Investigating on the Performance and Mechanism of Poly(styrene-methyl methacrylate-ethyl methacrylate-butyl acrylate) as Nano Sealing Agent in Oil-Based Drilling Fluids.

Conventional micron sealants are unable to effectively seal nanopores and fractures in shale formations, and the development of new nanomaterials has now become a major research focus to address the instability of shale gas wells. In this paper, oil-based drilling fluids (ODFs) sealants named SMEB (poly(styrene-methyl methacrylate-ethyl methacrylate-butyl acrylate)) were synthesized by free radical polymerization. The SMEB has been characterized by Fourier transform infrared spectroscopy (FTIR), laser scattering analysis (LSA), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). The effect of SMEB on the rheological properties of drilling fluids was evaluated by assessing the changes in the rheological parameters of ODFs before and after aging. In addition, the sealing performance of SMEB in ODFs was investigated by high-temperature, high-pressure (HTHP) fluid loss tests and HTHP dense core permeability tests. The results indicated that the particle size of SMEB ranged from 60.68 to 157.39 nm, with a median size of 89.62 nm. The initial decomposition temperature of SMEB was 334 °C, which was in line with the requirement of high-temperature resistance for materials used in shale gas wells. The addition of SMEB has minimal effect on the rheological properties of the drilling fluids and did not adversely affect its performance. At 150 °C and 3.5 MPa, the sealing efficiency of the simulated mud cake was 59.69% with a measured permeability of 0.77 × 10-4 mD at a concentration of 0.5 wt % SMEB. Additionally, when 0.5 wt % SMEB was applied to artificial cores at 105 °C and 3.5 MPa, the sealing efficiency was as high as 86.70%, and the corresponding permeability was 0.48 × 10-3 mD. SMEB demonstrated excellent sealing capabilities in both simulated mud cake and artificial cores, reducing and preventing drilling fluids filtrate flow into the formation. Therefore, SMEB can be applied to drilling fluids as a novel sealing agent and make a significant contribution to maintaining wellbore stability.

Safety and efficacy of consolidative stereotactic radiotherapy for oligo-residual EGFR-mutant non-small cell lung cancer after first-line third-generation EGFR-tyrosine kinase inhibitors: a single-arm, phase 2 trial.

Background: Prospective data is limited on the efficacy and safety of consolidative stereotactic radiotherapy (SRT) in metastatic epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients harboring oligo-residual disease (ORD) after first-line third-generation EGFR-tyrosine kinase inhibitors (TKIs). Methods: In this single-arm, phase II trial, 61 patients from two academic centers were enrolled from March 2021 to March 2023. All these patients had metastatic EGFR-mutant NSCLC and harbored ORD after first-line third-generation EGFR-TKIs. Consolidative SRT was performed and EGFR-TKIs were not held during SRT. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included overall survival and treatment-related adverse events (TRAEs). A prespecified propensity score matched (PSM) comparison was conducted with a contemporary cohort of patients who developed ORD but received EGFR-TKIs alone. This trial was registered with ClinicalTrails.gov, NCT04764214. Findings: All patients received consolidative SRT. With a median follow-up of 21.1 months, the median PFS was 29.9 (80% CI 22.4-32.4) months and the lower boundary exceeded the predefined threshold, meeting the primary endpoint. TRAEs occurred in 43 (70%) patients, with pneumonitis (27.9%) and esophagitis (26.2%) being the most common toxicities. Four patients (6.6%) reported grade ≥3 TRAEs, each for pneumonitis, esophagitis, leukopenia, and cranial radiation necrosis. PSM analysis showed significantly prolonged PFS in EGFR-TKI + SRT group compared to EGFR-TKI group (HR 0.46, 80% CI 0.20-0.61; p = 0.002). Interpretation: Consolidative SRT is associated with an encouraging PFS in first-line third-generation EGFR-TKI-treated metastatic NSCLC patients harboring ORD, with generally acceptable toxicities. Further confirmatory studies are warranted. Funding: Hui Lan Public Welfare and the Chinese Society of Clinical Oncology Foundation.

Feasibility of fractal dimension analysis for left ventricular trabecular complexity using cardiac computed tomography.

AIMS: To evaluate the consistency between fractal dimensions (FD) derived from cardiac computed tomography (CT-FD) and cardiac magnetic resonance (MR-FD) in assessing left ventricular trabecular complexity. METHODS: This retrospective study included 170 patients who underwent CCT and CMR scans within two weeks. Five short-axis cine images were selected at end-diastole: one basal, three mid, and one apical slice. Short-axis CCT views were reconstructed and aligned with the cine images. CT-FD and MR-FD values were calculated for each slice, with mean values determined for each patient. Severe left ventricular hypertrophy (LVH) was defined as a maximum wall thickness > 15 mm in end-diastolic cine images. RESULTS: The diastolic CT-FD and MR-FD values exhibited high consistency, with values of 1.253 ± 0.091 and 1.250 ± 0.102, respectively (n = 535, ICC = 0.882, 95 % CI: 0.861-0.899, P < 0.001). Similarly, the systolic CT-FD and MR-FD values demonstrated good consistency, with values of 1.268 ± 0.072 and 1.286 ± 0.093, respectively (n = 390, ICC = 0.720, 95 % CI: 0.669-0.765, P < 0.001). For subgroups of systolic NLVH and LVH, the ICCs were 0.773 (n = 305, CI: 0.723-0.814, P < 0.001) and 0.565 (n = 85, 95 % CI: 0.402-0.694, P < 0.001), respectively. The diagnostic efficacy of mean CT-FD aligned with that of mean MR-FD in distinguishing abnormal cardiac conditions from the CMR-negative group. CONCLUSIONS: CCT is a feasible method for assessing left ventricular trabecular complexity, with good agreement with CMR, except in cases of severe left ventricular hypertrophy during systole.

Biomechanical Study of Atlanto-occipital Instability in Type II Basilar Invagination: A Finite Element Analysis.

OBJECTIVE: Recent studies indicate that 3 morphological types of atlanto-occipital joint (AOJ) exist in the craniovertebral junction and are associated with type II basilar invagination (BI) and atlanto-occipital instability. However, the actual biomechanical effects remain unclear. This study aims to investigate biomechanical differences among AOJ types I, II, and III, and provide further evidence of atlanto-occipital instability in type II BI. METHODS: Models of bilateral AOJ containing various AOJ types were created, including I-I, I-II, II-II, II-III, and III-III models, with increasing AOJ dysplasia across models. Then, 1.5 Nm torque simulated cervical motions. The range of motion (ROM), ligament and joint stress, and basion-dental interval (BDI) were analyzed. RESULTS: The C0-1 ROM and accompanying rotational ROM increased progressively from model I-I to model III-III, with the ROM of model III-III showing increases between 27.3% and 123.8% indicating ultra-mobility and instability. In contrast, the C1-2 ROM changes were minimal. Meanwhile, the stress distribution pattern was disrupted; in particular, the C1 superior facet stress was concentrated centrally and decreased substantially across the models. The stress on the C0-1 capsule ligament decreased during cervical flexion and increased during bending and rotating loading. In addition, BDI gradually decreased across the models. Further analysis revealed that the dens showed an increase of 110.1% superiorly and 11.4% posteriorly, indicating an increased risk of spinal cord impingement. CONCLUSION: Progressive AOJ incongruity critically disrupts supportive tissue loading, enabling incremental atlanto-occipital instability. AOJ dysplasia plays a key biomechanical role in the pathogenesis of type II BI.

Comparison of pathologic response and survival outcomes between neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant immunochemotherapy (nICT) in patients with locally advanced esophageal squamous cell carcinoma: a propensity score-matched analysis.

BACKGROUND: In locally advanced, operable esophageal squamous cell carcinoma (ESCC), neoadjuvant immunochemotherapy (nICT) has shown results that are somewhat comparable to those of standard neoadjuvant chemoradiotherapy (nCRT). The impact of these neoadjuvant treatments on survival outcomes, however, has yet to be elucidated. METHODS: This study included 489 patients with locally advanced ESCC who underwent surgery at Sichuan Cancer Hospital after receiving neoadjuvant treatment between June 2017 and September 2023. Patients were categorized into nCRT and nICT groups based on whether they received neoadjuvant treatment. To mitigate potential biases and balance covariates between the two cohorts, 1:2 propensity score matching (PSM) was conducted using a caliper width of 0.05. RESULTS: After PSM, the baseline characteristics of the 360 patients remained balanced between the two groups. The findings indicated a superior pathological response in the nCRT group, as evidenced by significantly greater rates of complete response (32.87% vs 14.58%, P < 0.001) and favorable tumor regression grade (TRG), as well as reduced ypT stages and less perineural and angioinvasion, despite comparable ypN stages. Despite the improvement in complete pathological response (pCR) in the nCRT group, the 3-year disease-free survival (DFS) and overall survival (OS) rates did not significantly differ between the groups (DFS: 58.32% vs 56.16%, P = 0.67; OS: 69.96% vs 71.99%, P = 0.99). Crucially, The nICT group showed a lower incidence of grade 3 and 4 adverse events in Leukopenia (2.8% vs 29%; P < 0.001) and Neutropenia (2.8% vs 24%; P < 0.001) during neoadjuvant treatment, comparing with nCRT group. CONCLUSIONS: Our preliminary findings suggest that nICT followed by surgery offers comparable survival rates to nCRT, despite being less effective in pathologic outcomes. Nonetheless, nICT is a safe and feasible strategy for locally advanced ESCC, warranting further exploration to understand its impact on long-term survival.

Bifunctional mesoporous HMUiO-66-NH2 nanoparticles for bone remodeling and ROS scavenging in periodontitis therapy.

Periodontal bone defects represent an irreversible consequence of periodontitis associated with reactive oxygen species (ROS). However, indiscriminate removal of ROS proves to be counterproductive for tissue repair and insufficient for addressing existing bone defects. In the treatment of periodontitis, it is crucial to rationally alleviate local ROS while simultaneously promoting bone regeneration. In this study, Zr-based large-pore hierarchical mesoporous metal-organic framework (MOF) nanoparticles (NPs) HMUiO-66-NH2 were successfully proposed as bifunctional nanomaterials for bone regeneration and ROS scavenging in periodontitis therapy. HMUiO-66-NH2 NPs demonstrated outstanding biocompatibility both in vitro and in vivo. Significantly, these NPs enhanced the osteogenic differentiation of bone mesenchymal stem cells (BMSCs) under normal and high ROS conditions, upregulating osteogenic gene expression and mitigating oxidative stress. Furthermore, in vivo imaging revealed a gradual degradation of HMUiO-66-NH2 NPs in periodontal tissues. Local injection of HMUiO-66-NH2 effectively reduced bone defects and ROS levels in periodontitis-induced C57BL/6 mice. RNA sequencing highlighted that differentially expressed genes (DEGs) are predominantly involved in bone tissue development, with notable upregulation in Wnt and TGF-ß signaling pathways. In conclusion, HMUiO-66-NH2 exhibits dual functionality in alleviating oxidative stress and promoting bone repair, positioning it as an effective strategy against bone resorption in oxidative stress-related periodontitis.

Developing filamentous fungal chassis for natural product production.

The growing demand for green and sustainable production of high-value chemicals has driven the interest in microbial chassis. Recent advances in synthetic biology and metabolic engineering have reinforced filamentous fungi as promising chassis cells to produce bioactive natural products. Compared to the most used model organisms, Escherichia coli and Saccharomyces cerevisiae, most filamentous fungi are natural producers of secondary metabolites (SMs) and possess an inherent pre-mRNA splicing system and abundant biosynthetic precursors. In this review, we summarize recent advances in the application of filamentous fungi as chassis cells. Emphasis is placed on strategies for developing a filamentous fungal chassis, including the establishment of mature genetic manipulation and efficient genetic tools, the catalogue of regulatory elements, and the optimization of endogenous metabolism. Furthermore, we provide an outlook on the advanced techniques for further engineering and application of filamentous fungal chassis.

Computed tomography-based radiomics nomogram for prediction of lympho-vascular and perineural invasion in esophageal squamous cell cancer patients: a retrospective cohort study.

PURPOSE: Lympho-vascular invasion (LVI) and perineural invasion (PNI) have been established as prognostic factors in various types of cancers. The preoperative prediction of LVI and PNI has the potential to guide personalized medicine strategies for patients with esophageal squamous cell cancer (ESCC). This study investigates whether radiomics features derived from preoperative contrast-enhanced CT could predict LVI and PNI in ESCC patients. METHODS AND MATERIALS: A retrospective cohort of 544 ESCC patients who underwent esophagectomy were included in this study. Preoperative contrast-enhanced CT images, pathological results of PNI and LVI, and clinical characteristics were collected. For each patient, the gross tumor volume (GTV-T) and lymph nodes volume (GTV-N) were delineated and four categories of radiomics features (first-order, shape, textural and wavelet) were extracted from GTV-T and GTV-N. The Mann-Whitney U test was used to select significant features associated with LVI and PNI in turn. Subsequently, radiomics signatures for LVI and PNI were constructed using LASSO regression with ten-fold cross-validation. Significant clinical characteristics were combined with radiomics signature to develop two nomogram models for predicting LVI and PNI, respectively. The area under the curve (AUC) and calibration curve were used to evaluate the predictive performance of the models. RESULTS: The radiomics signature for LVI prediction consisted of 28 features, while the PNI radiomics signature comprised 14 features. The AUCs of the LVI radiomics signature were 0.77 and 0.74 in the training and validation groups, respectively, while the AUCs of the PNI radiomics signature were 0.69 and 0.68 in the training and validation groups. The nomograms incorporating radiomics signatures and significant clinical characteristics such as age, gender, thrombin time and D-Dimer showed improved predictive performance for both LVI (AUC: 0.82 and 0.80 in the training and validation group) and PNI (AUC: 0.75 and 0.72 in the training and validation groups) compared to the radiomics signature alone. CONCLUSION: The radiomics features extracted from preoperative contrast-enhanced CT of gross tumor and lymph nodes have demonstrated their potential in predicting LVI and PNI in ESCC patients. Furthermore, the incorporation of clinical characteristics has shown additional value, resulting in improved predictive performance.

Magnetically targeted lidocaine sustained-release microspheres: optimization, pharmacokinetics, and pharmacodynamic radius of effect.

OBJECTIVE: This study aimed to optimize the formulation of magnetically targeted lidocaine microspheres, reduce the microsphere particle size, and increase the drug loading and encapsulation rate of lidocaine. The optimized microspheres were characterized, and their pharmacokinetics and effective radii of action were studied. METHODS: The preparation of magnetically targeted lidocaine microspheres was optimized using ultrasonic emulsification-solvent evaporation. The Box-Behnken design method and response surface method were used for optimization. The optimized microspheres were characterized and tested for their in vitro release. Blood concentrations were analyzed using a non-compartment model, and the main pharmacokinetic parameters (half-life (t1/2 ), maximum blood concentration, area under the blood concentration-time curve (AUC), time to peak (Tmax ), and mean retention time (MRT) were calculated. Pathological sections were stained to study the safety of the microsphere tissues. A rabbit sciatic nerve model was used to determine the "standard time (t0 )" and effective radius of the microspheres. RESULTS: The optimized lidocaine microspheres exhibited significantly reduced particle size and increased drug loading and encapsulation rates. Pharmacokinetic experiments showed that the t1/2 , Tmax , and MRT of magnetically targeted lidocaine microspheres were significantly prolonged in the magnetic field, and the AUC0-48 and AUC0-∞ were significantly decreased. Its pharmacodynamic radius was 31.47 mm. CONCLUSION: Magnetically targeted lidocaine microspheres provide sustained long-lasting release, neurotargeting, nerve blocking, and high tissue safety. This preparation has a significantly low blood concentration and a slow release in vivo, which can reduce local anesthetic entry into the blood. This may be a novel and effective method for improving postoperative comfort and treating chronic pain. This provides a countermeasure for exploring the size of the magnetic field for the application of magnetic drug-carrying materials.

Evaluating the stage of deep vein thrombosis: the diagnostic accuracy of shear wave elastography and super-microvascular imaging.

Background: Assessing the age of deep vein thrombosis (DVT) is crucial for guiding treatment approaches. Two-dimensional shear-wave elastography (2D-SWE) and super-microvascular imaging (SMI), as emerging techniques for tissue elasticity assessment and intrathrombus microvascular analysis, are pivotal for accurate thrombus age determination. This research endeavors to classify DVT into acute, subacute, and chronic ages utilizing these imaging methods. Methods: The study is a prospective, single-center, inpatient investigation that utilized convenience sampling for participant recruitment. Patients with a symptom duration of <6 months who were found to have lower-extremity DVT on ultrasound (US) between January 2021 and March 2022 after craniocerebral trauma (CT) or bone injury (BI) operations were included in this study. Participants were divided into three groups based on the duration of DVT, measured from the first diagnosis of thrombosis by US to the follow-up with 2D-SWE and SMI: acute (≤14 days), subacute (15-30 days), and chronic (31 days to 6 months) All patients underwent 2D-SWE and SMI using an Aplio i700 Ultrasound System equipped with a PLT-1005BT line array probe. Diagnostic performance was assessed using the area under the receiver operating characteristic (ROC) curve. Results: The maximum value of the elastic modulus for DVT (DVT_Emax), the mean value of the elastic modulus for DVT (DVT_Emean), and SMI's flow distribution scoring pattern for DVT (SMI_scoring) emerged as significant predictors for acute and chronic, with high area under the ROC curve (AUC) of acute [AUC (95% confidential interval): 0.95 (0.89-0.97), 0.96 (0.91-0.98), 0.93 (0.88-0.97) in 39 patients] and chronic [AUC (95% confidential interval): 0.88 (0.81-0.93), 0.94 (0.88-0.97), 0.91 (0.84-0.95) in 51 patients], respectively. However, these indices had lower efficacy for subacute prediction [AUC (95% confidential interval): 0.51 (0.42-0.60), 0.54 (0.46-0.63), 0.53 (0.44-0.62), in 47 patients]. Combining DVT_Emean with SMI_scoring improved performance in predicting subacute: 0.90 (0.83-0.94) than related features alone. Conclusions: Both 2D-SWE and SMI can be used to assess acute and chronic DVT in patients with CT and BI after surgeries. This combination is a promising adjunctive technique for identifying the subacute phase of DVT in these patients.

Assessing the efficacy and quality of Life improvements of botulinum toxin type a with topical minoxidil versus topical minoxidil in male androgenetic alopecia: a randomized controlled trial.

Androgenetic alopecia (AGA) is a common type of hair loss in men and efficacy and safety of current medical treatment remain limited. Therefore, the present study aimed to investigate the efficacy and safety of botulinum toxin type A (BTA) combined with Minoxidil in patients with AGA. 60 male patients were included in this study and control group received topical 5% Minoxidil and the treatment group received BTA combined with topical 5% Minoxidil. BTA injections (60-70 U) were administered at 30-35 scalp sites. Head photographs were taken at baseline, 2nd, 4th, and 6th months. Clinical descriptions recorded scalp conditions, and patient satisfaction along with Dermatology Life Quality Index scores were documented. The treatment group (TG) showed significant hair growth differences compared to the control group (CG) at the 4th month (P < 0.001) and 6th month (P = 0.0046) post-treatment. TG had improved Investigator Global Assessment (IGA) scores in the 4th month (P = 0.0001) and 6th month (P = 0.0259) compared to CG. Patient satisfaction in TG for hair growth and scalp improvement was higher than CG (all P < 0.05). TG exhibited substantial quality of life improvement at the 4-month (P = 0.0009) and 6-month (P = 0.0099). No adverse reactions were observed post-botulinum toxin injection. BTA combined with Minoxidil effectively promotes hair growth, enhances the quality of life, and alleviates scalp symptoms in male AGA patients at 4th and 6th months, with no adverse effects compared to Minoxidil alone.Trial registration number: Ethics Committee of Shanghai Tongji Hospital (ID: K-2018-026).

Characterization and application of Bacillus velezensis D6 co-producing α-amylase and protease.

BACKGROUND: Research on the co-production of multiple enzymes by Bacillus velezensis as a novel species is still a topic that needs to be studied. This study aimed to investigate the fermentation characteristics of B. velezensis D6 co-producing α-amylase and protease and to explore their enzymatic properties and applications in fermentation. RESULTS: The maximum co-production of α-amylase and protease reached 13.13 ± 0.72 and 2106.63 ± 64.42 U mL-1, respectively, under the optimal fermented conditions (nutrients: 20.0 g L-1 urea, 20.0 g L-1 glucose, 0.7 g L-1 MnCl2; incubation conditions: initial pH 7.0, temperature 41 °C, 8% inoculation size and 30% working volume). Moreover, the genetic co-expression of α-amylase and protease increased from 0 to 24 h and then decreased after 36 h at the transcriptional level, which coincided with the growth trend of B. velezensis D6. The optimal reaction temperature of α-amylase was 55-60 °C, while that of protease was 35-40 °C. The activities of α-amylase and protease were retained by over 80% after thermal treatment (90 °C, 1 h), which indicated that two enzymes co-produced by B. velezensis D6 demonstrated excellent thermal stability. Moreover, the two enzymes were stable over a wide pH range (pH 4.0-8.0 for α-amylase; pH 4.0-9.0 for protease). Finally, the degrees of hydrolysis of corn, rice, sorghum and soybeans by α-amylase from B. velezensis D6 reached 44.95 ± 2.95%, 57.16 ± 2.75%, 52.53 ± 4.01% and 20.53 ± 2.42%, respectively, suggesting an excellent hydrolysis effect on starchy raw materials. The hydrolysis degrees of mackerel heads and soybeans by protease were 43.93 ± 2.19% and 26.38 ± 1.72%, respectively, which suggested that the protease from B. velezensis D6 preferentially hydrolyzed animal-based protein. CONCLUSION: This is a systematic study on the co-production of α-amylase and protease by B. velezensis D6, which is crucial in widening the understanding of this species co-producing multi-enzymes and in exploring its potential application. © 2024 Society of Chemical Industry.

Spatial heterogeneity of per- and polyfluoroalkyl substances caused by glacial melting in Tibetan Lake Nam Co due to global warming.

Per- and polyfluoroalkyl substances (PFASs) in high-latitude polar regions and the Tibetan Plateau have received widespread international attention. Here, we measured 18 PFASs and 11 major isomers in the lake water, sediment, and surrounding runoff of Lake Nam Co in 2020. The concentrations of ultrashort-chain trifluoroacetic acid (TFA) and perfluoropropanoic acid (PFPrA) and major isomers of perfluoooctanoic acid (PFOA) and perfluoooctane sulfonate acid (PFOS) in water bodies in high-latitude polar regions and the Tibetan Plateau are reported for the first time. The results showed that the concentration of ∑PFASs in glacial runoff was approximately 139 % greater than that in nonglacial runoff. The concentrations of ∑PFASs in the lake water and sediment in the southern lake with multiple glacial runoff events were approximately 113 % and 108 % higher, respectively, than those in the northern lake. The concentrations of short-chain perfluorobutanoic acid (PFBA) and ultrashort-chain TFA and PFPrA, which may be indicators of ice and snow melt, exhibited significant spatial heterogeneity. Overall, the spatial heterogeneity of PFAS concentrations in the water, sediment and surrounding runoff of Lake Nam Co may be caused mainly by glacial melting.

Triple digital guides for implant-supported restorations with alveoloplasty procedure in the esthetic zone.

OBJECTIVE: The principal aim of this report is to address the challenge of integrating prosthetic crowns with natural dentition in the esthetic zone. It highlights the utilization of a prosthetically driven treatment plan, designed to ensure predictable esthetic outcomes. CLINICAL CONSIDERATIONS: This report details a technique that utilizes three digital guides, all derived from a 3-dimensional digital smile design. The integration of a restoration guide, an implant drilling guide, and an alveoloplasty guide is described. These tools collectively facilitate the precise execution of both surgical and prosthetic procedures, enhancing treatment accuracy and esthetic integration. CONCLUSIONS: This technique considers the esthetic prosthetic crowns, implant positions, and alveoloplasty collectively. It enhances the predictability of esthetic outcomes in oral implantology and potentially provides an integrated prosthetically driven workflow in cosmetic dental treatments. CLINICAL SIGNIFICANCE: The application of multiple digital guides derived from the same prosthetically driven treatment significantly enhances the predictability of esthetic outcomes in oral implantology.

Activating α7nAChR suppresses systemic inflammation by mitigating neuroinflammation of the medullary visceral zone in sepsis in a rat model.

Our previous studies have shown that activating α7nAChRs suppresses systemic inflammation and immunity through the cholinergic anti-inflammatory pathway (CAP) in early sepsis. Now that the medullary visceral zone (MVZ) is the center of CAP and responsible for regulating systemic inflammation, what changes will occur in MVZ's pathology and function in sepsis, especially when interfering with α7nAChRs? Does activation of MVZ's α7nAChRs contribute to the inhibition of systemic inflammation? To clarify these issues, we explored the systemic inflammation and immunity state by detecting serum levels of TNF-α, IL-6, HMGB1, sCD14, and CD4+CD25+Treg and TH17 lymphocytes percentage, meanwhile, we analyzed the apoptosis of cholinergic and catecholaminergic neurons and the expressions of tyrosine hydroxylase (TH) and choline acetyltransferase (CHAT) in MVZ in sepsis and the interfering effects on α7nAChRs. In this study, we found that in sepsis, serum TNF-α, IL-6, HMGB1, sCD14, CD4+CD25+Treg, and TH17 lymphocytes significantly increased and the ratio of Treg/TH17 significantly decreased, cholinergic and catecholaminergic neurons underwent apoptosis with low expressions of TH and CHAT in MVZ; activation of α7nAChRs not only significantly decreased the levels of septic serum TNF-α, IL-6, HMGB1, sCD14, and TH17 lymphocytes (P ＜ 0.05), but also significantly reduced cholinergic and catecholaminergic neurons' apoptosis, and promoted expressions of TH/CHAT. Our study reveals that sepsis undermines MVZ through neuroinflammation which contributes to the uncontrolled systemic inflammation. Activating central α7nAChRs is not only helpful to restore MVZ's structure and function but also beneficial to subside the inflammatory storm in sepsis. Even if MVZ is damaged in sepsis, cholinergic neurons in MVZ still regulate the systemic inflammation stably.

Long-term outcomes of smoker and drinker with oesophageal squamous cell carcinoma after oesophagectomy: a large-scale propensity score matching analysis.

BACKGROUND: Oesophageal squamous cell carcinoma (OSCC) poses a considerable health burden, particularly in regions such as East Asia. This study aims to investigate the long-term outcomes of OSCC patients who are smokers and drinkers. MATERIALS AND METHODS: In this retrospective analysis, data from Sichuan Cancer Hospital and Institute Esophageal Cancer Case Management Database between January 2010 and December 2017 were examined. Patients were categorised into different groups based on their smoking and alcohol consumption history: None, Smoker, Non-Smoker, Smoke-Only, Drinker, Non-Drinker, Drinker-Only, and Both. Survival outcomes were compared between the groups using Kaplan-Meier analysis and propensity score matching (PSM). The primary outcome was overall survival (OS), measured from surgery to death or last follow-up in April 2022. RESULTS: The OS median was 45.4 months for all patients after oesophagectomy. Smokers had a significantly lower median OS of 36.6 months compared with Non-Smokers with 66.2 months (p<0.001). Similarly, Drinkers had a lower median OS of 34.4 months compared with Non-Drinkers with 52.0 months (p<0.001). PSM analysis confirmed the significant differences in OS between Smokers and Non-Smokers (p=0.002) and between Drinkers and Non-Drinkers (p=0.002). Subgroup analyses showed no significant differences in OS between Group Another and Group Both, Group Smoker-Only and Group Drinker-Only, and Group Drinker-Only and Group Both. (figure 4) CONCLUSION: Smoking and drinking were associated with significantly reduced OS in patients. However, no significant differences were found between the subgroups of patients who only smoked, only drank, or engaged in both habits.

Analysis of genomic copy number variations through whole-genome scan in Yunling cattle.

Yunling cattle is a new breed of beef cattle bred in Yunnan Province, China, which has the advantages of fast growth, excellent meat quality, improved tolerance ability, and important landscape value. Copy number variation (CNV) is a significant source of gene structural variation and plays a crucial role in evolution and phenotypic diversity. Based on the latest reference genome ARS-UCD2.0, this study analyzed the genome-wide distribution of CNVs in Yunling cattle using short-read whole-genome sequencing data (n = 129) and single-molecule long-read sequencing data (n = 1), and a total of 16,507 CNVs were detected. After merging CNVs with overlapping genomic positions, 3,728 CNV regions (CNVRs) were obtained, accounting for 0.61% of the reference genome. The functional analysis indicated significant enrichment of CNVRs in 96 GO terms and 57 KEGG pathways, primarily related to cell adhesion, signal transduction, neuromodulation, and nutritional metabolism. Additionally, 111 CNVRs overlapped with 76 quantitative trait loci (QTLs), including Subcutaneous fat thickness QTL, Longissimus muscle area QTL, and Marbling score QTL. Several CNVR-overlapping genes, including BZW1, AOX1, and LOC100138449, overlap with regions associated with meat color and quality QTLs. Furthermore, Vst analysis showed that PSMB4, ERICH1, SMC2, and PPP4R3A were highly divergent between Yunling and Brahman cattle. In summary, we have constructed the genomic CNV map of Yunling cattle for the first time using whole-genome resequencing. This provides valuable genetic variation resources for the study of the Yunling cattle genome and contributes to the study of economic traits in Yunling cattle.

Reduction in chemotherapy relative dose intensity decreases overall survival of neoadjuvant chemoradiotherapy in patients with locally advanced esophageal carcinoma.

BACKGROUND: Many patients undergo dose reduction or early termination of chemotherapy to reduce chemoradiotherapy-related toxicity, which may increase their risk of survival. However, this strategy may result in underdosing patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This study aimed to analyze the relationship between the relative dose intensity (RDI) and survival outcomes in patients with LA-ESCC. METHODS: This retrospective study assessed patients with LA-ESCC (cT2N + M0, cT3-4NanyM0) receiving neoadjuvant chemoradiotherapy (NCRT) with curative-intent esophagectomy. The patients received 2 courses of paclitaxel plus carboplatin (TC) combination radiotherapy prior to undergoing surgery. During NCRT, RDI was computed, defined as the received dose as a percentage of the standard dose, and the incidence of dose delays was estimated (≥ 7 days in any course cycle). The best RDI cutoff value (0.7) was obtained using ROC curve. The Kaplan-Meier survival curves were compared using the log-rank test, the treatment effect was measured using hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: We included 132 patients in this study, divided into RDI < 0.7 and RDI ≥ 0.7 groups using cut-off value of 0.7. RDI grade was an independent prognostic factor for OS. Baseline demographic and clinical characteristics were well balanced between the groups. There was no evidence that patients with RDI < 0.7 experienced less toxicity or those with RDI ≥ 0.7 resulted in more toxicity. However, patients with RDI < 0.7 who were given reduced doses had a worse overall survival [HR 0.49, 95% CI 0.27-0.88, P = 0.015]. The risk of a lower RDI increased with a longer dose delay time (P < 0.001). CONCLUSION: The RDI below 0.7 for avoiding chemoradiotherapy toxicity administration led to a reduction in the dose intensity of treatment and decreased overall survival.

Evidence for sustainably reducing secondary pollutants in a typical industrial city in China: Co-benefit from controlling sources with high reduction potential beyond industrial process.

Under China's strict industrial control measures, the reduction of secondary pollutants (O3 and secondary organic aerosols [SOA]) and precursors (volatile organic compounds [VOCs] and NOx) caused by industrial processes has encountered bottlenecks. In this study, the net O3 formation rate (Net [O3]) in summer and the self-reaction rate between peroxy radicals (Self-Rnxs) in winter are used to characterize the formation potentials of O3 and SOA, respectively. Assuming that the precursor reduction ratio based on emission inventories is approximately equal to that based on observed concentrations, this study combines emission inventory and observation-based model (OBM) methods to indicate the potential source of secondary pollutants reduction. The findings show that strict control measures implemented by local governments, particularly those targeting industrial processes and fossil fuel combustion, are effective in reducing VOCs and NOx emissions during summer, and the two sources result in 3.8 % and 5.3 % decrease in the Net (O3), respectively. Similarly, control measures focusing on industrial processes help to significantly reduce VOCs emissions during winter, resulting in an 8.0 % decrease in Self-Rnxs. However, current measures for industrial processes are stringent and have little potential for further reduction. Therefore, additional sources with higher reduction potentials beyond industrial processes should be subject to stringent controls in industrial cities. Given the limited emission reduction potential associated with industrial processes, this study provides perspectives for sustained reduction of secondary pollutants in industrial cities.

Toripalimab plus chemotherapy and radiotherapy for treatment-naive advanced esophageal squamous cell carcinoma: a single-arm phase 2 trial.

This single-arm phase 2 trial (ChiCTR2100046715) examined previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) who received four cycles of paclitaxel with carboplatin every 3 weeks. Toripalimab was infused intravenously every 3 weeks for 12 months, or until disease progression or intolerable toxicity. Radiotherapy that encompassed the primary lesions and metastases commenced in the third cycle. The median progression-free survival time was 9.8 months (95% confidence interval [CI]: 6.8-not estimable) in the intent-to-treat population, failing to meet the pre-specified primary endpoints. Secondary endpoints included an objective response rate of 45.5%, a disease control rate of 57.6%, and a median duration of response of 11.5 months (interquartile range, 6.4-15.0). The 1-year progression-free survival and overall survival rates were 41.9% (95% CI: 27.7-63.5) and 69.7% (95% CI: 55.7-87.3), respectively. Lymphopenia was the most frequent grade ≥3 adverse event (82%), and an esophageal fistula developed in three patients (9.1%). No treatment-related deaths occurred. In prespecified exploratory biomarker analysis, higher densities of CD8 + T cells, CD11c+ dendritic cells, and CD68+ macrophages correlated with improved tumor response and prognosis. Radiotherapy supplementation to first-line chemo-immunotherapy for treatment-naive advanced ESCC demonstrated some antitumor activity and manageable safety profiles, warranting further randomized controlled trials.