Association of Perioperative Skeletal Muscle Index Change With Outcome in Colorectal Cancer Patients.

BACKGROUND: The association between perioperative changes in the skeletal muscle index (SMI) and colorectal cancer (CRC) outcomes remains unclear. We aim to explore perioperative change patterns of SMI and evaluate their effects on long-term outcomes in CRC patients. METHODS: This retrospective cohort study included Stage I-III CRC patients who underwent curative resection between 2012 and 2019. SMI at the third lumbar vertebra level was calculated using computed tomography scans. Optimal cut-off values for SMI were defined separately for males and females and classified as high or low preoperatively and at 3, 6, 9 and 12 months postoperatively. SMI status was further categorized into different perioperative SMI change patterns: highpre-highpost, highpre-lowpost, lowpre-highpost and lowpre-lowpost. The association with recurrence-free survival (RFS) and overall survival (OS) was examined using Cox proportional hazards models. RESULTS: A total of 2222 patients (median [interquartile range] age, 60.00 [51.00-68.00] years; 1302 (58.60%) men; 222 (9.99%) with preoperative low SMI) were evaluated. During a median follow-up of 60 months, 375 patients (16.88%) died, and 617 patients (27.77%) experienced a recurrence. Multivariate Cox model analysis showed that, compared to patients with highpre-highpost, those with highpre-lowpost (HR = 3.32, 95% CI: 1.60-6.51; HR = 2.54, 95% CI: 1.03-6.26; HR = 2.93, 95% CI: 1.19-7.19, all p < 0.05) had significantly worse RFS and OS (HR = 4.07, 95% CI: 1.55-10.69; HR = 4.78, 95% CI: 1.40-16.29; HR = 9.69, 95% CI: 2.53-37.05, all p < 0.05), at postoperative 6, 9 and 12 months, respectively. Patients with lowpre-lowpost were an independent prognostic factor for worse OS at postoperative 12 months (HR = 3.20, 95% CI: 1.06-9.71, p = 0.040). Patients with lowpre-highpost had similar risk of RFS compared to those with highpre-highpost at postoperative 3, 6 and 12 months (HR = 1.49, 95% CI: 0.75-2.98; HR = 1.05, 95% CI: 0.45-2.43; HR = 1.36, 95% CI: 0.31-6.06, all p > 0.05) and similar risk of OS at postoperative 3, 6, 9 and 12 months (all p > 0.05). CONCLUSIONS: Patients with a high preoperative SMI that decline postoperatively have poor RFS and OS. Consistently low SMI also correlates with worse OS. Patients with low SMI but increased after resection are not an indicator of better prognosis. Routine measurement of postoperative, rather than preoperative, SMI is warranted. Patients with low SMI are at an increased risk for recurrence and death, especially within the first year after surgery.

Neurophysiological markers of disease severity and cognitive dysfunction in major depressive disorder: A TMS-EEG study.

Background: Transcranial magnetic stimulation-electroencephalography (TMS-EEG) is a powerful technique to study the neuropathology and biomarkers of major depressive disorder (MDD). This study investigated cortical activity and its relationship with clinical symptoms and cognitive dysfunction in MDD patients by indexing TMS-EEG biomarkers in the dorsolateral prefrontal cortex (DLPFC). Methods: 133 patients with MDD and 76 healthy individuals participated in this study. Single-pulse TMS was performed on the left DLPFC to obtain TMS-evoked potential (TEP) indices. TMS-EEG waveforms and components were determined by global mean field amplitude. We used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to measure participants' cognitive function. Results: Patients with MDD had a lower excitatory P180 index compared to healthy controls, and P180 amplitude was negatively correlated with the severity of depressive and anxiety symptoms in patients with MDD. In the MDD group, P30 amplitude was negatively associated with RBANS Visuospatial/ Constructional index and total score. Conclusions: TMS-EEG findings suggest that abnormal cortical excitation and inhibition induced by TMS on the DLPFC are associated with the severity of clinical symptoms and cognitive dysfunction in patients with MDD. P180 and P30 have the potential to serve as neurophysiological biomarkers of clinical symptoms and cognitive dysfunction in MDD patients, respectively.

Chlamydia trachomatis induces low-frequency, sustained CD4 T cell responses in most women, predominantly targeting chlamydial protease-like activity factor, CPAF.

BACKGROUND: Chlamydia trachomatis (CT) is a globally prevalent sexually transmitted infection (STI) that can result in pelvic inflammatory disease, ectopic pregnancy and infertility in women. Currently, there is no prophylactic vaccine. METHODS: This study examined T cell immunity in a cohort of women recently infected with CT. Participants were screened against peptides spanning 33 of 894 possible CT proteins, either ex vivo or using short-term cell lines (STCL). CT-specific T cells were characterized by IFN-γ ELISpot and flow cytometry. RESULTS: Ex vivo CT-specific T cells were rarely detected; however, following in vitro expanded CT-specific T cells were detected by IFN-γ ELISpot in 90% (27/30) of participants. Notably, over 50% of participants had T cell responses targeting chlamydial protease-like activity factor (CPAF). T cell epitopes were dispersed across the CPAF protein. Flow cytometry analysis of STCL found CT-specific cells, were mainly CD4+, produced IFN-γ and TNF-α and were sustained over 12 months. Ex vivo analysis suggested CT-specific T cells mostly exhibited a central memory phenotype. CONCLUSION: Our results indicate that CT infection elicits low-frequency, persistent CD4 T cell responses in most women and that the secreted protein, CPAF, is an immunoprevalent CT antigen. Altogether, these data support development and testing of CT vaccines that enhance CD4 T cells against CPAF.

Osthole attenuates asthma-induced airway epithelial cell apoptosis and inflammation by suppressing TSLP/NF-κB-mediated inhibition of Th2 differentiation.

OBJECTIVE: The aim of this study was to investigate the influence of osthole (OS) on asthma-induced airway epithelial cell apoptosis and inflammation by restraining Th2 differentiation through suppressing TSLP/NF-κB. METHODS: An asthma mouse model and an inflammation cell model were constructed with ovalbumin (OVA) and lipopolysaccharide (LPS), respectively. CD4 + T cells were treated with IL-4 to induce Th2 differentiation. Model mice were treated with OS (15,40 mg/kg) for 7 days, and 10 µg/mL OS was added to cell treatment groups. The levels of relevant indices were detected by RT‒qPCR, HE and Masson staining, Western blotting, ELISA and flow cytometry. RESULTS: In a mouse asthma model, TSLP expression was elevated, and the NF-κB pathway was activated. Therefore, OS could restrain the apoptosis and inflammation of airway epithelial cells. Downstream mechanistic studies revealed that OS can suppress Th2 differentiation by restraining the level of TSLP and NF-κB nuclear translocation, thus facilitating the proliferation of airway epithelial cells, restraining their apoptosis and inflammation, and alleviating airway inflammation in asthmatic mice. CONCLUSION: OS can inhibit Th2 differentiation by inhibiting the TSLP and NF-κB pathways, which can reduce the apoptosis and inflammation of airway epithelial cells caused by asthma.

Pharmacokinetic/Pharmacodynamic modelling of Saxagliptin and its active metabolite, 5-hydroxy Saxagliptin in rats with Type 2 Diabetes Mellitus.

BACKGROUND AND PURPOSES: It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect. METHODS: First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX. RESULTS: A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal Emax model and sigmoidal Emax with E0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (Tmax=0.11 h, t1/2, ka=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC50, EC50, 5-OH SAX=0.46EC50, SAX(parent), it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature. CONCLUSIONS: The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.

A novel Anaerobic Cathodic Dynamic Membrane Bioreactor (AnCDMBR) for efficient mitigating fouling and recovering bioenergy from municipal wastewater.

Concerns regarding membrane fouling and suboptimal bioenergy recovery have constrained the implementation of anaerobic membrane bioreactor (AnMBR) for treating low-strength municipal wastewater. This study presents a novel anaerobic cathodic dynamic membrane bioreactor (AnCDMBR) designed to address these challenges. A self-formed cathodic dynamic membrane (CDM) on inexpensive carbon cloth was developed to function as both a membrane and biocathode to achieve dual-function effects of mitigating membrane fouling and accelerating organics conversion. Compared with common dynamic membrane (1.52 kPa/d) and commercial membranes (7.52 kPa/d), the developed CDM presented a significantly reduced fouling rate (1.02 kPa/d), exhibiting the potential as a substitute for high-cost conductive membranes. Furthermore, efficient and stable biomethanation occurred in AnCDMBR with a superior methane yield rate of 0.26 L-CH4/g-COD (CH4 content > 95 %), which was 1.42 times higher than the control, linked to the higher activities of microbial metabolism and methanogenic-related key enzymes. Further analysis revealed that electrostimulation-induced niche differentiation of microbiota regulated interspecies interactions between electroactive microorganisms and complex anaerobic digestion microbiomes, facilitating organic matter conversion to methane and leading to superior bioenergy recovery. This study offered a new strategy for effectively mitigating fouling and recovering bioenergy from low-strength wastewater, potentially expanding the application of AnMBRs.

Genome-wide investigation of the OR gene family in Helicoverpa armigera and functional analysis of OR48 and OR75 in metamorphosis development.

The cotton bollworm, Helicoverpa armigera, is a significant global agricultural pest, particularly detrimental during its larval feeding period. Insects' odorant receptors (ORs) are crucial for their crop-feeding activities, yet a comprehensive analysis of H. armigera ORs has been lacking, and the influence of hormones on ORs remain understudied. Herein, we conducted a genome-wide study and identified 81 ORs, categorized into 15 distinct groups. Analyses of protein motifs and gene structures revealed both conservation within groups and divergence among them. Comparative gene duplication analysis between H. armigera and Bombyx mori highlighted different duplication patterns. We further investigated subcellular localization and protein interactions within the odorant receptor family, providing valuable insights for future functional and interaction studies of ORs. Specifically, we identified that OR48 and OR75 were abundantly expressed during molting/metamorphosis and feeding stages, respectively. We demonstrated that 20E induced the upregulation of OR48 via EcR, while insulin upregulated OR75 expression through InR. Moreover, 20E induced the translocation of OR48 to the cell membrane, mediating its effects. Functional studies involving the knockdown of OR48 and OR75 revealed their roles in metamorphosis development, with OR48 knockdown resulting in delayed pupation and OR75 knockdown leading to premature pupation. OR48 can promote autophagy and apoptosis in fat body, while OR75 can significantly inhibit apoptosis and autophagy. These findings significantly contribute to our understanding of OR function in H. armigera and shed light on potential avenues for pest control strategies.

Hypopituitarism after gamma knife radiosurgery for pituitary adenomas: long-term results from a single-center experience.

OBJECTIVE: The aim of this study was to investigate the incidence and risk factors of new-onset hypopituitarism after gamma knife radiosurgery (GKRS) for pituitary adenomas in a single center. METHODS: In this retrospective study, 241 pituitary adenoma patients who underwent GKRS from 1993 to 2016 were enrolled. These patients had complete endocrine, imaging, and clinical data before and after GKRS. The median follow-up time was 56.0 (range, 12.7-297.6) months. RESULTS: Fifty patients (20.7%) developed new-onset hypopituitarism after GKRS, including hypogonadism (n = 22), hypothyroidism (n = 29), hypocortisolism (n = 20), and growth hormone deficiency (n = 4). The median time to new-onset hypopituitarism was 44.1 (range, 13.5-141.4) months. The rates of new-onset hypopituitarism were 7%, 16%, 20%, 39%, and 45% at 1, 3, 5, 10, and 15 years, respectively. For those patients treated with a single GKRS, sex (p = 0.012), suprasellar extension (p = 0.048), tumor volume (≥ 5 cm3) (p < 0.001), tumor progression (p = 0.001), pre-existing hypopituitarism (p = 0.011), and previous surgery (p = 0.009) were significantly associated with new-onset hypopituitarism in univariate analysis. In the multivariate analysis, tumor volume (≥ 5 cm3) and tumor progression were associated with new-onset hypopituitarism (hazard ratio [HR] = 3.401, 95% confidence interval [CI] = 1.708-6.773, p < 0.001 and HR = 3.594, 95% CI = 1.032-12.516, p = 0.045, respectively). For patients who received 2 or more times GKRS, no risk factors associated with new-onset hypopituitarism were found. CONCLUSION: New-onset hypopituitarism was not uncommon after GKRS for pituitary adenomas. In this study, large tumor volume (≥ 5 cm3) and tumor progression were associated with new-onset hypopituitarism after a single GKRS.

Amide proton transfer-weighted MRI for assessing rectal adenocarcinoma T-staging and perineural invasion: a prospective study.

OBJECTIVE: To investigate the value of the pre-operative amide proton transfer-weighted (APTw) MRI to assess the prognostic factors in rectal adenocarcinoma (RA). METHODS: This prospective study ran from January 2022 to September 2023 and consecutively enrolled participants with RA who underwent pre-operative MRI and radical surgery. The APTw signal intensity (SI) values of RA with various tumor (T), node (N) stages, perineural invasion (PNI), and tumor grade were compared by Mann-Whitney U-test or t-test. The receiver operating characteristic curve was used to evaluate the diagnostic performance of the APTw SI values. RESULTS: A total of 51 participants were enrolled (mean age, 58 years ± 10 [standard deviation], 26 men). There were 24 in the T1-T2 stage and 9 with positive PNI. The APTw SI max, 99th, and 95th values were significantly higher in T3-T4 stage tumor than in T1-T2; the median (interquartile range) (M (IQR)) was (4.0% (3.6-4.9%) vs 3.4% (2.9- 4.3%), p = 0.017), (3.7% (3.2-4.1%) vs 3.2% (2.8-3.8%), p = 0.013), and (3.3% (2.8-3.8%) vs 2.9% (2.3-3.5%), p = 0.033), respectively. These indicators also differed significantly between the PNI groups, with the M (IQR) (4.5% (3.6-5.7%) vs 3.7% (3.2-4.2%), p = 0.017), (4.1% (3.4-4.8%) vs 3.3% (3.0-3.9%), p = 0.022), and (3.7% (2.7-4.2%) vs 2.9% (2.6-3.5%), p = 0.045), respectively. CONCLUSION: Pre-operative APTw MRI has potential value in the assessment of T-staging and PNI determination in RA. CLINICAL RELEVANCE STATEMENT: Pre-operative amide proton transfer-weighted MRI provides a quantitative method for noninvasive assessment of T-staging and PNI in RA aiding in precision treatment planning. KEY POINTS: The efficacy of APTw MRI in RA needs further investigation. T3-T4 stage and PNI positive APTw signal intensities were higher than T1-T2 and non-PNI, respectively. APTw MRI provides a quantitative method for assessment of T staging and PNI in RA.