One-step high-speed thermal-electric aerosol printing of piezoelectric bio-organic films for wirelessly powering bioelectronics.

Piezoelectric biomaterials hold a pivotal role in the progression of bioelectronics and biomedicine, owing to their remarkable electromechanical properties, biocompatibility, and bioresorbability. However, their technological potential is restrained by certain challenges, including precise manipulation of nanobiomolecules, controlling their growth across nano-to-macro hierarchy, and tuning desirable mechanical properties. We report a high-speed thermal-electric driven aerosol (TEA) printing method capable of fabricating piezoelectric biofilms in a singular step. Electrohydrodynamic aerosolizing and in situ electrical poling allow instantaneous tuning of the spatial organization of biomolecular inks. We demonstrate TEA printing of ß-glycine/polyvinylpyrrolidone films, and such films exhibit the piezoelectric voltage coefficient of 190 × 10-3 volt-meters per newton, surpassing that of industry-standard lead zirconate titanate by approximately 10-fold. Furthermore, these films demonstrate nearly two orders of magnitude improvement in mechanical flexibility compared to glycine crystals. We also demonstrate the ultrasonic energy harvesters based on the biofilms, providing the possibility of wirelessly powering bioelectronics.

Antibacterial activity and mechanism of colistin-loaded polymeric nanoparticles for combating multidrug-resistant Pseudomonas aeruginosa biofilms: A synergistic approach.

Multidrug-resistant P. aeruginosa (MDR-P. aeruginosa), associated with elevated morbidity, mortality, and readmission rates, presents a formidable challenge to eradication due to its robust resistance to antimicrobial agents and biofilm formation. Herein, self-assembling nanoparticles (NO-PE/PLL NPs) comprised of NO donor-conjugated γ-polyglutamic acid (GSNO-PGA), epsilon-poly-l-lysine (PLL) and colistin were fabricated. The negatively charged NO-PE/PLL NPs exhibited effective penetration through airway mucus, reaching the infection site where GSNO-PGA released NO in response to glutathione within biofilm. PLL worked synergistically with colistin (fractional inhibitory concentration index: 0.281), reducing the minimum inhibitory concentration (MIC) of colistin from 2 to 0.5 µg/mL. Benefiting from this synergistic antibacterial action and NO-mediated biofilm disruption, NO-PE/PLL NPs achieved a 99.99 % eradication rate against MDR-P. aeruginosa biofilms. Additionally, NO-PE/PLL NPs efficiently inhibited endotoxins-stimulated inflammation response. In a chronic pulmonary infection model, NO-PE/PLL NPs displayed the highest eradication efficiency (99.78 %) to infected mice, while having no adverse effects on their major organs or pulmonary functions. These results highlight NO-PE/PLL NPs as a promising therapeutic strategy for treating recalcitrant infections caused by MDR-P. aeruginosa biofilms.

Bioaerosols and VOC emissions from landfill leachate treatment processes: Regional differences and health risks.

The landfill leachate treatment process (LLTP) is a crucial anthropogenic source of bioaerosols and volatile organic compounds (VOCs) with potential environmental impacts and on-site health risks to plant workers. However, factors influencing microbial aerosol and VOC emissions remain poorly understood. We sampled and analyzed bioaerosols and VOCs in two process sections (oxidation ditch [OD] and reverse osmosis membrane [RO]) of LLTPs in northern (NLF) and southern (SLF) China. Bioaerosol concentrations were highest in OD, and particle size predominantly ranged from 0.654.7 µm. Microbial community analysis revealed distinct differences between geographical locations and process sections, with 332 genera identified. Genera such as Paenibacillus, Bacillus, and Pseudomonas were prevalent at all sampling sites. Oxygen-containing compounds (e.g., acetophenone and propionic acid) were the dominant VOCs, particularly in SLF-OD. Network analysis showed complex interactions, with Sphingomonas and ketones playing central roles in microbial and VOC communities, respectively. Partial least squares (PLS) modeling indicated a significant correlation between bioaerosols and VOCs. Specific microorganisms, such as TK10, Adhaeribacter, and Lachnospiraceae, were major contributors to emissions of hazardous VOCs (e.g., toluene and styrene). The ozone-generation potential and olfactory effect of the OD were significantly higher than those of RO; and those of SLF were higher than those of NLF. Health risk assessments indicated potential chronic toxicity and cancer risks associated with VOC exposure to specific compounds, such as trichloroethylene. Bioaerosol exposure occurred primarily through inhalation, particularly in male workers. This study establishes a theoretical foundation for the prevention and control of air-phase pollutant risks associated with LLTPs.

Transcriptomic Analysis Reveals Dynamics of Gene Expression in Liver Tissue of Spotted Sea Bass Under Acute Thermal Stress.

The spotted sea bass (Lateolabrax maculatus), a eurythermal species, exhibits strong adaptability to temperature variations and presents an ideal model for studying heat stress-responsive mechanisms in fish. This study examined the liver transcriptome of spotted sea bass over a 24-h period following exposure to elevated temperatures, rising from 25 to 32 °C. The results revealed significant alterations in gene expression in response to this thermal stress. Specifically, we identified 1702, 1199, 3128, and 2636 differentially expressed genes at 3, 6, 12, and 24 h post-stress, respectively. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify specific gene modules responsive to heat stress, containing hub genes such as aco2, eci2, h6pd, suclg1, fgg, fga, fgb, f2, and apoba, which play central roles in the heat stress response. Enrichment analyses via KEGG and GSEA indicated that upregulated differentially expressed genes (DEGs) are predominantly involved in protein processing in the endoplasmic reticulum, while downregulated genes are primarily associated with the AGE-RAGE signaling pathways. Additionally, 272 genes exhibited differential alternative splicing, primarily through exon skipping, underscoring the complexity of transcriptomic adaptations. These findings provide deeper insights into the molecular responses to thermal stress and are crucial for advancing the breeding of heat-resistant strains of spotted sea bass.

Diffusion behavior and environmental impact of odorants and TVOCs detected in a wastewater treatment plant for collaborative leachate treatment in Northwest China.

Wastewater treatment plants (WWTPs) are major sources of volatile gaseous compounds, especially in mixed-source systems such as domestic wastewater and landfill leachate. This study aimed to investigate the emission behavior and environmental impact of gaseous substances, such as hydrogen sulfide (H2S), ammonia (NH3), carbon sulfide (CS2), and phosphine (PH3), at a WWTP in Northwest China. Odorants were detected in the air surrounding the grid room (XGS), biochemical treatment tank (SHC), secondary sedimentation tank (ECC), and sludge dewatering room (NTS). For comparison, the upwind boundary (O-SF) and downwind boundaries (O-XF) monitoring points were used, with odor concentrations ranging from 3.95 to 725.27 odor units. The concentration ranges of the odorant substances were 5.27-88.69, 5.61-71.96, 5.70-32.63, and 0.12-5.87 mg/m3 for H2S, NH3, CS2, and PH3, respectively. Meteorological factors such as temperature, relative humidity, and wind speed and direction substantially influence odorant emissions. The concentrations of various odorants and volatile organic compounds (VOCs) detected at the O-XF monitoring point were higher than those detected at the O-SF monitoring point, indicating that the wind intensified their diffusion toward the downwind plant boundary. The average odor intensities of odorant substances emitted from wastewater or sludge treatment equipment were 3.37, 5.09, 4.42, 2.00, and 3.82 for total VOCs, H2S, NH3, CS2, and PH3, respectively. Among them four, with downwind diffusion, only H2S presented olfactory and chronic toxicity risks based on Gaussian plume model calculations. The hazard index ranking across monitoring sites was XGS > NTS > SHC > ECC > O-XF > O-SF. These findings emphasize the urgent need for effective measures to control and mitigate gaseous pollutants emitted by collaborative WWTPS, thereby protecting environmental quality and public health.

Characteristics, treatment, and outcomes of spontaneous renal artery dissection: a 10-year retrospective single-center experience.

Background: Spontaneous renal artery dissection (SRAD) is a rare cause of renal failure and renovascular hypertension, with the diagnosis often being delayed and treatment varying across different centers. The objective of this retrospective cohort study was to scrutinize the characteristics, treatment modalities, and outcomes of patients with SRAD at our center over the past ten years. Furthermore, the study sought to identify the most suitable treatment options for different categories of patients with SRAD. Methods: Data from 21 consecutive patients who presented with symptoms of SRAD from December 2013 to December 2023 were collected. Lesion characteristics, treatment options, blood pressure (BP) control, serum creatinine and estimated glomerular filtration rate (eGFR) were analyzed. A paired t-test was used for comparisons of BP, serum creatinine, and eGFR. An independent samples t-test was used to analyze baseline BP and BP change in different treatment groups. Results: The mean age, weight, and height of patients with SRAD was 49.2±13.0 (range, 18-69) years, 69.0±9.7 (range, 50-80) kg, and 1.7±0.1 (range 1.6-1.8) m, respectively. New-onset hypertension was found in 8 (38.1%) patients. Renal artery dissecting aneurysm and renal artery stenosis were found in 1 (4.8%) and 4 (19.0%) patients, respectively. Supportive medical treatment alone, endovascular intervention, and nephrectomy were required in 15, 4 and 2 cases, respectively. Stable renal function and satisfactory hypertension control were obtained in all treatment groups, with a median follow-up of 18.1 (range, 12-32) months. Conclusions: Medical management is a reasonable choice in most patients with SRAD. Interventional management is an efficacious strategy for the management of renovascular hypertension and the preservation of renal function.

Current status and prospect of gut and oral microbiome in pancreatic cancer: Clinical and translational perspectives.

Pancreatic cancer is a highly lethal malignancy, and its diagnosis and treatment continue to pose significant challenges. Despite advancements in surgical and comprehensive treatment methods, the five-year survival rate remains below 12 %. With the rapid development of microbiome science, the gut and oral microbiota, which are readily accessible and can be sampled non-invasively, have emerged as a novel area of interest in pancreatic cancer research. Dysbiosis in these microbial communities can induce persistent inflammatory responses and affect the host's immune system, promoting cancer development and impacting the efficacy of treatments like chemotherapy and immunotherapy. This review provides an up-to-date overview of the roles of both gut and oral microbiota in the onset, progression, diagnosis, and treatment of pancreatic cancer. It analyzes the potential of utilizing these microbiomes as biomarkers and therapeutic targets from a clinical application perspective. Furthermore, it discusses future research directions aimed at harnessing these insights to advance the diagnosis and treatment strategies for pancreatic cancer. By focusing on the microbiome's role in clinical and translational medicine, this review offers insights into improving pancreatic cancer diagnosis and treatment outcomes.

Intratumoral CXCL13+ CD160+ CD8+ T cells promote the formation of tertiary lymphoid structures to enhance the efficacy of immunotherapy in advanced gastric cancer.

BACKGROUND: Stage IV gastric cancer is a highly heterogeneous and lethal tumor with few therapeutic strategies. The combination of programmed cell death protein 1 inhibitors and chemotherapy is currently the standard frontline treatment regimen for advanced gastric cancer. Nevertheless, it remains a great challenge to screen the beneficiaries of immunochemotherapy and expand indications for this treatment regimen. METHODS: We conducted a pathological assessment to ascertain the importance of tertiary lymphoid structures based on the tissue samples collected from patients with stage IV gastric cancer (n=15) both prior to and following immunochemotherapy treatment. Additionally, we used spatial (n=10) and single-cell transcriptional analysis (n=97) to investigate the key regulators of tertiary lymphoid structures (TLSs). Multiplex immunofluorescence and image analysis (n=34) were performed to explore the association between tumor-infiltrating CXCL13+ CD160+ CD8+ T cells and TLSs. The relationship between CXCL13+ CD160+ CD8+ T cells and the responsiveness to immunotherapy was also evaluated by multiplex immunofluorescence and image analysis approaches (n=15). Furthermore, we explored the intrinsic characteristics of CXCL13+ CD160+ CD8+ T cells through various experimental techniques, including quantitative reverse transcription-PCR, western blot, and flow cytometry. RESULTS: We found that responders exhibited higher levels of TLSs and CXCL13+ CD160+ CD8+ T cells in biopsy tissues prior to immunochemotherapy compared with non-responders. Following conversion therapy, responders also had a higher percentage of mature TLSs and a higher number of CXCL13+ CD160+ CD8+ T cells in surgical resections. Moreover, we discovered that vitamin B6 in CD160+ CD8+ T cells could reduce the ubiquitination modification of HIF-1α by MDM2, thereby attenuating the degradation of HIF-1α. Consequently, this led to the transcriptional upregulation of CXCL13 expression, facilitating the recruitment of CXCR5+ B cells and the formation of TLSs. CONCLUSION: The number and maturity of TLSs, along with the extent of CXCL13+ CD160+ CD8+ T-cell infiltration, might function as potential indicators for assessing the effectiveness of immunotherapy in treating gastric malignancies. Furthermore, our research suggests that vitamin B6 could enhance the secretion of CXCL13 by CD160+ CD8+ T cells by reducing the degradation of HIF-1α. Additionally, we demonstrate that vitamin B6 supplementation or targeting pyridoxal kinase could substantially improve the efficacy of immunotherapies for gastric cancer.

Exploiting branched-chain amino acid metabolism and NOTCH3 expression to predict and target colorectal cancer progression.

Background: The interplay between colon adenocarcinoma (COAD) and branched-chain amino acid (BCAA) metabolism is not fully understood, presenting a crucial area for investigation. Methods: We developed a prognostic model based on BCAA metabolism using the least absolute shrinkage and selection operator (LASSO) regression algorithm. We employed qRT-PCR and Western blot analyses to examine NOTCH3 expression in COAD tissues versus adjacent non-cancerous tissues and various cell lines. We also investigated the impact of NOTCH3 on COAD cell proliferation, invasion, and migration through in vitro and in vivo experiments. Results: Our BCAA metabolism-related signature (BRS) distinguished between different immune features, tumor mutation burdens, responses to immunotherapy, and drug sensitivity among COAD patients. NOTCH3 was found to be overexpressed in COAD, promoting tumor growth as verified through various assays. The model effectively predicted COAD prognosis and patient responses to treatments, underscoring the potential of BCAA pathways as therapeutic targets. Conclusion: The BRS is instrumental in predicting the prognosis and therapeutic response in COAD, with NOTCH3 playing a significant role in the proliferation, invasion and migration of COAD. These findings suggest that targeting BCAA metabolism and NOTCH3 could advance COAD treatment strategies.

Causal Relationships of Circulating Inflammatory Proteins and Portal Vein Thrombosis: A Mendelian Randomization Study.

Portal vein thrombosis (PVT) is commonly encountered in patients with cirrhosis, challenging our understanding of its development, particularly the ambiguous contribution of inflammation. This study utilized Mendelian randomization (MR) to explore the causal impact of circulating inflammatory markers on PVT.Employing a two-sample MR framework, we merged genome-wide association study (GWAS) meta-analysis findings of 91 inflammation-associated proteins with independent PVT data from the FinnGen consortium's R10 release. A replication analysis was performed using a distinct GWAS dataset from the UK Biobank. Inverse variance weighting, MR-Egger regression, weighted median estimator, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier were used for analysis, supplemented by multivariable MR (MVMR) to adjust for cirrhosis effects.Findings indicate a significant inverse association between the genetically inferred concentration of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and PVT risk, evidenced by an odds ratio (OR) of 0.37 (95% confidence interval [CI]: 0.21-0.67; p = 9.2 × 10-4; adjusted for multiple testing p = 0.084). This association was corroborated in the replication phase (OR = 0.39, 95% CI: 0.17-0.93; p = 0.03) and through MVMR analysis (OR = 0.34, 95% CI: 0.15-0.79; p = 0.012). Sensitivity analyses disclosed no evidence of heterogeneity or pleiotropy.Our investigation emphasizes the 4E-BP1 as a protective factor against PVT, underscoring its potential relevance in understanding PVT pathogenesis and its implications for diagnosis and therapy.

Comparisons of laparoscopic and robotic pancreaticoduodenectomy using barbed and conventional sutures for pancreaticojejunostomy: a propensity score matching study.

BACKGROUND: There are limited data on the effect of different sutures and surgical approaches on the quality of pancreaticojejunostomy in minimally invasive pancreaticoduodenectomy (MIPD). This study compares the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) between the use of barbed sutures (BSs) and conventional sutures (CSs). METHODS: A retrospective cohort study was conducted on 253 consecutive patients who had undergone MIPD from July 2016 to April 2023. Patients were excluded if conversion to open surgery or open anastomosis was necessary. 220 patients were enrolled and divided into BS (n = 148) and CS (n = 72) groups. After 1:1 propensity score matching (PSM), 67 cases remained in each group. Univariate and multivariate analyses identified factors associated with CR-POPF. Comparisons were also made between laparoscopic (LPD) and robotic (RPD) pancreaticoduodenectomy. RESULTS: After PSM, BSs were associated with significantly lower rates of CR-POPF (7.5 vs. 22.4%, P = 0.015) and severe complications (Clavien-Dindo ≥ III) (7.5vs. 19.4%, P = 0.043). No significant differences were found in operative time, length of postoperative hospital stay, or other major morbidities. Multivariate analyses revealed BMI ≥ 22 kg/m2 (OR = 5.048, 95% CI: 1.256-20.287, P = 0.023) and the use of BSs (OR = 0.196, 95% CI: 0.059-0.653, P = 0.008) as the independent predictors of CR-POPF. There were no significant differences in postoperative outcomes between the LPD and RPD groups, but RPD was associated with significantly shorter operative time (402.8 min vs. 429.4 min, P = 0.015). CONCLUSIONS: In conclusion, using BSs for PJ during MIPD is feasible and has the potential to reduce CR-POPF and severe complications.

A bibliometric analysis of follicular thyroid carcinoma: Current situation, hot spots, and global trends.

BACKGROUND: Follicular thyroid carcinoma (FTC), the second most prevalent thyroid cancer after papillary thyroid cancer (PTC), tends to metastasize distantly, leading to poorer outcomes. Despite substantial research, a holistic bibliometric analysis of FTC literature is lacking. This study aims to fill this gap by employing bibliometric methods to track FTC research evolution. METHODS: English FTC publications were systematically gathered from the Web of Science. Bibliometric analysis, using R, VOSviewer, CiteSpace, and Excel, synthesized data and explored global research trends and topics. RESULTS: From 2000 to 2023, 9086 authors from 1953 institutions across 75 countries contributed to 1776 papers in 491 academic journals on FTC. The last two decades have witnessed a steady increase in publications related to FTC, with the United States leading in terms of publication volume. The United States dominated both in publications and citations, with the National Cancer Institute and Sheue-Yann Cheng as leading contributors. The journal 'Thyroid' featured the most publications, while the 'Journal of Clinical Endocrinology and Metabolism' ranked highest in citation frequency. Research focused on gene expression analysis and preoperative diagnostics, with recent trends shifting toward prognosis management and machine learning due to advances in medical technology and increased health awareness. CONCLUSION: This comprehensive bibliometric analysis has mapped the landscape of FTC research, highlighting key contributors, institutions, and thematic trends. Current discourse predominantly revolves around genetic analysis, prognostic determinants, and preoperative diagnostics in FTC. This foundational work guides future FTC research, providing insights into its evolution.

Structure-function interrelationships and associated neurotransmitter profiles in drug-naïve benign childhood epilepsy with central-temporal spikes patients.

OBJECTIVES: To explore the interrelationships between structural and functional changes as well as the potential neurotransmitter profile alterations in drug-naïve benign childhood epilepsy with central-temporal spikes (BECTS) patients. METHODS: Structural magnetic resonance imaging (sMRI) and resting-state functional MRI data from 20 drug-naïve BECTS patients and 33 healthy controls (HCs) were acquired. Parallel independent component analysis (P-ICA) was used to identify covarying components among gray matter volume (GMV) maps and fractional amplitude of low-frequency fluctuations (fALFF) maps. Furthermore, we explored the spatial correlations between GMV/fALFF changes derived from P-ICA and neurotransmitter maps in JuSpace toolbox. RESULTS: A significantly positive correlation (p < 0.001) was identified between one structural component (GMV_IC6) and one functional component (fALFF_IC4), which showed significant group differences between drug-naïve BECTS patients and HCs (GMV_IC6: p < 0.01; fALFF_IC4: p < 0.001). GMV_IC6 showed increased GMV in the frontal lobe, temporal lobe, thalamus, and precentral gyrus as well as fALFF_IC4 had enhanced fALFF in the cerebellum in drug-naïve BECTS patients compared to HCs. Moreover, significant correlations between GMV alterations in GMV_IC6 and the serotonin (5HT1a: p < 0.001; 5HT2a: p < 0.001), norepinephrine (NAT: p < 0.001) and glutamate systems (mGluR5: p < 0.001) as well as between fALFF alterations in fALFF_IC4 and the norepinephrine system (NAT: p < 0.001) were detected. CONCLUSION: The current findings suggest co-altered structural/functional components that reflect the correlation of language and motor networks as well as associated with the serotonergic, noradrenergic, and glutamatergic neurotransmitter systems. CLINICAL RELEVANCE STATEMENT: The relationship between anatomical brain structure and intrinsic neural activity was evaluated using a multimodal fusion analysis and neurotransmitters which might provide an important window into the multimodal neural and underlying molecular mechanisms of benign childhood epilepsy with central-temporal spikes. KEY POINTS: Structure-function relationships in drug-naïve benign childhood epilepsy with central-temporal spikes (BECTS) patients were explored. The interrelated structure-function components were found and correlated with the serotonin, norepinephrine, and glutamate systems. Co-altered structural/functional components reflect the correlation of language and motor networks and correlate with the specific neurotransmitter systems.

The Effect of Rifapentine and Rifampicin on Serum Voriconazole Levels Persist for 5 Days and 7 Days or More After Discontinuation in Tuberculosis Patients with Chronic Pulmonary Aspergillosis.

Purpose: Voriconazole, a first-line therapeutic agent for chronic pulmonary aspergillosis, is metabolized by the cytochrome 450 enzymes, specifically CYP2C19 and CYP3A4. Rifampicin and rifapentine act as inducers of the cytochrome P450 enzyme. The current study explored the potential drug interactions arising from the co-administration of voriconazole with either rifampicin or rifapentine, as well as the duration of this effect on serum voriconazole levels after discontinuation of rifampicin or rifapentine. Patients and Methods: A retrospective study was conducted in tuberculosis patients with chronic pulmonary aspergillosis. These patients underwent a combination therapy involving voriconazole and rifampicin or rifapentine, or they were treated with voriconazole after discontinuation of rifampicin or rifapentine. The serum concentrations of voriconazole at steady-state were monitored. Data on demographic characteristics and the serum voriconazole levels were used for statistical analyses. Results: A total of 124 serum voriconazole concentrations from 109 patients were included in the study. The average serum concentration of voriconazole fell below the effective therapeutic range in patients treated with both voriconazole and rifampicin or rifapentine. Notably the co-administration of rifapentine led to a substantial (>70%) decrease in serum voriconazole levels in two patients. Moreover, this interfering effect persisted for at least 7 days following rifampicin discontinuation, while it endured for 5 days or more after discontinuation of rifapentine. Conclusion: Concomitant use of voriconazole and rifampicin or rifapentine should be avoided, and it is not recommended to initiate voriconazole therapy within 5 or 7 days after discontinuation of rifapentine or rifampicin. Therapeutic drug monitoring not only provides a basis for the adjustment of clinical dose, but also serves as a valuable tool for identifying drug interactions.

Adeno-associated-virus-mediated delivery of CRISPR-CasRx induces efficient RNA knockdown in the mouse testis.

Rationale: In male mammals, many developmental-stage-specific RNA transcripts (both coding and noncoding) are preferentially or exclusively expressed in the testis, where they play important roles in spermatogenesis and male fertility. However, a reliable platform for efficiently depleting various types of RNA transcripts to study their biological functions during spermatogenesis in vivo has not been developed. Methods: We used an adeno-associated virus serotype nine (AAV9)-mediated CRISPR-CasRx system to knock down the expression of exogenous and endogenous RNA transcripts in the testis. Virus particles were injected into the seminiferous tubules via the efferent duct. Using an autophagy inhibitor, 3-methyladenine (3-MA), we optimized the AAV9 transduction efficiency in germ cells in vivo. Results: AAV9-mediated delivery of CRISPR-CasRx effectively and specifically induces RNA transcripts (both coding and noncoding) knockdown in the testis in vivo. In addition, we showed that the co-microinjection of AAV9 and 3-MA into the seminiferous tubules enabled long-term transgene expression in the testis. Finally, we found that a promoter of Sycp1 gene induced CRISPR-CasRx-mediated RNA transcript knockdown in a germ-cell-type-specific manner. Conclusion: Our results demonstrate the efficacy and versatility of the AAV9-mediated CRISPR-CasRx system as a flexible knockdown platform for studying gene function during spermatogenesis in vivo. This approach may advance the development of RNA-targeting therapies for conditions affecting reproductive health.

In vivo detection of the epimer metabolites of sweroside via ultra-performance liquid chromatography time-of-flight mass spectrometry combined with DNPH derivatization.

The metabolites of sweroside were first investigated in vivo with ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS) in combination with 2,4-dinitrophenylhydrazine derivatization. In addition, the mass detection sensitivity of the major metabolites, epinaucledal and naucledal, via UPLC-TOF-MS was significantly enhanced, and the epimer metabolites were distinctly discovered from plasma following gavage of sweroside in rats. The plasma concentration of epinaucledal and naucledal was quantified via UPLC-TOF-MS in negative mode using erythrocentaurin as the internal standard. The maximum mean plasma concentrations of naucledal and epinaucledal were 75.36 ± 20.10 and 43.52 ± 15.60 ng/ml within 2 h, respectively, following gavage of sweroside at 20 mg/kg. Moreover, the area under the concentration-time curve of naucledal was three times that of epinaucledal. The metabolic process of conversion of sweroside to epinaucledal and naucledal was deduced, and the pharmacological effects of epinaucledal and naucledal will clarify the clinical efficacy of sweroside.

Efficacy of Whole-Brain Radiotherapy Plus Simultaneous Integrated Boost (SIB-WBRT) for Lung Cancer Brain Metastases.

Objective: To investigate the outcomes of SIB-WBRT in patients with brain metastases and analyze the impact of some factors on prognosis. Materials and Methods: This single-arm retrospective study analyzed patients with brain metastases who were treated with SIB-WBRT at Peking Union Medical College Hospital from September 2015 to December 2021. The primary endpoint was intracranial progression free survival (iPFS). Secondary endpoints included overall survival (OS), intracranial new foci, and tumor control. The Kaplan-Meier method was then used to depict and estimate iPFS, OS, intracranial neoplasia, and tumor control. Finally, the Cox model was used to analyze the association between some relevant factors and outcomes. Results: A total of 107 patients were included and the median iPFS in these patients treated with SIB-WBRT was 13.4 (95% CI: 4.2-22.6) months, with 68.0% (95% CI: 57.4%-78.6%) and 50.8% (95% CI: 38.3%-63.3%) iPFS at 6- and 12-months. The median local control was 37.6 (95% CI: 28.3-46.8) months, with local control rates of 84.3% (95% CI: 80.6%-88.0%) and 73.3% (95% CI: 68.2%-78.4%) at 6- and 12-months. The median time to appearance of new intracranial foci was 17.4 (95% CI: 14.1-20.8) months, and the 6- and 12-month control rates were 74.5% (95% CI: 64.5%-84.5%) and 61.5% (95% CI: 49.0%-74.0%). The number of brain metastases in patients before treatment was significantly associated with iPFS (HR=0.4, 95% CI: 0.2-0.973, P=0.043). Conclusions: The iPFS, local control, and intracranial new foci of patients with brain metastases after treatment with SIB-WBRT were acceptable. In addition, the number of brain metastases in patients before treatment may be associated with iPFS.

Leptin-mediated suppression of lipoprotein lipase cleavage enhances lipid uptake and facilitates lymph node metastasis in gastric cancer.

BACKGROUND: Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process. METHODS: Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation. RESULTS: We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis. CONCLUSIONS: Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.

Learning curve of robotic pancreatoduodenectomy by a single surgeon with extensive laparoscopic pancreatoduodenectomy experience.

With the development of robotic systems, robotic pancreatoduodenectomies (RPDs) have been increasingly performed. However, the number of cases required by surgeons with extensive laparoscopic pancreatoduodenectomy (LPD) experience to overcome the learning curve of RPD remains unclear. Therefore, we aimed to analyze and explore the impact of different phases of the learning curve of RPD on perioperative outcomes. Clinical data were prospectively collected and retrospectively analyzed for 100 consecutive patients who underwent RPD performed by a single surgeon. This surgeon had previous experience with LPD, having performed 127 LPDs with low morbidity. The learning curve for RPD was analyzed using the cumulative sum (CUSUM) method based on operation time, and perioperative outcomes were compared between the learning and proficiency phases. Between April 2020 and November 2022, one hundred patients (56 men, 44 women) were included in this study. Based on the CUSUM curve of operation time, the learning curve for RPD was divided into two phases: phase I was the learning phase (cases 1-33) and phase II was the proficiency phase (cases 34-100). The operation time during the proficiency phase was significantly shorter than that during the learning phase. In the learning phase of RPD, no significant increases were observed in estimated blood loss, conversion to laparotomy, severe complications, postoperative pancreatic hemorrhage, clinical pancreatic fistula, or other perioperative complications compared to the proficiency phases of either RPD or LPD. A surgeon with extensive prior experience in LPD can safely surmount the RPD learning curve without increasing morbidity in the learning phase. The proficiency was significantly improved after accumulating experience of 33 RPD cases.

Robotic Versus Laparoscopic Pancreaticoduodenectomy for Pancreatic Cancer: Evaluation and Analysis of Surgical Efficacy.

BACKGROUND: Evidence is limited for the treatment of pancreatic cancer among minimally invasive pancreatoduodenectomy. METHODS: This retrospective analysis evaluated patients who underwent robotic pancreaticoduodenectomy (RPD) or laparoscopic pancreaticoduodenectomy (LPD) from April 2016 to April 2023. Their baseline and perioperative data, including operative time, R0 resection rates, and severe complications rates, were analyzed, and the follow-up data, such as disease-free survival (DFS) and overall survival (OS), were collected. RESULTS: A total of 253 cases of LPD and RPD were performed, and 101 cases with pancreatic cancer were included, of which 54 were LPD and 47 were RPD. The conversion rate (4.3% vs. 29.6%, p = 0.001) and blood loss (400 vs. 575 mL, p < 0.05) were lower in the RPD group. No significant difference was observed between the two groups in terms of operative time, vessel resection rates, and TNM-stage diagnosis; however, R0 resection rates (80.9% vs. 70.4%) and lymph node harvest (24.2 vs. 21.9) had a higher tendency in the RPD group, and postoperative length of stay was shorter in the RPD cohort (11 vs. 13 days). Moreover, improved 1- to 3-years DFS (75.7%, 61.7%, and 36.0% vs. 59.0%, 35.6%, and 21.9%) and OS (94.7%, 84.7%, and 50.8% vs. 84.1%, 63.6%, and 45.5%) was found in the RPD group in comparison with the LPD group. CONCLUSIONS: RPD had advantages in surgical safety and oncological outcomes compared with LPD, but was similar to the latter in perioperative outcomes. Long-term outcomes require further study.