Preoperative systemic inflammatory response index as a prognostic marker for distal cholangiocarcinoma after pancreatoduodenectomy.

BACKGROUND: The relationship between preoperative inflammation status and tumorigenesis as well as tumor progression is widely acknowledged. AIM: To assess the prognostic significance of preoperative inflammatory biomarkers in patients with distal cholangiocarcinoma (dCCA) who underwent pancreatoduodenectomy (PD). METHODS: This single-center study included 216 patients with dCCA after PD between January 1, 2011, and December 31, 2022. The individuals were categorized into two sets based on their systemic inflammatory response index (SIRI) levels: A low SIRI group (SIRI < 1.5, n = 123) and a high SIRI group (SIRI ≥ 1.5, n = 93). Inflammatory biomarkers were evaluated for predictive accuracy using receiver operating characteristic curves. Both univariate and multivariate Cox proportional hazards analyses were performed to estimate SIRI for overall survival (OS) and recurrence-free survival (RFS). RESULTS: The study included a total of 216 patients, with 58.3% being male and a mean age of 65.6 ± 9.6 years. 123 patients were in the low SIRI group and 93 were in the high SIRI group after PD for dCCA. SIRI had an area under the curve value of 0.674 for diagnosing dCCA, showing better performance than other inflammatory biomarkers. Multivariate analysis indicated that having a SIRI greater than 1.5 independently increased the risk of dCCA following PD, leading to lower OS [hazard ratios (HR) = 1.868, P = 0.006] and RFS (HR = 0.949, P < 0.001). Additionally, survival analysis indicated a significantly better prognosis for patients in the low SIRI group (P < 0.001). CONCLUSION: It is determined that a high SIRI before surgery is a significant risk factor for dCCA after PD.

Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma.

E1A binding protein (p300) is a promising therapeutic target for the treatment of cancer. Herein, we report the discovery of a series of novel inhibitors with an (S)-3-fluoropyrrolidin-2-one scaffold targeting p300 bromodomain. The best compound 29 (CZL-046) shows potent inhibitory activity of p300 bromodomain (IC50 = 3.3 nM) and antiproliferative activity in the multiple myeloma (MM) cell line (OPM-2 IC50 = 51.5 nM). 29 suppressed the mRNA levels of c-Myc and IRF4 and downregulated the expression of c-Myc and H3K27Ac. Compared to the lead compound 5, 29 exhibits significantly improved in vitro and in vivo metabolic properties. Oral administration of 29 with 30 mg/kg achieved a TGI value of 44% in the OPM-2 xenograft model, accompanied by good tolerability. The cocrystal structure of CREB binding protein bromodomain with 29 provides an insight into the precise binding mode. The results demonstrate that 29 is a promising p300 bromodomain inhibitor for the treatment of MM.

Tailoring the Li+ Intercalation Energy of Carbon Nanocage Anodes Via Atomic Al-Doping for High-Performance Lithium-Ion Batteries.

Graphitic carbon materials are widely used in lithium-ion batteries (LIBs) due to their stability and high conductivity. However, graphite anodes have low specific capacity and degrade over time, limiting their application. To meet advanced energy storage needs, high-performance graphitic carbon materials are required. Enhancing the electrochemical performance of carbon materials can be achieved through boron and nitrogen doping and incorporating 3D structures such as carbon nanocages (CNCs). In this study, aluminum (Al) is introduced into CNC lattices via chemical vapor deposition (CVD). The hollow structure of CNCs enables fast electrolyte penetration. Density functional theory (DFT) calculations show that Al doping lowers the intercalation energy of Li+. The Al-boron (B)-nitrogen (N-doped CNC (AlBN-CNC) anode demonstrates an ultrahigh rate capacity (≈300 mAh g-1 at 10 A g-1) and a prolonged fast-charging lifespan (862.82 mAh g-1 at 5 A g-1 after 1000 cycles), surpassing the N-doped or BN-doped CNCs. Al doping improves charging kinetics and structural stability. Surprisingly, AlBN-CNCs exhibit increased capacity upon cycling due to enlarged graphitic interlayer spacing. Characterization of graphitic nanostructures confirms that Al doping effectively tailors and enhances their electrochemical properties, providing a new strategy for high-capacity, fast-charging graphitic carbon anode materials for next-generation LIBs.

Continuous Theta Burst Stimulation Inhibits Oxidative Stress-Induced Inflammation and Autophagy in Hippocampal Neurons by Activating Glutathione Synthesis Pathway, Improving Cognitive Impairment in Sleep-Deprived Mice.

Sleep deprivation (SD) has been reported to have a negative impact on cognitive function. Continuous theta burst stimulation (cTBS) shows certain effects in improving sleep and neurological diseases, and its molecular or cellular role in SD-induced cognition impairment still need further exploration. In this study, C57BL/6 mice were subjected to 48 h of SD and cTBS treatment, and cTBS treatment significantly improved SD-triggered impairment of spatial learning and memory abilities in mice. Additionally, cTBS reduced malondialdehyde levels, increased superoxide dismutase activities, and inhibited the production of inflammatory cytokines, alleviating oxidative stress and inflammation levels in hippocampal tissues of SD model mice. cTBS decreased LC3II/LC3I ratio, Beclin1 protein levels, and LC3B puncta intensity, and elevated p62 protein levels to suppress excessive autophagy in hippocampal tissues of SD-stimulated mice. Then, we proved that inhibiting oxidative stress alleviated inflammation, autophagy, and death of hippocampal neuron cells through an in vitro cellular model for oxidative stress, and cTBS treatment promoted the production of glutathione (GSH), the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the mRNA expression of GSH synthesis-related genes to enhance antioxidant capacity in hippocampal tissues of SD mice. An Nrf2 inhibitor ML385 or a GSH synthesis inhibitor BSO reversed the alleviating effects of cTBS treatment on oxidative stress-associated damage of hippocampal tissues and cognitive impairment in SD model mice. Altogether, our study demonstrated that cTBS mitigates oxidative stress-associated inflammation and autophagy through activating the Nrf2-mediated GSH synthesis pathway, improving cognitive impairment in SD mice.

Anteromedial cortical support reduction of intertrochanteric fractures-A review.

The intertrochanteric fracture is a common fragility fracture typically resulting from low-energy falls. The functional outcome of intertrochanteric fractures is closely linked to the patient's underlying physical condition, intraoperative procedures, and postoperative complications. In terms of surgery, while timely surgery and appropriate internal fixation have demonstrated favorable outcomes, attention to intraoperative reduction is crucial. In recent years, there have been further developments in the evaluation of reduction of intertrochanteric fractures, particularly in the anteromedial cortical reduction, and these advances have been further scientifically elucidated in terms of their ability to provide stable fracture reduction and resist loss of reduction. In order to gain a comprehensive understanding of the anteromedial cortex theory, this article reviewed the anatomy, related theoretical progress, and controversies in recent years.

Low-Contact Impedance Textile Electrode for Real-Time Detection of ECG Signals.

The quality of the electrocardiography (ECG) signals depends on the effectiveness of the electrode-skin connection. However, current electrocardiogram electrodes (ECGE) often face challenges such as high contact impedance and unstable conductive networks, which hinder accurate measurement during movement and long-term wearability. Herein, in this work, a bionic 3D pile textile as an ECGE with high electrical conductivity and flexibility is prepared by a facile, continuous, and high-efficiency electrostatic self-assembly process. Integrating pile textiles with conductive materials creates a full textile electrode for bioelectrical signal detection that can retain both the inherent characteristics of textiles and high conductivity. Moreover, the dense piles on the textile surface make full contact with the skin, mitigating motion artifacts caused by the sliding between the textile and the skin. The continuous conductive network formed by the interconnected piles allows the pile textile ECGE (PT-ECGE) to function effectively under both static and dynamic conditions. Leveraging the unique pile structure, the PT-ECGE achieves superior flexibility, improved conductivity, low contact impedance, and high adaptivity, washability, and durability. The textile electrode, as a promising candidate for wearable devices, offers enormous application possibilities for the unconscious and comfortable detection of physiological signals.

Ultrasonography-guided canal decompression combined with vertebroplasty and cement-augmented pedicle screw fixation for stage III Kümmell's disease with neurological deficits: a retrospective cohort study.

BACKGROUND: Percutaneous vertebroplasty or kyphoplasty is the preferred procedure for stage I and II Kümmell's diseases (KDs), but there exist controversies on the operative option of stage III KD. This study aimed at exploring the safety and efficacy of ultrasonography-guided canal decompression (UG-CD) combined with vertebroplasty and cement-augmented pedicle screw fixation (CA-PSF) for treating stage III KD with neurological deficit (ND). METHODS: Between September 2017 and December 2023, all patients who received the UG-CD combined with vertebroplasty and CA-PSF for managing stage III KD with NDs were reviewed retrospectively with their demographic and operation data, and complications recorded. Besides, the scores of Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI), together with imaging data including the kyphotic Cobb angle (KCA), wedge angle (WA), spinal canal area (SCA) at the narrowest level as well as anterior (AHR) and middle (MHR) height ratios were measured and compared between pre- and post-operation. RESULTS: A total of eleven patients with a mean age of 70.09 ± 2.98 years old were included in our study with their surgical time, hospitalization length, blood loss, and follow-up time being 150.91 ± 17.94 min, 202.09 ± 39.95 ml, 8.18 ± 1.17 days, and 16.91 ± 4.09 months, respectively. During the final follow-up, the KCA, WA, VAS scores, ODI scores, AHR, MHR, and SCA were significantly improved (P < 0.01). Intraoperatively, one case suffered a transient decrease in the motor evoked potential. Another case experienced a cerebrospinal fluid leakage postoperatively that was then successfully treated. CONCLUSION: UG-CD combined with vertebroplasty and CA-PSF could be a feasible procedure for safely and effectively handling stage III KD with NDs.

Oncofetal MCB1 Is a Functional Biomarker for HCC Personalized Therapy.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal protein that is upregulated in the preneoplastic lesions and serum of early HCC patients. Functional studies reveal that MCB1 modulated p53 protein degradation to promote T-IC generation and drive HCC initiation. Furthermore, the MCB1/p53 axis is shown to determine the responses of hepatoma cells to conventional chemotherapeutics and predict transcatheter arterial chemoembolization (TACE) benefits in patients. Importantly, MCB1 can mediate sorafenib/lenvatinib resistance by downregulating two essential drug targets fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 3 (VEGFR3) expression in a proteasome-dependent manner. Patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs), and patient cohorts analysis suggested that MCB1 levels in HCCs may determine the distinct responses to conventional therapeutics and targeted drugs. Furthermore, treatment of targeted drugs-resistant HCC with adeno-associated virus (AAV) targeting MCB1 or a proteasome inhibitor restores targeted drug response, suggesting their clinical significance in HCC combinational therapy. In conclusion, these findings demonstrate that MCB1 could act as a driver for HCC initiation, a contributor to drug resistance, and a biomarker for individualized HCC therapy.

Research Progress of Deep-Red to Near-Infrared Electroluminescent Materials Based on Organic Cyclometallated Platinum(II) Complexes.

In recent years, the near-infrared (NIR) light-emitting materials have attracted increasing attention due to the broad application prospects in the fields of military industry, aerospace, lighting, display and wearable devices. As the transition metal complexes, platinum(II) complexes have been shown to emit luminescence efficiently in NIR organic light-emitting diodes because of the unique d8 electron structure. This structure ensures that the platinum(II) complex molecules exhibit a high planarity, variety of excited states, and strong intermolecular interactions. This review summarizes the research progress of deep red to NIR organic light-emitting materials based on platinum(II) complexes in recent years and provides a certain reference for the further design and synthesis of NIR platinum(II) complex luminescent materials with superior performance.

Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery.

Secondary lymphedema (LE) following breast cancer-related surgery is a life-long complication, which currently has no cure. LE induces significant regional adipose tissue deposition, requiring liposuction as a treatment. Here, we aimed to elucidate the transcriptional, metabolomic, and lipidomic signature of the adipose tissue developed due to the surgery-induced LE in short- and long-term LE patients and compared the transcriptomic landscape of LE adipose tissue to the obesity-induced adipose tissue. Adipose tissue biopsies were obtained from breast cancer-operated females with LE from the affected and non-affected arms (n = 20 patients). To decipher the molecular properties of the LE adipose tissue, we performed RNA sequencing, metabolomics, and lipidomics combined with bioinformatics analyses. Differential gene expression data from a cohort of lean and obese patients without LE was used for comparisons. Integrative analysis of functional genomics revealed that inflammatory response, cell chemotaxis, and angiogenesis were upregulated biological processes in the LE arm, indicating a sustained inflammation in the edematous adipose tissue; whereas, epidermal differentiation, cell-cell junction organization, water homeostasis, and neurogenesis were downregulated in the LE arm. Surprisingly, only a few genes were found to be the same in the LE-induced and the obesity-induced adipose tissue expansion, indicating a different type of adipose tissue development in these two conditions. In metabolomics analysis, we found reduced levels of a branched-chain amino acid valine in the LE arm and downregulation of the mRNA levels of its transporter SLC6A15. Lipidomics analyses did not show any significant differences between the LE and non-LE arms, suggesting that other factors affect the lipid composition of the adipose tissue more than the LE in these patients. Our results provide a detailed molecular characterization of adipose tissue in secondary LE after breast cancer-related surgery. We also show distinct differences in transcriptomic signatures between LE-induced adipose tissue and obesity-induced adipose tissue, but only minor differences in metabolome and lipidome between the LE and the non-LE arm.

Survival benefit of adjuvant TACE for patients with hepatocellular carcinoma and child-pugh B7 or B8 after hepatectomy.

BACKGROUND & AIMS: The benefit of postoperative adjuvant transcatheter arterial chemoembolization (pTACE) for patients with hepatocellular carcinoma (HCC), especially those with Child-Pugh (CP) B, remains controversial. This study aimed to assess the survival benefit of pTACE for HCC patients with CP B. METHODS: Data from 297 HCC patients with CP B7 or B8 were analyzed, dividing them into groups with and without pTACE (70, 23.6% vs. 227, 76.4%). Propensity score matching (PSM) was used to control for confounding bias, and competing-risk regression was applied to address bias from non-cancer-specific death (NCSD). RESULTS: Preliminary findings suggest that pTACE did not increase the incidence of severe complications in HCC patients with CP B7 or B8. Survival analysis indicated that the group receiving pTACE had better overall survival and recurrence-free survival than the group without pTACE after PSM. Furthermore, competitive risk analysis revealed that pTACE was an independent prognostic factor associated with reduced cancer-specific death incidence (subdistribution hazard ratio [SHR] 0.644, 95%CI: 0.378-0.784, P = 0.011) and recurrence (SHR 0.635, 95% CI: 0.379-0.855, P = 0.001). Importantly, pTACE did not increase NCSD. Subgroup analysis corroborated these results. CONCLUSION: Adjuvant TACE demonstrates the potential to significantly enhance the long-term prognosis of HCC patients with CP B7 or B8 following hepatectomy, particularly those with multiple tumors, large tumor size, macrovascular or microvascular invasion, and narrow resection margin. Hence, pTACE should be considered for patients at high risk of recurrence following thorough evaluation.

Clinical value of a radiomics model based on machine learning for the prediction of prostate cancer.

OBJECTIVE: Radiomics models have demonstrated good performance for the diagnosis and evaluation of prostate cancer (PCa). However, there are currently no validated imaging models that can predict PCa or clinically significant prostate cancer (csPCa). Therefore, we aimed to identify the best such models for the prediction of PCa and csPCa. METHODS: We performed a retrospective study of 942 patients with suspected PCa before they underwent prostate biopsy. MRI data were collected to manually segment suspicious regions of the tumor layer-by-layer. We then constructed models using the extracted imaging features. Finally, the clinical value of the models was evaluated. RESULTS: A diffusion-weighted imaging (DWI) plus apparent diffusion coefficient (ADC) random-forest model and a T2-weighted imaging plus ADC and DWI multilayer perceptron model were the best models for the prediction of PCa and csPCa, respectively. Areas under the curve (AUCs) of 0.942 and 0.999, respectively, were obtained for a training set. Internal validation yielded AUCs of 0.894 and 0.605, and external validation yielded AUCs of 0.732 and 0.623. CONCLUSION: Models based on machine learning comprising radiomic features and clinical indicators showed good predictive efficiency for PCa and csPCa. These findings demonstrate the utility of radiomic models for clinical decision-making.

Isokinetic assessment of the female's soccer player's knee. A systematic review of outcomes measures.

BACKGROUND: Isokinetic normative data in females' soccer players is scarce in comparison to males. Furthermore, evaluation protocols employed to obtain those data in female's studies, strongly differ from each other, using different ranges of speeds and movement patterns, thus producing different output data. Thus, it is difficult for the researcher and the clinician to choose a correct protocol for knee isokinetic test in female soccer players. Aim of this paper is to review the literature to provide updated information on how to interpret a knee isokinetic testing in healthy females. METHODS: Google Scholar, PubMed, Sport Discus, and Psych info databases were queried, and 17 papers were selected. Following PRISMA methodology and PEDro scale, we classified the retrieved papers and assessed the quality. RESULTS: In this review some common features of isokinetic testing in female soccer players of various levels of qualification are highlighted. The isokinetic performance indexes widely accepted are the hamstring/quadriceps (H/Q) ratio and dominant/non-dominant (D/ND) ratio. It also emerges that, 3 reps at the speed of 60°/sec in knee flexion/extension are preferable due to the higher reliability and that the optimal H/Q ratio in healthy female soccer players of different level of qualification and age is 50%, while the interlimb differences (D/ND) should be below 10%. CONCLUSIONS: Normative data and methodologies reviewed can be useful for the isokinetic test of female soccer players. It emerges that simplifying test procedures limiting at few testing speed and considering selected H/Q and D/ND gives all the necessary relevant informations.

Carbon monoxide as a negative feedback mechanism on HIF-1α in the progression of metabolic-associated fatty liver disease.

Metabolic-associated fatty liver disease (MAFLD) encompasses various chronic liver conditions, yet lacks approved drugs. Hypoxia-inducible factor-1α (HIF-1α) is pivotal in MAFLD development. Our prior research highlighted the efficacy of the nano-designed carbon monoxide (CO) donor, targeting HIF-1α in a mouse hepatic steatosis model. Given heme oxygenase-1 (HO-1, a major downstream molecule of HIF-1α) as the primary source of intrinsic CO, we hypothesized that upregulation of HO-1/CO, responsive to HIF-1α, forms a negative feedback loop regulating MAFLD progression. In this study, we explored the potential negative feedback mechanism of CO on HIF-1α and its downstream effects on MAFLD advancement. HIF-1α emerges early in hepatic steatosis induced by a high-fat (HF) diet, triggering increased HO-1 and inflammation. SMA/CORM2 effectively suppresses HIF-1α and steatosis progression when administered within the initial week of HF diet initiation but loses impact later. In adipose tissues, concurrent metabolic dysfunction and inflammation with HIF-1α activation suggest adipose tissue expansion initiates HF-induced steatosis, triggering hypoxia and liver inflammation. Notably, in an in vitro study using mouse hepatocytes treated with fatty acids, downregulating HO-1 intensified HIF-1α induction at moderate fatty acid concentrations. However, this effect diminished at high concentrations. These results suggest the HIF-1α-HO-1-CO axis as a feedback loop under physiological and mild pathological conditions. Excessive HIF-1α upregulation in pathological conditions overwhelms the CO feedback loop. Additional CO application effectively suppresses HIF-1α and disease progression, indicating potential application for MAFLD control.

Highly stable scalable production of porous graphene-polydopamine nanocomposites for drug molecule sensing.

As atenolol overdosing can lead to severe health complications, the rapid detection of atenolol intake in point-of-care settings is highly desirable. The recent advancement of redox analytical methodologies has facilitated the efficacious quantification of these compounds for drug analysis, but their performance still presents challenges in practical applications. This study addresses these challenges by controlling the electropolymerization of polydopamine (PDA) on highly porous laser-induced graphene (LIG) electrodes with enhanced electrochemical redox activity for the detection of drug molecules such as atenolol, with minimized interference with the other active substances to induce variation of electrochemical behavior. The enhanced sensitivity of atenolol is attributed to the superhydrophilicity and increased number of active surface sites and -NH2 groups in the PDA polymer through a controlled polymerization process. Moreover, the simulation results further reveal that highly sensitive sensing of atenolol molecules relies on optimal adsorption of the atenolol molecule on dopamine or dopaminequinone structural units. The resulting sensors with high repeatability and reproducibility can achieve a low detection limit of 80 µM and a sensitivity of 0.020 ± 0.04 µA/µM within a linear range from 100 to 800 µM. The materials and surface chemistry in the electrode design based on highly porous LIG provide insights into the integration and application of future scalable and cost-effective electrochemical sensors for use in point-of-care or in-field applications.

Nicotinamide enhances Treg differentiation by promoting Foxp3 acetylation in immune thrombocytopenia.

Imbalanced nicotinamide adenine dinucleotide (NAD+) homeostasis has been reported in multiple autoimmune diseases and supplementation with NAD+ precursors has consistently demonstrated positive therapeutic benefits for these conditions. Immune thrombocytopenia (ITP) is an acquired autoimmune disease, in which the decreased number and impaired function of regulatory T cells (Tregs) contribute to the main pathogenesis. Here we found NAD+ level was decreased in the plasma and CD4+ T cells of ITP patients. Supplementation with NAD+ precursor nicotinamide (NAM), but not nicotinamide mononucleotide (NMN), increased Treg frequency and ameliorated thrombocytopenia in an ITP murine model. Moreover, whilst both NAM and NMN restored cytosolic NAD+ level in the CD4+ T cells from ITP patients, only NAM promoted Treg differentiation. Mechanistically, Sirtuin1 (Sirt1), a major consumer of NAD+, was highly expressed in the CD4+ T cells of ITP patients, potentially contributing to the low level of NAD+. NAM, which could act as Sirt1 inhibitor, promoted Foxp3 acetylation and stability in induced Tregs derived from naïve CD4+ T cells of ITP patients. These findings suggest that NAM holds promise as a novel therapeutic strategy for restoring immune balance in ITP.

Responsive Magnetic Particle Imaging Tracer: Overcoming "Always-On" Limitation, Eliminating Interference, and Ensuring Safety in Adaptive Therapy.

Magnetic particle imaging (MPI) has emerged as a novel technology utilizing superparamagnetic nanoparticles as tracers, essential for disease diagnosis and treatment guidance in preclinical animal models. Unlike other modalities, MPI provides high sensitivity, deep tissue penetration, and no signal attenuation. However, existing MPI tracers suffer from "always-on" signals, which complicate organ-specific imaging and hinder accuracy. To overcome these challenges, we have developed a responsive MPI tracer using pH-responsive PdFe alloy particles coated with a gatekeeper polymer. This tracer exhibits pH-sensitive Fe release and modulation of the MPI signal, enabling selective imaging with a higher signal-to-noise ratio and intratumoral pH quantification. Notably, this responsive tracer facilitates subtraction-enhanced MPI imaging, effectively eliminating interference from liver uptake and expanding the scope of abdominal imaging. Additionally, the tracer employs a dual-function mechanism for adaptive cancer therapy, combining pH-switchable enzyme-like catalysis with dual-key co-activation of ROS generation, and Pd skeleton that scavenges free radicals to minimize Fe-related toxicity. This advancement promises to significantly expand MPI's applicability in diagnostics and therapeutic monitoring, marking a leap forward in imaging technology.

Comparative analysis of reproductive hormones, serum biochemical indexes and ovarian metabolites in Muscovy breeder duck at different laying stages.

The hypothalamic-pituitary-gonadal (HPG) axis regulates egg laying through control hormones secretion in poultry. In this study, the serum hormones (12 samples per stage), serum biochemical indexes (12 samples per stage), and ovarian metabolites (8 samples per stage) of Muscovy breeder ducks were detected at prelaying stage (PT), start of laying stage (ST), high laying stage (HT), and the end of laying stage (ET). The serum hormones of Muscovy ducks were measured at 8:00, 13:00, 18:00, 23:00, and 4:00 within 1 d. The TG, TP, ALB, and GLB were significantly increased, while HDL-C was significantly decreased at ST as compared to PT (P < 0.05). Serum Na, Cl, Ca, P, and K showed significant rise at ST as compared to PT. Serum Na, Cl, Ca, and K were significantly declined, while P was significantly increased at ET as compared to HT (P < 0.05). Serum FSH, LH, PRL, E2, P4 levels peaked at ST (P < 0.05) with only FSH and LH fluctuated significantly within 1 ovulation cycle at ST (P < 0.05). Differential metabolites showed continued ovarian aging. The decline of nucleic acid metabolism occured in ST, the decline of sugar metabolism occurred in ET, and the decline of amino acid metabolism continued at all stages. Temporal expression patterns and correlation analyses indicated a high correlation between ovarian cAMP and serum reproductive hormone levels across different reproductive stages. In conclusion, this study revealed the changes in serum hormones, serum biochemical indicators, and ovarian metabolites, as well as the relationship between serum hormones and ovarian metabolites.

Antigen-independent activation is critical for the durable antitumor effect of GUCY2C-targeted CAR-T cells.

BACKGROUND: Chimeric antigen receptor (CAR)-T cells face many obstacles in solid tumor therapy, including heterogeneous antigen expression and inefficient T cell persistence. Guanylyl cyclase C (GUCY2C) has been identified as a suitable tumor antigen for targeted therapy due to its intestinal-restricted expression pattern in normal tissues and steady overexpression in gastrointestinal tumors, especially colorectal cancer. An antigen-sensitive and long-lasting CAR-T cell targeting GUCY2C was investigated in this study. METHODS: Using constructed tumor cell lines with various GUCY2C expression densities, we screened out an antigen-sensitive single chain variable fragment (scFv) that enabled CAR-T cells to efficiently eradicate the GUCY2C lowly expressed tumor cells. CAR-T cells with different compositions of the hinge, transmembrane and costimulatory domains were also constructed for selection of the long-lasting CAR-T format with durable antitumor efficacy in vitro and in tumor-bearing mice. The underlying mechanism was further investigated based on mutation of the hinge and transmembrane domains. RESULTS: We found that the composition of the antigen-sensitive scFv, CD8α hinge, CD8α transmembrane, and CD28 costimulatory domains boosted CAR-T cells to rapidly kill tumors, maintain high expansion capacity, and long-term efficacy in various colorectal cancer models. The durable antitumor function was attributed to the optimal CAR tonic signaling that conferred CAR-T cells with autonomous activation, proliferation, survival and cytokine release in the absence of antigen stimulation. The tonic signaling was associated with the length and the cysteine residues in the CD8α hinge and transmembrane domains. CONCLUSIONS: This study demonstrated a potent GUCY2C-targeted CAR-T cell for gastrointestinal tumor therapy and highlights the importance of adequate tonic signaling for effective CAR-T cell therapy against solid tumors.

Central NUCB2/nesfatin-1 signaling ameliorates liver steatosis through suppression of endoplasmic reticulum stress in the hypothalamus.

BACKGROUND & AIMS: Nucleobindin-2 (NUCB2)/nesfatin-1, a signal with recognized anorexigenic and insulin-sensitizing properties in peripheral tissues, is expressed within the hypothalamus. However, the potential involvement of central nesfatin-1 signaling in the pathophysiology of hepatic steatosis remains unknown. This study aimed to determine whether and how central NUCB2/nesfatin-1 plays a role in liver steatosis. METHODS: We generated Nucb2 knockout (Nucb2-/-) rats and administered continuous intracerebroventricular (ICV) nesfatin-1 infusion, while observing its effect on liver steatosis. The molecular mechanism of action of nesfatin-1 was elucidated via proteomics, phosphoproteomics and molecular biology methods. RESULTS: Herein, we present compelling evidence indicating diminished NUCB2 expression in the hypothalamus of obese rodents. We demonstrated that chronic ICV infusion of nesfatin-1 mitigated both diet-induced obesity and liver steatosis in high-fat diet (HFD)-fed Nucb2-/- rats by regulating hypothalamic endoplasmic reticulum (ER) stress and Akt phosphorylation. Furthermore, we revealed that the increase in hypothalamic insulin resistance (IR) and ER stress induced by tunicamycin infusion or Ero1α overexpression exacerbated hepatic steatosis and offset the favorable influence of central nesfatin-1 on hepatic steatosis. The metabolic action of central nesfatin-1 is contingent upon vagal nerve transmission to the liver. Mechanistically, nesfatin-1 impedes ER stress and interacts with Ero1α to repress its Ser106 phosphorylation. This leads to the enhancement of Akt activity in the hypothalamus, culminating in the inhibition of hepatic lipogenesis. CONCLUSIONS: These findings underscore the importance of hypothalamic NUCB2/nesfatin-1 as a key mediator in the top-down neural mechanism that combats diet-induced liver steatosis.