Greedy Ensemble Hyperspectral Anomaly Detection.

Hyperspectral images include information from a wide range of spectral bands deemed valuable for computer vision applications in various domains such as agriculture, surveillance, and reconnaissance. Anomaly detection in hyperspectral images has proven to be a crucial component of change and abnormality identification, enabling improved decision-making across various applications. These abnormalities/anomalies can be detected using background estimation techniques that do not require the prior knowledge of outliers. However, each hyperspectral anomaly detection (HS-AD) algorithm models the background differently. These different assumptions may fail to consider all the background constraints in various scenarios. We have developed a new approach called Greedy Ensemble Anomaly Detection (GE-AD) to address this shortcoming. It includes a greedy search algorithm to systematically determine the suitable base models from HS-AD algorithms and hyperspectral unmixing for the first stage of a stacking ensemble and employs a supervised classifier in the second stage of a stacking ensemble. It helps researchers with limited knowledge of the suitability of the HS-AD algorithms for the application scenarios to select the best methods automatically. Our evaluation shows that the proposed method achieves a higher average F1-macro score with statistical significance compared to the other individual methods used in the ensemble. This is validated on multiple datasets, including the Airport-Beach-Urban (ABU) dataset, the San Diego dataset, the Salinas dataset, the Hydice Urban dataset, and the Arizona dataset. The evaluation using the airport scenes from the ABU dataset shows that GE-AD achieves a 14.97% higher average F1-macro score than our previous method (HUE-AD), at least 17.19% higher than the individual methods used in the ensemble, and at least 28.53% higher than the other state-of-the-art ensemble anomaly detection algorithms. As using the combination of greedy algorithm and stacking ensemble to automatically select suitable base models and associated weights have not been widely explored in hyperspectral anomaly detection, we believe that our work will expand the knowledge in this research area and contribute to the wider application of this approach.

Toxic Effects of Methamphetamine on Reproductive Systems, Embryo Development, and Newborns: An Evidence-Based Review.

Methamphetamine (METH), an amphetamine-type stimulant, has been extensively abused globally in the past decades. METH use causes great harm to the major systems of the human body. Specifically, METH has a negative impact on the hypothalamic- pituitary-testicular axis, testicular structure, sperm function, ovarian folliculogenesis, oocyte quality, embryo development, and newborns. However, the mechanisms underlying these toxic effects have not yet been fully described. This study reviews the evidence concerning the impact of METH on male and female reproduction in the context of the testis, sperm, ovaries, oocytes, reproductive hormones, embryo development, and newborns, discussing the potential pathophysiological mechanisms in the reproductive toxicity induced by METH.

Simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with nimotuzumab for locally advanced esophageal squamous cell carcinoma (ESCC): A phase II clinical trial.

OBJECTIVE: To evaluate the feasibility, safety and efficacy of concurrent simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with nimotuzumab in the treatment of locally advanced esophageal squamous cell cancer (ESCC). METHODS: Eligible patients were histologically proven to have locally advanced ESCC, and were unable to tolerate or refuse concurrent chemoradiotherapy (CCRT). Enrolled patients underwent concurrent SIB-IMRT in combination with nimotuzumab. SIB-IMRT: For the planning target volume of clinical target volume (PTV-C), the prescription dose was 50.4 Gy/28fractions, 1.8 Gy/fraction, 5fractions/week, concurrently, the planning target volume of gross tumor (PTV-G) undergone an integrated boost therapy, with a prescription dose of 63 Gy/28fractions, 2.25 Gy/fraction, 5 fractions/week. Nimotuzumab was administered concurrently with radiotherapy, 200 mg/time, on D1, 8, 15, 22, 29, and 36, with a total accumulation of 1200 mg through intravenous infusion. The primary endpoint of the study was the safety and efficacy of the combined treatment regimen, and the secondary endpoints were 1-year, 2-year, and 3-year local control and survival outcomes. RESULTS: (1) From December 2018 to August 2021, 35 patients with stage II-IVA ESCC were enrolled and 34 patients completed the full course of radiotherapy and the intravenous infusion of full-dose nimotuzumab. The overall completion rate of the protocol was 97.1%. (2) No grade 4-5 adverse events occurred in the entire group. The most common treatment-related toxicity was acute radiation esophagitis, with a total incidence of 68.6% (24/35). The incidence of grade 2 and 3 acute esophagitis was 25.7% (9/35) and 17.1% (6/35), respectively. The incidence of acute radiation pneumonitis was 8.6% (3/35), including one case each of Grades 1, 2, and 3 pneumonitis. Adverse events in other systems included decreased blood cells, hypoalbuminemia, electrolyte disturbances, and skin rash. Among these patients, five experienced grade 3 electrolyte disturbances during the treatment period (three with grade 3 hyponatremia and two with grade 3 hypokalemia). (3) Efficacy: The overall CR rate was 22.8%, PR rate was 71.4%, ORR rate was 94.2%, and DCR rate was 97.1%.(4) Local control and survival: The 1-, 2-, and 3-year local control (LC) rate, progression-free survival(PFS) rate, and overall survival(OS) rate for the entire group were 85.5%, 75.4%, and 64.9%; 65.7%, 54.1%, and 49.6%; and 77.1%, 62.9%, and 54.5%, respectively. CONCLUSIONS: The combination of SIB-IMRT and nimotuzumab for locally advanced esophageal cancer demonstrated good feasibility, safety and efficacy. It offered potential benefits in local control and survival. Acute radiation esophagitis was the primary treatment-related toxicity, which is clinically manageable. This comprehensive treatment approach is worthy of further clinical exploration (ChiCTR1900027936).

[Proposal and Analysis of "Ternary" Model of Sensitization for Proton Therapy].

In order to improve the biological effect of proton therapy, the authors first propose a new method of boron-based proton-enhanced radiotherapy in a " ternary " radiotherapy mode, based on the existing sensitizing effect of proton radiotherapy: i.e, Boron-based mediators (11B and 10B) induce the proton-hydrogen-boron fusion reaction of the low-energy protons arriving at the Bragg peak region of the tumor target area (p+11B→3α) and thermal neutron capture (10B+n→7Li3+(0.84 MeV)+4He2+(1.47 MeV)+γ(0.477 MeV)), which release low-energy α-particles with high LETs to enhance the biological effect of proton dose in the target area, thus improve the clinical effect of proton therapy. Then, the advantages and disadvantages of the "ternary" model were analyzed from the theoretical basis and current research status, and finally, the "ternary" model is summarized and prospected.

Effect of Cyclic Ice Plug Deformation on Microstructure and Mechanical Behaviors of Nuclear-Grade Low-Carbon Tubular Steel.

This study subjected nuclear-grade 20# pipeline steel to cyclic freeze-thaw ice plugging tests, simulating the plastic deformation experienced by pipes during ice plug removal procedures. Subsequently, the dislocation morphology and mechanical properties of the specimens post cyclic ice plugging were examined. The cyclic ice plugging process led to an increase in the dislocation density within the specimens. After 20 and 40 cycles of ice plugging, the internal dislocation structures evolved from individual dislocation lines and dislocation tangles to high-density dislocation walls and dislocation cells. These high-density dislocation walls and cells hindered dislocation motion, giving rise to strain hardening phenomena, thereby resulting in increased strength and hardness of the specimens with an increasing number of ice plugging cycles. In addition, a large stress field was generated around the dislocation buildup, which reduced the pipe material's plastic toughness. The findings elucidate the effects of cyclic ice plugging on the microstructure and properties of nuclear-grade 20# pipeline steel, aiming to provide a theoretical basis for the safe and stable application of ice plugging technology in nuclear piping systems.

Microplastics enhanced the allelopathy of pyrogallol on toxic Microcystis with additional risks: Microcystins release and greenhouse gases emissions.

Cyanobacteria blooms (CBs) caused by eutrophication pose a global concern, especially Microcystis aeruginosa (M. aeruginosa), which could release harmful microcystins (MCs). The impact of microplastics (MPs) on allelopathy in freshwater environments is not well understood. This study examined the joint effect of adding polystyrene (PS-MPs) as representative MPs and two concentrations (2 and 8 mg/L) of pyrogallol (PYR) on the allelopathy of M. aeruginosa. The results showed that the addition of PS-MPs intensified the inhibitory effect of 8 mg/L PYR on the growth and photosynthesis of M. aeruginosa. After a 7-day incubation period, the cell density decreased to 69.7 %, and the chl-a content decreased to 48 % compared to the condition without PS-MPs (p < 0.05). Although the growth and photosynthesis of toxic Microcystis decreased with the addition of PS-MPs, the addition of PS-MPs significantly resulted in a 3.49-fold increase in intracellular MCs and a 1.10-fold increase in extracellular MCs (p < 0.05). Additionally, the emission rates of greenhouse gases (GHGs) (carbon dioxide, nitrous oxide and methane) increased by 2.66, 2.23 and 2.17-fold, respectively (p < 0.05). In addition, transcriptomic analysis showed that the addition of PS-MPs led to the dysregulation of gene expression related to DNA synthesis, membrane function, enzyme activity, stimulus detection, MCs release and GHGs emissions in M. aeruginosa. PYR and PS-MPs triggered ROS-induced membrane damage and disrupted photosynthesis in algae, leading to increased MCs and GHG emissions. PS-MPs accumulation exacerbated this issue by impeding light absorption and membrane function, further heightening the release of MCs and GHGs emissions. Therefore, PS-MPs exhibited a synergistic effect with PYR in inhibiting the growth and photosynthesis of M. aeruginosa, resulting in additional risks such as MCs release and GHGs emissions. These results provide valuable insights for the ecological risk assessment and control of algae bloom in freshwater ecosystems.

Targeting TRIM40 signaling reduces esophagus cancer development: A mechanism involving in protection of oroxylin A.

Oroxylin A (OA), a naturally active O-methylated flavone derived from Scutellaria baicalensis, is regarded as a potential drug with strong anticancer effects. Unfortunately, our understanding of the antineoplastic mechanism of oral exposure to such flavonoids is inadequate. Growing evidence has confirmed the important role of OA in the regulation of oxidative stress- and inflammatory-response-induced tissue injury. However, it remains unknown whether OA is capable of mitigating esophagus cancer (EC) progression and its potential molecular mechanism. Furthermore, the tripartite motif containing 40 (TRIM40) is a ubiquitin ligase that mediates the immune response. The potential molecular function of TRIM40 in regulating EC is largely unknown. We confirmed that OA-triggered oxidative stress markedly upregulates TRIM40. During the OA challenge, increased TRIM40 reduced oxidative stress and promoted the ER stress response. Inversely, deletion of TRIM40 facilitated oxidative stress and blocked cancer cell growth in vivo and in vitro. Mechanistically, in response to OA treatment, TRIM40 directly interacts with Keap1 and promotes ubiquitin-proteasome degradation, thus leading to the promotion of Nrf2 nuclear translocation and its downstream cascade activation, which increases antioxidant defense and cell survival. TRIM40 expression was positively correlated with Nrf2 expression and negatively associated with Keap1 expression in EC xenografts and human specimens. In addition, high TRIM40 expression correlates with poor patient survival in EC. The findings suggested that oral exposure to OA significantly mitigates EC development by targeting TRIM40 activity. These findings further elucidated the potential role of TRIM40 in EC progression by mediating Keap1 degradation, which could be considered a therapeutic target for the treatment of such a disease.

Effects of nanoplastic exposure routes on leaf decomposition in streams.

Polystyrene nanoparticles (PS NPs) released from plastic products have been demonstrated to pose a threat to leaf litter decomposition in streams. Given the multitrophic systems of species interactions, the effects of PS NPs through different exposure routes on ecosystem functioning remain unclear. Especially dietary exposure, a frequently overlooked pathway leading to toxicity, deserves more attention. A microcosm experiment was conducted in this study to assess the effects of waterborne and dietary exposure to PS NPs on the litter-based food chain involving leaves, microbial decomposers, and detritivores (river snails). Compared to waterborne contamination, dietary contamination resulted in lower microbial enzyme activities and a significantly higher decrease in the lipid content of leaves. For river snails, their antioxidant activity was significantly increased by 20.21%-69.93%, and their leaf consumption rate was significantly reduced by 16.60% through the dietary route due to the lower lipid content of leaves. Besides, the significantly decreased nutritional quality of river snails would negatively influence their palatability to predators. The findings of this study indicate that dietary exposure to PS NPs significantly impacts microbial and detritivore activities, thus affecting their functions in the detritus food chain as well as nutrient cycling.

IL-6 Inhibitor Tocilizumab Reduces Bone Resorption Around Implants with Bacterial Infection During Osseointegration: A Pilot Study in Rabbits.

PURPOSE: To evaluate the effect of interleukin-6 (IL-6) inhibitor (tocilizumab) on bacterial infection-associated bone resorption around implants during osseointegration in rabbits. MATERIALS AND METHODS: At total of 24 male, 9-monthold New Zealand white rabbits were included, and their two mandibular anterior teeth were extracted. Three months after extraction, 24 one-piece Dentium implants (Ø 2.5 mm, intraosseous length of 12 mm) were inserted in the anterior mandible, and the rabbits were divided into four groups (n = 6 per group). Different treatment methods were used in each group: blank control group (BC); only silk ligation (negative control [NC]); silk ligation and injection with minocycline hydrochloride ointment (positive control [PC]); and silk ligation and injection with tocilizumab at 8 mg/kg via the auricle vein (experimental [EP]). Eight weeks later, the animals were sacrificed, and samples were collected and then analyzed using microcomputed tomography (microCT) scanning, immunohistochemical analysis, and histologic analysis. RESULTS: From the microCT measurement, the ratio of the bone volume to the total volume (BV/TV) in the EP group was 67.00% ± 2.72%, which was higher than that in the other three groups (58.85% ± 2.43% in the BC group, 55.72% ± 2.48% in the PC group, and 36.52% ± 3.02% in the NC group). From immunohistochemical analysis, the expression of IL-6 was found to be higher in the NC group than in the BC, PC, and EP groups, but there was no statistical difference between these three groups. Furthermore, the RANKL (receptor activator of nuclear factor-κB ligand) expression was the lowest in the EP group, followed by the BC group, the PC group, and the NC group, which had the highest expression; there was no difference between the NC and PC groups. Upon histologic analysis, significant new bone was found on the implant surfaces in the EP group, sparse and less new bone could be seen in the BC and PC groups, and the most serious bone resorption occurred in the NC group. CONCLUSIONS: Tocilizumab, an inhibitor of IL-6, has a certain effect in preventing bone loss around implants caused by bacterial infection during the osseointegration period.

The management pattern and outcomes of chronic thromboembolic pulmonary hypertension: rationale and design for a Chinese real-world study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. METHODS AND DESIGN: The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. CONCLUSIONS: As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. REGISTRATION NUMBER IN CLINICALTRIALS.GOV: NCT05311072.

Response of a simulated aquatic fungal community to nanoplastics exposure and functional consequence on leaf decomposition.

Nanoplastics pose a potential threat to a wide variety of aquatic organisms. Despite the awareness of this existing hazard, the impact of nanoplastics on natural fungal communities remains a research gap. In this study, five dominant fungi species, isolated from a stream ecosystem, were used to explore the effects of different nano-polystyrene (nano-PS) particles concentrations on a simulated fungal community. Specifically, the evaluation was conducted regarding the fungal growth, reproductivity, structural composition, and ecological function in leaf litter decomposition. A 15-day exposure experiment showed that 100 µg/L nano-PS significantly reduced the microcosm pH. The extracellular enzyme activities of ß-glucosidase, leucine-aminopeptidase, and peroxidase were significantly promoted by nano-PS exposure for 5 days or 15 days. Total sporulation rate significantly decreased after the 15-day exposure to 1 and 100 µg/L nano-PS and significantly increased under 10 µg/L nano-PS. In contrast, nano-PS concentrations had no effects on fungal biomass. In addition, the reduced relative abundance of Geotrichum candidum lowered its contribution to leaf decomposition, resulting in a decreased litter decomposition rate of a 24.5-27.9 % after exposure. This suggests that 1-100 µg/L nano-PS inhibited leaf decomposition by inhibiting fungal reproduction and reducing the contribution of specific fungal species. In addition, the findings highlight the importance of exploring the potential mechanisms of the interaction between nanoplastics and fungal species.

Pre-school children single inhalation anesthetic exposure and neuro-psychological development: a prospective study and Mendelian randomization analysis.

Background: For children who are unable to cooperate due to severe dental anxiety (DA), dental treatment of childhood caries under Dental General Anesthesia (DGA) is a safe and high-quality treatment method. This study aims to evaluate the impact on neurocognitive functions and the growth and development of children 2 years after dental procedure based on previous research, and further establish a causal relationship between general anesthesia (GA) and changes in children's neurocognitive functions by incorporating Mendelian Randomization (MR) analysis. Methods: Data were collected and analyzed from 340 cases of S-ECC procedures of preschool children conducted in 2019. This involved comparing the neurocognitive outcomes 2 years post-operation of preschool children receiving dental procedures under general anesthesia or local anesthesia. Physical development indicators such as height, weight, and body mass index (BMI) of children were also compared at baseline, half a year post-operation, and 2 years post-operation. We performed a Mendelian randomization analysis on the causal relationship between children's cognitive development and general anesthesia, drawing on a large-scale meta-analysis of GWAS for anesthesia, including multiple general anesthesia datasets. Results: Outcome data were obtained for 111 children in the general anesthesia group and 121 children in the local anesthesia group. The mean FSIQ score for the general anesthesia group was 106.77 (SD 6.96), while the mean score for the local anesthesia group was 106.36 (SD 5.88). FSIQ scores were equivalent between the two groups. The incidence of malnutrition in children in the general anesthesia group was 27.93% (p < 0.001) before surgery and decreased to 15.32% (p > 0.05) after 2 years, which was not different from the general population. The IVW method suggested that the causal estimate (p = 0.99 > 0.05, OR = 1.04, 95% CI = 5.98 × 10-4-1.82 × 103) was not statistically significant for disease prevalence. This indicates no genetic cause-and-effect relationship between anesthesia and childhood intelligence. Conclusion: There were no adverse outcomes in neurocognitive development in 2 years after severe early childhood caries (S-ECC) procedure under total sevoflurane-inhalation in preschool children. The malnutrition condition in children can be improved after S-ECC procedure under general anesthesia. Limited MR evidence does not support a correlation between genetic susceptibility to anesthesia and an increased risk for intelligence in children.

Suitability of agronomic water saving in karst areas and its enlightenment in the karst desertification control.

The special "dual" hydrogeological structure in karst areas causes rainfall easily "leaking" into the ground, resulting a unique "karst drought". In these areas, drought and insufficient water resources seriously restrict the sustainable development of agriculture. In order to restore the ecology of karst desertification, develop ecological industries, improve the utilization efficiency of water resources, and advance water-saving agriculture in such areas, literature review method was applied to discuss the suitability of agronomic water-saving measures in karst areas. The results are as follows. (1) Agronomic water-saving measures including tillage, mulching, water-fertilizer coupling, chemical regulation, crop allocation and deficit irrigation can all enhance the crop WUE. For example, deep tillage and deep loosening increased the WUE by 15.1 % and 15.9 % respectively. The WUE of spring wheat under straw mulching increased by 17.17 %-43.01 % compared with that under mulching film. Increased density of intercropping corn and wheat saved 9.85 % of water. (2) The cultural or natural particularity of karst areas limits the application of all agronomic water-saving measures in karst areas, and therefore choices and adjustments are necessary according to local conditions: ① No tillage should be adopted because of the high output of labor force; ② straw mulching need to be crushed; ③ the coupling of water and fertilizer reaches better effect when applied to crops several hours before rainfall; ④ the shallow soil layer and the complexity of preparing water retaining agent make it unsuitable to use water retaining agent; ⑤ agroforestry with dwarf and dense planting is more suitable; ⑥ crop deficit irrigation can be carried out by using ecological small pools. Based on the above results, proposes are offered in the following. First, it is necessary to construct the optimal model of regional water and fertilizer coupling in karst areas, and apply composite agronomic water-saving measures. Second, it is suggested to establish a model of coordinating forest, grain and grass, and vigorously develop ecologically derivative agroforestry. Third, there is a necessity to strengthen the research and development of technology about soil and water leakage monitoring and resistance, and intensify studies on "five waters" transformation at the basin scale. The research results and implication are an important reference for developing water-saving agriculture, solving the shortage of agricultural water resources, ensuring the sustainability of agriculture and improving farmers' living standards. Rational use of agronomic water-saving measures is of great significance to enhance the utilization efficiency of water resources and boost regional economy in karst desertification areas.

Equal allocation, demand priority or negotiated allocation? How to allocate water resources in the Tigris and Euphrates River Basin efficiently.

The Tigris and Euphrates River Basin is an important water supply, but it suffers from water scarcity. It is necessary to carry out reasonable allocation of water resources in this region. Since water resources issues in this region are of multinational interest, international cooperative distribution efforts are needed. Common water resources allocation modes include equal allocation, demand priority or negotiation allocation. In order to derive the applicable range of various water resources allocation modes, this article constructs three differential game models and compares and analyzes the equilibrium results obtained by the models. Finally, the study shows that when the cost of developing water resources is small and the revenue obtained from developing water resources is large, the water-scarce region can obtain the maximum benefit by adopting the demand priority mode. Otherwise, the water-scarce region can obtain the maximum benefit by adopting the negotiation allocation mode. This study can inform the allocation, strategic interaction and cooperation of dynamic water resources in the two river basins.

Aging-Associated Metabolite Methylmalonic Acid Increases Susceptibility to Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by pulmonary fibroblast overactivation, resulting in the accumulation of abnormal extracellular matrix and lung parenchymal damage. Although the pathogenesis of IPF remains unclear, aging was proposed as the most prominent nongenetic risk factor. Previous studies have indicated that propionate metabolism undergoes reprogramming in the aging population, leading to the accumulation of the by-product methylmalonic acid (MMA). This study aims to explore alterations in propionate metabolism in IPF and the impact of the by-product MMA on pulmonary fibrosis. The present study revealed alterations in the expression of enzymes involved in propionate metabolism within IPF lung tissues, characterized by an increase in propionyl-CoA carboxylase and methylmalonyl-CoA epimerase expression, and a decrease in methylmalonyl-CoA mutase expression. Knockdown of methylmalonyl-CoA mutase, the key enzyme in propionate metabolism, in A549 cells induced a profibrotic phenotype and activated co-cultured fibroblasts. MMA exacerbated bleomycin-induced mouse lung fibrosis and induced a profibrotic phenotype in both epithelial cells and fibroblasts through activation of the canonical transforming growth factor-ß/Smad pathway. Overall, our findings unveil an alteration of propionate metabolism in IPF, leading to MMA accumulation, thus exacerbating lung fibrosis through promoting profibrotic phenotypic transitions via the canonical transforming growth factor-ß/Smad signaling pathway.

Serum ASGR2 level: an efficacy biomarker for balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension.

Background: This study aimed to employ plasma proteomics to investigate the molecular changes, pathway alterations, and potential novel biochemical markers associated with balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Pre- and post-BPA plasma samples from five CTEPH patients in the PRACTICE study were analyzed to identify differentially expressed proteins. Proteomic and bioinformatics analyses were conducted, and the identified proteins were further validated using ELISA assays in a separate cohort of the same study. Correlation and multivariate regression analyses were performed to investigate the associations between these differentially expressed proteins and clinical parameters. Results: Significantly higher serum levels of asialoglycoprotein receptor 2 (ASGR2) were detected in 5 CTEPH patients compared to those in healthy individuals but decreased significantly after successful BPA procedures. The decrease in serum levels of ASGR2 after the completion of BPA procedures was further validated in a separate cohort of 48 patients with CTEPH [0.70 (0.51, 1.11) ng/mL vs. 0.38 (0.27, 0.59) ng/mL, P < 0.001]. Significant associations were found between the pre-BPA ASGR2 level and clinical parameters, including neutrophil percentage (R = 0.285, P < 0.05), platelet (PLT) count (R = 0.386, P < 0.05), and high-density lipoprotein cholesterol (HDL-C) before BPA (R = -0.285, P < 0.05). Significant associations were detected between post-BPA serum ASGR2 levels and lymphocyte percentage (LYM%) (R = 0.306, P < 0.05), neutrophil-to-lymphocyte ratio (R = -0.294, P < 0.05), and pulmonary vascular resistance after BPA (R = -0.35, P < 0.05). Multivariate stepwise regression analysis revealed that pre-BPA ASGR2 levels were associated with HDL-C and PLT count (both P < 0.001), while post-BPA ASGR2 levels were associated with LYM% (P < 0.05). Conclusion: Serum levels of ASGR2 may be a biomarker for the effectiveness of BPA treatment in CTEPH patients. The pre-BPA serum level of ASGR2 in CTEPH patients was associated with HDL-C and the PLT count. The post-BPA serum level of ASGR2 was correlated with the LYM%, which may reflect aspects of immune and inflammatory status.

Pulmonary vascular resistance predicts the mortality in patients with bronchiectasis-associated pulmonary hypertension.

OBJECTIVE: Pulmonary hypertension is a severe complication of bronchiectasis, characterized by elevated pulmonary vascular resistance (PVR) and subsequent right heart failure. The association between PVR and mortality in bronchiectasis-associated pulmonary hypertension has not been investigated previously. METHODS: In the present study, a retrospective analysis was conducted on 139 consecutive patients diagnosed with bronchiectasis-associated pulmonary hypertension based on right heart catheterization, enrolled between January 2010 and June 2023. Baseline clinical characteristics and hemodynamic assessment were analyzed. The survival time for each patient was calculated in months from the date of diagnosis until the date of death or, if the patient was still alive, until their last visit. RESULTS: Patients with bronchiectasis-associated pulmonary hypertension exhibited estimated survival rates of 89.5, 70, and 52.9 at 1-year, 3-year, and 5-year intervals respectively, with a median survival time of 67 months. Multivariable Cox regression analysis revealed that increased age [(adjusted hazard ratio per year 1.042, 95% confidence interval (CI) 1.008-1.076, P = 0.015] and elevated PVR (adjusted HR per 1 Wood Units 1.115, 95% CI 1.015-1.224, P = 0.023) were associated with an increased risk of all-cause mortality. In contrast, higher BMI was associated with a decreased risk of all-cause death (adjusted hazard ratio per 1 kg/m2 0.915, 95% CI 0.856-0.979, P = 0.009). Receiver-operating characteristic analyses identified a cutoff value for PVR at 4 Wood Units as predictive for all-cause death within 3 years [area under the curve (AUC) = 0.624; specificity= 87.5%; sensitivity= 35.8%; P < 0.05]. Patients with a PVR greater than 4 Wood Units had a significantly higher risk of all-cause death compared with those with 4 Wood Units or less (adjusted hazard ratio 2.392; 95% CI 1.316-4.349; P = 0.019). Notably, there were no significant differences in age, sex, BMI, WHO functional class, 6-min walk distance, and NT-proBNP levels at baseline between patients categorized as having 4 Wood Units or less or greater than 4 Wood Units for PVR. CONCLUSION: Based on these data, PVR could serve as a discriminative marker for distinguishing between nonsevere pulmonary hypertension (PVR ≤ 4 Wood Units) and severe pulmonary hypertension (PVR > 4 Wood Units). The utilization of a PVR cutoff value of 4.0 Wood Units provides enhanced prognostic capabilities for predicting mortality.

Identification and functional analysis of floral terpene synthase genes in Curcuma alismatifolia.

MAIN CONCLUSION: CaTPS2 and CaTPS3 were significantly expressed in flowers of Curcuma alismatifolia 'Shadow' and demonstrated bifunctional enzyme activity, CaTPS2 generated linalool and nerolidol as products, and CaTPS3 catalyzed ß-myrcene and ß-farnesene formation. This study presents the discovery and functional characterization of floral terpene synthase (TPS) genes in Curcuma alismatifolia 'Shadow', a cultivar renowned for its unique fragrance. Addressing the gap in understanding the genetic basis of floral scent in this species, we identified eight TPS genes through comprehensive transcriptome sequencing. Among these, CaTPS2 and CaTPS3 were significantly expressed in floral tissues and demonstrated bifunctional enzyme activity corresponding to the major volatile compounds detected in 'Shadow'. Functional analyses, including in vitro assays complemented with rigorous controls and alternative identification methods, elucidated the roles of these TPS genes in terpenoid biosynthesis. In vitro studies were conducted via heterologous expression in E. coli, followed by purification of the recombinant protein using affinity chromatography, enzyme assays were performed with GPP/FPP as the substrate, and volatile products were inserted into the GC-MS for analysis. Partially purified recombinant protein of CaTPS2 catalyzed GPP and FPP to produce linalool and nerolidol, respectively, while partially purified recombinant protein of CaTPS3 generated ß-myrcene and ß-farnesene with GPP and FPP as substrates, respectively. Real-time quantitative PCR further validated the expression patterns of these genes, correlating with terpenoid accumulation in different plant tissues. Our findings illuminate the molecular mechanisms underpinning floral fragrance in C. alismatifolia and provide a foundation for future genetic enhancements of floral scent in ornamental plants. This study, therefore, contributes to the broader understanding of terpenoid biosynthesis in plant fragrances, paving the way for biotechnological applications in horticulture plant breeding.

Viral Hepatitis B Reactivation With Delayed Cholestatic Effect Secondary to Acalabrutinib.

One significant complication of hepatitis B virus includes reactivation (HBVr) in the context of the use of immunosuppressive agents, such as corticosteroids and rituximab, among others. Limited data exist on the topic of HBVr risk in the context of tyrosine kinase inhibitors for which there is no strong guidance recommendation. We describe the clinical characteristics, diagnostic challenges, and the clinical course of a single patient with recurrent mantle cell lymphoma who developed HBVr after treatment with acalabrutinib, a Bruton tyrosine kinase inhibitor.

A native SEC-MS workflow and validation for analyzing drug-to-antibody ratio and drug load distribution in cysteine-linked antibody-drug conjugates.

The development and optimization of Antibody-Drug Conjugates (ADCs) hinge on enhanced analytical and bioanalytical characterization, particularly in assessing critical quality attributes (CQAs). The ADC's potency is largely determined by the average number of drugs attached to the monoclonal antibody (mAb), known as the drug-to-antibody ratio (DAR). Furthermore, the drug load distribution (DLD) influences the therapeutic window of the ADC, defining the range of dosages effective in treating diseases without causing toxic effects. Among CQAs, DAR and DLD are vital; their control is essential for ensuring manufacturing consistency and product quality. Typically, hydrophobic interaction chromatography (HIC) or reversed-phase liquid chromatography (RPLC) with UV detector have been used to quantitate DAR and DLD in quality control (QC) environment. Recently, Native size-exclusion chromatography-mass spectrometry (nSEC-MS) proves the potential as a platformable quantitative method for characterizing DAR and DLD across various cysteine-linked ADCs in research or early preclinical development. In this work, we established and assessed a streamlined nSEC-MS workflow with a benchtop LC-MS platform, to quantitatively monitor DAR and DLD of different chemotype and drug load level cysteine-linked ADCs. Moreover, to deploy this workflow in QC environment, complete method validation was conducted in three independent laboratories, adhering to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q2(R1) guidelines. The results met the predefined analytical target profile (ATP) and performance criteria, encompassing specificity/selectivity, accuracy, precision, linearity, range, quantification/detection limit, and robustness. Finally, the method validation design offers a reference for other nSEC-MS methods that are potentially used to determine the DAR and DLD on cysteine-linker ADCs. To the best of our knowledge, this study is the first reported systematic validation of the nSEC-MS method for detecting DAR and DLD. The results indicated that the co-validated nSEC-MS workflow is suitable for DAR and DLD routine analysis in ADC quality control, release, and stability testing.