS in patients.

Elucidation of the beneficial role of co-fermented whole grain quinoa and black barley with Lactobacillus on rats fed a western-style diet via a multi-omics approach.

Long-term consumption of Western-style diet (WSD) can lead to metabolic disorders and dysbiosis of gut microbiota, presenting a critical risk factor for various chronic conditions such as fatty liver disease. In the present study, we investigated the beneficial role of co-fermented whole grain quinoa and black barley with Lactobacillus kisonensis on rats fed a WSD. Male Sprague-Dawley (SD) rats, aged six weeks and weighing 180 ± 10 g, were randomly assigned to one of three groups: the normal control group (NC, n = 7), the WSD group (HF, n = 7), and the WSD supplemented with a co-fermented whole grain quinoa with black barley (FQB) intervention group (HFF, n = 7). The findings indicated that FQB was effective in suppressing body weight gain, mitigating hepatic steatosis, reducing perirenal fat accumulation, and ameliorating pathological damage in the livers and testicular tissues of rats. Additionally, FQB intervention led to decreased levels of serum uric acid (UA), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). These advantageous effects can be ascribed to the regulation of FQB on gut microbiota dysbiosis, which includes the restoration of intestinal flora diversity, reduction of the F/B ratio, and promotion of probiotics abundance, such as Akkermansia and [Ruminococcus] at the genus level. The study employed the UPLC-Q-TOF-MSE technique to analyze metabolites in fecal and hepatic samples. The findings revealed that FQB intervention led to a regression in the levels of specific metabolites in feces, including oxoadipic acid and 20a, 22b-dihydroxycholesterol, as well as in the liver, such as pyridoxamine, xanthine and xanthosine. The transcriptome sequencing of liver tissues revealed that FQB intervention modulated the mRNA expression of specific genes, including Cxcl12, Cidea, and Gck, known for their roles in anti-inflammatory and anti-insulin resistance mechanisms in the context of WSD. Our findings indicate that co-fermented whole-grain quinoa with black barley has the potential to alleviate metabolic disorders and chronic inflammation resulting from the consumption of WSD.

Correlation between PD-1 and sPD-L1 expression levels in peripheral blood of DLBCL patients and their clinicopathological characteristics.

Molecular pathology and clinical characteristics play a crucial role in guiding treatment selection and predicting the prognosis of diffuse large B-cell lymphoma (DLBCL). The programmed cell death protein 1 (PD-1) and its ligand (PD-L1), have emerged as pivotal regulators of immune checkpoints in cancer. The objectives of this study are to investigate the correlation between the expression levels of PD-1 and soluble PD-L1 (sPD-L1) in the peripheral blood of DLBCL patients, analyze their clinicopathological characteristics, and identify the optimal beneficiary group for PD-1/PD-L1 blockade. Peripheral blood samples were collected from 36 DLBCL patients before their initial treatment at Shandong Cancer Hospital between December 2018 and July 2019. The expression levels of PD-1 and sPD-L1 were measured using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. The clinicopathological characteristics, including age, sex, Ann Arbor stage, International Prognostic Index (IPI) score, response to treatment, etc., were recorded for each patient. The surface expression of PD-1 on peripheral blood T cells was significantly higher in DLBCL patients compared to healthy controls. There was a significant association between elevated PD-1 expression levels and the advanced Ann Arbor stage (P=0.0153) as well as the B group (P=0.0184). Higher sPD-L1 levels were associated with the GCB subtype according to Hans's classification (P=0.0435). The expression levels of PD-1 and sPD-L1 in the peripheral blood of DLBCL patients are significantly correlated with advanced disease stage, B group, and GCB subtype according to Hans's classification. This suggests that the PD-1/PD-L1 axis play a critical role in specific subgroups of DLBCL. Targeting this axis could serve as a potential therapeutic strategy to enhance the clinical outcomes of DLBCL patients. Further studies are necessary to explore the prognostic implications of PD-1 and sPD-L1 expression levels in DLBCL patients.

Uncovering the effect and mechanism of Jiawei Xiaoyao Wan in treating breast cancer complicated with depression based on network pharmacology and experimental analysis.

BACKGROUND: Depression is a clinically common co-morbidity in breast cancer cases that brings negative outcomes on quality of life and potentially survival. Jiawei Xiaoyao Wan (JXW) is widely used in treating breast cancer and depressive disorder, but its potential pharmacological mechanisms remain elusive. PURPOSE: We aimed to explore the dual therapeutic effects and mechanisms of JXW acting on breast cancer complicated with depression (BCCD) by network pharmacology and in vivo experimental verification. METHODS: The chemical constituents of JXW were characterized using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-Q-TOF/MS). The targets related to constituents of JXW were predicted by the TCMSP and Swiss Target Prediction databases, and targets of breast cancer and depression were screened by the GeneCards and OMIM databases. Gene Ontology annotation and KEGG enrichment analysis were performed with the DAVID database. Ultimately, a BCCD mouse model induced by chronic restraint stress (CRS) was used to explore therapeutic effects and mechanisms of JXW against BCCD. The efficacy of JXW in the treatment of BCCD was evaluated based on behavioral tests, tumor volume and weight, and pathological examination. Additionally, the underlying mechanisms were explored by measuring the levels of neurotransmitter and inflammatory factors, as well as detecting the expression of genes or proteins associated with candidate targets and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway through RT-PCR, western blotting, and immunohistochemistry. RESULTS: Totals of 108 components were identified in JXW using LC-Q-TOF/MS. By network pharmacology analysis, 714 compound targets of JXW, 2114 breast cancer targets, 1122 depression targets, and 98 overlapping proteins were obtained. PPI network and KEGG analysis implied that TP53, ESR1, VEGFA, AKT1, IL6, TNF, EGFR and the JAK/STAT pathway might be the potential targets of JXW in treating BCCD. In vivo experiments indicated that JXW significantly ameliorated depressive symptoms and tumor progression in BCCD mice. Further mechanistic studies showed that JXW could reduce the levels of inflammatory factors, increase 5-HT level, and regulate mRNA expression levels of TP53, VEGFA, AKT1, IL6, TNF, and EGFR targets. Moreover, the expression levels of proteins related to the JAK2/STAT3 signaling pathway in BCCD mice were effectively regulated by JXW. CONCLUSION: JXW exerts dual therapeutic effects in a BCCD mouse via multiple targets. The underlying mechanisms might be associated with regulating the levels of neurotransmitter and inflammatory factors; more importantly, the JAK2/STAT3 pathway plays a significant role in this process.

Suicidal ideation in Chinese patients with advanced breast cancer: a multi-center mediation model study.

PURPOSE: The pathways underpinning suicide ideation (SI) and certain physical and psychological factors in patients with advanced breast cancer remain unclear. This study develops and validates a mediation model that delineates the associations between several multidimensional variables and SI in Chinese patients with advanced breast cancer. METHODS: Patients with advanced breast cancer (n = 509) were recruited as study participants from 10 regional cancer centers across China from August 2019 to December 2020. Participants were required to complete five questionnaires using an electronic patient-reported outcomes (ePRO) system: 9 item- Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), Insomnia Severity Index (ISI), 5-level EQ-5D (EQ-5D-5L), and MD Anderson Symptom Inventory (MDASI). Risk factors for SI were identified using multivariable logistic regression, and inputted into serial multiple mediation models to elucidate the pathways linking the risk factors to SI. RESULTS: SI prevalence was 22.8% (116/509). After adjusting for covariates, depression (odds ratio [OR] = 1.384), emotional distress (OR = 1.107), upset (OR = 0.842), and forgetfulness (OR = 1.236) were identified as significant independent risk factors (all p < 0.05). The ORs indicate that depression and distress have the strongest associations with SI. Health status has a significant indirect effect (OR=-0.044, p = 0.005) and a strong total effect (OR=-0.485, p < 0.001) on SI, mediated by insomnia severity and emotional distress. CONCLUSIONS: There is a high SI prevalence among Chinese patients with advanced breast cancer. Our analysis revealed predictive pathways from poor health to heightened SI, mediated by emotional distress and insomnia. Regular management of distress and insomnia can decrease suicide risk in this vulnerable population.

Relationship between fear of progression and symptom burden, disease factors and social/family factors in patients with stage-IV breast cancer in Shandong, China.

OBJECTIVE: To assess fear of progression (FoP)'s relationship with symptom burden and disease and social/family factors, as well as, determine the status of FoP in women with stage-IV breast cancer in Shandong, China. METHODS: Two hundred and sixteen women were recruited from the department of breast cancer internal medicine, Shandong Cancer Hospital and Institute. Data for this observational study were collected between October 2020 and January 2021 using the MD Anderson Symptom Inventory, the Fear of Progression Questionnaire-Short Form (FoP-Q-SF) and a participant information scale. SPSS 23.0 was used for statistical analysis. RESULTS: After excluding invalid responses, the data of 200 participants were analysed. The average total FoP-Q-SF score was 29.39 ± 9.39 (95% confidence interval, 21.81-27.64). The FoP level among the participants was relatively low. For disease and social/family factors, FoP statistically significantly differed by satisfaction with family emotional support and the Eastern Cooperative Oncology Group (ECOG) score. The ECOG score was positively correlated with FoP. Furthermore, symptom burden was positively correlated with FoP. CONCLUSIONS: Among patients with stage-IV breast cancer, satisfaction with family emotional support, ECOG score and symptom burden play key roles in FoP. Interventions, including providing appropriate emotional support from family, improving physical fitness and relieving symptom burden, must be considered in future studies, which may improve patients' overall physical and mental status and provide a supportive therapeutic environment.

Orbital septum attachment site on the levator aponeurosis sling for mild congenital blepharoptosis.

PURPOSE: This study aimed to investigate the value of the orbital septum attachment site on the levator aponeurosis (OSASLA) sling in correcting mild congenital blepharoptosis. METHODS: A total of 60 patients (92 eyes) with mild congenital blepharoptosis (levator function ≥ 8 mm) were treated in our hospital from January to October 2021, and relevant data of these patients were collected. All patients underwent OSASLA sling for ptosis correction. The distances from the superior tarsal border to the OSASLA were measured. The primary outcome was the number of postoperative changes in the marginal reflex distance 1 (MRD1). Pearson's correlation coefficient between the distance from the superior tarsal border to the OSASLA and the height of the upper eyelid elevated was analyzed. RESULTS: Fifty-eight patients (89 eyes) successfully underwent OSASLA sling surgery. The preoperative MRD1 was 1.4-3.6 mm (mean 2.1 ± 0.5 mm), and the postoperative MRD1 was 3.4-5.0 mm (mean 3.7 ± 0.6 mm). The distance from the superior tarsal border to the OSASLA sling was significantly and positively correlated with the height of the upper eyelid elevation (r = 0.7328, P < 0.0001). The eyelid margin positions of the patients did not regress substantially during 6-18 months of follow-up. CONCLUSIONS: Compared with the shortening of levator palpebrae superioris (LPS) and pleating of LPS, the OSASLA sling is a less invasive, more effective, and easy-operating surgery for mild congenital blepharoptosis.

Physical symptoms and anxiety and depression in older patients with advanced cancer in China: a network analysis.

BACKGROUND: Little is understood about the association between psychosomatic symptoms and advanced cancer among older Chinese patients. METHODS: This secondary analysis was part of a multicenter cross-sectional study based on an electronic patient-reported outcome platform. Patients with advanced cancer were included between August 2019 and December 2020 in China. Participants (over 60 years) completed the MD Anderson Symptom Inventory (MDASI) and Hospital Anxiety and Depression Scale (HADS) to measure symptom burden. Network analysis was also conducted to investigate the network structure, centrality indices (strength, closeness, and betweenness) and network stability. RESULTS: A total of 1022 patients with a mean age of 66 (60-88) years were included; 727 (71.1%) were males, and 295 (28.9%) were females. A total of 64.9% of older patients with advanced cancer had one or more symptoms, and up to 80% had anxiety and depression. The generated network indicated that the physical symptoms, anxiety and depression symptom communities were well connected with each other. Based on an evaluation of the centrality indices, 'distress/feeling upset' (MDASI 5) appears to be a structurally important node in all three networks, and 'I lost interest in my own appearance' (HADS-D4) had the lowest centrality indices. The network stability was relatively high (> 0.7). CONCLUSION: The symptom burden remains high in older patients with advanced cancer in China. Psychosomatic symptoms are highly interactive and often present as comorbidities. This network can be used to provide targeted interventions to optimize symptom management in older patients with advanced cancer in China. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900024957), registered on 06/12/2020.

Integrated metabolomics and transcriptomics revealed the anti-constipation mechanisms of xylooligosaccharides from corn cobs.

Xylooligosaccharides (XOSs) have recently garnered interest for their potential as an anti-constipation agent. In this study, we investigated the effects of XOSs derived from corn cobs on constipation in mice through a comprehensive analysis of both the metabolome and transcriptome. Our multi-omics approach revealed that XOSs primarily modulated butanoate metabolism and steroid hormone biosynthesis pathways, as well as key signaling pathways such as PPAR and NF-kappa B. Notably, we observed a decrease in inflammatory biomarker expression and an elevation of butyric acid metabolite levels with XOSs treatment. A deeper analysis of gene expression and metabolite alterations highlighted significant changes in genes encoding critical enzymes and metabolites involved in these pathways. Overall, these findings underscore the considerable potential of XOSs derived from corn cobs as a dietary supplement for effectively alleviating constipation.

A predictive nomogram for surgical site infection in patients who received clean orthopedic surgery: a retrospective study.

BACKGROUND: Surgical site infection (SSI) is a common and serious complication of elective clean orthopedic surgery that can lead to severe adverse outcomes. However, the prognostic efficacy of the current staging systems remains uncertain for patients undergoing elective aseptic orthopedic procedures. This study aimed to identify high-risk factors independently associated with SSI and develop a nomogram prediction model to accurately predict the occurrence of SSI. METHODS: A total of 20,960 patients underwent elective clean orthopedic surgery in our hospital between January 2020 and December 2021, of whom 39 developed SSI; we selected all 39 patients with a postoperative diagnosis of SSI and 305 patients who did not develop postoperative SSI for the final analysis. The patients were randomly divided into training and validation cohorts in a 7:3 ratio. Univariate and multivariate logistic regression analyses were conducted in the training cohort to screen for independent risk factors of SSI, and a nomogram prediction model was developed. The predictive performance of the nomogram was compared with that of the National Nosocomial Infections Surveillance (NNIS) system. Decision curve analysis (DCA) was used to assess the clinical decision-making value of the nomogram. RESULTS: The SSI incidence was 0.186%. Univariate and multivariate logistic regression analysis identified the American Society of Anesthesiology (ASA) class (odds ratio [OR] 1.564 [95% confidence interval (CI) 1.029-5.99, P = 0.046]), operative time (OR 1.003 [95% CI 1.006-1.019, P < 0.001]), and D-dimer level (OR 1.055 [95% CI 1.022-1.29, P = 0.046]) as risk factors for postoperative SSI. We constructed a nomogram prediction model based on these independent risk factors. In the training and validation cohorts, our predictive model had concordance indices (C-indices) of 0.777 (95% CI 0.672-0.882) and 0.732 (95% CI 0.603-0.861), respectively, both of which were superior to the C-indices of the NNIS system (0.668 and 0.543, respectively). Calibration curves and DCA confirmed that our nomogram model had good consistency and clinical predictive value, respectively. CONCLUSIONS: Operative time, ASA class, and D-dimer levels are important clinical predictive indicators of postoperative SSI in patients undergoing elective clean orthopedic surgery. The nomogram predictive model based on the three clinical features demonstrated strong predictive performance, calibration capabilities, and clinical decision-making abilities for SSI.

Efficacy and safety of Dimdazenil in the adult insomnia patients: a phase II randomized, multicenter, double-blind, placebo-controlled, and parallel-group study.

STUDY OBJECTIVES: To evaluate the efficacy and safety of Dimdazenil, a positive allosteric modulator with selectivity for α1, α5 subunit-containing GABAA receptors, on sleep variables in patients with insomnia disorder. METHODS: In this randomized, double-blind, placebo-controlled trial, adults (18-65 years) with insomnia disorder were randomized (1:1:1:1 to receive daily oral placebo, Dimdazenil (1.5, 2.5, or 5 mg) for 14 days. The primary efficacy outcome was the total sleep time (TST) on day 1/2 and day 13/14, measured by polysomnography. The secondary outcome measures included (1) latency to persistent sleep (LPS), sleep efficiency (SE), wake after sleep onset (WASO) and number of awakenings (NAW) on days 1/2 and day 13/14, and (2) the average subjective sleep latency (sSL), total sleep time (sTST), wake after sleep onset (sWASO) and number of awakenings (sNAW) recorded in sleep diary and sleep questionnaire, and the evaluation of insomnia severity index. Rebound insomnia, withdrawal, and treatment-emergent adverse events were also assessed. RESULTS: Of 569 patients screened, 288 (76.4% female) were randomized and received one dose. For the primary outcomes, TST was significantly improved in the Dimdazenil 1.5, 2.5, and 5 mg group compared with the placebo group at day 1/2, and significantly improved in the Dimdazenil 2.5 and 5 mg groups compared with the placebo group at day 13/14. The Least Squares Means (standard errors) and 95% Confidence Intervals for the three active doses compared to placebo are 25.5 (8.31), (9.16, 41.89) for the 1.5 mg dose; 17.4 (8.19), (1.29, 33.55) for the 2.5 mg dose; 22.8 (8.15), (6.72, 38.80) for the 5 mg dose on day 1/2. Corresponding data on day 13/14 are 7.6 (8.07), (-8.24, 23.53) and 19.3 (8.06), (3.43, 35.17) and 18.2 (7.95), (2.49, 33.80). LPS was significantly reduced in the Dimdazenil 5 mg group compared with the placebo group on day 1/2. SE was significantly improved in the Dimdazenil 1.5 and 5 mg group compared with the placebo group at day 1/2. In the subjective sleep parameters, sSL on average was significantly lower in the Dimdazenil 1.5, 2.5, and 5 mg groups compared with the placebo group. sTST on average was significantly higher in the Dimdazenil 1.5, 2.5, and 5 mg groups compared with the placebo group. The most common TEAEs were dizziness, vertigo, and weakness with no clinically relevant treatment-related serious adverse events. CONCLUSIONS: Dimdazenil of 1.5, 2.5, and 5 mg improved certain objective and subjective sleep outcomes in people with insomnia disorder, with a favorable safety profile. These findings suggested that Dimdazenil may represent a promising new treatment for insomnia disorder, a prevalent condition with limited effective and safe treatments available. CLINICAL TRIAL INFORMATION: A multicenter, randomized, double-blind, multidose, placebo parallel controlled phase II clinical study of EVT201 in the treatment of insomnia disorders (http://www.chinadrugtrials.org), with the number of CTR20150664.

Exploration of the structural mechanism of hydrogen (H2)-promoted horseradish peroxidase (HRP) activity via multiple spectroscopic and molecular dynamics simulation techniques.

Horseradish peroxidase (HRP) is an enzyme that is widely used in various fields. In this study, the effects of molecular hydrogen (H2) on the activity and structural characteristics of HRP were investigated by employing multiple spectroscopic techniques, atomic force microscopy (AFM) and molecular dynamics (MD) simulations. The results demonstrated that H2 could enhance HRP activity, especially in 1.5 mg/L hydrogen-rich water (HRW). The structural analysis results showed that H2 might alter HRP activity by affecting the active sites, secondary structure, hydrogen bonding network, CS groups, and morphological characteristics. The MD results also confirmed that H2 could increase the FeN bond distance in the active site, affect the secondary structure, and increase the number of hydrogen bonds. The MD results further suggested that H2 could increase the number of salt bridges, and lengthen the SS bonds in HRP. This study primarily revealed the mechanism by which H2 enhances the HRP activity, providing insight into the interactions between gas and macromolecular proteins. However, some of the results obtained via MD simulations still need to be verified experimentally. In addition, our study also provided a new convenient strategy to enhance enzyme activity.

Genetic and Phenotypic Analysis of Phage-Resistant Mutant Fitness Triggered by Phage-Host Interactions.

The emergence of phage-resistant bacterial strains is one of the biggest challenges for phage therapy. However, the emerging phage-resistant bacteria are often accompanied by adaptive trade-offs, which supports a therapeutic strategy called "phage steering". The key to phage steering is to guide the bacterial population toward an evolutionary direction that is favorable for treatment. Thus, it is important to systematically investigate the impacts of phages targeting different bacterial receptors on the fitness of the bacterial population. Herein, we employed 20 different phages to impose strong evolutionary pressure on the host Pseudomonas aeruginosa PAO1 and examined the genetic and phenotypic responses of their phage-resistant mutants. Among these strains with impaired adsorptions, four types of mutations associated with bacterial receptors were identified, namely, lipopolysaccharides (LPSs), type IV pili (T4Ps), outer membrane proteins (OMPs), and exopolysaccharides (EPSs). PAO1, responding to LPS- and EPS-dependent phage infections, mostly showed significant growth impairment and virulence attenuation. Most mutants with T4P-related mutations exhibited a significant decrease in motility and biofilm formation ability, while the mutants with OMP-related mutations required the lowest fitness cost out of the bacterial populations. Apart from fitness costs, PAO1 strains might lose their resistance to antibiotics when counteracting with phages, such as the presence of large-fragment mutants in this study, which may inspire the usage of phage-antibiotic combination strategies. This work provides methods that leverage the merits of phage resistance relative to obtaining therapeutically beneficial outcomes with respect to phage-steering strategies.

Dynamic analysis of circulating tumor DNA to predict the prognosis and monitor the treatment response of patients with metastatic triple-negative breast cancer: A prospective study.

Background: Limited data are available on applying circulating tumor DNA (ctDNA) in metastatic triple-negative breast cancer (mTNBC) patients. Here, we investigated the value of ctDNA for predicting the prognosis and monitoring the treatment response in mTNBC patients. Methods: We prospectively enrolled 70 Chinese patients with mTNBC who had progressed after ≤2 lines of chemotherapy and collected blood samples to extract ctDNA for 457-gene targeted panel sequencing. Results: Patients with ctDNA+, defined by 12 prognosis-relevant mutated genes, had a shorter progression-free survival (PFS) than ctDNA- patients (5.16 months vs. 9.05 months, p=0.001), and ctDNA +was independently associated with a shorter PFS (HR, 95% CI: 2.67, 1.2-5.96; p=0.016) by multivariable analyses. Patients with a higher mutant-allele tumor heterogeneity (MATH) score (≥6.316) or a higher ctDNA fraction (ctDNA%≥0.05) had a significantly shorter PFS than patients with a lower MATH score (5.67 months vs.11.27 months, p=0.007) and patients with a lower ctDNA% (5.45 months vs. 12.17 months, p<0.001), respectively. Positive correlations with treatment response were observed for MATH score (R=0.24, p=0.014) and ctDNA% (R=0.3, p=0.002), but not the CEA, CA125, or CA153. Moreover, patients who remained ctDNA +during dynamic monitoring tended to have a shorter PFS than those who did not (3.90 months vs. 6.10 months, p=0.135). Conclusions: ctDNA profiling provides insight into the mutational landscape of mTNBC and may reliably predict the prognosis and treatment response of mTNBC patients. Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 81902713), Natural Science Foundation of Shandong Province (Grant No. ZR2019LZL018), Breast Disease Research Fund of Shandong Provincial Medical Association (Grant No. YXH2020ZX066), the Start-up Fund of Shandong Cancer Hospital (Grant No. 2020-PYB10), Beijing Science and Technology Innovation Fund (Grant No. KC2021-ZZ-0010-1).

ZM suture combined with early functional exercise can promote finger functional recovery in patients with finger flexor tendon rupture.

OBJECTIVE: To investigate the efficacy of ZM suture combined with early functional exercise in repairing flexor tendons and its impact on finger function recovery in patients. METHODS: A retrospective analysis was conducted on 60 patients who sought medical treatment at the Orthopedics Hospital of Xingtai City from August 2019 to August 2022. Among them, 29 patients treated with the modified Kessler suture technique were assigned to the control group, while 31 patients treated with ZM suture technique were assigned to the observation group. Both groups of patients underwent early functional exercise after surgery and were followed up regularly for 6 months. Finger function, grip strength, pinch strength at 6 months after operation, upper limb function before and after treatment, visual analog pain scale (VAS) at 1 and 2 weeks postoperatively, quality of life, and incidence of complications were compared between the two groups. The risk factors affecting the prognosis of patients were analyzed. RESULTS: At 6 months postoperatively, the observation group showed significantly better finger function, grip strength and grip strength ratio, and upper limb function compared to the control group (all P<0.05). The observation group had significantly lower VAS scores at 1 and 2 weeks postoperatively and a significantly lower incidence of complications compared to the control group, while their quality of life was significantly better than that of the control group (all P<0.05). The choice of treatment method is an independent risk factor affecting the prognosis of patients (P<0.05). CONCLUSION: The ZM suture technique combined with early functional exercise has significant efficacy in repairing flexor tendons, effectively promoting finger function recovery in patients. It is also associated with a high level of safety and warrants clinical application and promotion.

Xylooligosaccharides from corn cobs alleviate loperamide-induced constipation in mice via modulation of gut microbiota and SCFA metabolism.

This study aimed to optimize the structure and efficacy of xylooligosaccharides (XOSs) from corn cobs in constipated mice. Structural analysis revealed that XOSs from corn cobs were composed of ß-Xyl-(1 →4)-[ß-Xyl-(1→4)]n-α/ß-Xyl (n = 0-5) without any other substituents. XOS administration significantly reduced the defecation time, increased the gastrointestinal transit rate, restored the gastrointestinal neurotransmitter imbalance, protected against oxidative stress, and reversed constipation-induced colonic inflammation. Fecal metabolite and microbiota analysis showed that XOS supplementation significantly increased short chain fatty acid (SCFA) levels and improved the gut microbial environment. These findings highlighted the potential of XOSs from corn cobs as an active ingredient for functional foods or as a therapeutic agent in constipation therapy.

Synthesis, physicochemical and emulsifying properties of OSA-modified tamarind seed polysaccharides with different degrees of substitution.

Octenyl succinic anhydride modified tamarind seed polysaccharides (OTSPs) with various degrees of substitution were first synthesized and characterized in this work. The structural, solid-state, solution and emulsifying properties of the OTSPs and the effect of the degree of substitution (DS) were investigated. The structural characterization confirmed the successful grafting of the OSA moiety into TSP and the chain extension of the OTSPs. The hydrophobicity of the modified polysaccharide molecules increased, the absolute value of the zeta potential increased, and the thermal stability decreased, which were positively or negatively correlated with the changes in DS. In contrast, the hydrolysis of polysaccharides in alkaline aqueous solution led to a decrease in molar mass and the rigidity of the molecules, which were not significantly related to DS. Particle size analysis showed that OTSPs tended to aggregate into relatively small agglomerates, which was confirmed by the results of morphological analysis. Most importantly, the instability indices of emulsions stabilized by TSP, arabic gum and OSA-starch were 0.521, 0.715, and 0.804, respectively, while for OTSPs this parameter was between 0.04 and 0.19 under the same conditions, indicating better physical stability of the OTSP-stabilized emulsions, especially for OTSP-30. Overall, OTSP has great potential as an emulsifier for oil-in-water emulsions, especially for emulsification and stabilization in food processing.

Self-assembly of tamarind seed polysaccharide via enzymatic depolymerization and degalactosylation enhanced ice recrystallization inhibition activity.

Polysaccharides are becoming potential candidates for developing food-grade cryoprotectants due to their extensive accessibility and health-promoting effects. However, unremarkable ice recrystallization inhibition (IRI) activity and high viscosity limit their practical applications in some systems. Our previous study found a galactoxyloglucan polysaccharide from tamarind seed (TSP) showing moderate IRI activity. Herein, the enhancement of the IRI performance of TSP via enzymatic depolymerization and degalactosylation-induced self-assembly was reported. TSP was depolymerized and subsequently removed ∼40 % Gal, which induced the formation of supramolecular rod-like fiber self-assembles and exhibited a severalfold enhancement of IRI. Ice shaping assay did not show obvious faceting of ice crystals, indicating that both depolymerized and self-assembled TSP showed very weak binding to ice. Molecular dynamics simulation confirmed the absence of molecular complementarity with ice. Further, it highlighted that degalactosylation did not cause significant changes in local hydration properties of TSP from the view of a single oligomer. The inconsistency between molecular simulation and macroscopic IRI effect proposed that the formation of unique supramolecular self-assemblies may be a key requirement for enhancing IRI activity. The findings of this study provided a new opportunity to enhance the applied potential of natural polysaccharides in food cryoprotection.

Characterization, complete genome sequencing, and CRISPR/Cas9 system-based decontamination of a novel Escherichia coli phage TR1 from fermentation substrates.

Phage contamination has become a major concern for industrial bacteria, such as Escherichia coli BL21(DE3), used in fermentation processes. Herein, we report a CRISPR/Cas9 defense system-based strategy to precisely prey and degrade phage DNA to decontaminate target phages. First, we isolated a novel phage from fermentation substrates with BL21(DE3) as the host, named TR1. It showed a typical podovirus morphology with a head diameter of 51.46 ± 2.04 nm and a tail length of 9.31 ± 2.77 nm. The burst size of phage TR1 was 151 PFU/cell, suggesting its strong fecundity in the fermentation system. Additionally, whole-genome sequencing revealed that phage TR1 has a DNA genome of 44,099 bp in length with a 43.8% GC content, encoding a total of 68 open reading frames. Comparative genomics and phylogenetic analysis designated this phage to be a new species of the genus Christensenvirus. To counteract phage TR1, we employed the CRISPR/Cas9 system-based strategy and constructed two phage-resistant E. coli strains, BL21-C and BL21-T, based on conserved genes. Both EOP assays and growth curves indicated strong phage resistance of the recombinant strains, without affecting cell growth. Therefore, this study aimed to provide a resilient strategy to respond to ever-changing phages and ongoing phage-host arm race in industrial fermentation environments by the personalized design of spacers in the recombinant CRISPR/Cas system-containing plasmid. More importantly, our research sparks the use of phage defense mechanism to prevent phage contamination in extensive biotechnological applications.