Sum rule comparison of narrowband and broadband sum frequency generation spectra and comparison with theory.

Earlier sum frequency generation (SFG) experiments involve one infrared and one visible laser, and a measurement of the intensity of the response, yielding data on the surface sensitive properties of the sample. Recently, both the real and imaginary components of the susceptibility were measured in two different sets of experiments. In one set, a broadband infrared laser was used, permitting observations at very short times, while in another set the infrared laser was narrowband, permitting higher spectral resolution. The differences in the spectrum obtained by the two will be most evident in studying narrow absorption bands, e.g., the band due to dangling OH bonds at a water interface. The direct comparisons in the integrated amplitude (sum rule) of the imaginary part of the dangling OH bond region differ by a factor of 3. Due to variations in experimental setup and data processing, corrections were made for the quartz reference, Fresnel factors, and the incident visible laser wavelength. After the corrections, the agreement differs now by the factors of 1.1 within broadband and narrowband groups and the two groups now differ by a factor of 1.5. The 1.5 factor may arise from the extra heating of the more powerful broadband laser system on the water surface. The convolution from the narrowband SFG spectrum to the broadband SFG spectrum is also investigated and it does not affect the sum rule. Theory and narrowband experiments are compared using the sum rule and agree to a factor of 1.3 with no adjustable parameters.

Clinical efficacy of tumor organoid-guided cancer therapy for locally advanced unresectable or metastatic breast cancer.

Patient-derived organoids (PDOs) may facilitate treatment selection. This retrospective cohort study evaluated the feasibility and clinical benefit of using PDOs to guide personalized treatment in metastatic breast cancer (MBC). Patients diagnosed with MBC were recruited between January 2019 and August 2022. PDOs were established and the efficacy of customized drug panels was determined by measuring cell mortality after drug exposure. Patients receiving organoid-guided treatment (OGT) were matched 1:2 by nearest neighbor propensity scores with patients receiving treatment of physician's choice (TPC). The primary outcome was progression-free survival. Secondary outcomes included objective response rate and disease control rate. Targeted gene sequencing and pathway enrichment analysis were performed. Forty-six PDOs (46 of 51, 90.2%) were generated from 45 MBC patients. PDO drug screening showed an accuracy of 78.4% (95% CI 64.9%-91.9%) in predicting clinical responses. Thirty-six OGT patients were matched to 69 TPC patients. OGT was associated with prolonged median progression-free survival (11.0 months vs. 5.0 months; hazard ratio 0.53 [95% CI 0.33-0.85]; p = .01) and improved disease control (88.9% vs. 63.8%; odd ratio 4.26 [1.44-18.62]) compared with TPC. The objective response rate of both groups was similar. Pathway enrichment analysis in hormone receptor-positive, human epidermal growth factor receptor 2-negative patients demonstrated differentially modulated pathways implicated in DNA repair and transcriptional regulation in those with reduced response to capecitabine/gemcitabine, and pathways associated with cell cycle regulation in those with reduced response to palbociclib. Our study shows that PDO-based functional precision medicine is a feasible and effective strategy for MBC treatment optimization and customization.

Pooled analysis of NeoCARH and NeoCART trials: patient-reported outcomes in patients with early-stage breast cancer receiving platinum-based or anthracycline-based neoadjuvant chemotherapy.

PURPOSE: Anthracycline-based or platinum-based neoadjuvant chemotherapy belongs to the standard treatment for early-stage breast cancer (EBC) that is either triple-negative or human epidermal growth factor receptor 2 positive (HER2 +). Currently, there is a paucity of data comparing their impact on health-related quality of life (HRQoL). METHODS: Triple-negative or HER2 + EBC from our two prospective randomized controlled trials, neoCARH and neoCART, were divided into two groups based on the neoadjuvant chemotherapy regimens they received: anthracycline-based or platinum-based group. HRQoL was the exploratory endpoint in these two trials, which was assessed using the European Organization for Research and Treatment of Cancer Quality of Life-Core30 and Breast23 questionnaires. The primary variable of interest was the C30 summary score (C30-SumSc). Assessments were carried out at baseline, after neoadjuvant chemotherapy, and 1 year and 2 years after diagnosis. RESULTS: The mean questionnaires' compliance rate was 95.0%. After neoadjuvant chemotherapy, 210 patients had evaluable HRQoL data, the mean least square change from baseline for the platinum-based group was - 15.997 (95% confidence interval (CI): - 17.877 to - 14.117), and it was - 20.156 (95% CI: - 22.053 to - 18.258) for the anthracycline-based group (difference: 4.159, 95% CI: 1.462 to 6.855, P = 0.003, minimal important difference = 3). For the majority of the domains of interest assessed by the C30 and BR23 questionnaires, the platinum-based group demonstrated superior outcomes in comparison to the anthracycline-based group. CONCLUSION: Patients receiving platinum-based or anthracycline-based regimens both experienced worsened HRQoL after neoadjuvant chemotherapy; however, the former provided relatively better HRQoL compared with the latter. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03140553. Registered 4 May 2017 (neoCARH). NCT03154749. Registered 16 May 2017 (neoCART).

Jujuboside B alleviates acetaminophen-induced hepatotoxicity in mice by regulating Nrf2-STING signaling pathway.

BACKGROUND: Jujuboside B (JuB) is the main bioactive saponin component of Chinese anti-insomnia herbal medicine Ziziphi Spinosae Semen, which has been reported to possess varied pharmacological functions. Even though it has been traditionally used to treat inflammation- and toxicity-related diseases, the effects of JuB on acetaminophen (APAP) overdose-induced hepatotoxicity have not been determined yet. METHODS: C57BL/6 J mice were pre-treated with JuB (20 or 40 mg/kg) for seven days before APAP (400 mg/kg) injection. After 24 h of APAP treatment, serum, and liver tissues were collected to evaluate the therapeutic effects. To investigate whether the Nrf2-STING signaling pathway is involved in the protective effects of JuB against APAP-induced hepatotoxicity, the mice received the DMXAA (the specific STING agonist) or ML385 (the specific Nrf2 inhibitor) during the administration of JuB, and Hematoxylin-eosin staining, Real-time PCR, immunohistochemical, and western blot were performed. RESULTS: JuB pretreatment reversed APAP-induced CYP2E1 accumulations and alleviated APAP-induced acute liver injury. Furthermore, JuB treatment significantly inhibited oxidative stress and the pro-inflammatory cytokines, as well as alleviated hepatocyte apoptosis induced by APAP. Besides, our result also demonstrated that JuB treatment upregulated the levels of total Nrf2, facilitated its nuclear translocation, upregulated the expression of HO-1 and NQO-1, and inhibited the APAP-induced STING pathway activation. Finally, we verified that the beneficial effects of JuB were weakened by DMXAA and ML385. CONCLUSION: Our study suggested that JuB could ameliorate APAP-induced hepatic damage and verified a previously unrecognized mechanism by which JuB prevented APAP-induced hepatotoxicity through adjusting the Nrf2-STING pathway.

[Mechanism of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" in treating cardiovascular diseases with syndrome of combined phlegm and stasis based on serum metabolomics].

This study aimed at investigating the mechanism of Trichosanthis Fructus-Allii Macrostemonis Bulbus(GX) in treating cardiovascular diseases in rats with the syndrome of combined phlegm and stasis. The rat model was established by a high-fat diet, ice-water bath combined with subcutaneous injection of adrenalin hydrochloride, and the syndrome score was determined. The serum samples of rats in the control, model, and GX groups were collected. Ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to analyze the metabolic profiles of the serum samples. The differential metabolites were screened and identified by partial least squares-discriminant analysis(PLS-DA) and orthogonal partial least squares-discriminant analysis(OPLS-DA). The intervention targets of GX-regulated metabolites and their metabolic pathways were searched against MetaboAnalyst. Gene Ontology enrichment was carried out to predict the biological pathways associated with the intervention targets of metabolic pathways. A total of 129 potential biomarkers were detected in the rat model with the syndrome of combined phlegm and stasis via metabolomics, and GX regulated 54 metabolites in several metabolic pathways such as linoleic acid metabolism, sphingolipid metabolism, and tricarboxylic acid cycle. The further screening against MetaboAnalyst showed that GX recovered the levels of nine metabolites associated with cardiovascular diseases with the syndrome of combined phlegm and stasis, which involved 69 targets in the pathways regarding cholesterol metabolism, fatty acid metabolism, inflammatory response, and glucose homeostasis and metabolism. The above-mentioned results suggested that GX can alleviate the symptoms of the rat model of cardiovascular diseases with the syndrome of combined phlegm and stasis by regulating the metabolism of linoleic acid, sphingosine, docosahexaenoic acid, rosemary acid, succinic acid, adenine, L-phenylalanine, L-valine and modulating the biological pathways such as cholesterol metabolism, fatty acid metabolism, inflammatory response, and glucose homeostasis and metabolism.

[Randomized,double-blind,parallel controlled,multicenter clinical trial of effectiveness and safety of Shexiang Zhuifeng Zhitong Ointment in alleviating pain in knee osteoarthritis(syndrome of cold-dampness obstruction)].

The Shexiang Zhuifeng Zhitong Ointment with the effects of dispelling wind, removing dampness, dissipating cold, and relieving pain is used for treating arthralgia, muscular pain, and sprain pain caused by cold-dampness obstruction. To evaluate the efficacy and safety of Shexiang Zhuifeng Zhitong Ointment in relieving the pain due to knee osteoarthritis(syndrome of cold-dampness obstruction), a randomized, double-blind, parallel controlled, multicenter clinical trial was conducted. The stratified randomization method was used to randomize the 240 subjects into a treatment group and a control group in a ratio of 1∶1. In each group, 60 patients received external application for 12 h and the other 60 patients received external application for 6 h. The treatment group received external application of Shexiang Zhuifeng Zhitong Ointment, while the control group received external application of Shexiang Zhuifeng Ointment. The treatment lasted for 21 days in both groups. Follow-up was conducted on days 7, 14, and 21 of treatment. The results based on the full analysis set were as follows.(1)In visual analog scale(VAS) score, the mean difference in the VAS score between baseline and 12 h post-treatment was 3.02 in the treatment group and 2.31 in the control group, with a significant difference(P<0.05). The mean difference in the VAS score between baseline and 6 h post-treatment was 3.19 in the treatment group and 2.48 in the control group, with a significant difference(P<0.05).(2)Response rate in terms of VAS score, after treatment for 12 h, the response rate was 93.22% in the treatment group and 73.33% in the control group, with a significant difference(P<0.05). After treatment for 6 h, theresponse rate in the treatment group was 88.33%, which was higher than that(63.33%) in the control group(P<0.05).The results showed that Shexiang Zhuifeng Zhitong Ointment applied for 12 and 6 h effectively relieved the knee joint pain of patients with knee osteoarthritis due to cold-dampness obstruction, as demonstrated by the reduced VAS score, Western Ontario and McMaster Universities Arthritis Index(WOMAC), stiffness, and joint function score. Moreover, Shexiang Zhuifeng Zhitong Ointment outperformed the positive control Shexiang Zhuifeng Ointment in terms of reducing the VAS score, demonstrating a definitetherapeutic effect on the pain due to knee osteoarthritis(syndrome of cold-dampness obstruction).In addition, Shexiang Zhuifeng Zhitong Ointment did not cause other adverse reactions except for mild allergic reactions, which were common in the external application of traditional Chinese medicine plasters on the skin, inseveral patients.Neither other adverse reactions nor abnormalities of liver and kidney functions and electrocardiogram were observed. This ointment had high safety and could be popularized in clinical application.

m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism.

Glycolytic reprogramming is one of the most important features of cancer and plays an integral role in the progression of cancer. In cancer cells, changes in glucose metabolism meet the needs of self-proliferation, angiogenesis and lymphangiogenesis, metastasis, and also affect the immune escape, prognosis evaluation and therapeutic effect of cancer. The n6-methyladenosine (m6A) modification of RNA is widespread in eukaryotic cells. Dynamic and reversible m6A modifications are widely involved in the regulation of cancer stem cell renewal and differentiation, tumor therapy resistance, tumor microenvironment, tumor immune escape, and tumor metabolism. Lately, more and more evidences show that m6A modification can affect the glycolysis process of tumors in a variety of ways to regulate the biological behavior of tumors. In this review, we discussed the role of glycolysis in tumor genesis and development, and elaborated in detail the profound impact of m6A modification on different tumor by regulating glycolysis. We believe that m6A modified glycolysis has great significance and potential for tumor treatment.

Analysis of cuproptosis-related lncRNA signature for predicting prognosis and tumor immune microenvironment in pancreatic cancer.

Pancreatic cancer (PC) is a highly malignant digestive tract tumor, with a dismal 5-year survival rate. Recently, cuproptosis was found to be copper-dependent cell death. This work aims to establish a cuproptosis-related lncRNA signature which could predict the prognosis of PC patients and help clinical decision-making. Firstly, cuproptosis-related lncRNAs were identified in the TCGA-PAAD database. Next, a cuproptosis-related lncRNA signature based on five lncRNAs was established. Besides, the ICGC cohort and our samples from 30 PC patients served as external validation groups to verify the predictive power of the risk signature. Then, the expression of CASC8 was verified in PC samples, scRNA-seq dataset CRA001160, and PC cell lines. The correlation between CASC8 and cuproptosis-related genes was validated by Real-Time PCR. Additionally, the roles of CASC8 in PC progression and immune microenvironment characterization were explored by loss-of-function assay. As showed in the results, the prognosis of patients with higher risk scores was prominently worse than that with lower risk scores. Real-Time PCR and single cell analysis suggested that CASC8 was highly expressed in pancreatic cancer and related to cuproptosis. Additionally, gene inhibition of CASC8 impacted the proliferation, apoptosis and migration of PC cells. Furthermore, CASC8 was demonstrated to impact the expression of CD274 and several chemokines, and serve as a key indicator in tumor immune microenvironment characterization. In conclusion, the cuproptosis-related lncRNA signature could provide valuable indications for the prognosis of PC patients, and CASC8 was a candidate biomarker for not only predicting the progression of PC patients but also their antitumor immune responses.

The role of bone marrow microenvironment on CAR-T efficacy in haematologic malignancies.

In recent years, chimeric antigen receptor-T (CAR-T) cell therapy has emerged as a novel immunotherapy method. It has shown significant therapeutic efficacy in the treatment of haematological B cell malignancies. In particular, the CAR-T therapy targeting CD19 has yielded unprecedented efficacy for acute B-lymphocytic leukaemia (B-ALL) and non-Hodgkin's lymphoma (NHL). In haematologic malignancies, tumour stem cells are more prone to stay in the regulatory bone marrow (BM) microenvironment (called niches), which provides a protective environment against immune attack. However, how the BM microenvironment affects the anti-tumour efficacy of CAR-T cells and its underlying mechanism is worthy of attention. In this review, we discuss the role of the BM microenvironment on the efficacy of CAR-T in haematological malignancies and propose corresponding strategies to enhance the anti-tumour activity of CAR-T therapy.

Combination of alpha-fetoprotein and neutrophil-to-lymphocyte ratio to predict treatment response and survival outcomes of patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of hepatocellular carcinoma (HCC). However, long-term survival outcomes and treatment response of HCC patients undergoing immunotherapy is unpredictable. The study aimed to evaluate the role of alpha-fetoprotein (AFP) combined with neutrophil-to-lymphocyte ratio (NLR) to predict the prognosis and treatment response of HCC patients receiving ICIs. METHODS: Patients with unresectable HCC who received ICI treatment were included. The HCC immunotherapy score was developed from a retrospective cohort at the Eastern Hepatobiliary Surgery Hospital to form the training cohort. The clinical variables independently associated with overall survival (OS) were identified using univariate and multivariate Cox regression analysis. Based on multivariate analysis of OS, a predictive score based on AFP and NLR was constructed, and patients were stratified into three risk groups according to this score. The clinical utility of this score to predict progression-free survival (PFS) and differentiate objective response rate (ORR) and disease control rate (DCR) was also performed. This score was validated in an independent external validation cohort at the First Affiliated Hospital of Wenzhou Medical University. RESULTS: Baseline AFP ≤ 400 ng/ml (hazard ratio [HR] 0.48; 95% CI, 0.24-0.97; P = 0.039) and NLR ≤ 2.77 (HR 0.11; 95% CI, 0.03-0.37; P<0.001) were found to be independent risk factors of OS. The two labolatory values were used to develop the score to predict survival outcomes and treatment response in HCC patients receiving immunotherapy, which assigned 1 point for AFP > 400 ng/ml and 3 points for NLR > 2.77. Patients with 0 point were classified as the low-risk group. Patients with 1-3 points were categorized as the intermediate-risk group. Patients with 4 points were classified as the high-risk group. In the training cohort, the median OS of the low-risk group was not reached. The median OS of the intermediate-risk group and high-risk group were 29.0 (95% CI 20.8-37.3) months and 16.0 (95% CI 10.8-21.2) months, respectively (P < 0.001). The median PFS of the low-risk group was not reached. The median PFS of the intermediate-risk group and high-risk group were 14.6 (95% CI 11.3-17.8) months and 7.6 (95% CI 3.6-11.7) months, respectively (P < 0.001). The ORR and DCR were highest in the low-risk group, followed by the intermediate-risk group and the high-risk group (P < 0.001, P = 0.007, respectively). This score also had good predictive power using the validation cohort. CONCLUSION: The HCC immunotherapy score based on AFP and NLR can predict survival outcomes and treatment response in patients receiving ICI treatments, suggesting that this score could serve as a useful tool for identification of HCC patients likely to benefit from immunotherapy.

A comprehensive analysis of coagulopathy during anti-B cell maturation antigen chimeric antigen receptor-T therapy in multiple myeloma, a retrospective study based on LEGEND-2.

Chimeric antigen receptor (CAR)-reprogrammed T cell therapy is a novel and powerful treatment against hematological malignancies. Cytokine release syndrome (CRS) and other potentially life-threatening toxicities are known side effects which need appropriate management and supportive care. Coagulopathy is a common and severe CAR-T-related adverse event, while a comprehensive profile of coagulopathy in patients with multiple myeloma (MM) undergoing CAR-T cell therapy has not been reported. Therefore, we performed a comprehensive analysis of coagulopathy in 51 patients with r/r MM given anti-B cell maturation antigen CAR-T cell therapy. We found that 49% of patients had coagulation disorders, and 29% of patients experienced disseminated intravascular coagulation (DIC). Severe CRS, abnormal liver function and higher tumor burden were risk factors for the CAR-T-related coagulopathy. We found that the serum IL-6 level and alanine aminotransferase level were potential indicators for CAR-T-related DIC. Furthermore, we found that coagulation disorders occurred within 1 month after CAR-T cell infusion, mainly between days 10 and 13, which was 2-5 days later than the beginning of CRS and simultaneous with the beginning of abnormal liver function and the peak of CRS. In addition, although patients with coagulation dysfunction had a trend for better outcomes and prognosis, no statistical significance was found. In conclusion, our research provided a comprehensive understanding of CAR-T-related coagulopathy in MM. Upon timely and standardized treatment, coagulopathy was manageable in most cases.

Luteimonas suaedae sp. nov., a novel bacterium isolated from rhizosphere of Suaeda aralocaspica (Bunge) Freitag & Schütze.

Light yellowish-white colonies of a bacterial strain, designated LNNU 24178T, were isolated from the rhizosphere soil of halophyte Suaeda aralocaspica (Bunge) Freitag and Schütze grown at Shihezi district, Xinjiang, PR China. Cells were Gram-stain-negative, non-flagellum-forming, rod-shaped and non-motile. The results of phylogenetic analysis based on the 16S rRNA gene sequence indicated that LNNU 24178T represented a member of the genus Luteimonas and shared the highest sequence similarity with Luteimonas yindakuii CGMCC 1.13927T (97.1 %) and lower sequence similarity (< 97.0 %) to other known species. The genomic DNA G+C content of LNNU 24178T was 68.8 %. The average nucleotide identity (ANI) values between LNNU 24178T and Luteimonas yindakuii CGMCC 1.13927T, Luteimonas mephitis DSM 12574T, Luteimonas arsenica 26-35T and Luteimonas huabeiensis HB2T were 78.7, 78.6, 78.4 and 80.0 %, respectively. The digital DNA-DNA hybridisation (dDDH) values between LNNU 24178T and L. yindakuii CGMCC 1.13927T, L. mephitis DSM 12574T, L. arsenica 26-35T and L. huabeiensis HB2T were 22.0, 22.3, 22.2 and 23.5 %, respectively. The respiratory quinone detected in LNNU 24178T was ubiquinone-8 (Q-8). The major fatty acids (> 5.0 %) of LNNU 24178T were identified as iso-C15 : 0 (33.9 %), iso-C17 : 0 (8.7 %), iso-C11 : 0 (6.2 %), iso-C16 : 0 (5.7 %), C16 : 0 (5.3 %) and summed feature 9 (iso-C17 : 1ω9c/10-methyl C16 : 0) (21.1 %). The major polar lipids of LNNU 24178T were diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), one unidentified phospholipid (PL), one unidentified glycolipid (GL) and three unidentified lipids. According to the data obtained from phenotypic, chemotaxonomic and phylogenetic analyses, strain LNNU 24178T represents a novel species of the genus Luteimonas, for which the name Luteimonas suaedae sp. nov. is proposed, with LNNU 24178T (= CGMCC 1.17331T= KCTC 62251T) as the type strain.

Retrievable Inferior Vena Cava Filter Trapped Embolus: A Risk Factor of Detachment of Thrombus Analysis Based on a Multicenter Prospective Observational Study.

PURPOSE: Up to now, the indications of inferior vena cava filter placement still remain controversial in the academic field. The aim of this study was to determine the risk factors of detachment of thrombus and to evaluate the necessity of inferior vena cava filter placement to prevent fatal pulmonary embolism. MATERIALS AND METHODS: A total of 2892 patients participated in the multicenter prospective observational study from January 1, 2018, to December 31, 2018, and underwent retrievable inferior vena cava filter (RIVCF) placement in 103 centers in China. The primary endpoint of the study was RIVCF trapped embolus detected by inferior vena cava venography/ultrasound/computed tomography scanning or visible macroscopic thrombus before or during RIVCF retrieval. The relative factors of RIVCF trapped embolus were analyzed accordingly. RESULTS: The average age of the patients was 61.0 (50.0-71.0) years. Retrievable inferior vena cava filter trapped embolus occurred in 308 patients (10.65%). The fracture location, surgery location, and endovascular intervention differed between RIVCF trapped embolus and non-RIVCF trapped embolus groups (p<0.001, respectively). By multivariate analysis, RIVCF trapped embolus were less common in older patients (odds ratio [OR]=0.998; p<0.001) and more common in patients with below-the-knee fracture (OR=1.093, p=0.038), thigh fracture (OR=1.118, p=0.007), and pelvis surgery (OR=1.067, p=0.016). In addition, compared with patients without endovascular intervention, patients with percutaneous mechanical thrombectomy (PMT) + catheter-directed thrombolysis (CDT) were more prone to develop RIVCF trapped embolus (OR=1.060, p=0.010). However, RIVCF trapped embolus was less common in patients with CDT (OR=0.961, p=0.004). CONCLUSIONS: Lower limb fracture, pelvis surgery, and PMT + CDT are prone to cause trapped embolus. As a trapped embolus often represents the possibility of severe pulmonary embolism, lower limb fracture, pelvis surgery, and PMT + CDT could be risk factors of fatal pulmonary embolism. Due to the low incidence of trapped embolus, it is not necessary to place filters in elderly patients and CDT-only patients. CLINICAL IMPACT: The purpose of this paper is to standardize the use of inferior vena cava filter and avoid unnecessary filter implantation through the summary and analysis of a large number of clinical data. At the same time, more attention should be paid to and active treatment should be given to high-risk groups of pulmonary embolism.

Tranexamic acid, as an adjunct to oxytocin prophylaxis, in the prevention of postpartum haemorrhage in women undergoing elective caesarean section: A single-centre double-blind randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of tranexamic acid (TXA) in reducing blood loss during elective caesarean sections in women with and without risk factors for postpartum haemorrhage (PPH). DESIGN: A double-blind, randomised placebo-controlled trial. SETTING: An academic tertiary referral centre in Singapore. POPULATION: Multiethnic women aged 21 years or older undergoing elective caesarean section. METHODS: Randomisation to intravenous TXA or normal saline (placebo) 10 minutes before skin incision. MAIN OUTCOME MEASURES: Calculated estimated blood loss (cEBL), derived from blood volume and haematocrit levels. RESULTS: Between June 2020 and October 2021, 200 women were randomised to the placebo or TXA groups. Women who received prophylactic TXA had a significantly lower mean cEBL compared with those receiving placebo (adjusted mean difference -126.4 mL, 95% CI -243.7 to -9.1, p = 0.035). The effect was greatest in those at high risk for PPH, with a reduction in cEBL (mean difference -279.6 mL, 95% CI -454.8 to -104.3, p = 0.002) and a lower risk of cEBL ≥500 mL (risk ratio [RR] 0.54, 95% CI 0.36-0.83, p = 0.007) and cEBL ≥1000 mL (RR 0.44, 95% CI 0.20-0.98, p = 0.016). Subgroup analysis showed benefit for women with preoperative haemoglobin <10.5 g/dL (mean difference -281.9 mL, 95% CI -515.0 to -48.8, p = 0.019). There was no significant difference in need for additional medical or surgical interventions. There were no maternal or neonatal adverse outcomes. CONCLUSION: Prophylactic TXA should be considered in women with risk factors for PPH, and those most likely to benefit are those with preoperative haemoglobin <10.5 g/dL.

Chronic ß-adrenergic stress contributes to cardiomyopathy in rodents with collagen-induced arthritis.

Patients with rheumatoid arthritis (RA) have a much higher incidence of cardiac dysfunction, which contributes to the high mortality rate of RA despite anti-arthritic drug therapy. In this study, we investigated dynamic changes in cardiac function in classic animal models of RA and examined the potential effectors of RA-induced heart failure (HF). Collagen-induced arthritis (CIA) models were established in rats and mice. The cardiac function of CIA animals was dynamically monitored using echocardiography and haemodynamics. We showed that cardiac diastolic and systolic dysfunction occurred in CIA animals and persisted after joint inflammation and that serum proinflammatory cytokine (IL-1ß, TNF-α) levels were decreased. We did not find evidence of atherosclerosis (AS) in arthritic animals even though cardiomyopathy was significant. We observed that an impaired cardiac ß1AR-excitation contraction coupling signal was accompanied by sustained increases in blood epinephrine levels in CIA rats. Furthermore, serum epinephrine concentrations were positively correlated with the heart failure biomarker NT-proBNP in RA patients (r2 = +0.53, P < 0.0001). In CIA mice, treatment with the nonselective ßAR blocker carvedilol (2.5 mg·kg-1·d-1, for 4 weeks) or the specific GRK2 inhibitor paroxetine (2.5 mg·kg-1·d-1, for 4 weeks) effectively rescued heart function. We conclude that chronic and persistent ß-adrenergic stress in CIA animals is a significant contributor to cardiomyopathy, which may be a potential target for protecting RA patients against HF.

Synthesis, antitumor evaluation and computational study of thiazolidinone derivatives of dehydroabietic acid-based B ring-fused-thiazole.

In an attempt to search for new natural product-based antitumor agents, a series of novel thiazolidinone derivatives of dehydroabietic acid-based B ring-fused-thiazole were designed and synthesized. The primary antitumor tests showed that compounds 5 m exhibited almost the best inhibitory activity against the tested cancer cells. The computational study suggested NOTCH1, IGF1R, TLR4, and KDR were the core targets of the title compounds, and the IC50 of SCC9 and Cal27 is strong correlation with the binding ability of TLR4 and compounds.

Mirror-image antiparallel ß-sheets organize water molecules into superstructures of opposite chirality.

Biomolecular hydration is fundamental to biological functions. Using phase-resolved chiral sum-frequency generation spectroscopy (SFG), we probe molecular architectures and interactions of water molecules around a self-assembling antiparallel ß-sheet protein. We find that the phase of the chiroptical response from the O-H stretching vibrational modes of water flips with the absolute chirality of the (l-) or (d-) antiparallel ß-sheet. Therefore, we can conclude that the (d-) antiparallel ß-sheet organizes water solvent into a chiral supermolecular structure with opposite handedness relative to that of the (l-) antiparallel ß-sheet. We use molecular dynamics to characterize the chiral water superstructure at atomic resolution. The results show that the macroscopic chirality of antiparallel ß-sheets breaks the symmetry of assemblies of surrounding water molecules. We also calculate the chiral SFG response of water surrounding (l-) and (d-) LK7ß to confirm the presence of chiral water structures. Our results offer a different perspective as well as introduce experimental and computational methodologies for elucidating hydration of biomacromolecules. The findings imply potentially important but largely unexplored roles of water solvent in chiral selectivity of biomolecular interactions and the molecular origins of homochirality in the biological world.

Adolescent Hypertension Induced by Obesity and the Efficacy of Comprehensive Intervention.

Context: With the development of the Chinese economy, people's quality of life has improved, obesity caused by excessive nutrition has increased among teenagers, and the age of patients with obesity-induced hypertension has become younger and younger. Objective: The study intended to analyze the factors affecting hypertension in adolescents to find methods to effectively prevent and treat hypertension in that age group. Design: The research team designed a prospective controlled study. Setting: The study took place at the First People's Hospital of Nantong in Nantong, Jiangsu, China from 2020 to 2022 years. Participants: Participants were 1000 students in Grades 7 to 9 at the Si'an middle school in Nantong, China. Intervention: From the 1000 participants, among of them 500 cases of hypertension. The research team (n = 500) participants who were obese and hypertensive and assigned them to the hypertension group, the control group (n = 500) participants with normal weights and no hypertension assigned them to a control group. Participants with obesity-induced hypertension received a comprehensive intervention. Outcome Measures: The research team used a questionnaire and a physical examination to collect data about participants' ages, heights, weights, demographic characteristics, waist circumferences, hip circumferences, and knowledge of hypertension and blood pressure and analyzed the relationships between those factors. The team measured blood pressure, blood lipids, blood glucose, and body mass index at baseline and postintervention. Results: Significant differences existed between the hypertension and control groups at general data: (1) weight-63.49 ± 13.22 kg and 52.59 ± 10.21 kg, respectively (P = .000); (2) waist circumference-75.44 ± 10.92 cm and 68.73 ± 8.15 cm, respectively (P = .001); (3) hip circumference-92.10 ± 7.98 cm and 85.95 ± 7.91 cm, respectively (P = .000); (4) body mass index (BMI)-22.12 ± 4.02 kg/m2 and 19.58 ± 3.34 kg/m2, respectively (P = .002); (5) waist-hip ratio-0.83 ± 0.08 and 0.81 ± 0.07, respectively (P = .003); and (6) waist-to-height ratio-0.46 ± 0.07 and 0.44 ± 0.06, respectively (P = .000). Only age (p=0.006), hip circumference(p=0.000), and BMI (P = .000) were significantly and positively correlated with hypertension. The regression coefficients for age, hip circumference, and BMI were 0.182, 0.062 and 0.096, respectively. The changes in the hypertension group's mean systolic blood pressure (SBP), diastolic blood pressure (DBP), BMI, body fat, trunk fat, abdominal fat, upper-limb fat, and lower-limb fat between baseline and postintervention were statistically significant. Significant decreases in the hypertension group's triglycerides, total cholesterol, and glycated albumin had occurred between baseline and postintervention (all P < .01), and that group's glucagon (P = .011) had significantly increased. No significant changes had occurred in that group's blood glucose, glycated hemoglobin, insulin, and insulin resistance index between baseline and postintervention (P < .05). Conclusions: Obesity increases the risk of hypertension, and comprehensive interventions can effectively prevent and treat adolescent hypertension.

ADAMTS12 promotes migration and epithelial-mesenchymal transition and predicts poor prognosis for pancreatic cancer.

BACKGROUND: ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family, a group of extracellular multifunctional enzymes, has been proven to play a pivotal role in the tumor. In pancreatic cancer, the role and mechanism of this family remain unclear. The present study aimed to figure out the hub gene of ADAMTSs and explore the exact roles in the prognosis and biological functions in pancreatic ductal adenocarcinoma (PDAC). METHODS: We used several databases to analyze the ADAMTS family and then screen out the hub genes. The expression of ADAMTS12 in 106 pairs of PDAC tumors and adjacent normal tissues was examined by immunohistochemistry, and its correlations with clinical parameters were further analyzed. The impacts of ADAMTS12 on the migration of PDAC cells were predicted by gene set enrichment analysis and confirmed by transwell assays. The potential impacts of ADAMTS12 on the epithelial-mesenchymal transition (EMT) were identified by database analysis and experimental proof of real-time quantitative polymerase chain reaction (qPCR) and Western blotting. RESULTS: Our study found that ADAMTS12 was a crucial gene in PDAC, and it was highly expressed in tumor tissues when compared to that in the adjacent tissues. ADATMS12 had predictive value of a poor prognosis for PDAC. The elevation of ADAMTS12 was parallel to the progression of PDAC. Inhibition of ADAMTS12 suppressed the migration of PDAC cells and interfered with the process of EMT. CONCLUSIONS: ADAMTS12 is a crucial member of ADAMTSs in PDAC and a predictor of poor prognosis. Additionally, based on its impacts on migration and metastasis in PDAC and the relationship with EMT, ADAMTS12 plays a role of an oncogene in PDAC and may be a promising target for treatment.

Chinese Expert Consensus on the Use of Biologics in Patients with Chronic Rhinosinusitis (2022, Zhuhai).

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disease in otolaryngology, mainly manifested as nasal congestion, nasal discharge, facial pain/pressure, and smell disorder. CRS with nasal polyps (CRSwNP), an important phenotype of CRS, has a high recurrence rate even after receiving corticosteroids and/or functional endoscopic sinus surgery. In recent years, clinicians have focused on the application of biological agents in CRSwNP. However, it has not reached a consensus on the timing and selection of biologics for the treatment of CRS so far. SUMMARY: We reviewed the previous studies of biologics in CRS and summarized the indications, contraindications, efficacy assessment, prognosis, and adverse effects of biologics. Also, we evaluated the treatment response and adverse reactions of dupilumab, omalizumab, and mepolizumab in the management of CRS and made recommendations. KEY MESSAGES: Dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP by the US Food and Drug Administration. Type 2 and eosinophilic inflammation, need for systemic steroids or contraindication to systemic steroids, significantly impaired quality of life, anosmia, and comorbid asthma are required for the use of biologics. Based on current evidence, dupilumab has the prominent advantage in improving quality of life and reducing the risk of comorbid asthma in CRSwNP among the approved monoclonal antibodies. Most patients tolerate biological agents well in general with few major or severe adverse effects. Biologics have provided more options for severe uncontrolled CRSwNP patients or patients who refuse to have surgery. In the future, more novel biologics will be assessed in high-quality clinical trials and applied clinically.